The Health
Consequences
Of Smoking

CHRONIC OBSTRUCTIVE
   LUNG DISEASE

a report of the
Surgeon General

1984

U.S. DEPARTMENT Of HEALTH AND HLMAN SERVICES
P&tic Health Sewiie
Offlce on Smckll end Heelth
Rockvlile, Maryland 20857

For sale by the Supermtendent of Documents. U.S. Government Prmtmg Office
             Washmgtan, D.C 2040`2


  It 15 a plP.sIIrP to tr2TSlnlt to the congress the surgeon
General's Report on the Health Consequences Of Smoking, a5
mandated by Section R(a) of the Public Health Cigarette Smoking
Act of 1969.  This is the Public Health Services' 16th report on
this topic ?nd,  likp 211 of the earlier Reports, it identifies
cigarette smoking as the chief preventable cause of death and
dlsahllity in our SOClety.

  The enclosed report deals with the relationship between smok-
ing and those disease cond~tlons described as chronic obstructive
1unp dlSCPSP,  particularly chronic bronchitis and emphyseme.
These diseases significantly increase patient loads in hospitals
and other health care facl!lties and escalate this Nztion's
health care costs.  including expenditures under the Medicaid and
MedIcare programs.

  This Department has a strong and ongoing comnitment to Its
Pr `ogrnmmatlc and research effor*s I" the field Of disease prever.-
ti on.  In our view, it is essential to apprise ~ndlviduals of the
consequences of smoking.  A central part of our efforts is to
identify ways to help smokers quit smoking, and to encourage
indl"ld"alS, particularly the youth of this country, not to kgin
smoking.

Enclosure



FOREWORD

The 1984 Report on the Health Consequences of Smoking consti-
tutes a state-of-the-art review of the information currently available
regarding the occurrence and etiology of chronic obstructive lung
diseases.

Traditionally, chronic bronchitis and emphysema have been
subsumed under the term chronic obstructive lung diseases (COLD).
It is now recognized that COLD comprises three separate, but often
interconnected, disease processes: (1) chronic mucus hypersecretion,
resulting in chronic cough and phlegm production; (2) airway
thickening and narrowing with expiratory airflow obstruction; and
(3) emphysema, which is an abnormal dilation of the distal airspaces
along with destruction of alveolar walls. The last two conditions can
develop into symptomatic ventilatory limitation.
Although there were scientific reports of a link between cigarette
smoking and respiratory symptoms as early as 1870, it was not until
the comprehensive review in the first Report of the Advisory
Committee to the Surgeon General in 1964 that the nature of the
observed association was officially recognized by the Public Health
Service.

At that time the committee concluded that
Cigarette smoking is the most important of the causes of chronic
bronchitis in the United States and increases the risk of dying from
chronic bronchitis and emphysema. A relationship exists between
cigarette smoking and emphysema, but it has not been established that
the relationship is causal.
On the basis of the evidence reviewed in this volume, we are now
able to reach a much stronger conclusion:
Cigarette smoking is the major cause of chronic obstructive lung
disease in the United States for both men and women. The
contribution of cigarette smoking to chronic obstructive lung
disease morbidity and mortality far outweighs all other factors.
The Importance of Chronic Obstructive Lung Disease
Previous Reports on the health consequences of smoking empha-
sized the impact of cigarette smoking on mortality from smoking-
related disease. It is estimated that more than 60,000 Americans
died last year owing to chronic obstructive respiratory conditions

vii


(chronic bronchitis, emphysema, and COLD and allied conditions).
From available epidemiologic and clinical evidence, it may be
reasonably estimated that approximately 80 to 90 percent of these
are attributable to smoking. Over 50,000 of the COLD deaths can
therefore be considered preventable and premature because these
individuals would not have died of COLD if they had not smoked.
While smoking-related COLD mortality is less than estimates for
smoking-related deaths due to coronary heart disease (170,000) and
those due to cancer (130,000), it nonetheless represents a significant
number of excess deaths.

COLD morbidity has a greater impact upon society than COLD
mortality. Death from COLD usually occurs only after an extended
period of disability, and many individuals with disability from COLD
will die from other causes before the disease progresses to a degree of
severity likely to cause death. The progressive loss of lung function
that characterizes COLD can lead to severe shortness of breath,
limiting the activity level. In recognizing the morbidity associated
with these diseases, it is important to realize that the frequency of
activity limitation with COLD exceeds that reported for any other
major disease category. In 1979, 52 percent of individuals with
emphysema reported that it limited their activity; 27 percent said it
resulted in one or more bed days that year; and 73 percent reported
at least one visit to a doctor during the preceding year due to
emphysema. Forty percent more people with emphysema than with
heart conditions reported limitation of activity. More recently, the
National Center for Health Statistics has estimated that over 10
million Americans suffer from either chronic bronchitis or emphyse-
ma.

The Changing Pattern of Mortality

The 1980 and 1982 Surgeon General's Reports (The Health
Consequences of Smoking for Women and The Health Consequences of
Smoking: Cancer) reported a rapidly increasing rate of lung cancer
among women compared with the rate for men. As this Report
documents, the mortality ratio between men and women for COLD is
also narrowing. In just 10 years, while total deaths from COLD
increased from 33,000 in 1970 to 53,000 in 1980, the male-to-female
ratio narrowed from 4.3:1 in 1970 to 2.3:1 in 1980. This epidemic
increase in COLD among women reflects their later uptake of
smoking when compared with men.

Findings of the 1984 Report

The mortality ratios for COLD in cigarette smokers compared with
nonsmokers are as large as or larger than for lung cancer, the

. . .
Vlll


disease most people usually associate with smoking. In heavy
smokers, this risk can be as much as 30 times the risk in
nonsmokers. Perhaps even more important, in studies of cross-
sections of U.S. populations, cigarette smoking behavior is often the
only significant predictor for COLD. Even after 30 years of intensive
investigation, only cigarette smoking and a,-antiprotease deficiency
have been established as being able to cause COLD in the absence of
other agents.

The decline in lung function with age is steeper in smokers than in
nonsmokers, and the rate of decline increases with an increasing
number of cigarettes smoked per day. This excess decline in lung
function in smokers reflects the progressive lung damage that can
eventually lead to symptoms of COLD and ultimately death.
Therefore, it is not surprising that the risk of death from COLD
increases with an earlier age of smoking initiation, number of
cigarettes smoked per day, and deep inhalation of the smoke.

Abnormal lung function can be demonstrated in some cigarette
smokers within a few years of smoking initiation. These changes
initially reflect inflammation in the small airways of the lung and
may reverse with cessation. Beginning in their late twenties, some
smokers start to develop abnormal measures of expiratory airflow,
an excess decline in lung function that continues as long as they
continue to smoke. Some of these smokers will develop enough
functional loss to become symptomatic, and some of those who
become symptomatic will develop enough functional loss to die of
COLD. When the smoker quits, the rate of functional decline slows,
but there is little evidence to suggest that the smoker can regain the
function that has been lost.

We are also beginning to understand that the impact of cigarette
smoke on the lung is not limited to the active smoker. Children of
smoking parents have an increased risk of bronchitis and pneumonia
early in life, and seem to have a small, but measurable, difference in
the growth of lung function.

One of the major advances described in this volume is in the
understanding of the mechanisms by which cigarette smoking causes
COLD, particularly emphysema. There is now a clear, plausible
explanation of how emphysema might result from cigarette smoking.
The inflammatory response to cigarette smoke results in an in-
creased number of inflammatory cells being present in the lungs of
cigarette smokers. These cells can increase the amount of elastase in
the lung, and elastase is capable of degrading elastin, one of the
structural elements of the lung. In addition, cigarette smoke is
capable of oxidative inactivation of a,-antiprotease, a protein
capable of blocking the action of elastase. The net result is an excess
of elastase activity, degradation of elastin in the lung, destruction of
alveolar walls, and the development of emphysema.

ix


Research scientists continue to expand our understanding of the
process by which cigarettes damage the lung, but the important
public health focus must shift to how to prevent children from
becoming cigarette smokers and how to help those who now smoke to
quit.

Helping Smokers Quit

Smokers can realize a substantial health benefit from quitting
smoking, no matter how long they have smoked. As this Report
states, sufficient evidence now exists to document lung function
improvement in smokers who have quit. Ex-smokers can look
forward to improved future health, avoiding long-term and possibly
severe disability, or even death, from COLD.

Two chapters in this Report summarize research studies using two
vastly different cessation approaches. One focuses on the role of
physicians in assisting patient populations to quit smoking; the other
looks at communitywide intervention programs. Both can have a
significant impact on reducing the number of smokers in our
population.

In January of this year, the Food and Drug Administration
approved a nicotine chewing gum that physicians can prescribe for
their patients as an aid to cessation. Studies have shown encouraging
results when the gum is used as part of a complete behavior
modification program. It must be cautioned, however, that nicotine
chewing gum is not a magic cure. Smokers must be strongly
motivated to quit or they are unlikely to meet with long-term
success.

Public Attitudes and Knowledge

In 1981, a Federal Trade Commission staff report on cigarette
advertising revealed that a sizable portion of the population is not
aware of the link between cigarette smoking and chronic bronchitis
and emphysema. The report cited a 1980 Roper survey finding that
59 percent of the population, including 63 percent of smokers, did not
know that smoking causes most cases of emphysema. Over a third of
the general population and almost 40 percent of smokers do not
know that smoking causes many cases.

It is quite clear that physicians and other health professionals
must redouble their efforts to persuade more smokers to quit. As in
previous years, I call upon all segments of the health care communi-
ty to provide assistance and encouragement in whatever way
possible to reduce the health impact of cigarette smoking on our
society, by helping their patients to quit smoking and by encouraging
our young people not to take up the habit. It is only through efforts

X


such as these that we can reduce our country's terrible burden of
disability and death due to cigarette smoking.

Edward N. Brandt. Jr., M.D.
Assistant Secretary for Health

xi


PREFACE

This Report The Health Consequences of Smoking: Chronic Ob-
structive Lung Disease completes an examination by the Public
Health Service of the three principal disease entities associated with
cigarette smoking. In 1982, the Service presented an indepth review
of tobacco's relationship to cancer, and in 1983, a review of its
relationship to cardiovascular disease. This 1984 Report evaluates
the contribution that tobacco makes to the suffering and premature
deaths due to the chronic obstructive lung diseases, including
emphysema and chronic bronchitis.

Cigarette smoking is causally related to chronic obstructive lung
disease, just as it is to cancer and coronary heart disease; severe
emphysema would be rare were it not for cigarette smoking. The
evidence presented in this Report supports my judgment and the
judgment of five preceding Surgeons General that cigarette smoking
is the chief, single, avoidable cause of death in our society and the
most important public health issue of our time.

This Report, as were all previous Surgeon General's Reports
dealing with cigarette smoking, is the work of many experts both
within and outside the Federal establishment. To these authors,
editors, and reviewers I again express my great respect and sincere
thanks.

C. Everett Koop, M.D.
Surgeon General

. . .
Xl,,


ACKNOWLEDGMENTS

This Report was prepared by the Department of Health and
Human Services under the general editorship of the Office on
Smoking and Health, Joanne Luoto, M.D., M.P.H., Director. Manag-
ing Editor was Donald R. Shopland, Technical Information Officer,
Office on Smoking and Health.

Senior scientific editor was David M. Burns, M.D., Assistant
Professor of Medicine, Division of Pulmonary and Critical Care
Medicine, University of California at San Diego, San Diego, Califor-
nia. Consulting scientific editors were John H. Holbrook, M.D.,
Associate Professor of Internal Medicine, University of Utah Medi-
cal Center, Salt Lake City, Utah; and Ellen R. Gritz, Ph.D., Director,
Macomber-Murphy Cancer Prevention Program, Division of Cancer
Control, Jonsson Comprehensive Cancer Center, University of
California at Los Angeles, Los Angeles, California.
The editors wish to acknowledge their grateful appreciation to the
National Heart, Lung, and Blood Institute, Claude Lenfant, M.D.,
Director, for the Institute's invaluable assistance in the compilation
of this volume.

The following individuals prepared draft chapters or portions of
the Report:

Brenda E. Barry, Ph.D., Research Associate, Environmental Science
and Physiology, Harvard School of Public Health, Boston, Massa-
chusetts

Richard A. Bordow, M.D., Associate Director of Respiratory Medi-
cine, Brookside Hospital, San Pablo, California, and Assistant
Clinical Professor of Medicine, University of California at San
Francisco, San Francisco, California
Joseph D. Brain, Sc.D., Professor of Physiology and Director,
Respiratory Biology Program, Harvard School of Public Health,
Boston, Massachusetts

A. Sonia Buist, M.D., Professor of Medicine, department of Medicine,
Oregon Health Sciences University, Portland, Oregon
Louis Diamond, Ph.D., Professor and Dire&or- of the Pharmacody-
namics and Toxicology Division, University of Kentucky College of
Pharmacy, Lexington, Kentucky

xv


Terence A. Drizd, Statistician, Medical Statistics Branch, Division of
Health Examination Statistics, National Center for Health Statis-
tics, Public Health Service, Department of Health and Human
Services, Hyattsville, Maryland

Millicent W. Higgins, M.D., Professor of Epidemiology and Professor
of Internal Medicine, Department of Epidemiology, The University
of Michigan School of Public Health, Ann Arbor, Michigan
Gary W. Hunninghake, M.D., Director, Pulmonary Disease Division
and Professor, Department of Internal Medicine, The University of
Iowa Hospitals and Clinics, Iowa City, Iowa
Philip Kimbel, M.D., Chairman, Department of Medicine, The
Graduate Hospital, Philadelphia, Pennsylvania
Edgar C. Kimmel, Pharmacodynamics and Toxicology Division,
University of Kentucky College of Pharmacy, Lexington, Ken-
tucky

Charles Kuhn, M.D., Department of Pathology, Jewish Hospital at
Washington University Medical Center, St. Louis, Missouri
Alfred L. McAlister, Ph.D., The University of Texas Health Science
Center at Houston, Houston, Texas
John McCarren, M.D., Division of Pulmonary and Critical Care
Medicine, University of California at San Diego, San Diego,
California

Linda L. Pederson, Ph.D., Department of Epidemiology and Biosta-
tistics, University of Western Ontario, London, Ontario, Canada
John A. Pierce, M.D., Department of Medicine, Washington Univer-
sity Medical Center, St. Louis, Missouri
Jonathan M. Samet, M.D., Associate Professor of Medicine, The
University of New Mexico School of Medicine, Albuquerque, New
Mexico

Robert M. Senior, M.D., Professor of Medicine, Respiratory and
Critical Care Division, Jewish Hospital at Washington University
Medical Center, St. Louis, Missouri
Frank E. Speizer, M.D., Associate Professor of Medicine, Harvard
Medical School, and Associate Chief, Charming Laboratory, Brig-
ham and Women's Hospital, Boston, Massachusetts
Ira B. Tager, M.D., M.P.H., Division of Infectious Disease, Beth Israel
Hospital and Channing Laboratory, Brigham and Women's Hospi-
tal, and Assistant Professor of Medicine, Harvard Medical School,
Boston, Massachusetts

William M. Thurlbeck, M.D., F.R.C.P.0, Professor of Pathology,
Department of Pathology, The University of British Columbia,
Vancouver, British Columbia, Canada
Martin J. Tobin, M.D., M.R.C.P.I., Assistant Professor of Medicine,
Division of Pulmonary Medicine, Department of Internal Medi-
cine, The University of Texas Health Science Center at Houston,
Houston, Texas

xvi


Adam Wanner, M.D., Professor of Medicine and Chief, Division of
Pulmonary Diseases, University of Miami School of Medicine,
Miami Beach, Florida

Scott T. Weiss, M.D., M.S., Associate Chief, Pulmonary Division,
Beth Israel Hospital, and Assistant Professor of Medicine, Har-
vard Medical School, Boston, Massachusetts

The editors acknowledge with gratitude the following distin-
guished scientists, physicians, and others who lent their support in
the development of this Report by coordinating manuscript prepara-
tion, contributing critical reviews of the manuscript, or assisting in
other ways.

Oscar Auerbach, M.D., Senior Medical Investigator, Veterans Ad-
ministration Medical Center, East Orange, New Jersey
John Bailar III, M.D., Ph.D., Office of the Assistant Secretary of
Health, Office of Disease Prevention and Health Promotion,
Washington, D.C.

David V. Bates, M.D., F.R.C.P.0, Professor of Medicine, Department
of Health Care and Epidemiology, The University of British
Columbia, Vancouver, British Columbia, Canada
Benjamin Burrows, M.D., Division of Respiratory Science, University
of Arizona College of Medicine, Tucson, Arizona
Jacqueline Coalson, Professor of Pathology, School of Medicine,
University of Texas at San Antonio, San Antonio, Texas
Allen B. Cohen, M.D., Ph.D., Executive Associate Director and
Professor of Medicine, The University of Texas Health Center at
Tyler, Tyler, Texas

Manuel G. Cosio, M.D., Director, Pulmonary Laboratories, Royal
Victoria Hospital, Montreal, Quebec, Canada
Manning Feinleib, M.D., Dr.P.H., Director, National Center for
Health Statistics, Public Health Service, Department of Health
and Human Services, Hyattsville, Maryland
Benjamin G. Ferris, Jr., M.D., Professor of Environmental Health
and Safety, Department of Physiology, Harvard School of Public
Health, Boston, Massachusetts

Gareth M. Green, M.D., Professor and Chairman, Department of
Environmental Health Sciences, The Johns Hopkins University
School of Hygiene and Public Health, Baltimore, Maryland
Clarence A. Guenter, M.D., F.R.C.P.(C), Professor and Head, Depart-
ment of Medicine, The University of Calgary Foothills Hospital,
Calgary, Alberta, Canada

Ian T. T. Higgins, M.D., Professor of Epidemiology, Department of
Epidemiology, The University of Michigan School of Public
Health, Ann Arbor, Michigan

John R. Hughes, M.D., Assistant Professor, Department of Psychia-
try, University of Minnesota, Minneapolis, Minnesota

xvii


Suzanne S. Hurd, Ph.D., Director, Division of Lung Diseases,
National Heart, Lung, and Blood Institute, National Institutes of
Health, Bethesda, Maryland

Roland H. Ingram, Jr., M.D., Director, Respiratory Division, Brig-
ham and Women's Hospital, and Parker B. Francis Professor of
Medicine, Harvard Medical School, Boston, Massachusetts
Aaron Janoff, Ph.D., Professor and Experimental Pathologist, De-
partment of Pathology, School of Medicine and University Hospi-
tal, State University of New York at Stony Brook, Stony Brook,
New York

Lynn T. Kozlowski, Ph.D., Scientist, Clinical Institute of the Addic-
tion Research Foundation, Toronto, Ontario, Canada
Claude Lenfant, M.D., Director, National Heart, Lung, and Blood
Institute, National Institutes of Health, Bethesda, Maryland
Peter T. Macklem, M.D., F.R.S.C., Physician-in-Chief, Royal Victoria
Hospital, and Professor and Chairman, Department of Medicine,
McGill University, Montreal, Quebec, Canada
James 0. Mason, M.D., Director, Centers for Disease Control,
Atlanta, Georgia

Kenneth M. Moser, M.D., Professor of Medicine and Director,
Division of Pulmonary and Critical Care Medicine, School of
Medicine, University of California at San Diego, San Diego,
California

C. Tracy Orleans, Ph.D., Division of Psychosomatic Medicine,
Department of Psychiatry, Duke University Medical Center,
Durham, North Carolina

Terry F. Pechacek, Ph.D., Assistant Professor, Division of Epidemiol-
ogy, School of Public Health, University of Minnesota, Minneapo-
lis, Minnesota

Solbert Per-mutt, M.D., Professor of Medicine, Department of Medi-
cine, Division of Pulmonary Medicine, The Johns Hopkins Univer-
sity School of Medicine, Baltimore, Maryland
Cheryl L. Perry, Ph.D., Assistant Professor, Division of Epidemiolo-
gy, School of Public Health, University of Minnesota, Minneapolis,
Minnesota

Richard Peto, M.A., M.&Z., I.C.R.S., Clinical Trial Service Unit,
Radcliffe Infirmary, University of Oxford, Oxford, England
Thomas L. Petty, M.D., Professor of Medicine, and Director, Webb
Waring Lung Institute, University of Colorado Health Sciences
Center, Denver, Colorado

James L. Repace, Office of Policy Analysis, U.S. Environmental
Protection Agency, Washington, D.C.
Attilio D. Renzetti, Jr., M.D., University of Utah Medical Center,
Salt Lake City, Utah

John Repine, M.D., Webb Waring Lung Institute, Denver, Colorado


xv111


Eugene Rogot, Statistician, Division of Epidemiology and Clinical
Applications, National Heart, Lung, and Blood Institute, National
Institutes of Health, Bethesda, Maryland
Marvin A. Sackner, M.D., Director, Medical Services, Mount Sinai
Medical Center, and Professor of Medicine, University of Miami
School of Medicine, Miami Beach, Florida
Roy J. Shephard, M.D., Ph.D., Director of School of Physical and
Health Education, University of Toronto, Toronto, Ontario, Cana-
da

Gordon L. Snider, M.D., Professor of Medicine and Director, Pulmo-
nary Center, Boston University School of Medicine, Boston,
Massachusetts

Donald F. Tierney, M.D., Department of Medicine, School of Medi-
cine, Center for the Health Sciences, University of California at
Los Angeles, Los Angeles, California
Nicholas J. Wald, M.R.C.P., F.F.C.M., Professor, Department of
Environmental and Preventive Medicine, The Medical College of
St. Bartholomew's Hospital, University of London, London, Eng-
land

James B. Wyngaarden, M.D., Director, National Institutes of Health,
Bethesda, Maryland

The editors also acknowledge the contributions of the following
staff members and others who assisted in the preparation of this
Report.

Erica W. Adams, Copy Editor, Information Programs Division,
Informatics General Corporation, Rockville, Maryland
Richard H. Amacher, Director, Clearinghouse Projects Department,
Informatics General Corporation, Rockville, Maryland
John L. Bagrosky, Associate Director for Program Operations, Office
on Smoking and Health, Rockville, Maryland
Richard J. Bast, Medical Translation Consultant, Information Pro-
grams Division, Informatics General Corporation, Rockville, Mary-
land

Charles A. Brown, Programmer, Data Processing Services, Informat-
its General Corporation, Rockville, Maryland
Clarice D. Brown, B&Statistician and Epidemiologist, Office on
Smoking and Health, Rockville, Maryland
Joanna B. Crichton, Copy Editor, Clearinghouse Projects Depart-
ment, Informatics General Corporation, Rockville, Maryland
Alicia Doherty, Information Specialist, Clearinghouse Projects De-
partment, Informatics General Corporation, Rockville, Maryland
Danny A. Goodman, Information Specialist, Clearinghouse Projects
Department, Informatics General Corporation, Rockville, Mary-
land

xix


Kit Hagner, Clerk-Typist, Office on Smoking and Health, Rockville,
Maryland

Rebecca C. Harmon, Publications Manager, Information Programs
Division, Informatics General Corporation, Rockville, Maryland
Karen Harris, Clerk-Typist, Office on Smoking and Health, Rock-
ville, Maryland

Douglas M. Hayes, Publications Systems Supervisor, Publishing
Services Division, Informatics General Corporation, Riverdale,
Maryland

Patricia E. Healy, Technical Information Clerk, Office on Smoking
and Health, Rockville, Maryland
Shirley K. Hickman, Data Entry Operator, Clearinghouse Projects
Department, Informatics General Corporation, Rockville, Mary-
land

Margaret H. Hindman, Publications Specialist, Information Pro-
grams Division, Informatics General Corporation, Rockville, Mary-
land
Robert S. Hutchings, Associate Director for Information and Pro-
gram Development, Office on Smoking and Health, Rockville,
Maryland

Leena Kang, Data Entry Operator, Clearinghouse Projects Depart-
ment, Informatics General Corporation, Rockville, Maryland
Margaret E. Ketterman, Public Information and Publications Spe-
cialist, Office on Smoking and Health, Rockville, Maryland
Julie Kurz, Graphic Artist, Information Programs Division, Infor-
matics General Corporation, Rockville, Maryland
Roberta L. Litvinsky, Secretary, Office on Smoking and Health,
Rockville, Maryland

William R. Lynn, Program Operations Technical Assistance Officer,
Office on Smoking and Health, Rockville, Maryland
Edward W. Maibach, Health Promotion Specialist, Informatics
General Corporation, Rockville, Maryland
Dixie P. McGough, Publications Specialist, Information Programs
Division, Informatics General Corporation, Rockville, Maryland
Patricia A. Mentzer, Data Entry Operator, Clearinghouse Projects
Department, Informatics General Corporation, Rockville, Mary
land

Kurt D. Mulholland, Graphic Artist, Information Programs Division,
Informatics General Corporation, Rockville, Maryland
Judy Murphy, Writer-Editor, Office on Smoking and Health, Rock-
ville, Maryland

Sally L. Nalley, Secretary, Office on Smoking and Health, Rockville,
Maryland

Ruth C. Palmer, Secretary, Office on Smoking and Health, Rockville,
Maryland

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Raymond K. Poole, Production Coordinator, Clearinghouse Projects
Department, Informatics General Corporation, Rockville, Mary-
land

Roberta A. Roeder, Secretary, Clearinghouse Projects Department,
Informatics General Corporation, Rockville, Maryland
Anne C. Ryon, Copy Editor, Information Programs Division, Infor-
matics General Corporation, Rockville, Maryland
Linda R. Sexton, Information Specialist, Clearinghouse Projects
Department, Informatics General Corporation, Rockville, Mary-
land

Linda R. Spiegelman, Administrative Officer, Office on Smoking and
Health, Rockville, Maryland

Evelyn L. Swarr, Administrative Secretary, Data Processing Ser-
vices, Informatics General Corporation, Rockville, Maryland
Karen Weil Swetlow, Copy Editor, Clearinghouse Projects Depart-
ment, Informatics General Corporation, Rockville, Maryland
Debra C. Tate, Publications Systems Specialist, Publishing Services
Division, Informatics General Corporation, Riverdale, Maryland
Jerry W. Vaughn, Development Technician, University of California
at San Diego, San Diego, California

Jill Vejnoska, Writer-Editor, Information Programs Division, Infor-
matics General Corporation, Rockville, Maryland
Aileen L. Walsh, Secretary, Clearinghouse Projects Department,
Informatics General Corporation, Rockville, Maryland
Dee Whitley, Computer Operator, Data Processing Services, Infor-
matics General Corporation, Rockville, Maryland
Louise Wiseman, Technical Information Specialist, Office on Smok-
ing and Health, Rockville, Maryland
Pamela Zuniga, Secretary, University of California at San Diego,
San Diego, California

xxi


TABLE OF CONTENTS

Foreword .............................................................. vii


Preface                                             ...
      ................................................................ x111

Acknowledgments ................................................... xv

1. Introduction, Overview, and Conclusions . . . . . . .._... . . . . . 1

2. Effect of Cigarette Smoke Exposure on Measures of
Chronic Obstructive Lung Disease Morbidity . . . . . . . . . 17

3. Mortality From Chronic Obstructive Lung Disease
Due to Cigarette Smoking . . . . , , . . . . . . . . . . . . . . . . . . . . . . . . . . . 185

4. Pathology of Lung Disease Related to Smoking..... 219

5. Mechanisms by Which Cigarette Smoke Alters the
Structure and Function of the Lung . . . . . . . . . . . . . . . . . . . 251

6. Low Yield Cigarettes and Their Role in Chronic Ob-
structive Lung Disease . . . . ..**.............................. 329

7. Passive Smoking . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 361

8. Deposition and Toxicity of Tobacco Smoke in the
Lung . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 413

9. Role of the Physician in Smoking Cessation ......... 451

10. Community Studies of Smoking Cessation and Preven-
  tion ............................................................... 499


Index .................................................................. 535


xx111


CHAPTER 1. INTRODUCTION,
       OVERVIEW, AND
        CONCLUSIONS


CONTENTS

Introduction

Organization and Development of the 1984 Report
Historical Perspective

-Overview

Conclusions of the 1984 Report
  COLD Morbidity
  COLD Mortality
Pathology of Cigarette-Induced Disease
  Mechanisms of COLD
  Low Tar and Nicotine Cigarettes
  Passive Smoking

Deposition and Toxicity of Tobacco Smoke in the
Lung

Role of the Physician in Smoking Cessation
Community Studies of Smoking Cessation and
Prevention


Introduction

Organization and Development of the 1984 Report

Each year the Office on Smoking and Health (OSH), working in
close collaboration with scientists, researchers, and others, compiles
the annual Surgeon General's Report The Health Consequences of
Smoking for submission to the U.S. Congress as part of the
Department's responsibility to report new and current information
on the topic as required under Public Law 91-222. This Report is the
third to examine in detail specific disease entities related to
smoking. The 1982 Report was a comprehensive assessment of the
relationship between tobacco use and various cancers, and the 1983
Report examined this relationship for cardiovascular diseases. The
1984 volume represents a state-of-the-art comprehensive review of
tobacco use and the development of chronic obstructive lung
diseases.

The scientific content of this Report is the work of experts in the
field of chronic obstructive lung disease research both within the
Department of Health and Human Services and from outside the
Federal Government. Individual manuscripts were written by ex-
perts who are nationally and internationally recognized for their
scientific understanding of the etiology of chronic obstructive lung
diseases, particularly the relationship with cigarette use.

Manuscripts received from authors were extensively reviewed by
numerous outside experts familiar with these specific areas. The
entire Report was then submitted to a broad-based panel of 11
distinguished lung disease experts and to experts within the U.S.
Public Health Service for their review and comments.
The 1964 Report includes a Foreword by the Assistant Secretary
for Health of the Department of Health and Human Services and a
Preface by the Surgeon General of the U.S. Public Health Service.
The body of the Report consists of 10 chapters, as follows:

o  Chapter  1.

o  Chapter  2.





0  Chapter  3.



o  Chapter  4.

o  Chapter  5.



o  Chapter  6.



o  Chapter  7.

o  Chapter  8.

Introduction, Overview, and Conclusions
Effect of Cigarette Smoke Exposure on Mea-
sures of Chronic Obstructive Lung Disease
Morbidity
Mortality From Chronic Obstructive Lung Dis-
ease Due to Cigarette Smoking
Pathology of Lung Disease Related to Smoking
Mechanisms by Which Cigarette Smoke Alters
the Structure and Function of the Lung
Low Yield Cigarettes and Their Role in Chronic
Obstructive Lung Disease
Passive Smoking
Deposition and Toxicity of Tobacco Smoke in
the Lung

5


o Chapter 9.  Role of the Physician in Smoking Cessation
o Chapter 10.  Community Studies of Smoking Cessation and
           Prevention

Historical Perspective

The relationship between cigarette smoking and chronic obstruc-
tive lung disease (COLD) was among the first recognized and is now
the best understood of the diseases caused by smoking. Sigmund
reported as early as 1870 that heavy smokers suffered "affections" of
the nose, mouth, and throat more frequently and in a more virulent
fashion. In 1897, Mendelssohn reported the incidence of "affections"
of the respiratory tract to be 60 percent greater in smokers than in
nonsmokers, as well as somewhat greater in those who inhaled
compared with smokers who did not inhale.

Overview

Scientists from a variety of disciplines have investigated the role of
cigarette smoking in the development of COLD; today we can trace
the progressive decline in lung function in smokers with increasing
smoke exposure, describe the concurrent pathologic changes, demon-
strate that both COLD prevalence and COLD death are limited
largely to smokers, and describe in detail a plausible mechanism by
which cigarette smoking can lead to the development of emphysema.
Some gaps in the understanding of the details of this process may
still exist, but the experimental and epidemiologic evidence leaves
no room for reasonable doubt on the fundamental issue: cigarette
smoking is the major cause of COLD in the United States.

The earliest recognized response to cigarette smoke is an increase
in airway resistance that occurs with the inhalation of smoke by the
smoker. This increase in resistance is a response to the irritants in
the smoke, as is coughing, which is more frequent in smokers than in
nonsmokers, even among adolescents. By the time smokers become
young adults, a substantial proportion of them will have developed
pathologic changes in their small airways. These abnormalities are
demonstrable using a variety of physiologic tests, and are a result of
pathologic changes or inflammation in the airways less than 2 mm
in diameter. Part of this small airways response, but perhaps a later
manifestation of it, is the development of smooth muscle hypertro-
phy, goblet cell hyperplasia, and mild peribronchiolar fibrosis. The
prevalence of abnormalities on tests of small airways function
increases as these young smokers grow older, and is greater in heavy
smokers than in light smokers. While it is clear that changes in the
small airways represent an early response to cigarette smoking and
that they are a significant finding in the pathophysiology of COLD, it
is not clear that abnormal function of the small airways, per se, is

6


useful as a marker for identifying who will progress to develop
symptomatic COLD. It may identify a large group of smokers who
manifest an irritant response to smoke in the small airways, of
whom only a subset actually develop symptomatic airflow obstruc-
tion.

Measurable differences in tests of expiratory airflow exist between
smokers and nonsmokers after age 25. Smokers as a group have a
more rapid decline in F'EV, with age than that observed in
nonsmokers, and the decline is even greater among heavy smokers.
However, this increased rate of decline in lung function is not
distributed evenly, even among smokers with similar smoking
histories. Some smokers have a far more rapid decline than the
average smoker, and clearly those individuals who have developed
symptomatic chronic airflow obstruction have had a larger total
decline in lung function than the average smoker. This has led to the
suggestion that individuals with a particularly rapid decline in FEV,
early in life may represent a group especially susceptible to the later
development of symptomatic COLD. The nature of this susceptibility
remains unclear, but differences in depth or pattern of inhalation,
variations in the cellular and biochemical response of the lung to
smoke, differences in immune or repair mechanisms, and childhood
infections or exposure to environmental tobacco smoke as a child
have been suggested as potential factors.

The accumulation of lung damage, marked by the excess decline in
F'EV, and other measures of expiratory airflow, can lead to shortness
of breath and other symptoms that characterize clinically significant
COLD. These symptoms can result in disability due to ventilatory
limitation and may vary from patient to patient in severity and
duration. Many patients with clinically disabling COLD die with the
disease rather than because of it. Death from COLD usually results
only after extensive lung damage and commonly occurs because of
failure of the severely damaged lungs to maintain adequate gas
exchange.

The cessation of cigarette smoking has a substantial salutary
impact on the incidence and progression of COLD. Cigarette smokers
who quit prior to developing abnormal lung function are unlikely to
go on to develop ventilatory limitation; when the abnormalities are
demonstrable only on tests of small airways function, cessation often
results in a reversal of these changes and a return to normal
function. The presence of significant fixed reduction in measures of
expiratory airflow usually reflects the presence of substantial lung
damage. Cessation of smoking at this stage of COLD results in a
slowing in the rate of decline in lung function with age, in
comparison with that in continuing smokers. After a period of
cessation, this rate of decline in function may approximate the rate
found in nonsmokers, but there is little evidence to suggest that

7


those who quit are able to regain their prior excess functional loss.
Therefore, those who quit continue to have reduced lung function
when compared with those who have never smoked, but their lung
function begins to decline less rapidly with age when compared to
the lung function of those who continue to smoke.
The importance of cigarette smoking as a causative factor in
COLD is emphasized by cross-sectional studies of populations in the
United States where often the only major predictor for developing or
dying of COLD is smoking behavior. In the absence of cigarette
smoking, clinically significant COLD is rare.

As the smoker enters the sixth decade of life, pathologically
definable pulmonary emphysema begins to become evident. In older
age groups, mild to moderate emphysema is present in most smokers
and is rare in nonsmokers. Once again, however, only a small
percentage of smokers develop severe emphysema; this minority
includes a disproportionate number of heavy smokers.

A mechanism for smoking-induced emphysematous lung injury
has been proposed and continues to evolve as our understanding of
cellular and biochemical responses of the lung increases. Emphyse-
ma can be produced by the presence of excessive amounts of elastase
(an enzyme capable of degrading the structural elements of lung
tissue) or by the absence of a,-antiprotease (a protein that inhibits
the action of elastase). As part of the inflammatory response to
cigarette smoke, an increased number of inflammatory cells are
present in the lungs of smokers; these cells may result in an
increased amount of elastase being present in the lung. In addition,
cigarette smoke can oxidize the a,-antiprotease in the lung, further
contributing to the imbalance between levels of elastase and levels of
a,-antiprotease. The net result can be excess elastase activity,
leading to degradation of elastin in the lung, destruction of alveolar
walls, and development of emphysema.

The text of this Report discusses in detail the relationship of
cigarette smoking to COLD morbidity and mortality, the pathology
of smoking-induced COLD, some of the mechanisms by which
smoking results in COLD, the impact on the lung of low tar and
nicotine cigarettes and of involuntary smoke exposure, the deposi-
tion and toxicology of tobacco smoke, and the role of the physician
and of community intervention programs in smoking cessation.

The overall conclusion of this Report is clear: Cigarette smoking
is the major cause of chronic obstructive lung disease in the
United States for both men and women. The contribution of
cigarette smoking to chronic obstructive lung disease morbidi-
ty and mortality far outweighs all other factors.

8


Conclusions of the 1984 Report
COLD Morbidity

1. Cigarette smoking is the major cause of COLD morbidity in the
United States; 80 to 90 percent of COLD in the United States is
attributable to cigarette smoking.

2. In population-based studies in the United States, cigarette
smoking behavior is often the only significant predictor for the
development of COLD. Other factors improve the predictive
equation only slightly, even in those populations where they
have been found to exert a statistically significant effect.
3. In spite of over 30 years of intensive investigation, only
cigarette smoking and a,-antiprotease deficiency (a rare genet-
ic defect) are established causes of clinically significant COLD
in the absence of other agents.

4. Within a few years after beginning to smoke, smokers experi-
ence a higher prevalence of abnormal function in the small
airways than nonsmokers. The prevalence of abnormal small
airways function increases with age and the duration of the
smoking habit, and is greater in heavy smokers than in light
smokers. These abnormalities in function reflect inflammatory
changes in the small airways and often reverse with the
cessation of smoking.

5. Both male and female smokers develop abnormalities in the
small airways, but the data are not sufficient to define possible
sex-related differences in this response. It seems likely, how-
ever, that the contribution of sex differences is small when age
and smoking exposure are taken into account.

6. There is, as yet, inadequate information to allow a firm
conclusion to be drawn about the predictive value of the tests of
small airways function in identifying the susceptible smoker
who will progress to clinical airflow obstruction.

7. Smokers of both sexes have a higher prevalence of cough and
phlegm production than nonsmokers. This prevalence in-
creases with an increasing number of cigarettes smoked per
day and decreases with the cessation of smoking.

8. Differences between smokers and nonsmokers in measures of
expiratory airflow are demonstrable by young adulthood and
increase with number of cigarettes smoked per day.

9. The rate of decline in measures of expiratory airflow with
increasing age is steeper for smokers than for nonsmokers; it is
also steeper for heavy smokers thRn for light smokers. After
the cessation of smoking, the rate of decline of lung function
with increasing age appears to slow to approximately that seen
in nonsmokers of the same age. Only a minority of smokers will
develop clinically significant COLD, and this group will have

9

480-144 0 - 85 - 2


demonstrated a more extensive decline in lung function than
the average smoker. The data are not yet available to
determine whether a rapid decline in lung function early in life
defines the subgroup of smokers who are susceptible to
developing COLD.

10. Clinically significant degrees of emphysema occur almost
exclusively in cigarette smokers or individuals with genetic
homozygous a,-antiprotease deficiency. The severity of em-
physema among smokers increases with the number of ciga-
rettes smoked per day and the duration of the smoking habit.

COLD Mortality

1. Data from both prospective and retrospective studies consis-
tently demonstrate a uniform increase in mortality from COLD
for cigarette smokers compared with nonsmokers. Cigarette
smoking is the major cause of COLD mortality for both men
and women in the United States.

2. The death rate from COLD is greater for men than for women,
most likely reflecting the differences in lifetime smoking
patterns, such as a smaller percentage of women smoking in
past decades, and their smoking fewer cigarettes, inhaling less
deeply, and beginning to smoke later in life.

3. Differences in lifetime smoking behavior are less marked for
younger age cohorts of smokers. The ratio of male to female
mortality from COLD is decreasing because of a more rapid rise
in mortality from COLD among women.

4. The dose of tobacco exposure as measured by number of
cigarettes or duration of habit strongly affects the risk for
death from COLD in both men and women. Similarly, people
who inhale deeply experience an even higher risk for mortality
from COLD than those who do not inhale.

5. Cessation of smoking leads eventually to a decreased risk of
mortality from COLD compared with that of continuing
smokers. The residual excess risk of death for the ex-smoker is
directly proportional to the overall lifetime exposure to ciga-
rette smoke and to the total number of years since one quit
smoking. However, the risk of COLD mortality among former
smokers does not decline to equal that of the never smoker
even after 20 years of cessation.

6. Several prospective epidemiologic studies examined the rela-
tionship between pipe and cigar smoking and mortality from
COLD. Pipe smokers and cigar smokers also experience higher
mortality from COLD compared with nonsmokers; however,
the risk is less than that for cigarette smokers.
7. There are substantial worldwide differences in mortality from
COLD. Some of these differences are due to variations in

10


terminology and in death certification in various countries.
Emigrant studies suggest that ethnic background is not the
major determinant for mortality risk due to COLD.

Pathology of Cigarette-Induced Disease

1. Smoking induces changes in multiple areas of the lung, and the
effects in the different areas may be independent of each other.
In the bronchi (the large airways), smoking results in a modest
increase in size of the tracheobronchial glands, associated with
an increase in secretion of mucus, and in an increased number
of goblet cells.

2. In the small airways (conducting airways 2 or 3 mm or less in
diameter consisting of the smallest bronchi and bronchioles) a
number of lesions are apparent. The initial response to
smoking is probably inflammation, with associated ulceration
and squamous metaplasia. Fibrosis, increased muscle mass,
narrowing of the airways, and an increase in the number of
goblet cells follow.

3. Inflammation appears to be the major determinant of small
airways dysfunction and may be reversible after cessation of
smoking.

4. The most obvious difference between smokers and nonsmokers
is respiratory bronchiolitis. This lesion may be an important
cause of abnormalities in tests of small airways function, and
may be involved in the pathogenesis of centrilobular emphyse-
ma. The severity of emphysema is clearly associated with
smoking, and severe emphysema is confined largely to smok-
ers.

Mechanisms of COLD

1. Increased numbers of inflammatory cells are found in the
lungs of cigarette smokers. These cells include macrophages
and, probably, neutrophils, both of which can release elastase
in the lung.

2. Human neutrophil elastase produces emphysema when in-
stilled into animal lungs.

3. Alpha,-antiprotease inhibits the action of elastase, and a very
small number of people with a homozygous deficiency of a,-
antiprotease are at increased risk of developing emphysema.
The a,-antiprotease activity has been shown to be reduced in
the bronchoalveolar fluids obtained from cigarette smokers
and from rats exposed to cigarette smoke.

4. The protease-antiprotease hypothesis suggests that emphyse-
ma results when there is excess elastase activity as the result
of increased concentrations of inflammatory cells in the lung

11


and of decreased levels of a,-antiprotease secondary to oxida-
tion by cigarette smoke.

5. Cigarette smokers have been shown to have a more rapid fall in
antibody levels following immunization for influenza than
nonsmokers. Whole cigarette smoke has been shown to depress
the number of antibody-forming cells in the spleens of experi-
mental animals.

6. Cigarette smoke produces structural and functional abnormali-
ties in the airway mucociliary system.
7. Short-term exposure to cigarette smoke causes ciliostasis in
vitro, but has inconsistent effects on mucociliary function in
man. Long-term exposure to cigarette smoke consistently
causes an impairment of mucociliary clearance. This impair-
ment is associated with epithelial lesions, mucus hypersecre-
tion, and ciliary dysfunction.

8. Chronic bronchitis in smokers and ex-smokers is characterized
by an impairment of mucociliary clearance.
9. Both the particulate phase and the gas phase of cigarette
smoke are ciliotoxic.

Low Tar and Nicotine Cigarettes

1. The recommendation for those who cannot quit to switch to
smoking cigarette brands with low tar and nicotine yields, as
determined by a smoking-machine, is based on the assumption
that this switch will result in a reduction in the exposure of the
lung to these toxic substances. The design of the cigarette has
markedly changed in recent years, and this may have resulted
in machine-measured tar and nicotine yields that do not reflect
the real dose to the smoker.

2. Smoking-machines that take into account compensatory
changes in smoking behavior are needed. The assays could
provide both an average and a range of tar and nicotine yields
produced by different individual patterns of smoking.

3. Although a reduction in cigarette tar content appears to reduce
the risk of cough and mucus hypersecretion, the risk of
shortness of breath and airflow obstruction may not be
reduced. Evidence is unavailable on the relative risks of
developing. COLD consequent to smoking cigarettes with the
very low tar and nicotine yields of current and recently
marketed brands.

4. Smokers who switih from higher to lower yield cigarettes show
compensatory changes in smoking behavior: the number of
puffs per cigarette is variably increased and puff volume is
almost universally increased, although the number of ciga-
rettes smoked per day and inhalation volume are generally

12


unchanged. Full compensation of dose for cigarettes with lower
yields is generally not achieved.

5. Nicotine has long been regarded as the primary reinforcer of
cigarette smoking, but tar content may also be important in
determining smoking behavior.

6. Depth and duration of inhalation are among the most impor-
tant factors in determining the relative concentration of smoke
constituents that reach the lung. Considerable interindividual
variation exists between smokers with respect to the volume
and duration of inhalation. This variation is likely to be an
important factor in determining the varying susceptibility of
smokers to the development of lung disease.

7. Production of low tar and nicotine cigarettes has progressed
beyond simple reduction in'tobacco content. Additives such as
artificial tobacco substitutes and flavoring extracts have been
used. The identity, chemical composition, and adverse biologi-
cal potential of these additives are unknown at present.

Passive Smoking

1. Cigarette smoke can make a significant, measurable contribu-
tion to the level of indoor air pollution at levels of smoking and
ventilation that are common in the indoor environment.
2. Nonsmokers who report exposure to environmental tobacco
smoke have higher levels of urinary cotinine, a metabolite of
nicotine, than those who do not report such exposure.
3. Cigarette smoke in the air can produce an increase in both
subjective and objective measures of eye irritation. Further,
some studies suggest that high levels of involuntary smoke
exposure might produce small changes in pulmonary function
in normal subjects.

4. The children of smoking parents have an increased prevalence
of reported respiratory symptoms, and have an increased
frequency of bronchitis and pneumonia early in life.
5. The children of smoking parents appear to have measurable
but small differences in tests of pulmonary function when
compared with children of nonsmoking parents. The signifi-
cance of this finding to the future development of lung disease
is unknown.

6. Two studies have reported differences in measures of lung
function in older populations between subjects chronically
exposed to involuntary smoking and those who were not. This
difference was not found in a younger and possibly less exposed
population.

7. The limited existing data yield conflicting results concerning
the relationship between passive smoke exposure and pulmo-
nary function changes in patients with asthma.

13


Deposition and Toxicity of Tobacco Smoke in the Lung
1. The mass median aerodynamic diameter of the particles in
  cigarette smoke has been measured to average approximately
  0.46 pm, and particulate concentrations have been shown to
  range from 0.3 x lo9 to 3.3 X 10' per milliliter.
2. The particulate concentration of the smoke increases as the
  cigarette is more completely smoked.
3. Particles in the size range of cigarette smoke will deposit both
  in the airways and in alveoli; models predict that 30 to 40
  percent of the particles within the size range present in
  cigarette smoke will deposit in alveolar regions and 5 to 10
  percent will deposit in the tracheobronchial region.
4. Acute exposure to cigarette smoke results in an increase in
  airway resistance in both animals and humans.
5. Exposure to cigarette smoke results in an increase in pulmo-
  nary epithelial permeability in both humans and animals.
6. Cigarette smoke has been shown to impair elastin synthesis in
  vitro and elastin repair in vivo in experimental animals
  (elastin is a vital structural element of pulmonary tissue).

Role of the Physician in Smoking Cessation
1. At least 70 percent of North Americans see a physician once a
  year. Thus, an estimated 38 million of the 54 million adults in
  the United States who smoke cigarettes could be reached
  annually with a smoking cessation message by their physician.
2. Current smoking prevalence among physicians in the United
  States is estimated at 10 percent.

3. While the majority of persons who smoke feel that physician
advice to quit or cut down would be influential, there is a
disparity between physicians' and patients' estimates of cessa-
tion counseling, with physician advice being reported by only
approximately 25 percent of current smokers.
4. Studies of routine (minimal) advice to quit smoking delivered
by general practitioners have shown sustained quit rates of
approximately 5 percent. Followup discussions enhance the
effects of physician advice.

5. A median of 20 percent of pregnant women who smoke quit
spontaneously during pregnancy. That proportion can be
doubled by an intervention consisting of health education,
behavioral strategies, and multiple contacts.
6. Large controlled trials of cardiovascular risk reduction have
demonstrated that counseling on individual specific risk fac-
tors, including smoking cessation techniques, can be effective.
7. Studies of pulmonary and cardiac patients indicate that
severity of illness is positively related to increased compliance

14


in smoking cessation. Survivors of a myocardial infarction have
smoking cessation rates averaging 50 percent.
8. Nicotine chewing gum has been developed as a pharmacologi-
cal aid to smoking cessation, primarily to alleviate withdrawal
symptoms. Cessation studies conducted in offices of physicians
who prescribe the gum have produced mixed results, however,
with outcome depending on motivation and intensity of adjunc-
tive support or followup.

9. Physician-assisted intervention quit rates vary according to the
type of intervention, provider performance, and patient group.
In general, quit rates in recent research appear to be lower
than in older studies.

Community Studies of Smoking Cessation and Prevention

1. Community studies of smoking cessation and prevention are
becoming an established paradigm for public health action
research. Such studies emphasize large-scale delivery systems,
such as the mass media, and include community organization
programs seeking to stimulate interpersonal communication in
ways that are feasible on a large-scale basis.

2. Although there are methodological limitations to nearly all
communitywide studies, the results yield fairly consistent
positive results, indicating that large-scale programs to reduce
smoking can be effective in whole populations. Person-to-
person communication appears to be a necessary part of a
successful community program to reduce smoking.

3. Further research is needed, with both improved methodology
and more emphasis on low socioeconomic status groups that
have not yet shown population trends toward reduced smoking.
4. Several promising directions for research are clear, but the
most important future trends will be toward the establishment
of smoking reduction programs within existing health services,
the combination of chronic disease prevention with mental
health promotion via mass media and community intervention,
and the development of social policy to establish integrated
strategies for smoking cessation and prevention.

15


CHAPTER 2. EFFECT OF CIGARETTE
         SMOKE EXPOSURE ON
         MEASURES OF
         CHRONIC
        OBSTRUCTIVE LUNG
         DISEASE MORBIDITY

17


CONTENTS

Introduction

Early Changes in Response to Cigarette Smoking
Acute Response to Cigarette Smoke
  Chronic Response to Cigarette Smoke
    Smoking and Tests of Small Airways Function
     in Population Studies
    Dose-Response Relationship Between Amount
     Smoked and Small Airways Dysfunction
    How Soon Do Changes in Small Airways
      Function Occur?

  Male-Female Differences in the Responses of
   the Small Airways to Cigarette Smoking
Effect of Smoking Cessation on Small Airways
Function

Relationship Between Small Airways Disease and
Chronic Airflow Obstruction
Summary

-

Chronic Mucus Hypersecretion
  Introduction

Measurement of Cough and Phlegm in Epidemiologic
Studies

Prevalence of Cough and Phlegm
Relationship of Cough and Phlegm to Smoking
  Effects of Smoking Cessation
  Dose-Response Relationships
Relationship of Cough and Phlegm to Sex and Age
Relationship of Cough and Phlegm to Airflow
Obstruction
Summary

                         I__.--__-_.~- __-_
-
Chronic Airflow Obstruction
  Introduction
  Prevalence of Airflow Obstruction
  Determinants of Airflow Obstruction
     Introduction
    Cigarette Smoking and Chronic Airflrlw
      Obstruction

19


Dose-Response Relationships
Factors Other Than Cigarette Smoking
ABH Secretor Status
Air Pollution
Airways Hyperreactivity
Alcohol Consumption
Atow

    Childhood Respiratory Illness
     Familial Factors
    Occupation
    Passive Exposure to Tobacco Smoke
    Respiratory Illnesses
     Socioeconomic Status
Development of Airflow Obstruction
Summary

Emphysema
  Introduction
  Definition of Emphysema
Types of Emphysema
  Detection of Emphysema
Quantification of Emphysema
Pulmonary Function in Emphysema
Mechanical Properties of the Lungs in Emphysema
  Aging and Lung Structure
Emphysema and Cigarette Smoking
    Observations in People
     Studies Using Post-Mortem Material
     Dose-Response Relationships
     Studies of Alphal-Proteinase-Inhibitor-Deficient
        Individuals
      Homozygous Deficient-PiZZ
      Heterozygous Deficient-PiMZ
    Observations in Experimental Animals
  Summary

Summary and Conclusions

Appendix Tables

References

20


INTRODUCTION

This chapter describes the sequential development of smoking-
induced chronic lung disease, traced from the early structural
changes limited to the small airways to the severe and widespread
changes involving the small airways, large airways, and lung
parenchyma. Chronic obstructive lung disease (COLD) develops
relatively slowly, and the progression of lung injury and alterations
in function can be followed using an individual smoker's symptoms
and performance on a variety of pulmonary function tests. Early in
the duration of the smoking behavior, a person may be asymptomat-
ic, but often there are abnormalities demonstrable in the small
airways that probably represent an inflammatory response to the
constituents of cigarette smoke. Later, usually after 20 or more years
of smoking, a constellation of symptoms and functional changes may
develop, particularly in heavy smokers and in those who will later
develop clinically significant COLD. The clinical picture of cigarette-
induced chronic lung injury includes three separate, but often
interconnected, disease processes. They are (1) chronic mucus
hypersecretion (cough and phlegm), (2) airway narrowing with
expiratory airflow obstruction, and (3) abnormal dilation of the distal
airspaces with destruction of alveolar walls (emphysema). Patients
with severe COLD commonly have some degree of all three pro-
cesses, but individual patients vary significantly in the relative
contribution of the processes to their overall disease state.

Some alteration in lung structure or function is demonstrable in
the majority of long-term smokers, but only a minority of smokers
will develop clinically limiting COLD. In fact, only 10 to 15 percent
of smokers will develop moderate or severe airflow obstruction
(Bates 1973; Fletcher et al. 1976).

This chapter details the relationship between cigarette smoking
and morbidity from COLD. The relationship of cigarette smoking to
changes in the small airways is described first, followed by discussion
of the role of smoking to chronic mucus hypersecretion, chronic
airflow obstruction, and emphysema.

21


EARLY CHANGES IN RESPONSE TO CIGARETTE SMOKING

The tests of small airways function were developed in the late
1960s and early 19SOs, and grew out of a series of studies calling
attention to the functional importance of disease in the small
airways. Macklem and Mead (1967) predicted that there could be
considerable peripheral airway obstruction that might influence the
distribution of ventilation but would have little effect on lung
mechanisms; subsequently, Anthonisen et al. (19681 and Ingram and
Schilder (1967) demonstrated the existence of early functional
changes in smokers. These investigators showed that in a group of
patients with clinically mild chronic bronchitis and normal lung
function measured by spirometric tests, all had abnormalities of
regional gas exchange, as determined by Xenonl"3. They attributed
this finding to peripheral airway disease and suggested that the
functionally important lesion in chronic bronchitis may be in the
small airways. Brown and coworkers (19691, using excised lobes of
dog and pig lung, demonstrated that considerable obstruction may be
present in the airways smaller than 2 mm with little or no effect on
overall pulmonary resistance. Hogg and coworkers (1968), using a
retrograde catheter technique, measured central and peripheral
airway resistance in excised normal and emphysematous human
lungs and found that the peripheral airway resistance (accounting
for only 25 percent of total airway resistance in the normal lungs
(Macklem and Mead 1967)) was greatly increased in the lungs with
emphysema. In an early structure-function correlation study, these
investigators correlated the physiologic findings with histologic and
bronchographic evidence of mucus plugging and narrowing and
obliteration of small airways. Woolcock and coworkers (1969) report-
ed that a group of bronchitic subjects with normal responses to
routine lung function tests (lung volumes, flow rates, and diffusing
capacity) demonstrated a decrease in the dynamic-to-static compli-
ance ratio with increasing breathing frequency. These studies
provided clear evidence that there can be measurable obstruction in
airways 2 mm in diameter or smaller with little or perhaps no
detectable influence on total airway resistance, and, therefore, on
lung function measured by conventional tests such as lung volumes,
spirometry, and diffusing capacity.

With the concept of small airways disease firmly established, a
number of new tests considered capable of detecting the abnormality
were introduced, along with reinterpretation of existing tests. The
new measures included frequency dependence of compliance, the
single breath NP test for the measurement of closing volumes (closing
volume as a percent of vital capacity [CV/VC%] and closing capacity
as a percent of total lung capacity [CC/TLC%]), the slope of the
alveolar plateau, maximal expiratory flow volume (MEFV) curves
using gases of differentdensities, and moment analysis of the forced

22


expiration. The measurements obtained from the MEFV curve,
breathing gases of different densities, are (a) the difference in
maximal flow at 50 and 75 percent of the forced vital capacity
breathing air and breathing a helium-oxygen (He&) mixture
(AVrnax50% and AV&, and (b) a measurement of the lung volume at
which the air and He02 curves cross, the volume of isoflow (VisoV).
Tests already in common use included the volume-time curve (the
spirogram) and the MEFV curve breathing air. The measurements
obtained from standard tests that were thought to be sensitive to
mild airflow obstruction are (a) from the spirogram, the forced
expiratory flow between 75 and 85 percent. of the forced vital
capacity (FEF75-85~); and (b) from the MEFV curve: maximal flow at
50 and 75 percent of the forced vital capacity, V,, 50% and V,, 75%.

The important question of structure-function correlation in tests
of small airways function has received much attention over the past
5 years, and has been addressed via a series of attempts to correlate
physiologic tests with the actual structural changes observed in lobes
or lungs obtained at thoracotomy or post mortem.

Fulmer and coworkers (1977) correlated measurements of dynamic
compliance with measurements of small airway diameter obtained
from lung biopsies in patients with idiopathic pulmonary fibrosis.
These investigators demonstrated a highly significant correlation
between dynamic compliance and an overall estimate of small
airways diameter.

Cosio and coworkers (1978) and Berend et al. (1979) did pulmonary
function tests before lung resection and correlated the function tests
with morphologic abnormalities that divided the subjects into four
groups based on increasing degree of pathologic change. They found
that an index of overall histologic small airways disease could be
related to CC/TLC, Visof, and the slope of the alveolar plateau of
the single breath N2 test (Figure 1); inflammation, fibrosis, and
squamous metaplasia were the most important lesions. The impor-
tant conclusions that can be drawn from this study are that
abnormalities of both spirometry and the special tests of small
airways function are associated with structural changes in the
peripheral airways, and that inflammation is the most important
cause of obstruction to flow in small airways dysfunction.

Berend and coworkers (1979) noted a significant relationship
between narrowing of the peripheral airways and CV/VC and
FEFZWSS. In contrast to the study of Cosio et al. (1978), the slope of
the alveolar plateau did not correlate with peripheral airway
narrowing, and the volume of isoflow was essentially useless because
of its high variability. They found that the FEVl was also related to
peripheral airway narrowing.

Berend (1982) has recently provided new information by reanalysis
and expansion of his earlier study. In measurements of small and

23


loo0



800



600

Smoktng Index
  ag/yr
          10

          0.7
L-   06


          05

I II III IV

FEV,WVC

   MMF           RV
percent predicted     percent predcted

1 1 1 1 2

  I II Ill IV

140





100

I II III IV       I II Ill IV

Pathology groups

FIGURE l.--Comparison of increasing small airways
      disease (Groups I to Iv) to smoking index and
      various pulmonary diction tests, by mean +:
        S.E.
`P <o.os.
"P <O.Ol.
SOURCE: Cmio et al. (1978).

TABLE l.-Correlation coefficients (r) between morphologic
     variables and tests of pulmonary function

mv,   hiMFR 0~0    RL

Slope
phaee III   CVNC TLCCI

Bronchiolar diameter   0.28    0.37    0.46 '   -0.36      -0.06    -0.03    0.20
Total path scare     -0.39   -0.42'  -0.48'    0.03       0.22     0.30     -
Inflammation wore   -0.55   -0.46'  -0.41    0.17       0.61_     0.50    -
Reid index        -0.50'   -0.41   -0.34    0.31       0.06     0.07   -0.37
Emphysema        -0.33   -0.45 '  -0.43    0.28       0.45     0.19   -0.72s

lP<O.o!5.
`P<O.Ol.
`P<O.M)l

large airway lesions, he found that inflammation correlates best
with the slope of the alveolar plateau, FEVI, CVNC, and the
FEFZJUZ (Table 1).

Petty and coworkers (1981) studied a younger group of subjects
(average age, 32) who came to autopsy. They found that inflamma-

24


tion and increased muscle in the small airways correlate with
CC/TLC and that the slope of the alveolar plateau correlates with
inflammation, increased muscle in the small airways, and increased
intraluminal cells and mucus.

Berend and Thurlbeck (1982) obtained volume-pressure and
MEFV curves with air and HeOn in 25 excised human lungs obtained
at autopsy from nonhospitalized patients (age 57, +_13 years) who
died suddenly from nonrespiratory causes. The emphysema grade
was measured, and the total pathological score was determined from
four variables: inflammation, smooth muscle hyperplasia, fibrosis,
and pigmentation. Correlations were then made between the mea-
surements obtained from the MEFV curves with air and He02 and
the morphology. A significant correlation was obtained between
maximal flow (tTmax) and the inflammation score, fibrosis score, and
emphysema grade. Small airways dimensions correlated poorly with
V,, 75% and V - so%, and VisoV showed no signifkant correlation
with any small airways measurement or score.

Cosio and coworkers (1980) have also studied lungs obtained at
autopsy, but did not attempt to provide structure-function correla-
tion. They examined the lungs of smokers and nonsmokers and
showed that structural changes in the small airways are more severe
in smokers than in nonsmokers, with the main lesions being
inflammation, goblet cell metaplasia, and hypertrophied muscle. In
smokers, all the airways less than 2 mm were about equally
involved. This study used slightly older subjects than an earlier
study by the same investigators. In the earlier study, goblet cell
metaplasia, increased smooth muscle, and airway narrowing were
not observed, suggesting that perhaps these lesions are a later stage
in the evolution of the response to injury in the small airways.

In another study of lungs obtained at autopsy, Salmon and
coworkers (1982) correlated morphologic measurements of the cen-
tral and peripheral airways and the alveolar surface-to-volume ratio
with the slope of the alveolar plateau measured in the lung post
mortem. They found a significant inverse correlation between the
slope of the alveolar plateau and the peripheral airway diameter, but
no signifkant relationship between the slope of the alveolar plateau
and the alveolar-tisurface volume ratio, once age had been con-
trolled. They concluded from these findings that the slope of the
alveolar plateau does indeed assess the properties of the peripheral
airways.

Mink and Wood (1980) performed physiologic studies on the lungs
of six men (average age, 66 years) who died of atherosclerotic heart
disease. Morphometrics were performed on one lung of each of two of
the subjects, The physiologic studies involved ventilating a lung
through a main-stem bronchus in a volume displacement plethysmo
graph with two catheters placed to record pressure: one in the lower

25


lobe to measure lateral bronchial pressure and the other within the
plethysmograph to record pleural surface pressure. MEFV curves
were obtained in lungs ventilated with either air or a He02 mixture.
They found that an abnormal response to breathing He02 is not
necessarily indicative of either airway or parenchymal disease, and
concluded that the ability of the He02 breathing to discriminate
between normal and obstructed peripheral airways is affected by
large between-subject variation in normal maximal flow, which is
probably due to normal variation in the caliber of the central
airways. They therefore questioned the use of MEFV curves breath-
ing air and He02 as a means of distinguishing between peripheral
and central airflow obstruction or as a means of identifying mild
airflow obstruction due to structural changes in the small airways. A
similar conclusion was reached by MacNee and coworkers (1983).

These structure-function correlation studies have provided fairly
convincing evidence that at least some of the tests purported to
measure small airways function can indeed identify structural
changes in the small airways. These changes appear initially to
involve macrophage accumulation around respiratory bronchioles,
with subsequent development of epithelial abnormalities in the
terminal bronchioles. With cumulative injury over a long period,
chronic inflammation leads to fibrosis and perhaps to an increase in
the amount of smooth muscle. These are strictly airway lesions. The
alveolar wall destruction of emphysema is not as clearly related to
the tests of small airways function (Petty et al. 1981).

Acute Response to Cigarette Smoke

Before the tests of small airways function were introduced in the
late sixties and early seventies, it was established that smoking a
cigarette results in an immediate increase in airway resistance and a
decrease in expiratory flow (Attinger et al. 1958; Chiang and Wang
1970; Clarke et al. 1970; Nadel and Comroe 1961; Robertson et al.
1969; Simonsson 1962; Zamel et al. 1963; Sterling 1967). It was
thought that this response is mediated by the vagus nerve, and may
be suppressed by isoproterenol and atropine (Nadel and Comroe
1961; Sterling 1967; Zamel et al. 1963).

Using the MEFV curve and closing volume, Da Silva and Hamosh
(1973) showed a decrease in the maximum expiratory flow at 50
percent of the vital capacity, with the MEFV curve assuming a
concave shape in 21 subjects immediately following cigarette smok-
ing. Sob01 et al. (1977) found the greatest change following smoking
in airway resistance and specific conductance, with significant but
lesser changes in the l-second forced expiratory volume (FEVll, the
forced expiratory flow over the middle half of the forced vital
capacity (FEFzHwJ, and the ratio of FEVl to the forced vital capacity
(FVC), FEVl/FVC. Neither study found a change in closing volume.

26


From this limited information, it can be reasonably c(rl)( Iucltf.j ti,:it
the large airways, rather than the small :~irway~, IP.G~QIH! ;ls~~~t..i~ 10
the inhalation of cigarette smoke.

Chronic Response to Cigarette Smoke

In the late 18OOs, Mendelssohn (18973 repurtd ttlnt ;;v:akiny !~:l:i I
deleterious effect on the respiratory system. The ea!!y stti::its L.Y 7.1:
hampered by the lack of sensitive physiologic tests c)t` 1u1,~: !:.!i:. : i 5.:
and relied heavily on differences between smokers and nonsmoi;!~r~
in the prevalence of respiratory symptoms. Confirmation of' the
structural basis of excessive respiratory symptoms see!1 ir. :kw
smokers came from the classic paper by Reid in 1954, in whi::!! slit:
described the pathology of chronic bronchitis I Reid 19,511 Vwtilat $1.
ry limitation usually occurs late in the course of COLD. I:: r'c.~t:rz~t.
the inflammatory response of the small airw:-ivs i+ rj~~rr~~:t;~  1,
relatively early in life in cigarette smokers.

Smoking and Tests of Small Airways Functh in Pop~~l:~fj:~~
Studies

A large number of studies using tests of small airways func:ion
have been conducted over the past 15 years in groups and popula-
tions of various sizes, ages, and other characteristics. In some vf
these studies, the investigators have developed their own normal test
ranges from a group of asymptomatic nonsmokers, but the normal
ranges obtained by others (Buist and Ross 1973a, b; McCarthy et al.
1972; Collins et al. 1973) have been more commonly used.

In one of the earliest reported studies using the single breath Na
test, Buist and coworkers (Buist and Ross 1973b; Buist et al. 19731
examined 1,073 persons attending a screening center, of whom 524
were current cigarette smokers. Among the smokers, an abnormal
CV/VC was found in 35 percent, an abnormal CC/TLC in 44 percent,
and an abnormal slope of the alveolar plateau in 47 percent. When
the three measurements obtained from the single breath Nz test
were taken in conjunction, 64 percent of the smokers and 61 percent
of the ex-smokers had an abnormal test result. In contrast, only 11
percent of the smokers had an abnormal FEVl and 21 percent had an
abnormal FEF~H~s. This study suggested that the prevalence of
measurable small airways dysfunction among cigarette smokers
exceeds 50 percent. It must be kept in mind, however, that this study
was carried out in a screening center and was therefore presumably
biased toward a high disease prevalence.

A collaborative study was conducted in three North American
cities (Montreal and Winnipeg, Canada, and Portland, OregonliBuist
et al. 1979a) to avoid the pitfall of using a biased volunteer
population. Random population samples were used in two of the

27


cities and a random sample of a working population in the third.
Only people aged 25 to 54 were studied. Among the nonsmokers in
each of the three cities, the age-related regressions for the single
breath Nz variables (CV/VC, CC/TLC, and the slope of the alveolar
plateau) and for FEVJFVC had very similar slopes. As a result, a
combined set of reference values was derived and used for compari-
son with the smokers and ex-smokers. No single test consistently
showed the greatest prevalence of abnormality among the three
cities. The slope of the alveolar plateau was abnormal most often in
the women who smoked, and the CC/TLC was abnormal most often
in the men who smoked. However, the prevalence of abnormalities
was considerably lower than that reported in the screening center
population study described above. Among the smokers for the three
cities combined, CV/VC was abnormal in 17 percent of the men and
in 26 percent of the women, CC/TLC was abnormal in 32 percent of
the men and in 29 percent of the women, and the slope of the
alveolar plateau was abnormal in 13 percent of the men and in 37
percent of the women. In comparison, the FEVi/FVC ratio was
abnormal in 7 percent of the men who smoked and in 25 percent of
the women who smoked.

In another large-scale study, Knudson and Lebowitz (19771 used
the single breath Nz test in a random, stratified, cluster sample of
1,900 white, non-Mexican-American residents of Tucson, Arizona.
These investigators established their own reference values from the
asymptomatic nonsmokers, and then compared their smokers to the
reference values. Figure 2 reveals the prevalence of an abnormal test
result in three groups: normals, asymptomatic smokers, and symp
tomatic subjects (a group comprised largely of smokers). For the
V,, 75% and slope of phase III as well as for combined parameters of
the MEFV curve and single breath Nz test, asymptomatic smokers
had approximately twice the prevalence of abnormal test results
compared with the normal nonsmoking population. When the
analysis was limited to the population aged 25 to 54, the results were
even more striking. Of the asymptomatic smokers, 21.5 percent had
an abnormal V,, 75~~ and 33.9 percent had some abnormality on
either the single breath N2 test or the MEFV curve.

Manfreda and coworkers (1978) studied population samples strati-
fied by sex, age, and smoking habits from a rural community
(Portage la Prairie) and an urban community (Charleswood) in
Manitoba. They tested 246 persons in Portage la Prairie and 256
subjects in Charleswood. Reference values for asymptomatic non-
smokers were established for the single breath Nz test variables and
for FEVJFVC and RV/TLC. In both communities, the slope of the
alveolar plateau was abnormal (more than 2 SD from the mean)
more often in smokers than in nonsmokers in both sexes (Figure 3).

28


0 I Normal subjecls
a II Asymptomatlc smokers

m III Symptomabc SubteCtS

SlW     FEV,    CVlVC%
Phase III   FEVJFVC  CC/TLC%
VU   V+ilmae4   Phase Ill
     v+ilmfun    (N,)

Srgle seawe test

Combmeo parameter

FIGURE Z.-The relative sensitivity in three adult groups
      of a single sensitive test and of combined
      measurements for maximal expiratory flow
      volume (MEFV) versus` closing volume (CV)
NOTE: I = normal; II = asymptomatic smokers; III = symptomatic subjects
SOURCE: Knudson and Lebowitz (1977).

Detels and coworkers (1979) studied population samples in two
California communities,  one being exposed to photochemi-
cal/oxidant pollutants (3,465 subjects). They used the single breath
N2 test, but measured the change in N2 concentration between 750
and 1,250 cm3 of expired air (ANLw,c.-IzoJ rather than the more
traditional way of looking at the slope of the alveolar plateau. They
found that the mean values for ANZXWSO) and CV/VC were
consistently higher for smokers than for nonsmokers.

Tockman and coworkers (1976) studied two groups of subjects
selected from the Baltimore metropolitan area and not known to
have disease. One group consisted of neighborhood control subjects
participating in an epidemiologic study of obstructive pulmonary
disease, and the other consisted of teachers in the Baltimore public
schools who volunteered for a study of health and disease. Of the 133
subjects studied, 78 were smokers and 55 were nonsmokers. The
investigators analyzed their data in a slightly different way from the
approach used in the studies described above, in that they looked for
differences between the age-related regression equations for the
various tests in smokers and nonsmokers. They found significant
differences between the adjusted mean smoker and nonsmoker

29


FBGIXE Q.-Prevalence of lung function abnormalities
      among smokers in an urban and a rural
       community
.$I b' 2': 5 2!. I lp-.ls i,t ai ( IS*i

values, hut no differences associated with age for CC/TLC, the slope
of the alveol:ir plateau, RV/TLC, the steady state diffusing capacity,
and t,he number of respiratory symptoms. Differences between
smoker and nonsmoker mean values and an increasing difference
between smokers and nonsmokers with increasing age were found
for the FEVI, FEFsxs, v,,, 50, and moment analysis. The research-
ers suggest that the first group of tests may measure an all-or-none
response that occurs relatively soon after the onset of smoking and is
not affected by duration of smoking, and that the second group of
tests may measure the effect of continued smoking, thus reflecting
the increasing abnormality associated with longer exposure. This
th,:ory should be tested as part of an evaluation of the predictive
value of small airways function.

Nemery and coworkers (1981) used the single breath N2 test and
MEFV curves to study a group of 272 European blue-collar workers,
q:e-r! 45 to 55, from a steel plant near Brussels, Belgium. They first
::htained reference values from their asymptomatic nonsmokers and
ib>f:`r:ed their limit of normality as the 95th percentile for each of the
T~.~;tr~. CC/TI,C and the slope of the alveolar plateau had the highest
~,~~..~...:iPtl~r of abnormality among the smokers (47 and 44 percent,


respectively), followed by CV/VC% (34 percent), V,,, 75% (33 percent),
and V,,, 50% (30 percent). When the indices derived from the single
breath Nz test were combined, 60 percent of their smokers had an
abnormality in one or more of the measurements obtained from the
test, whereas 52 percent had an abnormality in one or more
measurements obtained from the forced expiratory maneuver. They
pointed out that combining the measurements obtained from a test
increases its sensitivity but decreases its specificity.

In addition to the studies described above, which involved fairly
large population groups, numerous studies have been carried out in
smaller groups (McCarthy et al. 1972; Stanescu et al 1973; Gelb and
Zamel 1973; Cochrane et al. 1974; Abboud and Morton 1975; Marcq
and Minette 1976). These studies have also found the measurements
obtained from the single breath NZ test and MEFV curve to be
abnormal more often among smokers than among nonsmokers.

There have been very few published studies using MEFV curves
with air and He02 in reasonably large population groups. This is
probably because the test is more difficult to perform than the single
breath NB test or the forced expiration maneuver, and because of the
wide range of within-individual and between-individual variability
associated with these tests. Lam and coworkers (1981) obtained
spirometry and MEFV curves with air and He02 in 423 subjects
participating in epidemiologic health surveys in British Columbia.
The subjects consisted of four groups: nonsmokers and smokers not
exposed to air pollutants at work, and nonsmoking and smoking
grain elevator workers. Reference values were established from the
78 healthy, asymptomatic nonsmokers who were not exposed to any
air pollutant at work. They found that in the subjects not exposed to
air pollutants at work, 0 max 50 was the best test for discriminating the
effects of cigarette smoking, but &o,, 50 and VisoV were not
significantly different between the smokers and the nonsmokers.
Interestingly, the FEVl was the best discriminator of the effect of
grain dust, and there was poor concordance among the FEV1, V,, 50
and AT,,, 50, and Visoo. They concluded that a comparison of MEFV
curves breathing air and He02 is less helpful than the standard
MEFV curves in distinguishing the effects of smoking and the effects
of exposure to an air pollutant.

A careful evaluation of moment analysis in a reasonably large
population group of adults has not been published. The limited
information in the literature comes from studies of small groups of
children (Neuberger et al. 1976; Liang et al. 1979; MacFie et al. 1979)
and adults (Permutt and Menkes 1979; MacFie et al. 1979). These
preliminary studies look promising, but a more extensive evaluation
of the technique in carefully chosen population groups must be
carried out before conclusions are reached on the value of this
approach. Moment analysis is particularly sensitive to changes in

31


the terminal part of the forced expiratory spirogram, which is
particularly sensitive to an artifact in the MEFV curve when volume
is measured by a spirometer at the mouth rather than by plethys-
mography. This artifact relates to the fact that there are volume
changes due to gas compression that are measured by plethysmogra-
phy but not by a spirometer at the mouth. The appropriate method
to measure volume in moment analysis is by plethysmography, but
very few such measurements have been made, most measurements
having been made by spirometry. The magnitude of the resulting
error has not been assessed.

In summary, the prevalence of abnormalities observed in any
group of smokers depends on the age and characteristics of the group
(how they were selected), on the reference values used (external
reference values or reference values obtained from the population
under study), and the cutoff used to define abnormality. However,
this prevalence is uniformly higher in smoking than in nonsmoking
populations. In a randomly selected sample of the general population
below age 55, at least a third (and usually more) of the smokers can
be classified as having small airways dysfunction.

Dose-Response Relationship Between Amount Smoked and Small
Airways Dysfunction

In general, population-based studies involving adults of all ages
with a reasonable range of cigarette consumption consistently show
a fairly strong dose-response relationship between the number of
cigarettes smoked and the degree of impairment.

Burrows and coworkers (1977a1, studying a randomly stratified
cluster sample of Tucson, Arizona, households comprised of 2,360
white, non-Mexican-American adults over age 14, found a highly
significant quantitative relationship between pack-years of smoking
and functional impairment, as measured by v-7546, FEVI percent
predicted, and FEVl/FVC percent. The shift in the mean FEVl
percent predicted and the distribution of the FEVl percent predicted
with increasing cigarette consumption is illustrated in Figure 4.

Buist and coworkers found a positive correlation between total
cigarette consumption and the frequency of abnormalities in tests of
small airways function in 524 smokers attending an emphysema
screening center. However, tests of significance were not reported in
the description of the relationship between pack-years and CV/VC
and CC/TLC (Buist et al. 1973). Tests of significance were reported in
the description of the relationship between the slope of the alveolar
plateau and cigarette consumption (Buist and Ross 1973b); no clear
relationship between daily cigarette consumption and an abnormal
slope of the alveolar plateau was found. Among women who smoked
more than 20 cigarettes a day, however, the prevalence of an
abnormal slope of the alveolar plateau was significantly increased;

32


-1 SD Mean + 1 SD

O-20 pack-years (578)

21-40 pack-years (2711

61 + pack-years (1001

40    60   60   100   120   140   160

      Percent ore&ted FEV,

FIGURE 4.-Percentage distribution of predicted forced
      expiratory volume in l-second (FEVI) values in
      subjects with varying pack-years of smoking

* Subjects with "respiratory trouble" before age 16 are excluded.
NOTE: Means, medians. and * 1 standard deviation of the data for each group are shown m the abscissae.
SOURCE Bumws et al. (1977s).

among men, a significant increase was found only for those who
smoked more than 40 cigarettes a day.

Somewhat similar conclusions were reached by Tockman and
coworkers (1976) in their study of healthy Baltimore residents. These
investigators found that the CC/TLC, the slope of the alveolar
plateau, RV/TLC, the steady state diffusing capacity, and respira-
tory symptoms were significantly different between smokers and
nonsmokers, but there were no significant age-related differences for
these variables. In contrast, tests of forced expiration (FEVI/FVC,
0 mm 50, and moment analysis) showed both differences between
smokers and nonsmokers and increasing smoker versus nonsmoker
differences with increasing age. These investigators interpreted
their findings as suggesting that the tests of small airways function
measure an all-or-none response that occurs at the onset of smoking
but is not affected by duration of smoking. They proposed that the

33


measurements obtained from a forced expiration maneuver probably
measure the effects of continued smoking and reflect increasing
abnormality associated with longer duration of smoking.

In their study of population samples in Manitoba, Manfreda and
coworkers (1978) found a significant relationship between the
current number of cigarettes smoked per day and the slope of the
alveolar plateau and CC/TLC in both sexes and RV/TLC in women.
These investigators found that an index of lifetime exposure to
smoke had no effect after accounting for the effect of current
smoking. Among all the lung function measurements, smoking
status accounted for the largest proportion of variance due to the
three smoking variables (smoker versus nonsmoker, number of
cigarettes smoked per day, and lifetime amount smoked). They
interpreted this finding as suggesting that responses on these lung
function tests are related more to whether one does or does not
smoke than to the amounts smoked.

Buist and coworkers, in the three-city collaborative study de-
scribed earlier (Buist et al. 1979a), considered the effect of smoking
in two ways, first by means of multiple regression analysis using age
and cigarette-years data from both smokers and nonsmokers. Using
the pooled data from the three cities, they found that cigarette
consumption had a significant effect on the CC/TLC, CV/VC, the
slope of the alveolar plateau, and FEVI/FVC (only in women). In this
analysis, the effect of aging was considerably greater than the effect
of smoking. The second approach involved data only from smokers,
and a linear regression of the percentage of the predicted value for
each variable on cigarette-years was obtained. A significant regres-
sion occurred in only one-third of the city/sex groups, and in each
case the regression coefficients were very small. They concluded that
a dose effect was not apparent when smokers only were considered,
using both cigarettes per day and years smoked as indicators of
cigarette consumption. They interpreted these findings similarly to
Manfreda and coworkers (1978): it could be smoking itself and not
the quantity of cigarettes smoked that is the crucial factor in the
development of early functional impairment. The researchers sug-
gest that absence of a clear-cut dose-response relationship in this
study may also have resulted from the limited age range (25 to 54
years) and the relatively few heavy smokers in the study. They also
speculate that the single breath NZ test variables, especially the slope
of the alveolar plateau, may be so "sensitive" that they reflect an on-
off effect of smoking rather than cumulative damage.

Dosman and coworkers (1976) looked for a dose-response relation-
ship in 49 smokers, aged 28 to 67, of whom 60 percent were attending
a smoking cessation clinic. They found a significant relationship
between a smoking index (cigarettes per day x years smoked) and
VisoV and V,,,, SO. They did not find a significant relationship

34


between symptoms and frequency dependence of compliance,
CC/TLC, the slope of the alveolar plateau, or V,,, 50 (Figure 5).

Beck and coworkers (1981,1982), in a cross-sectional study of three
communities (Lebanon and Ansonia, Connecticut, and Winnsboro,
South Carolina) sought a dose-response relationship in 1,209 smok-
ers. Dividing the sample into light smokers (1 to 20 cigarettes/day)
and heavy smokers (> 20 cigarettes/day!, they found a trend of
increasing dysfunction across smoking categories that was evident as
early as age group 15 to 24 for both men and women. A difference
between men and women occurred in terms of the relationship
between residual lung function (observed-predicted FEV,) and pack-
years of smoking. In male smokers, the combination of number of
cigarettes smoked per day and duration of smoking was the best
indicator of loss in lung function, as measured by residual lung
function (FEVI, V,,,, XP+, and VX,). For women smokers, pack-years
best explained lung function loss as measured by residual lung
function. These investigators thus found a very definite dose-re-
sponse relationship between the amount smoked and lung function
loss. They do point out, however, that smoking variables and age
accounted only for up to 15 percent of the variation in residual lung
function.

In summary, the data suggest a dose-response relationship
between number of cigarettes smoked per day and the prevalence of
abnormal results on tests of small airways function. That is, heavy
smokers are more likely to have abnormal small airways function
than light smokers. However, there is only a weak relationship
between the degree of abnormality in small airways function and the
number of cigarettes smoked per day or pack-years of smoking. In
contrast, tests obtained from the forced expiration maneuver have a
stronger dose-response relationship. This is consistent with the
theory that cigarette smoking induces an inflammatory response in
the small airways and that this response is more likely to happen in
heavy smokers, as measured by sensitive measures of small airways
function such as the single breath nitrogen test. The extent of
chronic airway disease that reflects the dose and duration of the
smoking habit is better measured by changes in the forced expirato-
ry maneuver.

How Soon Do Changes in Small Airway Function Occur!

The first study to look at the prevalence of abnormalities on tests
of small airways function by age in a large group of smokers was
reported by Buist and coworkers (1973aJ These investigators found
that abnormalities of small airways function could be detected before
age 30 by means of the single breath N2 test, with CV/VC
discriminating best between smokers and nonsmokers in the age
decade of the twenties (Figure 6).

35


160            '    . A

120

Cdyn a 100
Cst
(90 BPM)

  VlS.0~
Percent predacted

Slope phase III
Percent vreduted

       cc
Percen1 predicted

i Illax
Percent predIcted

symptoms score
                 D
         .

100

                 50


                  0
                        0     1    2    3    4

                          Symptoms score
FIGURE 5-A composite of six tests plotted against
       symptoms score
SQURCl? Downan et al. (1976).

36


a0

f-J 264 lvonsmohers
O  524 Smokers
3 266 Ex-smokers

60

2
E  40
a



  20




  0
  .v= 7   3  4.7  20  30  26  32  51  63  80  66  64  32   21  11  3

            7     a1     91    126    143    65     I1

            < 20   x-29   30-39   40-49  50-59  6049   70-79   I a0

                        Age (years)
FIGURE 6.-Prevalence of abnormal closing volume/vital
       capacity ratios in nonsmokers, smokers, and
      ex-smokers, by age decade
SOURCE: Bubr et al. (1973).

In their cross-sectional survey of residents in three separate
communities in Connecticut and South Carolina, Beck and cowork-
ers (1981, 1982) found that the age of onset of abnormalities in lung
function may occur as early as age 15 to 24. Their approach used
vesidual lung function (observed-predicted value) for FEV1, o,,,, 50%~
and o,, ~SB, with a negative residual indicating an observed value
below prediction. Negative residuals for all three measurements
began to occur in women in the age group 15 to 24 (Figure 7).
Significant differences among smoking categories-nonsmokers, ex-
smokers, light smokers (1 to 20 cigarettes/day), and heavy smokers
( > 20 cigarettes/day)-were seen for v,, 50% and o,, 75% in women
aged 15 to 24 and for FEVl in age group 25 to 34 (Figure 8). In male
smokers, negative residuals began to occur for all three measure-
ments in the age 25 to 34 group. Significant differences among the
smoking categories were seen for FEVl in the 35 to 44 age group and
for e,, 5040 and v,, 76% in the 45 to 54 age group.

Seely and coworkers (1971) found lower values for `?,, 50% and
`?,, 7590 in a group of high school students with 1 to 5 years of
smoking experience. These differences were significant in boys who
smoked more than 15 cigarettes per day and in girls who smoked
more than 10 cigarettes per day. Significant differences between the
smokers and nonsmokers were not found for FEVl.
Dosman and coworkers (1981) studied 1,202 adults, aged 25 to 59,
living in Humboldt, Saskatchewan. Among smokers in the 25 to 29

37


01

0

5   -01
5
E
-
2   42

u
  -03
1 Women (n -2.623)

  -0 4   0  Nonsmokers
     a Ex-smokers

-05   -  Light smokers (l-20 cigarettes/day)
   E3  Heavy smokers ( ,20 clgaretteslday)
06 o  ?? ???????*?*?

FIGURE 7.-Mean residual FEV, in women, by smoking
      status and age
SOURCE Beck et al / 1981~

O2 rAge7-14 15-24 2534 35-44 45-54 55-64 65,

-0.6

m LaghI smokers (l-20 cigarettes/day)
m Heavy smokers ( > 20 agarettes/day)
   No observations

FIGURE 8.-Mean residual FEVl in men, by smoking status
       and age
SOURCE Beck et al. tl9Bli

age group, 14.9 percent of the women and 18.5 percent of the men
had an abnormal test value for the slope of the alveolar plateau, for
CV/VC, or for both. Comparable rates of abnormality for FEVl/FVC

38


were 2.1 percent in women and 5.6 percent in men. For both the
slope of the alveolar plateau and CV/VC, the prevalence of abnormal
test value increased steadily with increasing age, so that 63.6 percent
of the female smokers aged 55 to 59 and 46.2 percent of the male
smokers aged 55 to 59 had abnormal values. Comparable rates for an
abnormal FEVl/FVC were 4.5 and 19.2 percent in the women and
men, respectively.

Walter and coworkers (1979) studied 102 Indian male medical
students in their late teens and early twenties. Of the 102 subjects,
60 were nonsmokers, 23 were light smokers (lifetime total of
< 10,000 cigarettes), and 19 were heavy smokers (lifetime total of
> 10,000 cigarettes). The researchers compared mean pulmonary
function values obtained from the spirograms across the smoking
categories. There was a consistent trend for all the lung function
variables examined (FEFZSSOQ, FEFzx,s, FEFKHOS, FEF~~~~i,
FEFsx~,, and FEVJFVCLwith the highest mean values being seen
in the nonsmokers, intermediate values in the light smokers, and the
lowest values in the heavy smokers. There were no significant
differences among the three groups in height and weight. No
information was given in this report about the type of cigarettes
smoked.

The consistency of results from the studies attempting to define
the age of onset of measurable abnormalities in tests of small
airways function is striking. Even though statistical significance was
not always found, the trend is clear and provides strong evidence
that measurable abnormalities of small airways function do occur in
some smokers within a few years of smoking onset.

Male-Female Differences in the Responses of the Small Airways
to Cigarette Smoking

When looking at variations between the sexes in response to
cigarette smoking, one must take into account possible differences in
the manner in which cigarettes are smoked, in the amount smoked,
and in environmental exposures that may interact with smoking.
Most investigators have found little or no difference based on sex for
the relationship between the various tests of small airways function
and age in nonsmokers. Thus, a difference between the sexes in
response to smoking, if it exists, probably represents a true biological
difference in the effect of smoking on lung function or variations in
exposure dose resulting from method of smoking or amount smoked.

Unfortunately, the information available in the literature about
sex-related differences in small airways response to cigarette smok-
ing is scanty and conflicting. Manfreda and coworkers (1978) found a
higher prevalence of abnormality in tests of small airways function
among male smokers than among female smokers in their study of
two communities in Manitoba. The opposite finding has been

39


reported by Buist and coworkers (Buist and Ross 1973a, b; Buist et al.
1973, 1979a) in their studies of a screening center population and of
population samples and groups in Montreal, Winnipeg, and Port-
land. It is quite possible that selection bias in the screening center
study limits the ability to extrapolate this study to the general
population. The three-cities study, however, did not suffer from that
flaw, and showed clear differences (women higher than men) in the
prevalence of abnormalities of CV/VC and the slope of the alveolar
plateau. The prevalence of abnormality of CC/TLC, on the other
hand, was slightly higher in male smokers than in female smokers
(32 and 29 percent, respectively). A surprising finding was that the
prevalence of FEVJFVC abnormality was considerably higher
among women who smoked than among men who smoked (25 and 7
percent, respectively).

At this point, a generalization is not yet possible on sex-related
differences in the response of the small airways to cigarette smoking.
However, it seems likely that the contribution of sex difference is
relatively small once age and dose are taken into account.

JBfect of Smoking Cessation on Small Airway Function

The correlation between abnormalities in tests of small airway
function and the pathologic changes of inflammation of the small
airways suggests that cessation of smoking may lead to a return
toward normal in these tests. A number of authors have examined
changes in tests of small airways function in cigarette smokers who
have quit.

Ingram and O'Cain (1971) examined six smokers with an abnormal
frequency dependence of compliance who quit smoking. After 1 to 8
weeks of cessation, values in all six returned to the normal range.

Bode et al. (1975) examined 10 subjects aged 29 to 61 with normal
FEVl values while they were active smokers and again 6 to 14
months after they had stopped smoking. Static volume pressure
curves, slope of phase III, and forced expiratory flow rates on air
were unchanged by cessation. However, the maximum expiratory
flow rates with helium at 50 and 25 percent of the vital capacity
increased, and the volume of isoflow and closing volume decreased.

McCarthy et al. (1976) followed 131 smokers aged 17 to 66 who
volunteered to attend a smoking cessation clinic. Cessation resulted
in a significant reduction in the closing capacity (CC/TLC%) and the
slope of phase III within 25 to 48 weeks in the 15 persons who were
able to abstain from cigarettes completely.

Buist et al. (1976) followed a group of 25 cigarette smokers who
attended a smoking cessation clinic and found that cessation
resulted in significant improvements in the closing volume
(CV,`VC%), closing capacity (CC/TLC%), and the slope of the
alveolar plateau (phase III) at 6 and 12 months following cessation.

40


CC/TLC

        CVNC

140 r

   4 \ \ & _____--- --*
120




100
   0 20
     . 10          .
       . 30
80 I:;

60 1

1        - O"m3S
        ---- Smolers

FIGURE 9.-Mean values for the ratio of closing volume to
     vital capacity (W/W), of closing capacity to
     total lung capacity (CC/TLC), and slope of
     phase III of the single breath NZ test (ANp/L),
     expressed as a percentage of predicted value
     (12, 13) in 15 quitters and 42 smokers, during
     30 months after two smoking cessation clinics
* A significant difference from the initial value at p< 0.05.
N0TF2 Data from amonth followup of the 1973 clinic and 4-month followup of the 1975 clinx have bean
combmed. 88 have Gmonth and B-month data for the 1973 clinic.
SOURCE: Buist et al. (197%).

This study was expanded using a second group of subjects (Buist et
al. 1979b) and a 30-month followup. Once again, the three parame-
ters of the single breath Nz test showed improvement in smokers who
quit; this improvement continued for 6 to 8 months, and then leveled
off (Figure 91. In addition, the values for the single breath Nz test in
those who quit returned to the levels predicted for nonsmokers,
suggesting that the changes in the small airways can be substantial-
ly reversed with cessation.

Bake et al. (1977) also showed an improvement in the slope of
phase III following cessation in a small group who were followed for
5 months.

In summary, abnormalities in the small airways are substantially
reversible in smokers who have not developed significant chronic
airflow obstruction. This suggests that the inflammatory response in
the small airways, which may be the earliest change induced by
smoking, is also a change that reverses with the cessation of chronic
exposure to the irritants in cigarette smoke.

41

480-144 0 - 85 - 3


Relationship Between Small Airways Disease and Chronic
Airflow Obstruction

There is no question that the information obtained over the past
15 years from studies of small airways function has helped to
describe more accurately the natural history of chronic airflow
obstruction. The practical question of the place of tests of small
airways function in clinical practice has not yet been resolved, and
will not be fully answered until longitudinal studies using the tests
have been completed. The important issue to be addressed is whether
the tests of small airways function can be be used to identify the
smoker who will progress to develop irreversible airflow obstruction.
This question can be answered satisfactorily only by following a
fairly large group of smokers prospectively over a period of time long
enough for some of the smokers to develop an abnormal FEVL If the
tests of small airways function can be used alone, or in conjunction
with other qualitative or quantitative data about risk factors, they
will clearly be useful to the practicing physician. If they are too
sensitive or have a poor predictive value, their use will be more
limited.

Buist and coworkers (1984) determined the positive and negative
predictive value of tests of small airways function in their study of
two cohorts followed prospectively over a `?- to ll-year period. They
found that the positive and negative predictive values of the tests of
small airways function varied greatly between the cohorts, largely
because of the different ages and prevalences of an abnormal FEVl
between the cohorts. They concluded that significant associations
existed between the single breath Nz test variables and spirometric
variables in smokers, but the weakness df these associations and the
high misclassification rates suggest that small airways disease does
not necessarily lead to clinical airflow obstruction.

Over a period of 8 years, Marazzini and coworkers (Marazzini et al.
1977, 1981) followed a group of 69 asymptomatic workers in an iron
foundry (49 smokers, 20 nonsmokers) living in the same area. They
found that 39 percent of the smokers and 15 percent of the
nonsmokers, initially diagnosed as having peripheral airways dis-
ease, developed central airways obstruction (defined as 1 or more of
the vital capacity WC), FEVl or FEVl/VC being more than 15
percent different from normal) within the ELyear followup.

An indirect way to assess the predictive value of the tests of small
airways function was proposed by Tattersall and coworkers (1978).
These investigators proposed that any valid test of chronic airflow
obstruction must yield results that are systematically worse in
middle-aged smokers than in middle-aged nonsmokers, and that such
a test should also correlate with the FEVl in middle-aged smokers.
Using these criteria in a cross-sect.ional study of a sample of working

42


men in West London, they concluded that the most informative and
repeatable tests were v max 75% and the slope of the alveolar plateau.
Nemery and coworkers (1981) addressed the question of the

significance of tests of small airways function in their study of 2,072
blue-collar workers, aged 45 to 55, from a steel plant near Brussels.
They found that smokers with an abnormal CC/TLC or slope of the
alveolar plateau and a normal FEVJFVC had a significantly lower
FEVl/(heightP than subjects with normal CC/TLC and slope of the
alveolar plateau. They interpret their data as suggesting that
smokers with small airways dysfunction experience a more rapid
decline in FEVl than smokers without small airways dysfunction,
leading to a higher susceptibility to long-term smoking effects in the
former group.

The opposite conclusion was reached by Fletcher (1976), who
examined the relationship between CV/VC, the slope of the alveolar
plateau, and FEVl in 200 male smokers aged 40 to 55. In this group,
he found a relatively poor correlation between FEVl and the single
breath Nz variables.

There is thus, as yet, inadequate information to allow a firm
conclusion to be drawn about the predictive value of the tests of
small airways function in identifying the susceptible smoker who is
going to progress toward clinical airflow obstruction. The tests of
small airways function are probably abnormal for many years before
the FEVl becomes abnormal in those smokers who go on to develop
airflow obstruction. However, many smokers with abnormal tests of
small airways function may never develop clinically significant
airflow obstruction. Therefore, functional changes in the small
airways may not always be related to the widespread alveolar
destruction seen in smokers or to the development of clinical airflow
obstruction. It may be that varying degrees of inflammation and
fibrosis occur in virtually all smokers, and that there is something
very different about the smokers who develop extensive airway or
emphysematous changes.

Summary

A number of tests have been developed that can identify small
airways dysfunction in individuals with normal lung volumes and
standard measures of forced expiratory airflow. These tests correlate
well with the presence of pathologic changes in the airways 2 mm or
less in diameter, particularly with peribronchiolar inflammation.
Cigarette smokers have a significantly higher frequency of abnormal
tests of small airways function. Heavy smokers have a greater
prevalence of small airways dysfunction than light smokers, but
there is only a weak dose-response relationship between numbers of
cigarettes smoked per day or duration of smoking and the extent of
small airways dysfunction. This suggests that the response of the

43


small airways may be an "all or nothing" inflammatory response to
cigarette smoke irritants rather than a progressive response repre-
senting a cumulative injury.

Cessation of cigarette smoking results in significant improvement
in small airways function, which in those smokers without evidence
of chronic airflow obstruction, may return to normal.
The relationship between changes in the small airways and the
development of chronic airflow obstruction remains unclear. It
seems likely that those smokers who will go on to develop ventilatory
limitation will have abnormal small airways function before the
FEVl becomes abnormal, but many smokers with small airways
dysfunction may never progress to significant airflow obstruction.
Therefore, the usefulness of tests of small airways function for
identifying those who will develop ventilatory limitation remains to
be established.

44


CHRONIC MUCUS HYPERSECRETION

Introduction

The association of cigarette smoking and chronic cough was
recognized by the general public in the term "smokers cough" well
before the demonstration of this association in epidemiologic studies.
Cough is the symptom most frequently experienced by smokers, and
it is often accompanied by excess mucus secretion resulting in
phlegm production or a "productive" cough. Chronic bronchitis was
defined by the Ciba Foundation Guest Symposium report (19591 as
"the condition of subjects with chronic or recurrent excess mucus
secretion into the bronchial tree." The position was taken that any
production of sputum was abnormal, and chronic was defined as
"occurring on most days for at least 3 months of the year for at least
2 successive years." Also, the sputum production could not be on the
basis of specific diseases such as tuberculosis, bronchiectasis, or lung
cancer.

Measurement of Cough and Phlegm in Epidemiologic
studies

The increasing use of standardized questionnaires in interviews to
ascertain the presence of cough, phlegm, or other symptoms of
respiratory disease has improved the quality of measurements of
prevalence and incidence of these symptoms and the validity of
comparisons within and between studies. Similar attention has been
given to developing questions about smoking habits, including
questions about the type and number of cigarettes used at the time of
interview and in the past. The first British Medical Research Council
(BMRC) questionnaire published in 1960 (Medical Research Council
1960) had been tested, revised, modified, and extended, and many
studies have resulted from its widespread use. However, difficulties
in using this questionnaire in epidemiological studies of populations
in the United States and the desire to collect additional information
led to modification in individual studies and to a loss of comparabili-
ty between studies. This motivated the American Thoracic Society
and the Division of Lung Diseases of the National Heart, Lung, and
Blood Institute to establish the Epidemiology Standardization
Project. Extensive methodological studies were done, standardized
questionnaires were developed, and techniques for measuring pulmo-
nary function and evaluating chest radiographs were proposed
(Ferris 1978). Samet (1978) has reviewed the history of the develop
ment of respiratory symptom questionnaires. Although many inves-
tigators now use the methods advocated by the BMRC or the
Epidemiology Standardization Project, several of the studies re-
viewed in this chapter of the Report are based on other, nonstandard
questionnaires. A comparison between studies of different popula-

45


tions, or the same population studied at different times, must be
made cautiously and only after careful consideration of technical
and methodological issues. Low rates of participation and use of
unrepresentative samples may cause biased estimates of the frequen-
cy and distribution of symptoms. Attitudes toward smoking have
changed, and comparisons of questionnaire responses and objective
measurements of smoking habits indicate that at least in some
situations, less reliance can now be placed on answers to questions
about smoking habits (MRFIT Research Group 1982). Estimates of
prevalence and incidence of respiratory symptoms are imprecise,
and too much importance should not be attached to relatively small
differences in rates of reporting cough and phlegm. Each author's
criteria for detecting the presence of cough or phlegm should be
considered, especially when combinations of symptoms or diagnostic
labels such as chronic bronchitis or mucus hypersecretion are used.
Notwithstanding methodological differences, however, consistent
patterns or trends found in many studies indicate that the associa-
tions between smoking and chronic mucus hypersecretion are real
and that the findings are widely applicable.

Prevalence of Cough and Phlegm

Unpublished data from the National Center for Health Statistics
estimate that there were almost 8 million persons with chronic
bronchitis in the United States in 1981 (3.4 million men, 4.5 million
women). This is probably an underestimate of the true frequency of
cough and phlegm in the population, since people who had these
symptoms were not counted as chronic bronchitics unless they
responded affirmatively to the question about bronchitis. On the
other hand, some cases of acute bronchitis may have been included
incorrectly and inflated the estimate. The apparently higher preva-
lence rates of chronic bronchitis in women than in men in the
National Health Interview Surveys in 1970 and 1979 (3.4 and 3.7
percent for women in 1970 and 1979, respectively, and 3.1 and 3.2
percent for men in 1970 and 1979) are probably due to ascertainment
being less complete for men (USDHEW 1980b). Prevalence rates of
chronic bronchitis ranged from 4.2 percent at ages under 17 years to
2.7 percent at 17 to 44 years, 3.6 percent at 45 to 64, and 4.5 percent
at ages over 65 years. The high rate in the youngest group is
presumably because of the inclusion of cases of acute bronchitis.

Standard questions about chronic cough were asked in the
National Health and Nutrition Examination Surveys (NHANES) of
representative samples -of the U.S. population. Some supplementary
questions were asked about phlegm and other respiratory symptoms,
and these data are presented in the appendix to this chapter.
Prevalence rates of diagnosed chronic cough in 18- to 74-year-old
participants in NHANES 1(1971-1975) were 3 percent for men and 2

46


0

4
I

31.1

r

16.7 ;

         12.0
10.2         Il.6

    7.1
r

1

1

1

FIGURE lO.-Percentage of recurring persistent cough
       attacks by sex and smoking status for adults
        25-74, United States, 1971-1975

NOTE. Light smoker: 1-14 cigarettes per day
     Moderate smoker- l&24 c,garettea per day
    Heavy smoker 2 25 ngarettes per day
SOURCE- Natmnal Canter for Health Statistics. Unpublished data from the first National Health Nutntion and
Exammauon Survev lNHANl?S Ia

percent for women; they increased with age from 1 percent at 18 to
24 years to 6 percent at 65 to 74 years for men, and from 1 percent at
18 to 24 years to 3 percent at 65 to 74 years for women (National
Center for Health Statistics, unpublished data).

The prevalence of self-reported recurring persistent cough by
smoking status for men and women of different ages is presented in
the appendix and in Figure 10 based on NHANES 1. For the entire
NHANES population, the prevalence of the persistent cough in-
creased threefold in male smokers and twofold in female smokers
compared with nonsmokers (Figure lo), and the prevalence of cough
increased with increasing cigarette consumption in both men and
women.

Relationship of Cough and Phlegm to Smoking

Relationships between smoking and cough or phlegm are strong
and consistent; they have been amply documented and are judged to
be causal (USPHS 1964, 1971; USDHEW 1979; USDHHS 1980a,
1981). Associations between smoking and cough or sputum are
apparent in the recent studies listed in Tables 2 and 3 and are
illustrated in Figures 11 and 12. Although cough, phlegm, and

47


chronic bronchitis occur in nonsmokers, prevalence rates are consis-
tently higher in cigarette smokers.

The excess prevalence of cough and phlegm in cigarette smokers
increases with the amount smoked (see below). The frequency of
reporting cough and phlegm is at least twice as high for smokers as
for nonsmokers except in some groups with minimal exposure.
Differences in prevalence rates between smokers and nonsmokers
tend to be greater at older ages among men, whereas differences in
rates between smoking and nonsmoking women tend to be as great
or greater at younger ages (Tables 2 and 3). Rates are not given for
pipe or cigar smokers in most of these studies, presumably because
the numbers of such smokers were too small for reliable rates; male
pipe smokers and cigar smokers in Tecumseh reported cough and
phlegm more frequently than nonsmokers or ex-smokers, but less
frequently than cigarette smokers (Higgins et al. 1977).

Individual studies have evaluated other factors as well as smoking,
but smoking has been judged the most important determinant of
symptom prevalence (Fletcher et al. 1976; Ferris et al. 1976; Kiernan
et al. 1976; Bouhuys 1977; Higgins et al. 1977). Consideration of
evidence from many different studies has led to the conclusion that
cigarette smoking is the overwhelmingly most important cause of
cough, sputum, chronic bronchitis, and mucus hypersecretion (Speiz-
er and Tager 1979; USDHHS 198Ob).

Effects of Smoking Cessation

Cross-sectional information on ex-smokers suggests that stopping
smoking is followed by a reduction in cough and phlegm because
symptoms are less prevalent than in current smokers, but these
symptoms are generally mere prevalent in ex-smokers than in
lifelong nonsmokers (Huhti et al. 1978; Gulsvik 1979; Park 1981;
Schenker et al. 1982). However, the differences between ex-smokers
and nonsmokers were either very small or absent in the studies
reported by Higgins et al. (1977) and Manfreda et al. (1978).

The longitudinal studies cited in Table 3 strengthen the evidence
from cross-sectional studies that cigarette smoking causes cough and
phlegm. Prevalence rates were higher at followup examinations in
persons who started to smoke after being nonsmokers at a previous
examination (Kiernan et al. 1976; Leeder et al. 19771. Rates of
reporting cough or phlegm decreased in smokers who stopped
smoking in two British studies (Kiernan et al. 1976; Leeder et al.
1977) and in populations in the United States (Ferris et al. 1976;
Friedman et al. 1980; Beck et al. 1982). Many people who stop
smoking report a rapid reduction in cough and phlegm. Although
remission of symptoms occurs in some persistent smokers, remission
rates are generally higher and incidence rates lower in those who
quit than in those who continue to smoke.

48


TABLE 2.-Prevalence (percent) of cough, phlegm, and other symptoms for nonsmokers (NS), smokers
     (SM), and es-smokers (EX), c rossactional studies

Author, year,
country

Poplllation

Other

Comments

Tager and      507 realidetlta,
Speizer.        esed 15-66+,
1976, U.S.       EastBostoll

  Chronic bmnchitie
     Men
NS           7.0
SM @chars)
l-6         8.7
5-10        25.0
10-N        28.6
>20        47.5

     Women
NS           4.6
SM @uck-years)
l-5         14.3
5-10        9.1
10-20        20.8

Chmnic bronchitie (cough and
phlegm >3 no&r for 2 years);
no sge trend for either eex after
adjusting for smoline; prevalence
greater for men than women at
each a@; significant increase in
chronic bronchitis with increased
lifetime cigarette consumption
for current smokers, but not
ex+.mokem


g   TABLE Z-Continued

Author, year,
country

Population          Cwxh            Phlegm              Other               Comments

Dean et al..
1978
United Kingdom

6,277 men and
6,459 women,
aged S-67,
England,
Scotland. and
W&S

Morning cough

NS        12.5
SM (filter)
:-7      19.6
6-12     32.8
13-17     36.3
18-22     44.0
23-27     50.6
28-32     56.8
33+     52.1

NS
SM (filter)
l-7
a12
l&17
18-22
23-h

9.8


16.9
25.8
29.6
45.1
56.6

NS
SM (filter)

Il.4


14.4
20.8
25.4
26.9
34.2
34.5
26.4

    Women
NS        7.5
SM (filter)
        13.8
        16.6
        16.6
        25.8
        34.3

Bronchitis syndrome

NS
SM (filter)

3.5


5.1
8.6
9.4
8.5
1.0
8.7
13.8

NS
SM (filter)

2.5


3.8
4.2
5.1
10.6
12.0

Bronchitis syndrome (cough and
phlegm 3 moe/yr, shortness of
breath); significant increase of all
symptoms with age; prevalence of
mugh, phlegm. and whesze
increased with number of
cigar&ten smoked; filter vs.
nonftiter cigarette effecta
small, nonsignificant for most
eymPbme


TABLE 2.-Continued

Author, year,
country

Population          cough

Other

Commenta

Higeins
1977.
U.S.

et al.,

4,699 men and
women, aged
B-74, Team&

Chronic bmnchitii
     Men
NS         5.1
Ex         2.6
SM
<m/day    13.4
2 2Lvday    29.9
Pipekigtk?   8.4

    Women
NS         3.5
Ex        4.7
SM
<2o/dav    4.8

Chronic bronchitis knugh and
phlegm 23 mo/yr); chronic
bronchitis increaeed with age
for male smokers; no age trend
apparent for male or female
nonsmokers; doee-response
relationship between chronic
bronchitis and cigarette smoking
(age adjusted)

z'xvda;    15.3


TABLE 2.-Continued


Author, year,
wuntry         Population          cough          Phlesm             Other              Commenta


Lhwitz and     2,857 men and          Chronic wu6h and/or phlegm                     Male prevaienax am8&tently
BIllTow&       women, aged 14-66,                 Men
1977, U.S.        Tucson                   NS          10.3                      greater than female only in older

                          SM (pack years)                          w grow; fresuencr of

                                 <6         29.0                       Bymptoms in& with age;


                                     6-20        35.8                     impossible to distinquiah effecta
                                                          of ag@ and increaeed duration
                                   21-40        47.9                       of 8mokin6
                                   41+        61.1

                                     Women
                                 NS          12.1
                         SM back-years)
                               <6         21.0
                                   6-20        33.1
                                  21-40        40.5
                                  41+        60.4


TABLE 2.-Continued

Author, year,
wuntry

Population         couch

Other

Commenta

Bland et al.,
1976,
Great Britain

6,320 f-year
secondary echo01
Children,
Derby&in?

Morning cough
    Boys
NS        3.1
SM once     2.9
oaaa.     4.0
1 per wk.   19.2


     Girl8
NS        1.8
SM one     4.5
occaa     6.0
1 wk.
  per     13.5
Cough at other timee
    fm
NS       20
SM once    27
0a-a.Y.    34
1 wk.
  per     47

    Gil8
NS        19
SM once    30
oa9e.    35
1 wk.
  per     47

  Breathkmness
    Boye
NS        12
SM once     14
occaa     22
1 wk.
  per     35


     Girls
NS        17
SM once     22
oaxla     29
1 wk.
  per     40

No questions on phlm; child's
smoking habita more important
than parer&' smoking habite;
parents' smoking hahita
independently related to mu&
eymptom frequencim for
boyaandgirla


$   TABLE 2.-Continued


   Author, year,
   country          Population          bush            Phlegm              Other               Comment.3

Huhti et al.,      1,162 men,
1978,         asd 25-65,
Finland         Hankaealmi

All day in winter
Age        NS
2x39        2
40-49        2
5049        5
m-69        4

Age       Jzx
25-39        -
40-49        -
50-59        4
60-69        12

Age       SM
B-39        9
40-49        19
50-59        19
60-69        30

AU day in winter
   NS
    5
    2
    8
    7

Ex
11
10
8
18

Chronic bronchitis
Age      NS
25-39 9
40-49 2
M-59      15
6043 19

        Ex
25-39 11
4049 14
50-59 11
60-69 26

SM          SM 1-14 g/day
14           25-39 29
29           a49 39
24           5049 31
27           60-69 39

For total group, aign&ant
increase with age of cough,
phlegm, and severe breathleas
neea; for nonsmokers, sign&ant
inc- with age for phk?gm
and breathleesnees only

SM 16-24 g/day
2639 13
40-49 45
50-59 46
60-69 46

SM 225 g/day
25-39 50
4049 63
50-59 57
al-69 53


TABLE 2.-Continued

Author, year,
-try

Population         coush

Phlegm

Other

Comment8

Manfreda et al..    273 men and 229      Most daye 23 molyr
1978         women, aged
          2455, two             CH' PLP"
           communitlea         NS   8.3    4.0
           inMnnitoha         Ex   8.1    2.9
                         SM  25.4   31.5

NS - 4.0
E!i -    10.0
SM 20.3   31.7

Moat day 2.3 mo/yr
    Men
    CH   PLP
NS   -    4.0
Ex   10.8    5.7
SM   16.9   24.7

   Women
NS   -    4.0
Ex   -    5.0
SM   10.2   26.4

Wheeze apart from colds

   CH   PLP
NS   4.2    8.0
M   10.8   14.3
SM   26.8   31.5

NS   3.5    8.0
Ex   12.1   20.0
SM   25.4   30.2

No consistent difference in
symptom prevalence for two
communities; higher prevalence
of mugh, phlegm, and wheeze
among emokem than
nonsmokers or exanokers;
`CH=ChdfSWOOd
`*PLP=Portage la Prairie


g TABLE 2.-Continued

Author, year,
anlntry

Population          cough

Other

Comments

Rawbone et al.,
1678,
Great Britain

10,498 secondary
school children,
aged 11-17,
Hounelow

A little mast dayn
Age      NS
11      26.4
13      16.7
15      13.4
      EXPEB'
11      20.6
13      17.3
15      11.3
       SM
11      24.3
13      25.9
16      27.4

A little every day
       NS
11       7.3
13       4.2
15       4.7
      EXPEB
11       7.0
13       4.7
15       3.5
       SM
11      26.2
13      17.8
16      13.4

With colds        Frequent adds
  NS               NS
22.8                36.0
26.3                32.3
24.6                34.3
EXPEB             EXPEB
32.3                42.2
31.2               36.1
26.6                36.3
SM               SM
56.1                51.1
49.6                60.4
63.6                39.8

' EXF%B (examokere end
experimental smokers combined);
sex differences not -cant;
nonstandard questions; higher
symptom prevalence in younger
children not explained


TABLE 2.-Continued

Author, year,
colmtry

Population          coush           Phlegm             Other               Commenta

Bouhuye et al..
1979,
U.S.

7,203 reaidente,
43-d 7-65+,
three ccxnmunitim

  Usual cough
   LB' AN"
     Men
NS    8   10
SM   27   32
   Women
NS    7   12
SM   13   17

WV

15
34


9
24

Smoking eigniiicantiy amociated
with cough, phlegm, wheeze, and
dyqmq prevalence increased
signiflcnntly with age, slightly
higher in urban oxnmunity;
women had lower prevalence of
phkgm and higher prevalence of
dppnea than men
o ???????*
???????

twl=wiiro

Burghard et al.,
1979,
France

29.136 &dents,        Morning                         Breathleumeas     Prevalence of 8ympt.onu increased
aged M-18.         NS        13.7                      NS        14.1     with incwasing cigarette
Badthin Department SM       25.7                       SM        22.2     consumption; girln had higher
             Day or night                             prevalenw of respiratory
             NS        16.9                             aymptanu for each emoking
              SM        29.1                                  --aw
                  chronic
              NS        2.7
              SM        6.6


TABLE 2.-Continued

Author, year,
country

Population          `hsh

Other

Comment8

culavik,       19,988 people,        Morning cough
1979,        aged 16-70.        NS         11
Norway         GE10             Ex         16
                          SM         36
                       Daytime cough
                          NS          4
                          Ex          7
                         SM         16
                       Cough 3 mmlyr
                          NS          3
                          Ex          5
                         SM         14

When awghing     Cough and phlegm perioda   Cough and phlegm increasedmore
NS         10      NS        6      with age for smokem (10-19
Ex         18      Ex         8      c&/day) than nonsmokers; no
SM         26      SM        16      significant relation&p between
                           age and prevalence of periods of
                           cough and/or phlegm;
                           dose-response relationship
                           between number of c@rettea and
                          symptoma reported; data not
                             given

Lid et al.,
l=t
France

899 men and women,
ased -t,
(av. 39), Paris

NS
SM


NS
SM

Men                           Respiratory aymptcuna (cough and/or
      16.0                      phlegm 3 moe/yr. for 2 years); not a
      25.4                       random sample; male and female
Women                          amokem had eimihr symptom
      8.1                       prevalence; female nonsmokera had
      26.6                      lower prevalence


TABLE 2.-Continued

Author, year,
country

Population         h?h           Phlegm              Other              Commente

Park,
1961,
KOll?Il

856 university
men and women,
seed 18-w
seoul

NS
Ex
SM


NS
Ex
SM

NS
Ex
SM

Morning
    16.0
    31.3
    34.0
Daytime
     4.2
     8.3
    10.9
Nightime
    13.5
    18.8
    19.9

NS
Ex
SM

NS
Ex
SM

NS
Ex
SM

Morning
    20.1
    22.9
    26.1
Daytime
     2.1
    14.6
    12.0
Niihtime
     7.3
    10.4
    13.2

Breathlessneea on exertion   Symptom prevalencea apparently
NS        23.2     not ageadjusted; eiguificance
Ex        25.0     levels not reported; nonetand-
SM        29.7     ard questions; eymptome current

Neukirch et al.,
1982.
FreIW

23% Becondary
school etudente,
43ed<ll-218
(me3n 14.9).
Peri.9

U.sual cough and/or phlegm
     Boys
NS           26.1
SM          34.9
      &la
NS           26.9
SM           44.7

21.8% of boys, 32.2% of girls
were current smokers; girl
smbkers had higher symptom
prevalence than boys if total
lifetime cigarette8 >4,000; resulta
probably not age adjusted

Schenker et al.,
1962,
U.S.

5,686 women,
aged 17-74 (mean
44.6), western
Pennsylvania,
telephone interviewn

Chronic cough       chronic phlegm    Wheeze moat daye or nigh&   Cough and phlegm meet strongly
NS        5.6      NS        4.5      NS         7.2     related to current cigarettes/day;
w        7.5       Ftx        6.7       Ex         8.3     tar content had independent
SM               SM              SM            effecte; age effect Been for
l-14     9.1         1-14      7.2         1-14     14.4     nonsmokera, but not current
15-24     17.0        15-24     16.7        15-24      16.5     smokers; symptom
25t     31.8        25+     24.8        St     28.0     prevalencee age adjusted


TABLE a.-Prevalence (percent of cough, phlegm, and other symptoms for nonsmokers (NS), smokers
     (SM), and ex-smokers (MI, longitudinal studies


Author, year,
country         Population       Smoking habits               SYmptoms                      Comments


Ferris et al.,      1,201 men and                       Cwrh           Phlegm        72.3% of men, 78.4% of
1976,        women, aged 25-74          1973           1967       1973      1967      1973     women followed up; 1973,
U.S.          in 1961, Berlin                              Men                      symptom prevalencea, ege
          New Hamphire         NS               6.0        8.5       8.9        7.6    @usted to compare with 1967,
                            Ex             20.5        9.7       23.3       15.9     showed little change
                           SM
                                 l-14          22.2       25.5       17.9       27.5
                                 15-24          35.4       26.5       31.6       30.0
                               25-34          26.1       26.7       33.8       32.4
                            St           50.6       56.4       37.1       51.9

                                             Women
                            NS               4.4        6.2        8.1        7.4
                            Ex               3.2       5.2        7.3       10.1
                            SM
                                  1-14          10.7       10.0       11.6        9.8
                               15-24          19.5       16.3       21.8        9.8
                               2544          27.2       16.1       22.5       21.8
                             St           44.7       31.0       43.1       41.2

Kieman et al.,    2,736 men and                        Cough day or night in winter         Effecta of cheat illnem before age
1976.        women, aged 26, born    1966       1971           1966               1971        2, father's vocation, and current
Great Britain     ill1946,eUIlllin       NS       NS            5.5                4.9        emokhg r$nikant; air pollution
           1966 and 1971        NS       SM            7.2                9.6 '        effect not aignif~cant; current
                           SM       SM            14.3               18.5 '        smoking had lanpst effects
                           SM       Ex            9.2                5.8         `Prevalence, 1966 vs. 1972
                                                                   P <0.05


TABLE 3.-Continued

Author, year,
cmntly

Population

Smoking hahits

Comments

Leeder et al.,     2,130 fathers,                        Cough/phlegm prevalence range        In male ersmokers, prevalence
1977,         mean age 31.0rt6.1,                         Men                      of cough/phlegm decreased
Great Britain     2,146 mothers,      let period   2nd period     1st syr period        2nd 3yr period      over time; no signiicant
          mean age 27.9f5.3,     NS       NS           8.69.6              9.2-11.1       change in prevalence in female
            children horn         NS       SM          4.6-16.9             13.3-20.5        er+mokera. but numhera
          19634965,          SM       SM          25.6-30.2            30.W4.0        were amall
         London, 6 year        SM       Ex          21.6-25.3             5.b20.7
         r0110wup                               Women
                          NS       NS           4% 6.8             5% 7.3
                            NS       SM          8.2-10.2            13.3-18.4
                           SM       SM          16.3-22.4             23.0-28.4
                           SM       Ex           4.1-22.5            12.2-14.3

Woolf and Zamel.   302 women, wed                   Cough and/or phlegm       Breathleesneas      60% followcxl up; all subjects
1960.          `E-54 at initial                        let exam   Findexam    let exam   Finalexam   maintained con&ent smoking
Canada        study. &year             NS            10        14        10         5      habita for 5 years
          followup                J%x             3        13        18         8
                                SM            56        54        25        21
---   ---_.-. -.  ___.-__. .~_..


TABLE 3.-Continued

Author, year,
muntry

Population

Smoking habits

Comments

Beck et al..
1982,
U.S.

1,262 white
residents, aged 7-55 t ,
Lebanon, Connect
icut, exams in
1972 and 1978

1972


NS
NS
SM
SM
FX

1978

NS
SM
SM
Ex
Bx

NS       NS
NS       SM
SM       SM
SM       Ex
Ex       Ex

Usual cowh
1972       1978
    Men
5        2
0        0
23       21
25        2'
7        6

7         4
0         0
20        14
26        12
10        3

usual phlegm
1972       1978


7         3
0         4
22        26
18         8
12        15


5         6
0         9
15        11
8        16
4         1

65% followed up; health indiaza
of respondents and non-
respondents similar; symptom
prevalence tended to decline, but
few changes were. significant;
`Prevalence, 1972 vs. 1978,
p <CL5


FIGURE Il.-Prevalence of chronic cough and/or chronic
       sputum among samples of men and women in
       Tucson, Arizona
SOURCE: Lebxvitz and Burrowa (1977).

Dose-Response Relationships

The most common measures of dose are the number of cigarettes
currently smoked per day and the pack-years of cigarette consump
tion; the latter estimates lifetime exposure by integrating the
number of cigarettes smoked (by pack) and the duration of cigarette
use. Errors of memory compromise the accuracy of retrospective
information, which may also be biased by differential recall in those

63


50.0 -





40.0 -





30.0 -





20.0 -




10.0 -

Ex-smokers

Nonsmokers

220

lo-19 \ smokers
    c4Qaretles~day

l-9

19-23    24-27   29-32   233

Tar (rtq/c@arette)

FIGURE 12.-Percentage of smokers with phlegm
      production (adjusted for age), according to tar
       yield of cigarettes
SOURCE: Higenbvttam et al (1980).

with and without smoking-related symptoms or diseases. Even
accurate reports of current smoking habits fail to take into account
all the sources of variation in exposure associated with the material
used in cigarette manufacture or generated in the burning of
cigarettes, The dose of noxious materials received is also influenced
by human behavior, including the number, volume, and timing of
puffs taken with each cigarette; retention of smoke in the mouth;
depth of inhalation; disposition of the cigarette between puffs; and
other aspects of smoking style that are not reproduced by the
smoking-machines used to measure tar and nicotine yield.

Prevalence rates of cough or phlegm, or both, generally increase as
the number of cigarettes smoked per day increases. The trends
illustrated in Figures 11 and 12 were present in both sexes and all
age groups (Lebowitz and Burrows 1977; Bean et al. 1978; Higgins et
al. 1977; Huhti et al. 1978; Higenbottam et al. 1980; Schenker et al.
1982). Bland et al. (1978) found a d-response relationship in
secondary school children, among whom rates of reporting cough
were higher in those who smoked most, even though levels of
cigarette consumption were generally reported to be low. At the
other extreme of the age range the trend is also apparent, even
though symptomatic smokers are more likely than asymptomatic
smokers to stop smoking or to reduce their cigarette consumption


(Higgins 1974;  Fl t h
                e c er 1976). Symptoms were more prevalent
among heavier smokers of filter cigarettes as well as of nonfilter
cigarettes (Dean et al. 1971). Prevalence rates of cough, phlegm,
chronic bronchitis, and mucus hypersecretion show a similar pattern
of association with pack-years of exposure (Tager and Speizer 1976;
Lebowitz and Burrows 1977). Pates of incidence and remission
observed in longitudinal studies add further support to the strong
evidence that respiratory symptoms increase as exposure to cigarette
smoke increases (Table 3).

In their study of more than 18,000 male civil servants in London,
Higenbottam and colleagues (1980) found that the percentage of
smokers who produced phlegm increased with increased daily
cigarette consumption and also with increasing tar content of
cigarettes among those who smoked less than 20 cigarettes a day.
Symptoms were prevalent about equally among smokers of 20 or
more cigarettes per day, regardless of the tar yield of the brands they
used (Figure 12).

Schenker et al. (1982) reported the relationship of tar content of
cigarettes to respiratory symptoms in a cross-sectional telephone
survey of 5,686 adult women in rural Pennsylvania. The risk of
chronic cough and phlegm was more strongly affected by the number
of cigarettes smoked per day than by tar content. Cough and phlegm
were reported least often by never smokers and with increasing
frequency as the number of cigarettes smoked per day increased. Tar
content of cigarettes was significantly associated with symptoms of
chronic cough and phlegm--especially cough-and its effects were
independent of the number of cigarettes smoked per day in a
multiple logistic analysis. The risk (relative odds) of chronic cough
for smokers of high tar cigarettes (20 or more mg) was approximately
twice that for smokers of an equivalent number of low tar cigarettes
(10 or less mg). A limitation of this cross-sectional study was the
determination of tar content for current cigarettes only, rather than
for lifetime smoking habits. Although the apparent relationship
between tar content and symptoms could have been caused by
changes in smoking habits, this was considered unlikely because
symptomatic smokers tend to reduce their consumption of cigarettes
more than asymptomatic smokers (Fletcher et al. 1976) and may also
switch to low yield cigarettes. In this situation, any reported effect of
tar content on symptoms would be an underestimate.

In summary, the prevalence of symptoms increases with dose of
smoke exposure, when dose is measured by number of cigarettes
smoked per day or tar content of the cigarette smoked.

Relationship of Cough and Phlegm to Sex and Age
Prevalence rates of cough and phlegm ascertained in epidemiologi-
cal studies generally increase with age and are higher in men than

65


in women, as shown in Figure 11 and Tables 2 and 3. Rates also vary
with smoking habits. Rates in nonsmokers better clarify associations
of symptoms with age and sex than do rates in smokers, since they
are less confounded by variations in exposure to cigarette smoke.
However, recent evidence linking passive smoking with increased
prevalence of respiratory symptoms suggests that rates in nonsmok-
ers may be in excess of those that would be found in a population
completely free of exposure to cigarette smoke (Lefcoe et al. 1983;
Weiss et al. 1983).

Rates of reporting cough or phlegm or both were roughly equal in
nonsmoking men and women in several cross-sectional studies
(Bland et al. 1978; Higgins et al. 1977; Lebowitz and Burrows 1977;
Manfreda et al. 1978; Neukirch et al. 1982; Rawbone et al. 1978).
Rates were higher in nonsmoking men in some populations (Dean et
al. 1977; Liard et al. 1980; Tager and Speizer 1976). Bouhuys et al.
(1979) found no sex difference in the prevalence of cough, but a
higher rate of reporting phlegm in male nonsmokers (Table 2). In
most of these studies, the rates were not corrected for exposures to
other respiratory irritants in the workplace or in the general
environment.

In general, symptoms are more prevalent in male smokers than in
female smokers (Table 3). However, differences in prevalence rates
between the sexes are generally smaller or absent when comparisons
are made between men and women who smoke similar numbers of
cigarettes. Lebowitz and Burrows (1977) found that the excess
prevalence of symptoms in male smokers compared with female
smokers tended to be greatest at older ages, where there are also the
greatest differences in smoking behavior. Men in these birth cohorts
tend to have begun smoking earlier in life, smoke more cigarettes
per day, inhale more deeply, and smoke higher tar and nicotine or
unfiltered cigarettes. Two studies from France, Burghard et al.
(1979) and Neukirch et al. (1982), concentrated on high school
students. In general, the prevalence of smoking was similar for both
boys and girls for the two studies, although the Neukirch group
found a somewhat higher rate among the girls (46 percent versus 39
percent). Slightly more boys than girls, however, smoked more than
10 cigarettes per day. In these two studies, the prevalence of
symptoms was higher among female smokers than among male
smokers. These data suggest that the past differences in prevalence
of symptoms between the sexes is largely attributable to differences
in cigarette consumption. These differences were substantial in the
past, and are still present among older adults, whereas current
smoking practices are about the same in male and female adoles-
cents and young adults.

Prevalence rates of cough, phlegm, and chronic bronchitis in-
creased with increasing age in the U.S. population samples studied

66


by the National Center for Health Statistics (1981) and in several of
the cross-sectional studies cited in Table 2. However, differences in
rates of reporting symptoms among people of different ages may
relate to effects of aging, differences in current exposures, or
differences in exposure to cigarette smoke or other noxious agents in
the past. It is therefore difficult or impossible to use cross-sectional
data to separate effects of aging from effects of duration, dose, and
nature of cigarette smoke exposure throughout life. Longitudinal
studies provide information on time trends, both in exposure and in
onset and course of disease. Nevertheless, conclusions may be
incorrect if people who drop out of longitudinal studies are different
from those who continue to participate.

Prevalence of symptoms increased with increasing age among men
in cross-sectional data from Tucson (Figure ll), but the trend was
more apparent among smokers and ex-smokers than among non-
smokers. However, Lebowitz and Burrows (1977) could not distin-
guish between an association caused by increasing age and an
association due to increasing duration of exposure to cigarette smoke
in smokers because the two were so highly correlated. Among
women, symptoms were reported more frequently at ages 30 to 44
than at ages 15 to 29 (except by ex-smokers), but prevalence rates
were essentially the same for the three groups over age 30. Higgins
et al. (1977) found that there was no increase in cough and phlegm
with increasing age in male or female nonsmokers in Tecumseh
(Michigan), whereas prevalence rates increased with increasing age
in male smokers. The pattern in female smokers was similar to that
in Tucson and showed an increase with age up to age 30 or 40, but
rates declined with increasing age after age 50. The extent to which
these patterns related to amount smoked or duration of smoking was
not reported, but these older birth cohorts of women probably began
to smoke later in life and smoked fewer cigarettes per day, according
to national smoking survey data.

In other cross-sectional studies cited in Table 2, symptom preva-
lence increased with age in the populations studied (Bouhuys et al.
1979; Dean et al. 1977; Gulsvik 1979; Huhti et al. 1978; Tager and
Speizer 1976), but the trend was noted by Gulsvik to be less in
nonsmokers. Huhti et al. found a significant increase with age
among nonsmokers for phlegm and dyspnea only. Schenker et al.
(1982) observed a trend for nonsmokers but not for smokers, and
Tager and Speizer found that adjusting for smoking eliminated the
trend with age.

Prevalence rates of cough and phlegm on two occasions 3 to 6 years
apart are shown in Table 3 for five recent longitudinal studies of
populations in the United States, Canada, and Great Britain.
Kiernan et al. (1976), Leeder et al. (1977), Woolf and Zamel (1980),
and Beck et al. (1982) found little change in the prevalence of

67


symptoms among continuing nonsmokers during the followup inter-
val of up to 6 years. The rates among nonsmokers reported by Ferris
et al. (1976) are similar on the two occasions, but symptoms were
presented by smoking habits at followup only, and any effect of age
was deliberately adjusted out because the authors' purpose was to
evaluate effects of changes in smoking, changes in pollution, and
trends over time independent of changes in age. Cough and phlegm
appeared to be more frequent at followup in the persistent smokers
studied by Kiernan et al. (1976) and Leeder et al. (1977), and about
the same in women studied by Woolf and Zamel(1980) and in men
studied by Reck et al. (1982). However, rates were slightly lower at
followup in the female smokers followed by Reck. Even though
starting to smoke or quitting can be eliminated as the explanation
for increases or decreases in symptom prevalence over the course of
these studies, it is possible that changes in the number or type of
cigarettes smoked by persistent smokers influenced the prevalence
of symptoms. The duration of followup in all these studies was
relatively brief, and it is still difficult to distinguish between effects
of aging and effects of duration, amount, and nature of exposure to
cigarette smoke in smokers, even when major changes in smoking
behavior are controlled. However, available data suggest that age
itself is not the major factor responsible for differences in the
frequency or distribution of symptoms in populations of nonsmokers
and smokers.

Relationship of Cough and Phlegm to Airflow Obstruction

Many cross-sectional studies have found associations between
cough, phlegm, chronic bronchitis, or mucus hypersecretion and
reduced levels of pulmonary function. The forced expiratory volume
at 1 second (FEVI) has been measured in most clinical studies and in
nearly all epidemiological studies, and mean levels of FEVI are
generally slightly lower in groups of people who report respiratory
symptoms (USPHS 1964, 1971; USDHEW 1979; USDHHS 1980a,
1981). Recent studies have compared other measures of pulmonary
function in people with and without symptoms and have provided
longitudinal data on pulmonary function for symptomatic and
asymptomatic smokers and nonsmokers. Attention has been given to
understanding the natural history of chronic airways obstruction
and the interrelationships of respiratory symptoms, levels and rates
of decline of pulmonary function, and their independent and
interrelated associations with cigarette smoking. Several investiga-
tors have emphasized the desirability of identifying in advance those
smokers who will develop severe COLD; symptoms and other
characteristics have been evaluated as potential predictors of
morbidity or mortality from COLD.

68


Fletcher and colleagues (1976) found that the age-height standard-
ized FEVl at the initial survey of their population of working men in
London was inversely related to the volume of sputum produced in
the first hour after getting up. The regression of FEVl on age, given
height, was steeper for symptomatic cigarette smokers than for
asymptomatic smokers or nonsmokers. However, the authors cau-
tion that men may develop symptoms as they age and change from
one regression slope to the other.

Burrows et al. (1977a) found that an index of cough or sputum was
related to FEVl percent predicted when pack-years of smoking were
controlled in a multiple regression analysis. Regressions of FEVl
percent predicted on pack-years are shown for people with and
without chronic cough and sputum in Figure 13; the intercept at 0
pack-years was lower and the decline in FEVl with increasing pack-
years was significantly greater for those with chronic cough and
sputum than for those with no cough or sputum. The authors
calculated that values of FEVl were lower by about 10 percent in
people with cough and sputum, regardless of smoking habits, and
that values declined by about 4 percent of predicted for each 10 pack-
years of smoking in people with cough and sputum and by about 2
percent in subjects without productive cough. There was a signifi-
cant relationship between FEVI and pack-years of smoking in
asymptomatic smokers in this population. A weaker relationship
between cough and sputum and Vmax~% was also found to be
independent of pack-years of smoking; however, prediction equations
for flow rates have been revised substantially (Knudsen 19831, and
the extent to which relationships between the revised flow rates and
pack-years of smoking differ in symptomatic and asymptomatic
subjects has not been reported.

Dosman et al. (1976) found poor correlations between respiratory
symptoms and dynamic lung compliance, closing volume, closing
capacity, slope of phase III, and helium flow-volume curves in a
study of 49 smokers and 60 nonsmokers who were recruited from a
smoking cessation clinic, a personnel department, and the staff of a
laboratory.

In their community-based studies of children and adults, Bouhuys
and colleagues (1977) studied relationships between respiratory
symptoms and loss of lung function in smokers and nonsmokers.
They found that residual values (observed-predicted) of FVC, FEVl,
PEF, MEFsoa, and MEFzsz, were not significantly different in people
with no symptoms or only one symptom when analyses were done
separately for adult white male smokers and nonsmokers. When a
symptom score was used to combine information on usual cough,
usual phlegm, wheeze, and dyspnea, decrements in lung function
were greatest among those with most symptoms.

69


   1M)









   90


s
5
e
2    90









    70

Subjects with chronic
Subjects with chronic
cough and chronic
cough and chronic
Sputum (n = 247)
Sputum (n = 247)

chrome sputum (n = 1.803)

oL--.---
            20          40          60          80

Pack-years

Figure 13.-Percentage distribution of pred&&d forced
     expiratory volume in 1 second (FEVI) versus
      pack-year of cigarettes smoked, by cough and
      sputum history
SOURCE: Burrows et al. (1977a).

In a study (Detels et al. 1982) designed to assess the relative
sensitivity and specificity of symptoms, the flow-volume curve (FV),
the single breath nitrogen test (SBNT), and specific airway conduc-
tance (SGaw) for identifying COLD were compared with the
FEVl/FVC ratio and with one another in 1,201 residents of Los
Angeles 25 to 29 years old. The tests were done in 1978-1979 at a
followup examination of a previously defined cohort. Prevalence
rates of cough and sputum were 9 percent in never smokers, 26

70


percent in current smokers, and 33 percent in smokers of 20 or more
cigarettes a day. Prevalence rates of an abnormal FEVl/FVC ratio in
these groups were 8,23, and 33 percent, respectively (the FEVAWC
ratio was considered abnormal if it was below the 95th percentile for
never smokers without a history of respiratory illness). The research-
ers found that there was very little overlap between the presence of
productive cough and abnormal tests, and that none of the tests of
function showed reasonable concordance with this symptom. Lack of
reasonable concordance meant that none of the other tests were
abnormal in 50 percent or more of the individuals with productive
cough. In this study, the FEVl/FVC ratio was used as the standard
against which the sensitivities of the other tests were judged; the
sensitivity of the FEVAWC itself was evaluated by its agreement
with those tests found to be sensitive in the study. The lack of an
independent method for identifying COLD, the cross-sectional na-
ture of these data, and the way in which analyses were done restrict
the ability to make biological inferences about the independence of
the effects of cigarette smoking that lead to cough and sputum or to
chronic airflow limitation. However, the authors note their findings
are consistent with the hypothesis that effects of smoking on cough
and sputum are independent of effects on airflow limitation.

Insights into the course and pathogenesis of COLD have been
developed by Fletcher and his colleagues from observations made
during their 8-year longitudinal studies of levels and rates of decline
in lung function in middle-aged working men in London (Fletcher
1976; Fletcher et al. 1976). These investigators found that various
measures of sputum production were correlated with FEVl standard-
ized for height and age, and that this correlation was weakened only
slightly by adjusting for smoking habits. The researchers maintained
that the association between sputum production and pulmonary
function could be due entirely to a common causation. Some men
with mucus hypersecretion had normal FEVl; conversely, some men
with airflow obstruction did not report phlegm. Nevertheless, the
relationship between phlegm and reduced FEVl was strong enough
to give rise to an estimated reduction in FEVl of about 0.1 liters for
every ml of sputum expectorated in the first hour after getting up.
However, because decline in FEVl (FEV1 slope) was not related to
measures of sputum production when level of FEVl and smoking
habits were controlled, the researchers concluded that mucus
hypersecretion is not a cause of accelerated decline in FEV1.
Furthermore, there was no evidence that short-term changes in
sputum production were associated with short-term changes in
FEVl. The researchers concluded that the association between
expectoration and reduced FEVl is caused by the increased suscepti-
bility of some people to both expectoration and excessive loss of
FEVl when they are exposed to cigarette smoke or, presumably, to

71


other noxious materials. This study has made important contribu-
tions to understanding the natural history of chronic bronchitis and
emphysema, but the duration of followup was only 8 years, the men
were 30 to 59 years of age at the start of the study, and their mean
age was 51 years at the midpoint. Similar studies of younger men
and women and observations over longer periods of time are needed
to extend these findings.

Johnston et al. (1976) found that sputum volume was not related to
decline in FEVl in a lO-year followup study of chronic bronchitic
patients. There was no difference in sputum volume between
patients whose FEVl fell by more than 33 percent and controls
(matched on initial FEVl 1 whose FEVl did not fall. Furthermore,
sputum volume was reduced in response to stopping smoking or to
antibiotic treatment, whereas rate of decline of FEVi was unaffected.
In this and other studies (Higgins et al. 1970; Fletcher et al. 1976;
Peto et al. 1983) FEVl was strongly predictive of morbidity and
mortality, whereas respiratory symptoms were not.

Woolf and Zamel (1980) studied "normal" employed women aged
25 to 54 in a longitudinal study designed to identify smokers at
increased risk of developing COLD. Ventilatory function was mea-
sured at the beginning and at the end of a 5-year period during
which smoking habits and symptoms were ascertained annually.
Differences between initial and followup values of pulmonary
function tests were expressed as a percentage of the initial value and
compared in persistent nonsmokers and persistent smokers who
either consistently reported or consistently denied cough or sputum.
The decline in FEVi, FEVl/FVC, and FEFw7s% was greater in
symptomatic smokers than in asymptomatic nonsmokers, but not
significantly different in asymptomatic smokers compared with
either nonsmokers or symptomatic smokers. The average number of
cigarettes smoked during the course of the study was greater for
smokers with cough and sputum. Change in FEFs75% was evaluated
in individual smokers, and no association was detected between
cough and sputum and percentage change in this measure of lung
function. The investigators identified one group of smokers whose
decline in FEFZSSS was similar to that in nonsmoking women and
another group with a greater decline; cigarette consumption was
similar in the two groups. The investigators concluded that individu-
al susceptibility is an important determinant of the effect of
cigarette smoking, because some women develop symptoms and
others remain symptomless but experience rapid worsening of
ventilator-y function. However, they noted a tendency for both cough
and sputum and rapid worsening of ventilatory function to coexist.
The number of women in some groups was very small, and the
measure of decline in lung function used by these researchers does
not take into account regression to the mean or assess absolute

72


reduction; those with smaller initial values will have greater
percentage reductions for a constant absolute reduction in function.

Followup studies at 10 and 15 years of the Tecumseh, Michigan,
population showed that incidence rates of obstructive airways
disease were higher in men and women who reported cough, phlegm,
or both symptoms (chronic bronchitis) at entry compared with those
who denied these symptoms (Figure 14) (Higgins et al. 1982). Both
cough and chronic bronchitis were significant predictors of obstruc-
tive airways disease in men even when smoking habits were
controlled in multiple logistic analyses. However, respiratory symp-
toms were poorer predictors of impaired pulmonary function at
followup than were smoking habits and baseline levels of lung
function. In a multiple logistic model with age, smoking habits, and
level of lung function as risk factors, over 60 percent of the lo-year
incidence cases developed among men and women in the top 10
percent of the risk distribution, whereas only 36 percent of incidence
cases were in the top decile of risk when cough, rather than FEVl,
was used as a risk factor (Higgins 1984).

summary

Cigarette smoking is associated with respiratory symptoms, in-
cluding mucus hypersecretion, and with prevalence and incidence of
COLD manifested by irreversibly impaired pulmonary function.
While some smokers develop both conditions, and those with cough
and phlegm are at increased risk of developing airways obstruction,
the conditions can occur separately by mechanisms that are imper-
fectly understood but appear to be different. The excess risk of
reduced FEVl or COLD in symptomatic smokers compared with
asymptomatic smokers may be a reflection of increased susceptibili-
ty in some individuals. However, it may also be a measure of
increased dose of cigarette smoke, in that smokers who report cough
and phlegm tend to smoke more heavily than smokers who deny
these symptoms, and measures such as numbers of cigarettes smoked
per day are not precise enough to control adequately for the amount
of smoke exposure. The rate, number, and volume of puffing as well
as the depth of inhalation can vary substantially between smokers
and are important additional measures of cigarette smoke exposure
dose.

73

480-144 0 - 85 - 4


15

2
2
a
5

ru
3
3
R 5
I
t

0

Cough     Phlegm

Chronfc bronchlbs

Men

15 -









10 --









5 --

0  Absent

Cough

Phlegm   Chrorw bronchltls


CHRONIC AIRFLOW OBSTRUCTION

Introduction

Airflow obstruction is the physiol,ogicnl consequence of disease
processes that narrow the airway. ln asthma the obstruction is
reversible with pharmacologic bronchodilation, whereas the obstruc-
tion associated with airways damage and emphysema is often not
reversible. The terminology with regard to permanent airflow
obstruction has varied. The 1958 Ciba Foundation Guest Symposium
proposed "generalized obstructive lung disease," which was subdivid-
ed into "asthma" and "irreversible or persistent obstructive lung
disease" (1959); in the 1962 recommendations of the American
Thoracic Society, "chronic obstructive bronchitis" was the only
definition that mentioned abnormality of expiratory flow (American
Thoracic Society 1962). In 1975, a joint committee of the American
College of Chest Physicians and the American Thoracic Society
recommended the term "chronic obstructive pulmonary disease"
(American College of Chest Physicians and American Thoracic
Society 1975). Thurlbeck (1976, 1977) has advocated the use of
"chronic airflow obstruction," a functionally based definition that
does not specify the underlying disease processes. Previous Reports
of the Surgeon General have used varying terminology, including
"chronic bronchopulmonary disease" in 1964, "chronic obstructive
bronchopulmonary disease" in 1971, and "chronic obstructive lung
disease" in 1979 (USPHS 1964,197l; USDHEW 1979).

These definitions, however, cannot be readily applied to identify
specific populations. Physiologists, epidemiologists, and clinicians
often use differing approaches in determining whether airflow
obstruction is present (Fletcher 1978). Physiologists, with the
capability for making sophisticated laboratory measurements of
airflow obstruction, may regard subtle early abnormalities of flow as
definitive. In the community, epidemiologists have generally used
spirometry as the primary method for assessing airflow obstruction.
For epidemiologic purposes, airflow obstruction is usually defined by
a forced expiratory volume in 1 second (FEV1) less than a particular
level after standardization for sex, age, and height, or by a ratio of
the FEVl to the forced vital capacity (FVC) below a specified value.
Tests of forced exhalation, such as the FEVl, have the advantage of
sensitivity to abnormalities of both the lung parenchyma and the
airways (Mead 1979). Clinicians are more likely to detect and
diagnose airflow obstruction when it is advanced and symptomatic.
As would be anticipated, the differing approaches of physiologists,
epidemiologists, and clinicians may lead to differing estimates of the
frequency of airflow obstruction.

The natural history of chronic airflow obstruction in adults has
been partially described by several recent prospective investigations:

76


Howard (19701, Bates (1973), Sharp et al. (19731, Fletcher et al. (19761,
Fletcher and Peto (1977), Bosse et al. (19811, Beck et al. (19821, and
Clement and van de Woestijne (1982). Although these investigations
did not characterize the course of airflow obstruction across the
entire human lifespan, the results provide a conceptual model for
considering its development (Figure 15). Ventilator-y function, gener-
ally measured by the FEV1, increases during childhood and reaches a
maximum level during early adulthood (Cotes 1979; Knudson et al.
1983). From this peak; the FEVl gradually and progressively declines
with age. In people who develop airflow obstruction, a similar
gradual loss of function occurs, but at a more rapid rate (Fletcher et
al. 1976; Speizer and Tager 1979). Continued excessive loss of FEVl
eventually results in symptomatic airflow obstruction when ventila-
tory function reaches a level at which activities are limited and
dyspnea occurs. Evaluation by a physician for symptoms may lead to
a clinical diagnosis at this point in the natural history of the disease
process. This model may not satisfactorily describe the development
of airflow obstruction in all individuals (Burrows 19811, but the
accumulating evidence, reviewed below, indicates that a sustained
excessive loss of ventilatory function most often leads to the
development of clinically important chronic airflow obstruction.

In the conceptual model (Figure 151, there are three different
measures of the frequency of airflow obstruction in a particular
population: the prevalence of reduced ventilatory function as
measured by the FEV1, the FEVJFVC ratio, or other physiological
parameters; the prevalence of physician-diagnosed airflow obstruc-
tion; and the frequency of excessive functional loss in a population
followed over time. The first two measures can be determined from a
single cross-sectional survey, whereas the third requires longitudinal
observation. At present, scant data are available for the third
category. The prevalence of physician-confirmed airflow obstruction
is determined not only by the proportion of affected people in the
population, but also by the patterns of medical care access and usage
and the diagnostic practices of individual physicians. Furthermore,
the clinical labels applied by physicians to people with airflow
obstruction are variable and may include "chronic bronchitis,"
"emphysema, " "COLD," and other terms. Thus, estimates of disease
prevalence based on reported physician diagnoses may differ from
those derived from physiological assessment.

Prevalence of Airflow Obstruction

Numerous populations throughout the world have been surveyed
to assess the prevalence of airflow obstruction (Stuart-Harris 1968a,
1968b; Higgins 1974). Most often, the investigative techniques have
included a respiratory symptoms questionnaire and measurement of
pulmonary function, generally with a spirometer or peak flow meter.

76


   4








   3
zi
5
Z=
$

   2









   (

1
1

I          I          1          I         I

25         35         45         55         65         75

FIGURE 15.-Decline of FEVl at normal rate (solid line)
        and at an accelerated rate (dashed line)

NOTE. A: person who haa attained a "normal" manma FEV, during lung growth and development. B. person
whose maximal FEVa has been reduced by childhood respirator? infectmn
SOURCE: Ssmet et al. 11983,

The latter technique has the disadvantage of effort dependence.
Early recognition of the potential problem of observer bias led to the
development of standardized methods (Cochrane et al. 1951; Higgins
1974; Ferris 1978). Thus, most investigators throughout the world
have used the British Medical Research Council questionnaire in the
original form or with some modifications (Samet 19781. Standardiza-
tion has been less uniform for lung function measurements, but
minor variations in procedures would not introduce important
differences in disease prevalence among the various populations
examined.

Although many different populations have been surveyed since
the 195Os, surprisingly few published reports provide data concern
ing the prevalence of airflow obstruction in the general population


cT:Ables 4 and 5). Comparisons among the available studies are
limited by varying methodologies and inconsistent approaches in
calculating rates. For example, only crude rates are available in
some reports, and reference populations for age standardization also
vary. The investigations summarized in Tables 4 and 5 were selected
because t,hey offer estimates of the prevalence of airflow obstruction
in defined community-based samples. Those reports that describe
mean levels of lung function parameters but not their distributions
were excluded. Investigations of specific occupational groups were
also excluded because prevalence estimates based on such popula-
tions may be biased by the overrepresentation of healthy persons
(Monson 1980) and workplace exposures may have affected the
frequency of disease.
For the United States, the available information spans the time
period 1961 to 1979 and covers most geographic regions (Table 4).
Regardless of the definition, it is apparent that airflow obstruction is
common among adults in the United States. A higher proportion of
men than women is affected, and the prevalence increases with age
(Ferris and Anderson 1962; USPHS 1973; Lebowitz et al. 1975; Detels
et al. 1979; Samet et al. 1982). Few minority populations have been
studied. In New Mexico, Hispanic whites had a lower prevalence of
physician-diagnosed current chronic bronchitis or emphysema than
non-Hispanic whites Garnet et al. 1982). Although blacks have been
included in several surveys (Bouhuys et al. 19791, prevalence
e&mates for this racial group have not been published. The
available data (Table 4) do not permit a satisfactory assessment of
changes in prevalence rates with time over the years 1961 to 1979.
The National Health and Nutrition Examination Surveys
iNHANES 1) included spirometry in their evaluation of a represen-
tative sample of the U.S. population. The numerical values for these
measures are reported by age, sex, and smoking status for the white
population in the tables in the appendix to this chapter. The changes
in mean values of these measures between age groups are also
presented for white male and female smokers and nonsmokers in
Figures 16 through 23. Differences between smokers and nonsmok-
ers are evident for each of these spirometric measures. These
differences are portrayed for successive age groups at one point in
time, and therefore cannot be used to describe the changes with age
or smoking status that one would expect in an individual or
yJpdat.ion followed sequentially. These data represent only those
people in the study populat.ion who were willing and physically able
to mnximaliy exert themselves on the various spirometry tests;.
Others were discju11ified by the examining physician because of
  
eslstirig rn~~l~c:il f,
              ' aonditions. The sampling nonresponse was higher
anon:: ::.epments of i;;c~ population expected to perform less well on
the test i:icludi:l:: Y' ;,ie with existing airflow limitation. Therefore,


TABLE 4.-Prevalence of indices of airflow obstruction in selected U.S. adult populations

Author, year of study.               Number and typz
location, reference                  of population

Index

Prevalence (per loo)

Higgins and Kjelsbeq,
1969-1960, Tecumaeh,
Michigan u967)

4,500 men and women.
20 years or older,
community sample

Emphysema bawd on physician
history and examination

Me"
Women

4.1 '
1.1 '

Higgins, 19621979,
Tecumaeh, Michigan
(15183

4.916, 4,443, and 4,933
men and women, 16
to 74 yema old, in
1962&s, 1967-69,1978-79

Otmtrwtive airways disease:
FEV, leea than 65% predicted,
and FEV,/FVC ratio less
than 80%:

I!&&65
196769
19x5 79

Men


481
372
:I 7 2

Women


25t
142
22'

Ferris and Anderson. 1961.
Berlin, New Hampshire
(19fa

1,167 men and women,
community sample

Irreversible obstructive
lung disease, including
wheezing, dyspnen, or
FEV,/FVC ratio less than
60%

Men
Women

R.6l
8.1 '

Mueller et al., 1967, Glen-
wocd Springs, Colorado
(1971)


IT.!3 Public Health Service,
1970, united states (1973)

609 men and women,
community aample



116,000 men and women,
nationwide awnpie

Uwonic airway obstruction:
FF.V,/FVC ratio less than
60%



Preaen~+z of the condition
during the previous year

  Me"            1321
  Women           1.5'

--__--         -
    Chronic bronchitis
  Men            3.1 '
  Women           3.4 '
     Emphysema
    Men       1.0 I
   Women      0.3 '


E!   TABLE 4.-Continued

Author, year of study,               Number and type
location, reference                  of population

Index

Prevalence (per 100)

L&wit2 et al., 1972-1973,
Tucson, Arizona (1975)

3,605 men and women.
adukaandchildren.
community sample

Physiciarwonfn-med illness.
current

   Men over 44 yeam
Chronic bmncbitia      10.2
Emphysema          13.3 '

  Women over 44 years
Chronic bmncbitia      9.0 '
Emphysema         4.3 '

Knudson et al., 19721973.
Tucson, Arizona (1976)

3,605 men and women,
adulta and children.
community sample

FEV, and FEV,/FVC ratio
lower than 95th percentile
for "normal"

Asymptomatic cigarette smokera
m,               7.6 '
FEVJFVC           8.1 '

Detela et al., 1973-1974,
Burbank and Lancaster,
cdifornia (1979)

3,465 and 4,509 men
and women, in Burbank
and Lancaeter. respectively,
community luUnpleJ3

FFX, leaa than Em7 of
predicted value

     Lancaster
18-59 yla        0.8'
fioyrs          6.5 a


     Bul&lk
18-59 yra        1.0'
6ovrs          6.2'

Tager et al., 19751974,
East J3oe.h. Mamachuaetts
(197M

1,770 men and women,
wmmunity sample of
index subjecta and
their relatives

FEV, less than 65% of
predicted

Men
Women

5.6 '
3.4 '

Fen-in et al., 19761977,
six cities in the U.S.
(1979)

7.909 men and women.
community sample

FEY,/Fvc leas than, eaxlal

tDti%

Men
Women

5.0 '

1.9'


TABLE I.--Continued

Author, year of study,               Number and type
location, reference                  of population

Index

Prevalence (per 100)

Samet et al., 1976-1979,
Albuquerque, New Mexico
u982)

1,722 men and women,
canmunity sample

Phyxiciandiagnoeed current
chmnic bronchitis or
emphysema

Non-Hipanic whites
Men            3.6'
Women          3.4'

  Hispanic wbitea
Men            0.8'
Women           1.6'

' Crude rate.
`Age-adjlwted rate.
* Age and eewadjueted rate.


TABLE &-Prevalence of indices of airflow obstruction in selected adult non-U.!% populations

Author, year of study,              Number and type
location, reference                  of population                     Index               Prevalence (per 100)


Anderson et al., 1963.             558 men and women,            Obstructive lung disease,             Men            12.6'
Chilliwack, British              community sample              including wheezing, dyspnea,          `Women           87'
Columbia (19653                                     or FEV,/FVC ratio less than
                                                      60%
                                           FEV,/FVC ratio less than            Men            7.3 '
                                                      60%                        Women          3.5 '

Mimica, 1969, Croatia,            4,214 men and women.            FEV,/FVC ratio less than            Men            8.3 '
Yugoslavia (197Ti              samples of six                    60%                        Women           1.9'
                          oommunitiee

Sawicki. 1968, Krakow,            4,355 men and women,            FEV,/FVC ratio less than            Men            7.0'
Poland (2977)               community sample                 60%                       Women          5.0 '

Huhti et al.. 19681970,           1.162 men, community            FEV,/FVC ratio less than            Men            7.6 '
Hankaeahni. Finland (1978         l%SIlIple                        60%

Brown and Gajdusek, year           240 men and women,           Chronic obstructive airway           Men and
not stated. Weatern             community sample              disease: clinical and spim            women           7.9 '
Camline Islands (1978)                                         metric criteria

Anderson, year not stated,           770 men and women,             FEV,/FVC ratio leas than            Men            9.0 '
Lufa, Papua New Guinea          25 yeam or older,                60%                        Women           3.6 '
(1979)                   community sample


' Crude rate


the estimated means are probably overestimate> of the true popula-
tion values. Nevertheless, the figures clearly portray the magnitude
of the effect that smoking exerts on expiratorv flow rates in a
national population sample.

Airflow obstruction is also prevalent outside t.he United States
(Table 5). The disease can be identified in both technologically
advanced and less developed populations. As in the United States, in
other countries the prevalence of airflow oba.<ruction is higher
among men than among women.

lleterminants of Airflow Obstruction

In trodtrciion

Current understanding of the natural history of airflow obstruc-
tion suggests that risk factors operative during both childhood and
adulthood may influence the development of disease. In the concep-
tual model proposed in Figure 15, childhood factors might increase
the risk of airflow obstruction by lowering the maximum FEVl
attained during lung growth and development, `by predisposing to
increased FEVl decline during adulthood, OS by both mechanisms
(Speizer and Tager 1979). During adulthood, in the model of Figure
15, risk factors for airflow obstruction must increase the rate at
which lung function deteriorates.

Many endogenous and exogenous determinants of the develop-
ment of airflow obstruction have been postulated (Tables 6 and 7).
However, in spite of over 30 years of intensive investigation, the
available data are definitive only for cigarette smoking and for a,-
antitrypsin deficiency Bpeizer and Tager 1979; IJSDHHS 19801.

Cigarette Smoking and Chronic Airflou~ Obstruction

In nearly every population studied worldwide. cigarette smoking is
the predominant determinant for the prevalence of airflow obstruc-
t,ion (Tables 8, 9, and 10). The uncommon exceptions primarily
involve populations in whom severe chest infections or wood smoke
exposure may have an etiological role (Woolcock et al. 1973;
Anderson 1979a). The relationship between cigarette smoking and
airflow obstruction has been variably described in the published
reports. In some, the prevalence of airflow obstruction has been
considered; in others, mean values of lung fun&ion paramet,ers have
been compared across categories of smoking use. In severai more
recent analyses, multiple regression or other multivariate tech-
niques have been used fcr more careful characterization of dose
response relationships. Because t.he epidemiolnz;ic criteria for airflow
obstruction a:-e L;~:::ir~lly based on the FIX?], this section focuses on
stir&es tiiat have included meas~~:~~;:r~cn~s of this parameter. The
p?/pct& stivIr$ps ln-,*oi\,e con,~i:i:;~~t~ . ..tmnly.  TI~k!l!3 h .!rlii 91 and


Men

4000 -4

2500 -;
   I

   /
2000 -J

- Never smokers
--- Curw3 cigarette smokers

3500 -

`.
2222









7--
65-74

I                                              1669

                               !~- ._.-.-_~
25-34        3S44        4554        5-4        65-74

                    Age group

FIGURE 16.-Mean FEVI for white persons by smoking
       status, sex, and age, United States, 1971-1975

NOTE, Va1uc-s adJusted by the direct method to reflect the age distribution of the U.S population at the
m,dp,mt of the survey

SOllRCE. Satw,ncJ Center for Health Starlstics L'npubhshed data from the first National Health Nutrition and
Examlnatmn Survey INHANEY 11

84


4500 -


4000 4

- Never smokers
-- - Current agaretle smokers

\ \
\ \ \
  4199

FIGURE 17-eMean flow at 25 percent of FVC for white
     persons by smoking status, sex, and age,
      United States, 1971-1975

NOTE: Value8 adjusted by the direct method tc reflect the age distribution of tht US populatwn at the
midpoint of the survey.

SOURCE National Center for Health Statistics Unpublished data from the first Natmnal I&alth Nutrlt,,,n and
Eramuration Survey (NHANES 1).

85


                                     2793 `\
2500 ~.                                       , \
                        `\\

2000 -



1500

`\
`\\
  1069

iii-34        3-4        4554        5w34        6574

                   Age group

Women

FIGURE l&-Mean flow at 50 percent of FVC for white
       persons by smoking status, sex, and age,
        United States, 1971-1975
.UOTE Values i?d,uai b\ Lhr dlrecr nwthod tn reflect the qy d,stnbution 01 rhe L! S ppulat~on at the
mldpomr of ihe iliriry
SOUKC`F; Natiunal (`enrrr tur Health St~t,st,cs i:npublrched data Cram thv first Va~iun.it flralth Nutr,t,on and
Exem~natwn Survr\ sNffA\NE:S Li


2000



1500
^
5
s 1000
f

  500 1

Women

541          572

01 I - -----. racy car
   25-34        3544        45-54        55&4        6574
                     Age grwp

FIGURE lg.-Mean flow at 75 percent of FVC for white
      persons by smoking status, sex, and age,
       United States, 1971-1975

NOTE: Values adjusted by the dxrect method to reflect the age dlstributwn of the U.S population at the
mldpomt of the survey

SOURCE: National Center for Health Statistics. Unpublished data from the first Natmnal Health Nutrition and
Examinatmn Survey CNHANJZ.5 11

87


"1

85 - 60.7

Men

00 i
g
5  75               -. --._
f i             75.3    ---___
             7T.o`-----_--
  70                                   --__
                                       70.6  --I_ ---__

        -
65           Never smokers                            67.0

\fi      --- Cunet-11 ugarette smokers
04          I           I           I           I
    25-34        3544        45-54        55-6d        6574
                     Age grow

90 1

65 j

  80
z
5 75
f :

70 I

651

I
OY

WWllW!

63.6

          70.2         77.0

- ___--.-
75.4   -----7--o`--- --._ --
                     73.6

I           I           I           I           I

2534        35-w        45-54        55-64        65-74
                 Age wap

FIGURE 20.-Mean FEVl/FVC ratio for white persons by
      smoking status, sex, and age, United States,

1971-1975

NOTE Values adjusted by the direct method tn reflect the age distribution of the U.S. population at the
midpomt of the survey.

SOURCE. National Center for Health Statistics Unpublished data from the first National Health Nutntion and
Exammation Survey (KHANES 1).


Men

E 3ooo-
5
I" 2500.-

  2314
`\

                                    `.
2000-                                    `.
                   2085 ", , ,
                                             `,

15co-



IOOO-

- Never smokers
- - - Current cigarette smokers

`-.
1422

0 i,---m- -~- -.---_~ ..__ ~.~ ---~ ~..
   2534        35-44        45-54        55-64        65-74

                      Age group

3500,



3oal i

E 2500 i

c
3
z 2000 1

Women

FIGURE 21.-Mean MMEF for white persons by smoking
      status, sex, and age, United States, 1971-1975

NOTE: Values adjusted by the direct method to reflect the age distribution of the U.S. population at the
mldpoint of the survey.

SOURCE: National Center for Health Statistics. Unpublished data from the first National Health Nutrition and
Examination Survey (NHANES 11.

89


Men

6500 4

6000 i

7000 1

6500 -

5500 i

4500 -

4000 4

- Never smokers
--- Current agaretle smokers

2!%34       3-4       45-54

                 Age group

6000,


5500 -



5000 ~.



4500 _



4000

599 1        5923
--
594-7. ---. .

5634`\ \ \ \ \

\
\\
`.
434 1

3000                                         `\ \

2500

0
   25 32       3w4       4554       55+4       6574
                     Age group

FIGURE 22.-Mean MEFR for white persons by smoking
       status, sex, and age, United States, 1971-1975

NOTE: Values adJusti by the direct method to reflect the age distributmn of the US population at the
midpoint of the survey

SOURCE: National Center for Health Statlstia Unpublished data from the first National Health Nutntion and
Examinatmn Survey INHANES 11

90


  5500 1
  sooo-i



=
E 45001

5
2  4000-


3500 ;
      /

  3000 1
  01

4000 -7

  3500 i

^
E   I
s 3000;
z

  2500 i
   .>

3667
.

- Never smokers
- - - Current agarette smokers

~_--- .~~~-~~.-~T--- -
25-34        35-44        45-54

                   Age group

.---r..~---.-~--~
5M4        65-74

3712 -===\y,-.L- 26*3
                              `. . `. ----._---.
                                2712
                                          2533

o- i -_.. i.-~-.~

25-34        3544

4554
Age group

55-64        65-74

FIGURE 23.-Mean forced vital capacity for white persons
      by smoking status, sex, and age, United
       States, 1971-1975

NOTE Values udjusti by the direct method to reflect the age distribution of the US populatlan at the
midpoint of the survey.

SOURCE Kational Center for Health Sttltlstics Unpubhshed data from the first Natuxaal Health Nutrition and
Fxamlnstion Surwy fNHANEX lr

91


`CAtiLK 6..--Pusbulat~:d risk factors for airflow obstruction
      during childhood
_"  _.~ -.... -.- . ..-_ -I-.--

                  Actwe clgaret& smokmg
               :&ir pollubiun. indoor and outdoor
                  Airnajs hypeneartivity
                       A~WY

- .  . .._- .-LX.. - . I_-.-- -----be-.

-......- _ I-~II-. .-__ _.-. ..- .-_. _ .--..

, `3 .& .lSlED iit;+. F.~c'!I;~G FOR AIHF'LOW OFSTRLKTION DL'RIh'G ADULTHOOD

_-I- -.---.---m-w-^--. __I_

                   Actlre cqawtte smoking
                Alpha,-antltrjpsin deficient)
       _~_ _._ _.. .----__-----           _____-
   PI'TA iIVE ~1% P.1: IXXS FOR AIHFLGW OBSTRUC'I'ION DURING ADULTHOOD

    ABH secretor status
     Air pollution
  Airways hyperreactivity
   Alcohol consumption
       A~PY
Childhood respiratory illnesses
     Familial factors
     Occupation
Passive exposure to t&acco smoke
   Respiratory illnesses
    Scciwconomic status

occupational groups (Table 10) with exposures that have little or no
effect on lung function. The selected studies are all cross sectional in
design and thus describe the relationship between cigarette smoking
and lung function level at only a single point in time.

Investigations in the United States, spanning the time period 1958
to 1977, convincingly demonstrate that cigarette smoking is a strong
determinant of FEVl level and the prevalence of airflow obstruction
(Table 8). In every population for which prevalence data are
available, airflow obstruction is more common among smokers than
among nonsmokers (Mueller et al. 1971; Knudson et al. 1976; Detels
et al. 1979; Rokaw et al. 1980). In fact, in a multivariate analysis of
determinants of airflow obstruction in East Boston, lifetime cigarette
consumption was the only statistically significant predictor (Tager et
al. 1978). Data from populations outside the United States (Table 9)
and from a variety of occupational groups (Table 10) confirm the
importance of cigarette smoking. Effects of cigarette smoking on
FEVi level have been readily demonstrated in employed populations

92


TABLE &-Association between cigarette smoking and FEV, level in selected U.S. adult populations

Author, year of study,                   Number and type
location, reference                      of population

Findings

Ashley et al.. 1956.
Framingham, Massachusetts,
(1975)

1,236 men and women,
37 to 89 years of age

By linear regression, significant decline of FEX,/FVC ratio
with pack-years of cigarette consumption in men; similar
decline demonstrated in women, but not significant for all
ab!e mute

Higgine and Kjelsberg 19%
1980, Tecumeeh, Mich!gan
(1967)

-

Higgins et al., 1963, Marion
County. West Virginia
1196all




           I_..------

Higgins et al., 1962-1965,
l'rcumwh. lIichiian (1977)

5,140 men and women,
16 to 79 yeare of age





926 white men, 20
to 69 years of age







4,669 men and women,
20 to 14 years of age

-

   Age-adjusted mean FEV, Oiters)
                  Men       Women
Nonsmokers 3.32 2.34
Ex-smokera 3.31 2.34
Current smokers 3.12 2.26

      Mean FEV, (liters)
Nonsmokers 3.64
Ex+mokers                  3.25
Current smokers
1-14/day 3.67
15-2.4lday 3.51
> mday 3.30
    Mean normalized FEV, score
              Men          Women
Nonsmokers 10.2 10 1
Ex-emokers 9.9 10.0
Current smokers
c2O/day 9.8 9.9
2 2oMay 9.5 9.6
        -~.__l___-.__l~----


                                                          Prevalence of E'E:V : i FVC <: Go%
                                                                           Men           Women
Mlwl'r" ct n'. 1`W
   1 .
Glenwood, cid!LI                       f%)(l :xn and women.                 Nonsmokers           3             ;
                            %;! to 69 JY'Ul-8 or age                 Current smokers       19             2
(2971)      .-                                                                           ~.--
Fen% et al., 1967, &rlin,                  848 men and women,              By multiple r-ion, in men and women, FEV, drops by
New Iiampehire (197.3                   3OtcW)yearsofage              0.01 liters for each cigarette smoked per day
-.-._--      -. _-- _ _----- -~     ___--. .-.---__
Burrowe et al., 1972.-1!?7?.                  2369 men and women,             By multiple regression analysis, FEV, drops by 0.31 and
Tucson, Arizona iI                   above 14 years of age             0.24 percent of predicted value per pack-year of smoking
                                                    in men and women, respectively
.____ --- ---..----                    _-
Knudson et al., 19X1973.                  2,7.35 men and women,         Pravalence (%) of abnormal FEV, and/or FIW,/FVC
Tucson, Atiana (f97fJ                   all ages                    Asymptomatic nonsmokers               8.3
                                                  Asymptomatic smokers                13.3
            __-- ---. --.~
Tsger and S+vr, 1973.397!.                633 men and women,              By multiple regression, in men and women, significant
FM Ftiton. Massachusett                 15t years of age                reduction of an FJXV, score with increasing lifetime
/19707                                                 consumption, and in smokers compared with nonsmokers

Tagger et al., 197:%1974. East
Boston, Msssarhwe!k !!9,3

1,251 men and woman,

By multiple logistic analysis, lifetime cigarette consumption
only significant pradictor of airflow obstruction, defmed as
FEV, laea than 65% predicted

4.6W men and women,
7t yearsofage

By multiple regression analysis, significant dose-response
relationships of adjusted residual FJIV, with measurea of
cigarette smoking: duration, pack-years. and cigarettes per
day


TABLE %-Continued

Author, year of study,                  Number and type
location, reference                      of population

Findings

Ferris et al., 1974-1977,
U.S. communities (19791









Detele et al., Rokaw et al.,
1973-1975, Burbank, Lan-
mater, Long Beech,
California (lhtels et al..
1979, Rokaw et al., 1960)

8,480 men and women,
25to74yeareofage








Approximately 8,000
men and women, 18
yeare or older

Mean r&dual FEV, (liters) after correction for height and age

Lifetime packs           Men           Women

  None                0.25             0.06
  <3.ooo               0.21             0.04
3.~999             0.01            -0.05
9,ooo-17,999           -0.19            -0.20
2 l&o00              -0.45            -0.28
F'revalence (%Y of FEV, below 75% predicted, age and eex-adjusted



               Never smoked      Current smoker
1859 years old
Burbank             6.6             12.5
Lancaster            3.4             6.6
Long Bench            5.3             10.0

260 years old
Burbank             15.9             23.5
Lancaster            13.4            21.7


TABLE 9.-Association between cigarette smoking and lung function in sele&ed non-U.S. populations

Author, year of study,                    Number and type
location, reference                       of population

Findings

Hi, 1956, VaIe of
GlamorgaIl, wales mm

661 men and women,
25 to 74 yearn of age

lr men, reduced peak tlow rates and indirect maximum v&ntary
ventilation in smokers compared with nonsmokers;
no effect of smoking in women

Higgins et al., 1957
Stavely, England
(1959l

776 men, aged 25 to
34and55to64

     Mean indirect maximal breath capacity (liters)
             25ta34yrE       55ta64yl-n
Nonsmokers              145             101
Exsmokers              143              89
Current smokers
Light                140              87
HWVY                133              80

H&inn et al., 1966, Rhondda

537 men, aged 36 to 64,

Mean indimct maximal breathinx canacit~ titers). men

Fa&                                                                           -.   -
   Walea (1961)                         and 173 women,
                             aged55to64                                 Miners         Nonminers
                                                       Nonamokern              93.1           114.6
                                                     Ex+mokern               93.6           106.9
                                                       Current smokers
                                               Light                89.0           104.1
                                               HeavY                88.3            99.4
                                                     No effect of smoking in women


TABLE 9.-Continued

Author, year of study,                   Number and type
location, reference                       of population                        Findings


College of General Practitioners,                787 men and 762                 Age-adjusted mean PEFB' flitera/minute)
1966, Britain (1961)                   women, aged 40 to 64                              Men          Women
                                                     Nonsmokers               448            316
                                                        Ex-nmokern               417            300
                                                   Current smokers
                                                 1-lllday               412            314
                                             15-24/day               399            310
                                                 > 25lday                398            265

SluisCremer and Sichel,                  533 men, 36 yearn         Reduced FEV, and PEFR' with increased tobacco mnsumption
1962-1963, Carletonville,                      or older
South Africa (1Si!7~
Huhti, 1961. Harjavalta,                  420 men, 608 women,        All women, nonsmokers; in men, reduced FEV, and PEFB ' in
Finland (1967~                      aged4ot.oe4            smokers mmpared with nonsmokers
Wilhelmsen et al., 1963.                 339 men. aged 50
Gi5teborg, Sweden (1969)                                                  Mean FEV, (liters)
                                                     Nonsmokers                     3.72
                                                        &-smokers                     3.71
                                                     Current smokers
                                             1-14 g/day                    3.58
                                               > 15 g/day                    3.36

Huhti et al., 1968-1970,                  1,162 men, aged 25 to        Reduced FEV, in smokera compared with nonsmokers; increased
Hankaaalmi. Finland (1978)                     69                  prevalence of FEV,/FVC ratio lese than 60% in smokers


TABLE 9.-Continued

Author, year of study.
Iwatinn. reference

Number and type
of population

Findings

MimIca, 1969. Croatia,                    4,214 men and women,
Yugoslavia (1979                    35 to 54 years of age

Nonsmokers
Ex+mokers
Current smokers
Light
H-V

Mean FEV, (liters)
      Men
      3.56
      3.57


      3.42
      3.42

Women
2.62
2.70


2.64
2.66

Neri et al, 19691973.
Sudbury and Ottawa. Canada
11975

Manfreda et al, 1974,
Portage la Prairie and
Charleswoo& Canada
(197x)
--- --
Andemon. year not stated,
Karkar Island. Papua New
Gtinm 11976-I


Anderson, year not stated,
Lufa, Papua New Guinea
(2979)

5,466 men and women,
14 years of age
or older

502 men and women,
25toXiyearsofage



548 men and women, 25
years of age or older




733 men and women
25yearsofageor
older

Declining ratio of FEV!/FVC with number of cigarettes smoked
MY


Significant regression of FFV,/FVC ratio on number of
cigarettes smoked daily



     Age and heightadjusted mean FEV, (liters)
                    Men          Women
Nonsmokers                2.56           2.13
Smokers                  2.40           2.01
     Age and heighta&sted mean FEV, (liters)
                     Men          Women
Nonsmoker                2.58           2.36
Exsmoker                 2.62           2.27
Occasional                 2.57           2.29
R@idw                  2.63           243


TABLE IO.-Association between cigarette smoking and lung function level in selected occupational
       groups

Author, year of study,                      Number and type
location, reference                        of population

Findings

Sharp et al., 1960-1961,                 1.667 men, aged 43 to
Chicago, U.S. (1965)                  56 years. employed at
                           an electronics plant




..-_         --~___
Fletcher et al., 1961.                     1,136 men aged 30
London, England (2976)                 to 59, employed at bank
                                 or in maintenance of
                            transportation equipment







f, --__ i-                   --
Goldsmith et al. 1961 San
Francisco. U.S. ima'                  3,311 longshoremen

Mean FEV, (liters)


      Nonsmokers
      Smokers
      <one pack per day
      zone pack per day
AdJusted WV, (liters)


      Nonsmokers
      Ex*mokera
      Current smokenr
      l-4 cigarettes/day
      5-14 cigarettes/day
      15-24 cigarettes/day
      2 cigarettes/day
        25

Mean FEW, percent of predicted value

     Never smokera
      Examokera
     Current smokers
      10 cigaretti/day
      1139 cigarettes/day
      > 40 cigarettes/day

3.15


3.02
2.90




3.28
3.16


2.81
3.05
2.99
2.94




100
97


93
93
94


E   TABLE IO.-Continued


   Author. year of study,                    Number and type
   location, reference                       of population                        Rndinga


   Bidchum et al.. 1961, La                1,456 men employed in       Prevalence (per 100) of FTV,/FVC ratio less than 70 percent
   Angeles, U.S. (I96ZI                        various induetrien                   Nonsmokers                  1.6
                                                              Smokers                   18.8

   Coata et al.. 1962. Detroit,                 1,584 male and female        Reduced FFX, and FFX,/F'VC ratio in smokers of 25 or more
   U.S. (1965)                       pcwtal employees,          cigarettes daily compared with nonsmokers
                              aged 40 or older

Deneen et al., 1961-1983, New
York City, US. (2969)

12,500 males employed
88 postal or transit
workers

Age- end heightadjusted FJW, W..ere)

                 Pcetal workers

Transit workers

Band6 et al., 1980-1975.
Belgium (1980)

7.123 male military
personnel, * few
over age 45

               white    Nonwhite   White Nonwhite
  Nonsmokers        3.29      3.05     3.39    3.08
Cigarette smokers
  <25gperday     3.14      2.95     3.15    3.00
  2% B per &Y     3.06      2.93     3.02    2.95

By multiple regression, in crcesaxtional analyeie,
signiiiwnt effect of smoking on FEV, level after age 35

Cornstock et al.. 1962-1963
and 1967. U.S. and Japan
(19731

Three cme+eectional         Mean FJW, level as percent predicted
studies of men working                               U.S.          Jaw
for telephone company;                     Study 1     Study 2
U.S.-l,302 and            Cigarettea per day
1,194 subjects, aged                None           106         103        99
40 to 65. 6% in                   1-14           104         101        100
study; Japan--592                 15-24           98          92        98
subjecta, aged 40 to 60             2%            95          93         99


`I'ABLE l&--Continued

Author, year of study,                    Number and type
location, reference                       of p0pu1at10n

Fmdings

Khmla. 1964. Port Talbot,
United Kingdom (1971)






Schlesinger et al., 1966.

  7,701 males employees        Adjusted mean FEV, level (liters)
  in the ateel industry                Never amokem
/-                           Current smokers
                         i 15 cigarettealday
                          lb24 cigarett&day
                          25-34 cigar&tea/day
                         2 35 cigarettes/day
  4.331 male civil servants,       Mean value of the FEV,/FVC ratio

Israel (1972)

aged 45 or older

Nonsmokera
Jhmokem
Current smokers
1-19 cigarettes/day

-

3.70

3.57
3.48
3.41
3.37

-

76.0
74.3

73.9

2 20 cigarettes/day              72.7

Keateloot et al., 1968-1969,
Belgium (2976)


O'Donnell and de Hamel. 1969-
1970, New Zealand (1976)


Linn et al., 1973, San Fran-
cisco and Los Angeles,
U.S. (1976)

Rndelman et al.. year not
stated. Baltimore. U.S.
(1966)

4,961 males in the
Belgian military,
aged 15 to 59
1.079 male public
sewante, up to age
65

644 male and female
office workem aged
17 to 60

410 male volunteers,
aged2otQ103

By multiple regression, FEW, reduced by 0.14 liters in
smokers of 1-19 cigarettes daily and by 0.23 liters in
smokere of 20 or more daily
Beduoed mean FEV, in smokers of 10 or more cigarettes
daily; increaeed prevalent of FEX, below 80 percent of
predicted in smokers of more than two pa& daily
By analysis of covariance, significant reduction of FJXV, in
smokers compared with nonsmokers

By partial regression analysis, significant reduction of
FEW, in current and former cigarette smokem

c
0


e   TABLE 10.~-Continued

Author. year of study,                      Number and type
location, reference                         of population

FlllilllgS

Woolf and Suero, year not
stated. Toronto (1971)








Krumholz and Hedrick. year
not steti, Dayton. U.S.
(1973l

298 female volunteers
employed at commercial
film, aged 25-54








227 male executives.
aged 3.544, selected
to include nonsmokers
(n = 136) and long-
term smokers (n=91)

Adjwted mean levels


Nonsmokers
Exsmokers
Current smokers
70 cigarettes/week
71-140 cigarettes/week
2 140 cigarettes/week

Mean values



Nonsmokers
Smokers

EV,       FEV,/FVC ratio
2.65            a.7
2.64            85.0


2.63            86.2
2.50            85.1
2.45            84.1
               ___-



EV,          FEV,IFvC
3.80              71.3
3.42              73.6

Grimes and Hanes. year not
stated, Los Angeles, U.S.
(1973)

Lefcoe and Wonnacott. year
not stated. western Ontario,
Canada ( 1974

1,059 male and
female insurance
company employees

1,072 males in four
occupational groups

By multiple regression, significant reduction of FEV, level
in male smokers but not in female smokers


By multiple regression. significant reduction of FEY, in
current cigarette smoken

Higgenbottam et al.. year not
stated, London. England (1980)

18.403 male civil
sewants. aged
4ota64

Reduced FEV, io cigarette smokers compared with nonsmokers,
increased effect with increasing daily amount in current
smokers


(Table lo), even though people with symptomatic airflow obstruction
may be likely to retire from their jobs.

Recently, predictors of the incidence of airflow obstruction have
been examined with multivariate techniques in data from popula-
tion samples in Tecumseh, Michigan (Higgins et al. 19821, and in
Tucson, Arizona (Lebowitz et al. 1984). In Tecumseh, the strongest
predictors of airflow obstruction (defined as an FEVl less than 65
percent of predicted) were age, the number of cigarettes smoked
daily, changing smoking habits, and the initial FEVl level (Higgins
et al. 1982). The addition of other variables to the predictive model
did not greatly improve its validity. In Tucson, these same variables,
along with certain symptoms and illnesses, and skin test reactivity
were significant predictors (Lebowitz et al. 1984). During the 10
years of followup of a population sample in Finland, incidence cases
of chronic airflow obstruction (defined as FEV1/FVC ratio less than
60 percent) were observed only in those who continued to smoke
(Huhti and Ikkala 1980). These studies of incidence highlight the
importance of cigarette smoking in t.he etiology of airflow obstruc-
tion; new cases are rare among nonsmokers.

Dose-Response Relationships

Dose-response relationships between FEVl level and the amount
of cigarette smoking have been described with simple descriptive
statistics and further characterized by multiple regression analysis.
In cross-sectional data, the FEVl level varies inversely with the
amount smoked. Although the variation in mean FEVl levels among
strata of smoking appears clinically unimportant, the distributions
of values in smokers and nonsmokers are quite different (Figure 4).
Cigarette smokers more often have abnormal lung function, regard-
less of the criteria applied to the population (Mueller et al. 1971;
Knudson et al. 1976; Burrows et al. 1977a; Detels et al. 1979; Rokaw
et al. 1980; Beck et al. 1981). This increased prevalence of abnormal
function is a result of the skewed distribution of function in smokers,
with a subgroup of the smokers showing a large decline rather than
the entire group shifting by a small amount (Figure 4). As noted in
this reference, however, there are decreasing numbers of smokers
with FEVI above the mean for nonsmokers as pack-years increase,
suggesting that all smokers are probably somewhat affected, even
though only a minority eventually develop clinically significant
airflow limitation.

In several populations, the relationship between cigarette smoking
and FEVl level has been examined in greater detail. Burrows et al.
(1977a) used linear multiple regression analysis to examine the
relationship between cigarette smoking and ventilatory function in a
population sample in Tucson, Arizona. Pack-years, a cumulative-
dose measure, was the strongest predictor of FEVi level among the

103


smoking variables considered. In currently smoking men and
women, the FEVi declined by approximately 0.25 percent of the
predict.ed value for each pack-year of cigarette smoking; the effect
was of a similar magnitude in ex-smokers. Using data from three
separate U.S. communities, Beck and colleagues (1981) assessed the
importance of six separate smoking variables: amount smoked daily,
use of filters, inhalation, age started, age stopped for ex-smokers, and
cumulative pack-years. For the FEVi, the strongest predictors in
male current smokers were the duration of smoking and the amount
smoked; in female current smokers, only pack-year was statistically
significant. The number of years of cessation was associated with
FEVl in male but not in female ex-smokers.

However, in both the multiple regression analysis reported by
Beck et al. (1981) and that reported by Burrows et al. (1977a), the
measured cigarette smoke variables accounted for only about 15
percent of the variation of age- and height-adjusted FEVi levels.
Unmeasured aspects of cigarette smoking, other environmental
exposures, and the characteristics of the smokers must contribute to
the unexplained variation. A role for the type of cigarette smoked
has not yet been established (USDHHS 19811, and the impact of
differences in depth or pattern of inhalation and other aspects of the
pattern of smoking remains to be investigated; they are discussed in
more detail in the chapter on low tar and low nicotine cigarettes.
Further studies of these aspects of cigarette smoking are needed to
monitor the consequences of changing cigarettes.

Factors Other Than Cigarette Smoking

A number of risk factors other than cigarette smoking have been
postulated as contributing to the development of airflow obstruction
(Table 7). Of these, a definite role for a,-antitrypsin deficiency has
been established, but only the small number of persons with
homozygous deficiency incur markedly increased risk (Morse 1978).
The current hypotheses on susceptibility to cigarette smoke postu-
late roles for childhood respiratory illnesses (USDHEW 1979;
Burrows and Taussig 1980; Samet et al. 19831, for endogenously
determined hypersensitivity of the lung, and for other genetic and
familial factors (Speizer and Tager 1979; USDHHS 1980aJ At
present, these hypotheses remain largely untested. The data are
similarly incomplete at present for the other factors listed as
putative risk factors in Table 7. The status of each is briefly reviewed
below.

ABH Secretor Status

Secretion of ABH antigens is a genetically determined trait that
follows an autosomal dominant inheritance pattern; approximately

104


70 to 80 percent of the population excrete antigen into the body
fluids (Cohen et al. 1980a). In a genetic-epidemiology study in
Baltimore, Maryland (Cohen et al. 1980a), ABH nonsecretors had
lower levels of FEVJFVC ratio and a higher proportion with
FEVJFVC ratio below 69 percent. Studies in France (Kauffmann et
al. 1982a, 1983) and in England (Haines et al. 1982) have confirmed
reduced expiratory flow rates in ABH nonsecretors. In contrast,
ABH secretor status did not predict the development of obstructive
airways disease in the Tecumseh, Michigan, population (Higgins et
al. 1982).

Air Pollution

Although exposure to air pollution at high levels may exacerbate
the clinical condition of persons with chronic lung disease, a causal
role for air pollution in the development of airflow obstruction has
not been established (Tager and Speizer 1979; USDHHS 1980b).
However, smoking is the major predictor for chronic airflow
obstruction in areas of high as well as low atmospheric air pollution.

Airways Hyperreactivity

Orie and colleagues in the Netherlands (Orie et al. 1960) speculat-
ed that bronchial hyperreactivity and allergy may predispose to
asthma and chronic bronchitis. Findings from two small longitudinal
studies have suggested that airways reactivity may influence indi-
vidual susceptibility to cigarette smoke. Barter and colleagues
followed 56 patients with mild chronic bronchitis during a 5-year
period (Barter et al. 1974; Barter and Campbell 1976). The rate of
decline of FEVl increased with the degree of airways reactivity, as
measured by reversibility with isoproterenol or responsiveness to
methacholine. Britt et al. (1980) measured change of FEVl in 20
young adult male relatives of patients with chronic obstructive
pulmonary disease. The decline of FEVl was approximately five
times larger in the nine subjects with a positive methacholine
challenge test. In patients with clinically diagnosed airflow obstruc-
tion, airways reactivity is also associated with more rapid decline of
lung function (Kanner et al. 1979). Because airway reactivity would
affect the FEV, directly as well as possibly influence the susceptibili-
ty to smoke, it is difficult to ascertain from these data whether the
relationship between airway reactivity and COLD is direct or
spurious.

Alcohol Consumption

The epidemiological data on alcohol consumption are conflicting.
A study of former alcoholics demonstrated an excess prevalence of
lung function abnormalities, including airflow obstruction (Emergil

105

480-144 0 - 85 - 5


and Sobol 1977). In the Tucson population, alcohol consumption was
a significant predictor of ventilatory function after the effect of
smoking was controlled (Lebowitz 1981). The findings of an investiga-
tion in Yugoslavia were similar (Saric et al. 1977). However, two
large U.S. investigations did not demonstrate adverse effects of
alcohol intake (Cohen et al. 1980b; Sparrow et al. 1983a).

Cross-sectional data from the Tucson population suggest increased
susceptibility to cigarette smoke in atopic people (Burrows et al.
1976). In subjects aged 15 to 54, the prevalence of an FEVAWC ratio
below 90 percent of predicted value increased with skin test
reactivity among both smokers and nonsmokers. Subsequent reports
from this same study have not confirmed an overall relationship
between FEVl level and atopy, but indicate that atopy may predis-
pose to airfIow obstruction in a subset of the population (Burrows et
al. 1977a, 1983). Burrows and coworkers (1981) also reported an
increased level of IgE in smokers independent of their allergy skin
test reactions, and the interrelationship of these factors is currently
being examined.

Childhood Respiratory Illness

In a longitudinal investigation of 792 English working men,
Fletcher and coworkers (Fletcher et al. 1976) found a cross-sectional
association between childhood illness history and FEVl level. The
decline of FEVl level during the study's longitudinal phase was not
correlated with childhood illness variables. In contrast, a.nalyses of
cross-sectional data from a population sample in Tucson suggested
that childhood respiratory illnesses may increase susceptibility to
cigarette smoke (Burrows et al. 1977b). In this population, people
with a history of respiratory trouble before age 16 demonstrated
excessive decline of ventilatory function with increasing age and
with increasing cigarette consumption.

Familial Factors

Familial aggregation of lung function level, adjusted for age,
height, and sex, has been demonstrated in populations in the United
States and elsewhere (Higgins and Keller 1975; Tager et al. 1976;
Schilling et al. 1977; Mueller et al. 1980). However, a recent report
suggests that the familial aggregation of lung function may be a
reflection of the familial aggregation of body habitus (Lebowitz et al.
1984). Relatively modest correlations of FEVI level have been
demonstrated between siblings and between parent-child pairs. The
role of familial factors is further supported by investigations
demonstrating increased prevalence of airflow obstruction in rela-

106


tives of diseased subjects (Kueppers et al. 1977; Tager et al. 1978;
Cohen 1980). This familial factor cannot be explained by familial
resemblance of a,-antitrypsin phenotype or of ABH secretor status
(Kueppers et al. 1977; Cohen 1980). In the Tecumseh population,
however, family history of airflow obstruction did not predict the
incidence of this disease. The results of twin studies are also
consistent with genetic influences on FEVl level and suggest that
genetic factors may influence susceptibility to cigarette smoke
(Webster et al. 1979; Hankins et al. 1982; Hubert et al. 1982).

Occupation

Several population-based investigations suggest that occupational
exposures other than those recognized as causing lung injury may
have some effect on lung function level. In Tecumseh, mean age and
height-adjusted FEVl scores in men were highest in farmers and
lowest in laborers; the differences were not explained by smoking
and were present in nonsmokers (Higgins et al. 1977). Similarly, in
Tucson, men reporting employment in certain high risk industries or
exposure to specific harmful agents had a higher prevalence of
abnormal lung function (Lebowitz 1977a). In a Norwegian case-
control study, men employed in workplaces characterized as polluted
were at increased risk for clinically diagnosed emphysema (Kjuus et
al. 1981). Longitudinal studies of industrial populations also show
that occupational exposures may increase the rate of decline of
FEVl (Jedrychowski 1979; Kauffmann et al. 1982b; Diem et al. 1982).
For example, Kauffmann et al. (1982b) found that FEVl change
during a 12-year period varied with job exposures in an employed
industrial population. Effects of dust, gas, and heat were present, as
was evidence for a dose-response relationship between increasing
exposure and a greater rate of decline. In these studies, however,
smoking effects were generally much greater than the occupational
effects.

Passive Exposure to Tobacco Smoke
Passive exposure is discussed in detail elsewhere in this Report.

Respiratory Illnesses

In an 8-year followup study of London men, chest infections were
not associated with a rate of FEVl decline (Fletcher et al. 1976). The
findings of several smaller longitudinal studies were similarly
negative with regard to respiratory infection (Howard 1970; John-
ston et al. 1976). It is now apparent that mucus hypersecretion and
airflow obstruction are separate pathophysiological entities that
have a common cause-cigarette smoking (Fletcher et al. 1976; Peto
et al. 1983).

107


Socioeconomic Status

Weak effects of socioeconomic status on lung function level have
been demonstrated in community samples in Tecumseh (Higgins et
al. 1977) and in Tucson (Lebowitz 197713). In both populations, lung
function appeared to be influenced independently by socioeconomic
status indicators, even after controlling for cigarette smoking. In the
Tecumseh study, FEVI increased slightly with increasing income and
education level (Higgins et al. 1977); in the Tucson study, the
proportion of people with an abnormal FEVl varied in a similar
pattern with these indices (Lebowitz 1977al. Effects of socioeconomic
status were present in nonsmokers in both investigations. Stebbings
(19711, in a sample of nonsmokers in Hager&own, Maryland, also
demonstrated an association between lung function level and
socioeconomic status.

In summary, there is evidence that a number of factors other than
cigarette smoke may influence lung function, but the influence of
these factors is small relative to the effect of smoking, and the major
question is whether they can influence susceptibility to cigarette-
induced lung injury rather than whether they, of themselves, result
in lung disease in nonsmokers.

Development of Airflow Obstruction

At this time, the natural history of airflow obstruction has been
only partially described; a population has not yet been followed from
childhood to the development of airflow obstruction during adult-
hood. However, the available data from separate investigations cover
the entire course of the disease and support the conceptual model
proposed in Figure 15.
With aging, measures of function begin to deteriorate after age 25
to 30. In nonsmokers without respiratory disease, cross-sectional
data generally show that the FEVl declines by 20 to 30 ml per year
(Dickman et al. 1969; Morris et al. 1971; Cotes 1979; Crapo et al.
1981). Longitudinal data have been confirmatory (Tables 11 and 12).
For example, Tockman (19791 measured the FEVi loss during an 8
year period in 399 male nonsmokers. In most, the FEVl declined at
25 ml annually; a few, with an initial FEVl lower than 2.5 1, lost 34
ml annually.

Sufficient excessive loss leads to the development of airflow
obstruction. However, many questions remain unanswered concern-
ing this process of functional deterioriation. It is unclear whether
the loss always occurs uniformly or if it develops in stages with
intermittent and relatively steep declines (Bates 1979; Burrows
1981). The concept that the decline is nearly always gradual receives
strong support from the findings of the &year longitudinal study
conducted by Fletcher and coworkers (1976). In this investigation of

108


TABLE IL-Association between cigarette smoking and longitudinal change in lung function in
      selected population samples

Author, years of study,                      Number and type
location, reference                         of population

Findings

Higgins and Oldham, 1954-1959
Rhondda Fach. Wales (196.9~

253 male miners, ex-
miners, and nonmining
controls

Annual decline of indirect maximal breathing capacity (liters/min)
                      Miners, ex-miners
               controls    without pneumoconiosis
Nonsmokers            1.6            0.8
Es-smokers            0.7            1.8
Current smokers
  1-14 g/day          1.3            1.7
  115g/day          1.6            2.2

Ashley et al.. 195S1968,
Framingham. U.S. 11975)

399 men and 636 women.
aged 37 to 69 in 1958

lo-year change in FEV,IFVC ratio
(agestandardized to overall distribution for each sex)
                       Men
Nonsmokers                  0.21
Gmtmued smokers              -1.3
stopped. 1953-1963              0.51

Women
-3.6
-4.1
-4.6

Higgins et al.. 1957-1966.                    594 men, aged 25-34



Annual decline of FEVw, (ml/year) bv age and smoking in 1957

&ely.                                                                           --
   England (1968b)                         or 55-64 in 1957                     2534 ;rs     5Gl yrs
                                                         Nonsmokers             21             32
                                                         Exsmokem              29            44
                                                         Current smokers
                                                   1-14glday           37             54
                                                       2 15gida.v           38             37


E   TABLE 1 l.-Continued

Author, years of study.                     Number and type
location, reference                        of population

Huhtl and Ikkala. 196-1971.
Harjavalta. Finland (1980)






Wilhelmsen et al.. 1963-1967.
Goteborg. Sweden (1969)

492 men and 671 women,
aged 40 to 64 in 1961






313 men, aged 50
in 1963

Annual decline of FEV, (ml/year)

Nonsmokers
Ex-smokers
Continued smokers
Stopped. 196-1971
Annual decline of FEV, (ml/year)
Nonsmokers
Ex-smokers
Current smokers
I-llg/day
2 15glday
StQDDd. 1963-1967

Men
33
45
44
51



43
33


70
70
40

Women
27
27
39
35


   _ -- _ -. .,"II***.u~u

Author. years of study.                     Number and type
locatlon. reference                        of population                        Findings


Oxho] et al.. 1963-1973,                    269 men. aged <Xl           Annual dechne of FEV, imllyear)
Coteborg. Sweden (same popu-                     in 1963
latlon as Wllhelmsen et al.                                           Nonsmokers                      40
19691 I19761                                                    L-smokers                      37
                                                         Current smokers                   58
                                               stopped, 1963-1973                 49


Van der Lende et al,                         894 men and women.         Mean annual decline of FEV,
Vlaardmgen. 1967-19'78, and                 aged 25 and older                          IJnadJusted      Adjusted
Vlagtwedde. 1967 -1976.                                              Nonsmokers               13.3            16.6
Netherlands I19811                                                  Ex-smokers               15.8           13.4
                                                 Plpe/agar               24 4            22.6
                                                        ~ 4 g'clg                36            8.7
                                                   5-14 g/c1g               22 2           20.9
                                                   15-24 g/cig               31.4           282
                                                    125 g/c1g               35 n           34.0


Krzyzanowski. 196&1973.                    2,572 men and women,        Annual d&me of FEV, ImliyearI
Cracow. Poland I 19X0)                     aged 19 to 70                                     Men         Women
                                                            Nonsmokers                56           44
                                                         Contmued smokers            73           53


E  TABLE 12.-Association between cigarette smoking and longitudinal change in lung function in
        selected occupational or other groups

Author. years of study,                     Number and type
location, reference                          of population

Findings

Cornstock et al, 1962-1963 to
1967 or 1969. various locatlons
U.S. llY70)




Howard, 1956 to 1967.
Sheffield. England I lY701




LJeMeyere and Vuylsteek. 1967
to 1970, Ghent, Belgium 11971)

670 male telephone
company employees,
aged4oto65



159 male employees of
an engineermg works






627 male railroad
workshop employees

Decline in FEV, ilitersl between surveys


       Nonsmokers
      Ex-smokers
       All smokers

Annual declme m FEVW lmliyearl

     Nonsmokers
      Ex-smokers
     Current smokers

Annual decline m FEV, (ml/year)

     Nonsmokers
     Ex-smokers
     Current smokers
      1-14 g/day
      2 15 g/day
     stowed. 196-1971

0.28
0.17
0.41




0.036
0.025
0.031




   92
   96


   96
   88
   84


TABLE 12.-Continued

Author, years of study,                     Number and type
location, reference                          of population

Findings

Fletcher et al., 1961 to
1969. London, England
t197b-I









Kauffmann et al.. 1960 to
1972, Paris. France (19791







Jedrychowski, 1966 to 1973,
Cracow. Poland 11979)





Poukkula et al.. 1967 to
1977. Oulu. Finland

792 male transport
maintenance or bank
workers, aged 30 to
59 at entry







575 male factory
workers. aged 30 to
54in 1960






166 male employees of
a fertilizer factory




659 male pulp mill
employees, aged 18 to
64 in 1967

Annual decline of FEV, (ml/year)

      Nonsmokers                 36
      Ex-smokers                 31
     Continued smokers
       ' 5 rigs/day              44
       5-15 ctgs/day             46
       1525 cigsiday             54
       > 25 ctgslday             54
Annual decline of FEV, iml/year). adjusted for initial level

      Nonsmokers                 40
      Ex-smokers                 44
      Current smokers
        c 15 g/day               46
        ? 15 g/day               51
5-year decline of FEV, as percent of mean, by 1973 smoking

       Nonsmokers                 3
      Ex-smokers                  5
      Current smokers               7

Annual decline of FEV, (ml/year)

I.9821

-

Nonsmokers
Ex-smokers
Continued smokers
stopped, 1967-1977

37
39
49
48


E   TABLE 12.-Continued


   Author. years of study,                     Number and type
    locatton. reference                         of population                          Findings

Woolf and Zamel. years not
gtven. Toronto. Canada r IY8O)xoI









BOW et al, lYfxLlY68 to
1YtwlY74. Boston. II s
( I.WII

302 female volunteers,
aged 25 to 54 at entry









H50 male volunteers

5.year change m FEV, as percent of initial value


      Nonsmokers                   15
      Rx-smokers                   0 8
     Smokers
       <. 70 clgslweek               0.4
      71-140 ctywveek         `):    3.t,,
       140 cigs! week          48

Annual declme of FEV, imllyearr.
adjusted for age and mtttal level
      Nonsmokers               0.053
      Ex-smokers                0.057
      Current smokers            0085

Love and Mtllcr. 1957 to 1973                      1.677 male coalmmers

II-year declme tn FEV, Ilttersl

Iaverage followup. 1 I
years). UnIted Ktngdom ~l.Y&?b

Nonsmokers                0.41
b-smokers                0.48
IntermIttent smokers           0.52
Current smokers             0.53


792 employed men, the individual patterns of temporal change of the
FEVl were strongly variable, but the loss generally occurred
gradually. Fletcher et al. further demonstrated that FEVl levei
correlated with FEVl slope, a finding that they termed the "horse-
racing effect." Correlation between slope and level would be antici-
pated, if functional loss occurs gradually. This correlation has
important implications for intervention; those losing FEVl more
rapidly should become identifiable early as they develop a reduced
FEVl level. Other studies, however, do not agree with either the
pattern of FEVl decline or the "horse-racing" effect. Rapid declines
to levels compatible with clinical disease or followed by a prolonged
plateau have been described (Howard and Astin 1969; Howard 1970;
Johnston et al. 1976). In a followup study of Canadian men with
chronic bronchitis, steep declines of FEVl without subsequent
improvement were frequently observed (Bates 1973). Additionally,
correlation of FEVl level and slope has been. found in most other
longitudinal investigations (Howard 1970; Petty et al. 1976; Huhti
and Ikkala 1980; Bosse et al. 1981; Clement and van de Woestijne
1982; Kauffmann et al. 1982b), but not in all (Barter et al. 1974;
Krzyzanowski 1980).

Another unanswered question concerning functional deterioration
is whether gradual decline occurs in a linear or a nonlinear fashion
(Fletcher et al. 1976). Sufficient numbers of people have not yet been
followed to distinguish alternative patterns, although the available
data indicate acceleration of the decline with aging (Emergil et al.
1971; Fletcher et al. 1976).

In spite of these uncertainties concerning the development of
airflow obstruction, the available data indict cigarette smoking as
the primary risk factor for excessive loss of FEVl (Tables 11 and 12).
The findings in both general population samples (Table 11) and
occupational and volunteer cohorts (Table 12) have been similar.
Recent reports from Belgium (Bande et al. 1980; Clement and van de
Woestijne 1982) and from Connecticut (Beck et al. 19821, not readily
summarized in tabular form, also described a strong effect of
smoking on FEVl decline. A few studies have not shown increased
loss in cigarette smokers (Howard 1970; De Meyere and Vuylsteek
1971). Even in people with clinically diagnosed airflow obstruction,
continued smoking maintains the excess decline of FEVl (Hughes et
al. 19821, although not all findings are consistent (Ogilvie et al. 1973;
Johnston et al. 1976).

Dose-response relationships have been found in many investiga-
tions between the amount smoked during followup and the FEVl
decline (Tables 11 and 12). The reported increases from the lowest to
the highest smoking categories range up to 10 to 15 ml annually.
Although this additional loss in heavier smokers appears small, if
sustained for long periods of time it would shorten the time interval

115


Never smoked

or not suscepbbk?

Its effects

- Stopped at 45

Death

25                    50                       75

Age (years)

FIGURE X-Risks for men with varying susceptibility to
      cigarette smoke and consequences of smoking
         cessation
NOTE: + = death.

SOURCE: Fletcher and Pet0 (1977).

to the development of functional impairment. So far, favorable
effects of filter tip smoking and declining tar content on the rate of
decline have not been shown (Fletcher et al. 1976; Sparrow et al.
1983b).
Generally, sustained smokers experience a greater loss than those
who stop during followup. In the study by Fletcher et al. (1976) of
London men, subjects who stopped smoking at the beginning of the
followup period lost FEVI at the same rate as never smokers. The
results of two U.S. studies of ex-smokers are similar (Bosse et al.
1981; Beck et al. 1982). This reduced loss in ex-smokers emphasizes
the importance of active smoking and the immediate benefits of
smoking cessation (Figure 24). Smokers with reduced FEVI may be
protected from developing clinically significant loss by timely
smoking cessation (Fletcher and Peto 1977).

The distribution of FEVI decline has been characterized and
described for some populations, including patient groups (Burrows
and Earle 1969; Howard 1974; Barter et al. 19741, population samples
(Milne 19781, and occupational cohorts (Howard 1970; Fletcher et al.
1976). Similar data are also available for the mid-maximum expira-
tory flow, another measure of ventilatory function (Bates 1973;
Woolf and Zamel 1980). In each of these investigations, the distribu-
tion of FEVI decline is unimodal (Figure 25); that is, a distinct
population with more rapid decline is not sharply separated from
those with lesser rates. The modes and medians of the distributions

116


60



70

Mean

   60       Nonsmokers and
Q           a-smokers
ii   50
e
6
i   40



   30
1
   20

10

      0
           -160 -140 -120  -100  -60   -60   40   -20    0   +20

FIGURE 25.-Distribution of &year FEVl slope in 792
        London men
SOURCE: Fletcher et al. (1976).

are generally negative, but some subjects have had positive slopes
during the relatively brief followup period of investigations conduct-
ed up to this time.

The distributions tend to be skewed by subjects losing FEVl more
rapidly. The proportion of cigarette smokers is increased among
those in the tail of excess loss (Figure 25). For example, Clement and
van de Woestijne (1982) examined subjects with excess FEVl decline
in a prospective study of 2,406 members of the Belgian Air Force.
Losses beyond those expected from nonsmokers affected 6 percent of
nonsmokers, 7.5 percent of light smokers (< 20 cigarettes/day), and
12 percent of heavy smokers ( > 20 cigarettes/day).

The shape of the distribution of FEVl decline has important
implications for the development of airflow obstruction. Smokers are
not sharply separated from nonsmokers (Figure 251, but more often
lose FEVl at a rapid rate. Because of this spectrum of severity, not all
smokers develop significant airflow obstruction. Although the fac-
tors that lead to excessive loss in individual smokers remain
uncertain, they may include differences in the pattern of smoking. It
is apparent, however, that this susceptible minority can be protected
by smoking cessation.

117


summary

During the 20 years that have elapsed since the 1964 Surgeon
General's Report, the relationship between cigarette smoking and
airflow obstruction has been intensively investigated. Surveys of
community samples and other groups have established that airflow
obstruction is a common condition in the United States and
elsewhere. In some populations, as high as 10 percent of adults are
affected.

Determinants of lung function level and of the prevalence of
airflow obstruction have now been examined in many populations
throughout the world. Cigarette smoking is the strongest predictor of
abnormal measures of ventilatory function. A causal relationship
between cigarette smoking and airflow obstruction is supported by
the consistency of the many published reports, the strength of the
association, and the evidence for dose-response.

Many risk factors for airflow obstruction other than cigarette
smoking have been postulated, including other harmful environmen-
tal exposures and the inherent susceptibility of the smoker. Homozy-
gous a,-antitrypsin deficiency can explain only a minute proportion
of the disease burden. The development of airflo-w obstruction by
only a minority of smokers indicates that the interaction of smoking
with other factors may influence the risk for specific smokers.
Current research emphasizes the potential roles of childhood respira-
tory illness and airways hyperresponsiveness.

Longitudinal studies have now partially described the prolonged
natural history of airflow obstruction. Excessive loss of ventilatory
function, beyond that expected from aging alone, results in the
development of disease in cigarette smokers. Only a susceptible
minority of cigarette smokers lose function at a rate that will
eventually cause clinically significant impairment. For this group,
timely smoking cessation can prevent the development of disease.

118


EMPHYSEMA

JA-oduction

Pulmonary emphysema is frequently present in the lungs of
individuals with chronic obstructive lung disease. This section has
three purposes: (1) to review the definition, types, and quantification
of emphysema; (2) to summarize the physiological and radiographic
feature of emphysema; and (3) to discuss critically the relationship of
smoking to emphysema, based upon observations in people and in
experimental animals. Current concepts of the pathogenesis of
emphysema are reviewed elsewhere.

Definition of Emphysema

The generally accepted definition of emphysema is an anatomic
condition of the lung characterized by abnormal dilation of air
spaces distal to the terminal bronchioles accompanied by destruction
of air space walls (American Thoracic Society 1962; Heard et al.
1979). Difficulties with this definition have been discussed by
Thurlbeck (1983). Normal air space dimensions have not been
determined, and criteria of destruction have not been defined. These
limitations hamper attempts to investigate the earliest lesions of
emphysema and the subtle effects of environmental agents on lung
structure.

Types of Emphysema

British pathologists pointed out in the forties and fifties that
emphysematous lesions in certain people involved the respiratory
bronchioles, which appeared as grossly enlarged airspaces in the
center of the primary lung lobules surrounded by normal lung. In
other individuals, the alveolar ducts were involved early, and even
mild involvement appeared grossly as a coarsening of the architec-
ture of the entire lobule. They designated the two polar patterns of
emphysema as centrilobular emphysema (CLE) and panlobular
emphysema (PLE) (Heppleston and Leopold 1961). Many lungs either
show both types of emphysema or are unclassifiable. Of 122 lungs
with emphysema examined by one pulmonary pathologist, 73 were
-considered mixed or unclassifiable and 49 were clearly CLE or PLE
(Mitchell et al. 1970). When the agreement of three pathologists was
required, only 27 of the original 122 lungs remained classifiable and
95 were mixed or could not be classified. There were no statistically
significant differences between the groups classified as PLE or CLE
in any clinical variables. The only nonsmokers in either group had
CLE, and the proportion of light smokers (less than 25 pack-years)
was very similar between groups. In this study and others (Anderson
and Foraker 19731, CLE was most severe in the upper lobes and PLE
was uniformly distributed. According to Thurlbeck (19761, a common

119


combination is CLE in the upper lobes and PLE in the lower lobes;
where lobectomies are used for correlation, typing of emphysema is
therefore a particularly empty exercise. When emphysema is far
advanced, it is often impossible to recognize the site of the initial
involvement. Thus, it is not clear whether the differences in
prevalence of CLE and PLE are real or represent differences in
interpretation by different observers.

Several localized types of emphysema occur in areas around scar
tissue (paracicatricial), along interlobar and interlobular septa
(paraseptal), and as bullous lesions (which represent the most
advanced and extreme distortion of normal lung structure). Bullous
deformities occur with any type of emphysema, including CLE and
PLE. Occasionally, bullous lesions occupy huge intrapulmonary
volumes.

Detection of Emphysema

The detection of emphysema requires suitably prepared lung
specimens. At a minimum, this means the lung must be fued in
inflation (Thurlbeck 1964). Fume fixation or fixation by instillation
of liquid fixative through the airways is satisfactory, but for optimal
evaluation of the latter group, barium impregnation or paper-
mounted whole-lung sections should be used. Because lungs with
emphysema frequently also have some degree of intrinsic airways
disease, the severity of emphysema and the clinical state of the
patient may not correlate directly. Pathologists can easily recognize
mild degrees of emphysema that are rarely associated with clinical
disability.

Quantification of Emphysema

There are a number of techniques for quantifying the volume of
lung involved with "obvious" emphysema that are adequately
reproducible and correlate well with one another (Thurlbeck 1976;
Bignon 1976). Semiquantitative or subjective scoring methods as
well as point counting have been used. These approaches all require
lungs inflated to a relevant volume, usually one approximating total
lung capacity during life. This can be achieved by a distending
pressure of 25 cm H& (Thurlbeck 1979; Berend et al. 1980).

In the scoring method, the lung is divided into a number of units
and the severity of emphysema in each unit is scored (mild,
moderate, or severe receive 1,2, or 3 points, respectively). The scores
for each unit are summed to give a total score for the lung (Ryder et
al. 1969). Alternatively, lung slices may be matched by visual
comparison to a set of graded standards to achieve an emphysema
score (Thurlbeck et al. 1970). These methods include both severity
and extent of emphysema, and although they involve subjective
judgments, they have proved to be remarkably reproducible.

120


In the point counting approach, regularly spaced points are
superimposed on a lung slice. Each point is recorded as falling on
normal parenchyma, emphysematous parenchyma, or nonparenchy-
ma (conducting airways or vessels). The volume proportion of
emphysematous lung is recorded. This method can be objective (e.g.,
if an emphysematous space is taken to be one greater than 1 mm in
diameter), but it includes only extent and not severity of emphyse-
ma.

Morphometric methods carried out on histologic sections, exempli-
fied by the mean linear intercept (Lm) (Thurlbeck 1967a, b), are
strictly objective, but they require careful attention to problems of
sampling and are time consuming and insensitive to focal disease.
For measurements of the Lm, histologic sections are made of blocks
selected by stratified random sampling. The average distance
between alveolar walls is determined from the number of intersec-
tions of alveolar walls with a line of known length. The internal
surface area of the lung can be calculated when the volume of the
lung is known (Hasleton 1972).

Pulmonary Function in Emphysema

Because unequivocal proof of the presence of emphysema requires
direct examination of lung tissue, the strategies used to characterize
the pulmonary function abnormalities associated with emphysema
have either involved comparison of functional data collected during
life with autopsy or surgical material or have used measurements
made exclusively on post-mortem specimens. Two important conclu-
sions from these studies should be noted at the outset. First,
impaired air flow during maximal expiratory maneuvers, as reflect-
ed in reduced values for the FEV1, FEVIS, and FEF~~s, is neither
sensitive nor specific for emphysema. It is possible to have severe
emphysema without clinical obstructive lung disease (Thurlbeck
1977). It is also possible to have severe chronic obstructive lung
disease without having emphysema, even though most patients with
advanced chronic obstructive lung disease have some degree of
emphysema (Mitchell et al. 1976). Second, none of the tests used to
identify early obstructive lung disease, such as closing volume, the
single breath NZ curve, or frequency dependence of compliance,
distinguish diminished elastic recoil that may be related to emphyse-
ma (see below) from increased resistance in small airways (Buist and
Ducic 1979). Even the determination of density dependence of
maximum expiratory airflow, once felt to be specific for detecting
abnormalities in the caliber of small airways, is not immune to the
effects of lung elastic recoil. A decreased effect on maximal
expiratory air flow of using low density gas can be caused by
decreased elastic recoil (Gelb and Zamel 1981).

121


Pulmonary function testing of individuals with proven emphyse-
ma often shows increases of residual volume, functional residual
capacity, and total lung capacity and decreases of maximal expirato-
ry air flow (Boushy et al. 1971; Park et al. 1970; reviewed in
Kidokoro et al. 1977). However, because individuals with emphysema
commonly also have intrinsic airway disease (Casio et al. 1978)
affecting the results of these pulmonary function tests in the same
direction as emphysema, it is clear that these tests are not specific
for emphysema. Accordingly, there has been interest in other, more
distinctive tests. Among readily applicable tests, the diffusing
capacity has proved to be directly related to the extent of emphyse-
ma (Park et al. 1970; Boushy et al. 1971; Berend et al. 19791,
presumably reflecting a diminution of internal surface area avail-
able for gas exchange. The usefulness of the diffusing capacity to
identify and estimate emphysema is limited, however, because the
measurement is not sensitive to low grades of emphysema (Symonds
et al. 1974) or specific for emphysema. Moreover, the results must be
interpreted carefully in smokers because the values for diffusing
capacity are lower than in nonsmokers, and the difference extends
even to young smokers who are not likely to have emphysema (Enjeti
et al. 1978; Miller et al. 1983).

Mechanical Properties of the Lungs in Emphysema

Measurements of the pressure-volume characteristics of the lung
have generally been regarded as a reliable means of physiologically
detecting and quantifying emphysema because (al patients with
emphysema often have increased lung distensibility and correspond-
ingly low transpulmonary pressures (loss of elastic recoil) and (b) the
severity of emphysema has seemed to correlate with the change in
elastic recoil. It has also been assumed that the regions of lung with
emphysema are the cause of the decreased lung elastic recoil, an
assumption that appears reasonable because elastic recoil results in
part from surface forces at the air-liquid interface and there is less
surface area in emphysema.

Recent observations challenge these concepts. Berend and Thurl-
beck (19821, using lungs obtained post mortem, could not demon-
strate a relationship between indices of lung elasticity and the grade
of emphysema in 48 lungs ranging in grade from 2 to 80 (on a scale of
100), and observed (Berend et al. 1981) in emphysematous lungs that
the relative increase in compliance of the lower lobes was greater
than the upper lobes, even though the emphysema was worse in the
upper lobes. Others have also reported poor correlations between
emphysema and elastic recoil. Silvers et al. (1980) found decreased
elastic recoil and increased total lung capacity in excised human
lungs with minimal emphysema, and Schuyler et al. (19781 noted in
hamsters given small doses of elastase intravenously that there was

122


decreased lung elastic recoil at low lung volumes, although the lungs
did not show morphometric changes. Guenter et al. (1981) noted that
mild emphysema produced by pepsin caused greater changes in lung
elasticity than similar degrees of lung destruction produced by
endotoxin-induced repetitive leukocyte sequestration. They suggest-
ed that these differences may be due to differences in the location of
the connective tissue injury within the lung.

Even among those who have reported an association between
emphysema and elastic recoil, the correlations have been best when
the emphysema was severe (Greaves and Colebatch 1980). Pare et al.
(1982) found a correlation between emphysema grade and elastic
properties of the lungs in 55 persons; however, in 5 whose surgically
removed lung tissue received emphysema scores between 20 and 70
(out of a maximum of lOO), the elastic properties of the lungs tested
preoperatively were indistinguishable from normal. While such
discrepancies probably reflect the limitations of relating the overall
elastic properties of both lungs to the morphology of a single lobe, it
must also be recognized that the sensitivity of the pressure-volume
diagram is limited, since a narrow range of pressure (to 20 cm HzO)
depicts the average retractive force from millions of air spaces and
the connective tissue network of the lung.

From these recent findings it must be concluded that the
relationship between elastic recoil and morphologic measures of
emphysema is not highly predictable, and that the decrease of elastic
recoil and increase of total lung capacity commonly seen in
emphysematous lungs may not result entirely from abnormal
mechanical properties in the areas showing emphysema. The
mechanical abnormalities may also derive from areas that appear
normal, although the possible reasons for this are obscure (reviewed
by Thurlbeck 1983). An alternate explanation for this discordance
between elastic recoil and morphologic emphysema may be the
problems of sampling and grading intrinsic to these morphologic
measures.

The work of Michaels et al. (1979) introduces a further complexity
to the use of pressur*volume curves as an indicator of emphysema.
They found that inhalation of a bronchodilator shifted the curve of
smokers in the direction of increased compliance, but had no effect
in nonsmokers (Figure 26). Cessation of smoking had the same effect
as a bronchodilator. These results were interpreted as indicating
that smoking causes some peripheral airway units to constrict and
become effectively closed. Thus, pressure-volume studies to detect
early changes compatible with emphysema in smokers may give
false negative results unless accompanied by studies with bronchodi-
lators.

123


90







60







70







60







50









0

/
I

- .smoken p 6.0.

[3--o Ncrwnckers
M Nonsmokers p B.D

I         I        I        1

4        6        12        16


       P(stat)cmH&

FIGURE 26.-The effect of nebulized bronchodilator on the
      pressure-volume characteristics of the lungs
       in 19 smokers (6 men and 13 women) and 16
       nonsmokers (9 men and 7 women)

NOTE: The mean age was approximately 40 years (range. 19 to 66) and smokers wed approximately 30
cigarettes per day. Male amoken, showed borderline significant differences in indicea of expiretory airflow and
single breath Nz test data as mmpsred with the male nonsmokers. but there was no diRerace in these testa
between female smokers and nonsmokers. As shown. smokers had significantly laes elastic recoil than nonsmokers.
After the bronchcdiletor, the difference between smokers and nonsmokers increased further. particularly at high
lung volume.
B.D. = broncodilator; % pred. TLC = percent predicted total lung capacity: Rstat) = transpulmonary preeeure.
*p<o.w `.p<O.Ol; "`p<o.o06.
SOURCE: Micbaels et al. (1979).

Aging and Lung Structure

With advancing age, structural and functional changes occur in
the lungs of virtually all adults, even those who have no known
exposure to specific inhalants through occupation or personal habits
(Fishman 1982; Campbell and Lefrak 1983). The elastic recoil of the
lungs declines with aging, and the residual volume to total lung
capacity ratio increases. These changes are seen even in people who
have never smoked, do not have signs or symptoms of cardiorespira-
tory disease, and have the normal (MM) phenotype of a,-antiprotein-

124


ase (Knudson et al. 1977). Also with aging, the average distance
between alveolar walls increases (Thurlbeck 1967a; Hasleton 19721,
the proportion of lung volume that is composed of alveoli decreases,
and the proportion of alveolar ducts increases (Ryan et al. 1965).

Whether the differences in the lungs that occur with aging are a
consequence only of the passage of time or are the result of subtle
environmental insults summed over many years is unanswerable.
They are "normal" or "abnormal" depending on whether one
regards "normal" as .a statistical concept or as the optimal state for
the tissue. In either case, the aging lung has some features similar to
emphysema. Age changes alone will not, however, contribute to or
obscure the diagnosis of centrilobular emphysema, which involves
mainly respiratory bronchioles, recognized macroscopically as focal
lesions against a background of normal lung. The age changes.may
overlap with early panlobular emphysema (Anderson et al. 1970).
However, since smokers usually die at an earlier age than nonsmok-
ers, aging cannot account for the differences observed between the
lungs of smokers and nonsmokers at autopsy.

Emphysema and Cigarette Smoking

Studies of people and of experimental animals conclusively link
cigarette smoking to the development and extent of emphysema.
This information is summarized in the following discussion.

Observations in People

Post-mortem material, used to approach the problem in the 1960s
and 19708, clearly established an association between smoking and
emphysema. Post-mortem lung tissue has continued to be used to
study emphysema, but the main goal of recent studies has been to
identify those physiologic features that correlate with emphysema
rather than to quantify the relationship between smoking and
emphysema. Studies of emphysema using surgically removed lung
tissue, a more recent approach to studying emphysema, have aimed
mainly at elucidating the physiology of the emphysematous lung.
The results of these studies have involved smokers almost exclusive-
ly because of the rarity of emphysema in nonsmokers.

Studies Using Post-Mortem Material

A number of studies have examined the relationship between
cigarette smoking and emphysema (Anderson et al. 1964, 1966;
Thurlbeck 1963; Thurlbeck et al. 1974; Ryder et al. 1971; Auerbach
et al. 1972, 1974; Spain et al. 1973). These data emphasize that not
only is cigarette smoking closely associated with the development
and extent of emphysema, but also it is extremely rare for the forms


of emphysema found in patients with COLD to be present to a
significant degree in nonsmokers.

Thurlbeck (1963) reported 19 patients who had severe emphysema
at autopsy. All 19 were cigarette smokers, in contrast to 18 smokers
out of 38 patients who did not have significant emphysema at
autopsy. Anderson et al. (1964) conducted a more systematic
evaluation of the relationship between cigarette smoking and the
degree of emphysema at autopsy. They found that 12 of 23 patients
without emphysema were cigarette smokers, whereas 55 of 84 with
mild emphysema, 30 of 33 with moderate emphysema, and 14 of 15
with severe emphysema were cigarette smokers. Petty et al. (1967)
reported similar findings, with 6 of 57 patients with moderate
emphysema at autopsy being nonsmokers and only 1 of 61 patients
with severe emphysema being a nonsmoker. Ryder et al. (1971) found
that of 21 patients whose lungs showed more than 25 percent
emphysema, only 1 was a nonsmoker.

Thurlbeck et al. (1974) examined the relationship of age to extent
of emphysema in smokers compared with nonsmokers in the
combined autopsy populations of the teaching hospitals in three
separate cities. The severity of emphysema was quantified using a
panel grading method, with a score under 25 representing mild
emphysema. They found that the degree of emphysema increased
slightly in nonsmokers beginning in the fifth decade and reached an
average score of 10 to 15 in men and 4 to 6 in women by the eighth
and ninth decades. In contrast, male smokers had an average score
of 25 to 30 by the seventh decade and maintained this level for the
next two decades.

Sutinen et al. (1978) (Table 13) examined the relationship between
prevalence and extent of emphysema and duration of the smoking
habit. As would be expected from previous studies, moderate or
severe emphysematous changes were limited to smokers. However,
these changes were also limited to those smokers who had smoked
for 20 or more years, and severe emphysema was reported only in
those who had smoked for 40 years or more. These data, coupled with
that of Thurlbeck et al. (1974) describing only mild emphysematous
changes in nonsmokers with advancing age, suggest that emphyse-
ma is a late pathologic change in cigarette-induced lung disease. This
correlates well with the clinical experience of severe emphysema
being rare prior to the fifth decade. It also suggests that cessation,
even among middle-aged smokers, may have substantial impact on
emphysema morbidity and mortality.

Dose-Response Relationships

Some studies have reported the extent of emphysematous change
in smokers of different numbers of cigarettes per day. Spain et al.
(1973) examined the lungs of 134 subjects who died suddenly and

126


TABLE lb-Correlation between the severity of emphysema
       at autopsy and total smoking duration

Prevalence of emphysema (percent1 by total smoking years

Grade of emphysema              0     1-19     2cL39     40 or more    Total

Ko emphysema
Mild
(grades 5 to 201
Moderate
(grades 30 to 50)
severe
(grade 60 or morel

61.6    81.6      21.2       0.8       43.1


38.4    15.4      69.7       50.0       45.8


             9.1       26.5        7.6


                     14.7        3.3

All grades                    36.4    15.4      788       91.8       56.9
Total number                  73     I3       33        34        I53

NOTE: P c O.C0@5; X2 test. wth groups of moderate and 8evere emphysema and of smoking times I-19 and 2%
39 years combtned
SOURCE Sutmen et al 119781

who had no previous history of lung disease. They found emphysema-
tous changes greater than grade 20 (mild emphysema) in 10 percent
of nonsmokers, 36 percent of smokers of less than one pack per day,
and 39 percent of smokers of more than one pack.

A much larger study was conducted by Auerbach et al. (1972,
19741, who examined whole lung sections from 1,443 men and 388
women autopsied between 1963 and 1970. Table 14 describes the
relationship of age, smoking habits, and degree of emphysema
graded on a scale of 0 to 9, with 9 representing severe emphysema. It
is clear that severe emphysema is limited to smokers, and that the
severity of emphysematous change at autopsy increases with in-
creasing number of cigarettes smoked per day during life. This study
also found that almost all (94.5 percent) smokers of more than one
pack per day had some degree of emphysema (slight, moderate,
advanced, or far advanced) (Table 15). In contrast, 93.8 percent of
nonsmokers had either none or minimal emphysema. This evidence
would suggest that emphysematous change is a nearly universal
phenomenon in heavy smokers, but is rare in nonsmokers, and that
it is the large ventilatory reserve of the lungs that restricts clinically
manifest disease to those individuals with far advanced emphysema.
Similar results were reported in a more limited number of autopsies
done on female smokers (Auerbach et al. 1974) (Table 16).

A study of microscopic lung sections from the autopsies of 1,436
men and 388 women was also reported by Auerbach et al. (19741, and
closely paralleled the results of the whole lung study. However, they
also reported the results in smokers who had quit for more than or
less than 10 years prior to death (Table 17). The degree of
emphysematous change was still related to the amount smoked, but

127


TABLE 14.-Degree of emphysema in current smokers= and
      in nonsmokers, according to age groups

`; 60

Cui-rent cigarette
  smoked

~ ':t   I7 1:   1 "t   2+ i

,x7         k
2         11

12
4
2
5

5.5

31

0 10
004

3s

0 83
0 13

17

2

40

:30

0 39
0 13

I%
4

4

0 95
0 16

          -
til         x2


0 YI        166
0 39        I) 11

23


1.29
0 26


4
1
4
2
1

12


190
0.X


2
10
13
5
1

31


2 15
0 17

3
9
17
12
4




-
4.5


2.37
0.16





5
9
3
1
1


19


3.59
0.35



8
23
10
7
2
1


51


2.98
WXI

2
24
130
50
P
4
3
-
Z?l

2.56   2.86
0 07    0.10

4
37
42
11
x
5
-
107


3.39
0 15




2
40
38
11
9
12
-
112


368
0 1:

62

3 37
020

-
44


3.91
0.n

SOURCE Auerbach et al ll972'

was less in those who had quit for more than 10 years prior to death,
suggesting that the cessation of smoking results in a slowing of the

128


TABLE 15.-Age-standardized percentage distribution of
      male subjects in each of four smoking
     categories, according to degree of emphysema

Degree of
emphysema

M) 75 (none)
l-1.75 (mmimaii
2-2.75 (sIghtI
33 75 Imoderate)
t9 00 (advan& to far adsanwl

`Packages da>
SOURCE. Auerbach et al (1972)

TABLE 16.-Means of the numerical values given lung
     sections at autopsy of female current smokers,
      standardized for age

SubJects who
never smoked
regularly

Current cigarette
  smoken

Number of subjects

Emphysema
Fibrosis
Thickening of arterioles
Thickening of arteries

252


0.05
0.37
0.06
001

<l Pk.     21 Pk.


33         64


1.37         1.70
2.89         3.46
1.26         1.57
040        0.64

NOTE: Numerical vatwm were determined by ratmg each lung se&ion on scale of O-4 for emphysema and
thickening of the artenoles. l&7 for fibrceu.. and (r-3 for thickenmg of th+ artenea
SOURCE: Averbach et al. C 19741

rate of progression of emphysematous change in those who quit
compared with those who continue to smoke.

Studies of Alpha,-Proteinase-Inhibitor-Deficient Individuals

The deficiency of a,-proteinase inhibitor is an experiment of
nature with broad implications for understanding the pathogenesis
of emphysema (Idell and Cohen 1983). Discovery of homozygous-
deficient subjects (type PiZZ) with only 10 percent of normal plasma

129


TABLE 17.-Means of the numerical values given lung
      sections at autopsy of male former cigarette
      smokers, standardized for age

Never smoked
regularly

stopped > 10 years

stopped <lO years

Number of
subjects

Emphysema

Fibrosis

Thickemng of
arterioles

Thickening of
arteries

175



0.09

0.40

0.10



0.02

<l Pack

   35



  0.24

  1.14

  0.57



0.04

Formerly smoked

>l Pack    <l Pack   >l Pack

   66        51      131



  0.70       1.08      1.69

  1.74       2.44      3.30

  0.93       1.25      1.59



  0.16       0.36     0.61

NOTE: Numeneal values for each finding were determined by rating each lung section on scales of S4 for
emphysema and thrckenmg of the arterioles, CL7 for librosis, and C-3 for thickenmg of the arteries.
SOURCE Auerbach et al (1974)

proteinase inhibitory activity and the demonstration of the frequent
early development of emphysema in such subjects (Ore11 and
Mazodier 1972) called attention to the critical step of fibrous tissue
proteolysis in the remodeling of lung structure. It also pointed to at
least one potential explanation for the variability in extent of
emphysema among smokers.

Together with data from animal experiments, the discovery of the
PiZZ defect and its association with emphysema has led to general
acceptance of a theory of imbalance between the extracellular levels
of proteinase and proteinase inhibitor in the lung as the cause of
panacinar emphysema in subjects with this deficiency. The patho-
genetic lessons learned from a,-proteinase-inhibitor deficiency also
afford plausible explanations for other forms of emphysema, espe-
cially emphysema associated with cigarette smoking.

Homozygous Deficien t-Pi22

In his classic description of the severe (PiZZ) deficiency of the aI-
proteinase inhibitor, Eriksson (1965) did not indicate an effect of
cigarette smoking on the development of emphysema. Later studies,
however, did recognize smoking as a potential aggravating factor
(Kueppers and Black 1974; Larsson 1978) and reported that PiZZ
persons  who smoked cigarettes were destined to experience
shortness of breath 10 to 15 years earlier (Figure 27) and to die
sooner than PiZZ persons who did not smoke (Figure 28).

130


I           Men

I    Smokers

Nonsmokers

T

women

Smokers

   .



81.
  . .
i
11.
  . . .
. . .  . .
  .
T
  .
  .
   .
  . .

Nonsmokers

   .
   .

   .

.

.
. .
i
0



o

FIGURE 27.-Age at onset of dyspnea in 169 PiZZ
      individuals separated according to sex and
       smoking history

NOTE The hormntal lines show the me&an values. The difference between nonsmokers and smokers was
highly s~gnrficant for both sexes and was 13 and 15 years for men and women. respezt~vely
SOURCE: Larsson /1978,

More recent studies, however, have shown considerable variation
in the rate of decline of lung function among middle-aged PiZZ
adults (Buist et al. 19831. In a comparison of 22 persons with PiZZ
phenotype who had never smoked with 36 PiZZ smokers, Black and
Kueppers (1978) found variability in symptoms and lung function
abnormalities in both groups. Smokers generally sought medical
attention earlier, and those who reached the older age groups, such
as 60 to 69, had smoked less and started to smoke later in life. There
was overlap in these characteristics between the age groups,
however, and some smokers did live into the 50 to 69 age range. In
this analysis, the correlations between pulmonary function test
abnormalities and pack-years of cigarette smoking were small.

The British Thoracic Society, in a multicentered study of PiZZ
individuals (Tobin et al. 19831, reported an association between

131


0 Nonsmokmg PiZ men and women

A All Swedish women
All Swedish men

20    30     40    60    60    70    60    90   100

              Age (IIT yeam)

FIGURE 28.-The cumulative probability of survival, given
      that 20 years of age is reached, in smoking
      and nonsmoking Swedish PiZZ individuals,
      compared with all Swedish men and women
NUI'E Surv~al was tugher for PlZZ nonsmokers than for PiZZ smokers in both exe8 above age 35
SOURCE. Lamson (19781

cigarette smoking and the onset of pulmonary symptoms and
deterioration of lung function, but demonstrated no significant
correlation between the quantity of tobacco consumed and the extent
of pulmonary dysfunction. A notable finding in this study, applicable
to other studies of the natural history of disease related to a1-
proteinase-inhibitor deficiency, was the impressive difference be-
tween individuals found because of medical complaints (index cases)
and those detected by surveys (nonindex cases). Nonindex cases had
better pulmonary function and survived longer than index cases,
irrespective of other variables such as age and smoking history. The
distinction between these two categories of subjects suggests the
importance of factors besides the PiZZ phenotype in the development
of symptomatic lung disease in PiZZ persons.

PiZZ individuals who smoke increase their risk for early onset of
symptomatic chronic obstructive lung disease and for a shortened
lifespan, compared with nonsmoking PiZZ individuals. However,
pulmonary function data have shown only limited differences in
diffusing capacity and elastic recoil between the smokers and the
nonsmokers (Black and Kueppers 1978).

132


He terozygous De ficien t-Pi117
The PiMZ phenotype of a,-antiproteinase inhibitor occurs in

approximately 3 percent of the population. Because of the high
frequency of emphysema in PiZZ persons, it is important to establish
whether PiMZ individuals also have an increased risk of emphysema
and chronic obstructive lung disease. From the unpredictability of
obstructive lung disease even among those with the PiZZ phenotype,
however, one might expect difficulty in discerning the effect of the
PiMZ phenotype.

Among adults with symptomatic chronic obstructive lung disease,
the PiMZ phenotype is more prevalent than expected (Mittman
1978). It is uncertain whether this means of subject identification is
appropriate, as was noted concerning index and nonindex PiZZ
individuals. Madison et al. (1981) emphasized the complexity of this
issue by noting that the PiMZ phenotype was only one of several
factors that appeared to be related to the risk of obstructive lung
disease. Other factors identified as relevant included smoking, a
family history of lung diseases, and being male.

From studies of children and young adults it is evident that the
PiMZ phenotype does not strongly predispose to chronic pulmonary
disease. Thus, PiMZ children (Buist et al. 1980) failed to show any
early changes of lung dysfunction analogous to what has been
observed in some young PiZZ individuals; PiMZ adults below the age
of 40 had the same results by spirometry and the single breath N2
test as PiMM individuals matched for smoking history (Buist et al.
1979b).

Numerous studies involving older subjects indicate that PiMZ
individuals preserve their lung function, as measured by spirometry,
compared with controls matched for smoking (Tattersall et al. 1979,
de Hamel and Carrel1 1981). The elastic properties of the lungs may
be different in PiMZ persons, but if there are differences, they are
small. Larsson et al. (1977) reported that 50-yearold PiMZ men who
smoked had reduced elastic recoil at total lung capacity compared
with PiMZ nonsmokers, even though they had no evidence of
impaired air flow. The PiMZ nonsmokers were indistinguishable
from PiMM nonsmokers. Tattersall et al. (1979) also found no effect
upon airflow in PiMZ middle-aged men, and a statistically nonsignif-
icant decrease in elastic recoil. Using an index of the slope of the
pressur+volume curve, Knudson and Kaltenborn (1981) found no
significant reduction in elastic recoil of PiMZ subjects compared
with matched PiM controls.

There is little direct information about the occurrence of emphyse-
ma among PiMZ individuals. In an autopsy study, Eriksson et al.
(1975) found emphysema among 13 of 26 subjects with diastase-
resistant PASpositive inclusions in the liver, compared with an
incidence of emphysema of only 18 percent in the controls. Although

133


these findings suggest an increased occurrence of emphysema with
the PiMZ phenotype, this study should be interpreted cautiously
because the smoking histories of the subjects and the quantification
of the emphysema were not included. Moreover, the significance of
the PAS-positive inclusions is not certain, because one recent study
found that such inclusions represented immunoreactive al-protein-
ase inhibitor in only half of the tissue studied (Qizilbash and Young-
Pong 1983).

It may be concluded from the studies involving a,-proteinase-
inhibitor-deficient people that for those with the PiMZ phenotype,
smoking has not been shown to promote a greater risk of emphysema
than it does in PiMM persons. In the rare individual with PiZZ, the
risk of emphysema is extremely high in both smokers and nonsmok-
ers, but PiZZ smokers experience an earlier onset and more severe
chronic obstructive lung disease than PiZZ nonsmokers.

Observations in Experimental Animals

Experimental animals have been subjected to cigarette smoke to
examine whether changes typical of emphysema result. As noted
below, it appears that cigarette smoke exposure can produce
emphysematous-like changes in the lungs under experimental
conditions, but the exposure must be quite prolonged and intense, or
additional factors must be employed to "sensitize" the lungs to the
effects of cigarette smoke.

Pioneering studies in dogs exposed to cigarette smoke, by Hernan-
dez et al. (1966) and by Auerbach et al. (19671, indicated effects
consistent with emphysema, but these reports did not include
quantitative morphology or data about the mechanical properties of
the lungs. Moreoever, the exposures may have created problems of
hypoxemia and infection that may have influenced the responses to
cigarette smoke. Contrary to these findings, in later studies, beagles
that inhaled cigarettes by face mask in four sessions per day for up to
1 year-an inhalation sufficient to raise the blood carboxyhemoglo-
bin saturation to 5.4 + 0.9 percent-had no statistically significant
changes in mean linear intercept or internal surface area, although
their large airways showed epithelial cell hyperplasia, proliferation
of goblet cells, and peribronchial inflammation (Park et al. 1977).

Recently, Hoidal and Niewoehner (1983) presented data suggesting
that cigarette smoke may be an important cofactor in the develop
ment of elastase-induced emphysema. They found that inhalation of
cigarette smoke led to severe emphysema in hamsters if used in
conjunction with doses of elastase that did not produce emphysema
when used alone. In this study, hamsters were exposed to cigarette
smoke for 15 minute periods, six times per day, 6 days per week for 7
weeks in standardized chambers. The animals were challenged with
small doses of elastase given intratracheally; controls consisted of

134


animals given either elastase or smoke exposure or neither. Animals
receiving only smoke or only elastase showed no changes of mean
linear intercept or volume-pressure relationship of the excised
lungs, compared with animals given neither elastase nor smoke
exposure. The combinations of smoking followed by elastase or
smoking both before and after elastase produced statistically signifi-
cant increases of mean linear intercept, displacement upward and to
the left of the volume-pressure curves (Figure 29), and marked
emphysema by light microscopy of inflation-fixed lungs. The mecha-
nism of the synergism between elastase and smoking was not
elucidated. One possibility considered was that cigarette smoke
impaired the repair mechanism normally triggered by elastase
exposure, a possibility supported by Osman et al. (19821, who found
that hamsters exposed to cigarette smoke after intratracheal elas-
tase did not show the heightened lung elastin synthesis typically
seen after lung injury produced by elastase.

summary

Clinically significant degrees of emphysematous lung destruction
are commonly present in individuals with COLD. Severe emphysema
occurs almost exclusively in cigarette smokers and those with
homozygous a,-antitrypsin deficiency. The extent of emphysematous
change increases with increasing numbers of cigarettes smoked per
day and with the duration of the smoking habit. While clinically
significant emphysema is limited to a minority of those who smoke,
most heavy smokers have some degree of emphysematous change by
the sixth decade of life.

Individuals with homozygous a,-antitrypsin deficiency have an
exceptionally high risk of developing emphysema. This risk is
present for both smokers and nonsmokers, but smokers with a,-
antiprotease deficiency develop clinical symptoms earlier in life. It is
unclear whether individuals with heterozygous antiprotease pheno-
types are at increased risk of developing COLD.

Summary and Conclusions

1. Cigarette smoking is the major cause of COLD morbidity in the
United States; 80 to 90 percent of COLD in the United States is
attributable to cigarette smoking.

2. In population-based studies in the United States, cigarette
smoking behavior is often the only significant predictor for the
development of COLD. Other factors improve the predictive
equation only slightly, even in those populations where they
have been found to exert a statistically significant effect.
3. In spite of over 30 years of intensive investigation, only
cigarette smoking and a,-antiprotease deficiency (a rare genet-

135


o NO smoke, no elastase
? ~ontmuous smoke, no elastase

* No smoke, elastase
0 Posf-elastase smoke
A Pre-elastase smoke
A ~ontmuous smoke. elastase

p. ,05 compared wlh
* No smoke. no elastase

I      I      I      I      I      I

5      10      15     20     25      30

         Pressure (cmHtO)

FIGURE 29.-The effects of combining cigarette smoking
      and elastase upon the pressure-volume
      characteristics of the lungs of experimental
         animals

N(rTE. The m vttro measurements of lung volume are shown as percentage of predicted total lung capacity
cTLCr relative to transpulmonary pressure of hamster lungs following m vwo exposure to venous combmatlons of
agarette smoke and mtratracheally admlnlstered pancreatic elastase Values are the mean t SEM of
messurement~ made dunng deflation Tbe animals that smoked and then recewed elastase tPre-Elastase Smoke)
and those that smoked both kfore and after elastase lContmous Smoke. E1asta.wI had slgmficant changes m the
elastx properties of the lungs There were no changes from control if elastase or smoking were used separately or
when smoking occurred onI?. after elastase
SOURCE Holdal and N,ewcehner / 19831

ic defect) are established causes of clinically significant COLD
in the absence of other agents.

4. Within a few years after beginning to smoke, smokers experi-
ence a higher prevalence of abnormal function in the small
airways than nonsmokers. The prevalence of abnormal small
airways function increases with age and the duration of the

136


smoking habit, and is greater in heavy smokers than in light
smokers. These abnormalities in function reflect inflammatory
changes in the small airways and often reverse with the
cessation of smoking.

5. Both male and female smokers develop abnormalities in the
small airways, but the data are not sufficient to define possible
sex-related differences in this response. It seems likely, how-
ever, that the contribution of sex differences is small when age
and smoking exposure are taken into account.

6. There is, as yet, inadequate information to allow a firm
conclusion to be drawn about the predictive value of the tests of
small airways function in identifying the susceptible smoker
who will progress to clinical airflow obstruction.

7, Smokers of both sexes have a higher prevalence of cough and
phlegm production than nonsmokers. This prevalence in-
creases with an increasing number of cigarettes smoked per
day and decreases with the cessation of smoking.

8. Differences between smokers and nonsmokers in measures of
expiratory airflow are demonstrable by young adulthood and
increase with number of cigarettes smoked per day.

9. The rate of decline in measures of expiratory airflow with
increasing age is steeper for smokers than for nonsmokers; it is
also steeper for heavy smokers than for light smokers. After
the cessation of smoking, the rate of decline of lung function
with increasing age appears to slow to approximately that seen
in nonsmokers of the same age. Only a minority of smokers will
develop clinically significant COLD, and this group will have
demonstrated a more extensive decline in lung function than
the average smoker. The data are not yet available to
determine whether a rapid decline in lung function early in life
defines the subgroup of smokers who are susceptible to
developing COLD.

10. Clinically significant degrees of emphysema occur almost
exclusively in cigarette smokers or individuals with genetic
homozygous al-antiprotease deficiency. The severity of em-
physema among smokers increases with the number of ciga-
rettes smoked per day and the duration of the smoking habit.

137


Appendix Tables


Ar.YYY a. --I'u v 1 IN wn~te adults, by smoking status, sex, and age, United States, 1971-1975

                    Both eexea                         Men                           Women
Cigarette smoking
etatua by age)      N      n    Mean SD     SE      N      "    Mean SD     SE      N      n    Mean SD SE

Never smokers
L&74                    3140'          21'                3669'           39'                2664'         191
25-34         6733    394 3607     791     51     2633     130    44.04     xi4     63     4099     264    3095     312    26
3.544        5278    291 3171    607     49     1669     61    3742     591     73     3609     210    2907     397    40
4.544         4642    353284a     594     35     1206     85    3487     626     72     3736    268    2631     401    29
55-64        3660    251 2511    589     31      &lo     59    3215     531     61     2781     192    2289     401    29
65-74        2875     235 2148    549     36      461     43    2856     627     96     2394     192    2oG6     402    36

Exsmokers
25-14                     3112           24                3623           37                 2651          28
25-34        2811     160 3677    810     60     1359     66    4303     627     92     1452     94    3091     441    55
35-44        3oF%     171 3566    767     69     1828     94    4013     643     70     1256     77    2916     361    44
45-54         3323    213 3155     742     65     2345     143    3414     663     69      978     70    2535     454    65
55-64        2669     181 2845     693     63     1826     130    3067     649     63      843     51    2319     456    90
6&7.!         1769     157 2366     6%     66     1270     121    2533     699     78      491)     36    2020     487    92

Smokers
25-74                    2378           20                 3281           32                 2514          n
,I 2fAu        6665     487 3567     752     44     4792     239    4037     639     51     4093     248    3018     433    41
34-Mb       5849    320 3166     655     47     3027     156    3507     639     71     '2822     162    2800     439    43
4554         5606     374 2761    623     37     n43     182    3126     579     49     2863     192    2411     437    40
55-64         3251     192 2416     631     50     1700     106    2736     632     63     1551     84    2w4     m    50
65-74         933     84 2071    653     66      534     56    2222     556     79      400     28    1669     714   155


g   TABLE A.--Continued


                           Both eexea                           Men                          Women
   Qarette smoking                                 ___
   status (by age)      N n    Mean SD     SE      N      n    Mean SD     SE      N      "     Mean SD SE

Light smokers
2s74
2534
3&44
454
55-64
65-74

Moderate smoker8
25-74
25-34
35-44
4.544
55-64
65-74

Heavy smokers
25-74
?A-34
35-44
45-54
5544
&74

2951           38                 3311
3425     650     97      879     43    3914
3106     618     93      308     17    37751
2683 490     73      383     24    3009
24@3     573     83      313     18    2919'
2150     737    165      131     11    222P

508
515
404
660
426

57
102
139
95
150
130

1283     70
a59     55
707     52
730     39
172     10

2626          52
3m     WY    88
2891     479    83
2507     437    76
2190     350    62
2095'    901   3%

25
51
47
51
70
124



38
80
64
92
121
150

2162     113
1267     72
1090     76
1043     57
304     21

2678           23                3335
3671     810     60     2534     123    4136
3217     646     68     1214     66    3593
2679     634     53     1145     75    3106
2406     589     63      690     45    2776
2023     609    105      261     28    22.79

40
69
99
79
60
126

2466
2991     393
2836     395
2368     429
1977     408
1693'    4.84

684
624
622
455
572

1735     112
1199     64
1570     104
597     37
203     16

4269     235
2413     130
2715     179
1287     82
464     44

2785           32                 3202
3514     699     70     1363     72    3927
3143     684     71     1505     75    3382
2930 649     70     1193     62    3164
2440     741    118      697     45    2619
2038' 606    151      130     16    2096'

52
82
89
75
133
172

2409
2979     393
2562     373
2411     440
lF&'    396
17&Y*    215

2417     136
2148     116
1779     118
922     53
154     18

597
646
579
737
638

1051     64
643     41
586     36
224      8
24      2

NOTE: N = weighted population estimate in thousands; n = number of people in sample; SD = standard deviatmn. SE = standard error.
I Adjusted by the direct method to reflect the age distribution of the U.S. populatmn at the midpoint of the survey.
' Doe8 not meet ntanti of reliability.
SOURtX National Center for Health Statiirca. Unpublished data fmm the first National Health Nutrition and Examination Survey (NHANFS 1).


TABLE B.-Flow at 25 percent of FVC for white adults, by smoking status, sex, and age, United
      states, 1971-1975

                     Both sex.88                         Men                           Women
Cigarette smoking                                                          -

statue by age)      N      n    Mean SD     SE      N      n     Mean SD     SE      N      "    Mean SD SE

Never smokers
25-74
2544
35-44
4554
5.544
65-74

Exsmokers
w74
2534
3b4.4
4.544
5544
6s74

Smokers
25-74
2534
35-44
4554
55-64
65-74

6733     394
5278     291
4942     353
3660     251
2675     235

2811     160
3086     171
3323     213
2669     181
1769     157

487
320
374
192
84

6253'
6639
6377
5742
5368
46%

6093
6835
7020
6270
5763
4918

5647
6760
6157
5471
5123
3954

1591
1464
1566
1397
1576

1855
`2041
1896
1764
1946

1694
1740
1658
1815
1566

47'                7261'
98     2633     130    7871
114     1669     81    7715
90     1206     85    7262
101      880     59    6543
102      481     43    6097

62                 7095
203     1359     66    6042
176     1828     94    7956
164     2345     143    6765
144     1826     130    6261
WI     1270     121    5194

47                 6362
102     4792     239    7606
123     3027     158    6848
92     2743     182    6130
132     1700     108    5567
181      534     56    4199

1513
1545
1796
1593
1951

1715
!2059
1919
1820
2091

1663
1675
1763
2061
1745

91'                5343'          36'
157     4099     264    5847    1042    89
176     3609     210    5758     952    80
213     3736     268    5252    1141    70
265     2781     192    4996    1091    83
298     2394     192    4331 1303   108

107                 5188          67
285     1452     94    5705    1126   165
232     1258     77    5659     965   116
185      978     70    5Q34    1176   151
160      I343     51    4749 1058   197
265      499     36    4213    1278   197

88                 5002          52
126     4093     248    5769    1061    83
160     2822     162    5415 1200   102
137     2863     192    4840    1233   106
223     1551      84    4636    1372   169
238      400     28    3627    1274   255


c
4   TABLE B.--Continued

L..

                          Both sexm                         Men                         Women
   Cigarette smokmg -
   data8 (by age)      N      n     Mean SD     SE      N      "     Mean SD     SE      N n    Mean SD SE

Light smokers
2574
2.534
3544
45-54
!i5-64
65-74

Moderate smokers
a-74
25-34
3.5-M
45-54
55-64
G-74

Heavy smokers
2.5-74
75-34
3!i44
4544
5.544
6574

2162     113
1267     72
1090     76
1043     57
304     21

4269
2413
2715
1287
464




2417
2146
1779
922
154

23.5
130
179
82
44

136
116
118
53
18

5834
6549
KM
5545
5222
3779

5661
6909
6384
5269
5065
3950

5485
6691
5964
5712
5090
415!'2

1652
1461
1476
1534
1272

1719
1786
1490
1787
1717

1659
1815
1940
2117
1653

91                6569
209      879     43    1688
211      308     17    7250'
217      383     24    6373
238      313     18    6096'
345      131     11    37421

66                 6430
136     2534     123    7647
194     1214     66    7348
111     1145     75    5821
202      690     45    5576
304      261     28    4356

85                 6219
l&i     1363     72    7468
198     1506     75    6363
207     1193     82    6326
321      697     45    5322
401      130     16    4180'

1690
1634
1572
1616
1279

1667
1736
1661
1897
1692

1640
1902
1920
2288
1758

142                 5171
293     1283     70    5769
369      959     55    5653
311      707     52    5096
399      730     39    4849
462      172     10    3807'

118
164     1735     112
236     1199     64
183     1570     104
334      597     37
404      203     16

151
225     1054     64
261      643     41
251      586     36
434      224      8
463      24      2

4967
5831
5408
4867
4475
3427'



4822
5685
5031
4458
437P2
4023 2

1071
1193
1203
1333
1266

1120
1212
1202
1439
1285

1018
1084
1257
1202
904

112
140
188
193
249
489

76
132
170
137
265
319

111
176
18f
26f
3.x
62!

NOTE: N = Weighted population estimate. in thousanda; n = number of people in sample; SD = standard deviation; SE = standard error.
' Adjusted by the direct method to reflect the age distribution of the U.S. population at the midpoint of the survey.
' Doea not meet Btandards of reliability
~UWE National Center for Health Statistics. Unpublished data from the first Natmnal Health Nutrition and Examination Survey (NHANES 1).


TABLE C.-Flow at 50 percent of J?VC for white adults, by smoking status, sex, and age, United
      states, 1971-1975

                      Both eexee                          Men                          Women
Cigarette smoking
status (by age)      N      "    Mean SD     SE      N      "     Mean SD     SE     N      "    Mean SD SE

Never smokers
25-74
25-34
3544
4544
55-64
65-74

            3743 '          38'                40831
6733    394    4361    1194     69     2633     130    4998
5278     291    3904    1164     84     1669     81    4315
4942     353    3366    1212     84     1206     85    3972
3660    251    3090    1087     74      880     59    3736
2875     235    2535    1045     73      461     43    3157

86'
128
152
150
l&l
174

3342'
3964
3713
3170
2886
2410

34'
78
91
90
72
84

1255
1221
1287
1220
1060

4099     264
3609     210
3736     x33
2781     192
2.394     192

963
989
1119
955
996

Ex-smokers
25-74
25-34
35-44
45-54
s-64
65-74

Smokers
25-74
25-34
3!i-44
45-54
55-64
65-74

      3579     59          4188      67          3123     81
2811     160    4329    1292 120     1359     66    5029    1243
3086     171    4249    1364 129     18'28     94    4702    1410
332.3     213    3474    1404    114     2345     143    3749    1426
2669     181    3110    1411    118     1826     130    3294    1362
1769     157    2524    1296    121     1270     121    2578    1364

195     1452     94    3674     949   114
180     1258     77    3590    1037   160
143      978     70    2816    1091   147
127     843     51    nil    1432   293
153      499     36    2384    1092   167

3475
4546
3764
3257
2193
1889

59
103
140
92
146
175

z
3325
2604
2361
1965

54
90
98
94
144
252

3169           39
4126    1268     74
3552    1296     87
2924    1208     76
2567    1248 107
1922    1220    159

s&35    487
5849    320
5606    374
3251     192
933     84

4792     239
3027     158
2743     182
1700     108
534     56

1296
1399
1278
1364
1174

4093     248
2822     162
2863     192
1551     84
400     28

1037
1137
1040
1062
1279


;:   TABLE C.-Continued

                      Both eexen                          Men                         Women
Cigarette smoking                                                                           -___-

status by age)      N      n    Mean SD     SE      N      n     Mean SD     SE      N      n    Mean SD SE

Light smokers
25-74
2534
35-44
4544
5s64
t&74

Mcderate smokera
&I4
25-34
35-44
45-a
!s-&
65-74

Heavy smokers
25-74
25-34
3544
45-54
55-64
66-74

                                                                           102
2162     113          1230                            1248                             994   162
1267     72          1076                             943                            1054 166
1090     76          864                             969                             771 103
1043     57          1375                            1643                            1080 200
304     21          1252                             883                           1415 425

3313
3964
3630
2911
2756
2056

74
169      879     43
151      308     17
107      383     24
205      313     18
292      131     11

3676
4617
4190'
3150
3542'
1706'

110
222     1263     70
226      959     55
197      707     52
395      730     39
366      172     10

2984
3516
3450
2781
2420
2321'

                       57                                                          71
4269     235          1239     96     2534     123          1297                             872 47
2413     130          1182    124     1214     66          1198                             llcfl   142
2715     179          1205    111     1145     75         1243                           1125 140
1287     82          1186    167      690     45          1191                           1134 245
464     44          1239    218      261     28          1316                          1047 266

3207
4246
3781
n75
2665
1881

3561
4640
4039
3079
2873
2131

79
126     1735     112
171     1199     64
124     1570     104
207      597     37
n9      203     16

2888
3671
3520
2553
2425
1558'

                        68                                                           110
2417     136          1333    153     1363     72          1306                           1295 247
2148     116          1469    166     1505     75                                        1103 185
1779     118          1355    147     1193     82          1377                           1062 222
922     53          1123    173      697     45          1222                             651 232
154     18          1113    285      130     16          1059                             703 490

3043
4067
3239
3152
2284
1760'

3287
4326
3456
3458
2379
1559'

92
197     1054     64
m      64.3     41
168      5%     36
221      224      8
274      24      2

2828
3733
n3i
2526
1997'
28.34'

NOTE N = weight& population eetunata. in thousanda; n = number of people io sample; SD = ntandard deviation; SE = standard error.
' Adjusted by the direct method to reflect the age distribution of the U.S. population st the midpoint of the .wrvey.
* Doea not meet standards of reliiiity.
SOURCF.. National Center for Health Statistics. Unpublished data from the funt National Health Nutrition and Examination Survey (NHANFS 1).


TABLE D.-Flow at 75 percent of FVC for white adults, by smoking status, sex, and age, United
      states, 1971-197s


                    Both eexe8                         Men                          Women
Cigarette smokii
&ha (by age)      N      II    Mean SD     SE      N      n    Mean SD     SE      N      n    MWII    SD SE


Never smokers
25-74                     1230'          28'               1329'          42'               1073 '         24'
25-34         6733     394    1776     714     52     Xi33     130 2065     649     72     4099     264    1690     691 62
36-44         5278     291    1277     621     49     1669     81    1478    8.43 129     3609    210    1184     456 32
`a-54         4942     353    1044     636     44     1206     85    1184     664     14     3736    268 999 620 53
55-64         3660     251     737     611     36      880     59     978     612     83     2781     192     661     449 34
65-74         2675     235 609     463     32      481     43     795     4x3     64     2394     192     572     465 38

Exsmokers
25-74                     1152           29                 1403           41                  992          37
25-34         2811     160 1696     678    61     1359     66    1925     664 109     1452     94    1480     616 72
354         3086     171 1460 664     62     1828     94    1623     693     92     1258     77 1224     538 59
45-54         3323     213 10%     625     48     2346     143    1148     666     59      978     70     734     376 53
5544         2669     181     734     541     54     1826     130     178     446     41      843     51     638     694 156
65-74         1769     157     588     506     43     1270    121     592     516     47      499     36     578     481 87

Smokers
2574                     967           22                1053           29                  889          34
25-34         8885     487 1530     688     41     4792     239    1665     665     60     4093     248    1373     692 65
3M.4         5849     320    1062    552     34     3027     158    1134     599     57     2822     162     985     4% 35
45-54         5606     374     778     511     31     2743     182     866     530     41     2x63     192     693     478 43
c5.564         3251     192 631    536 42     1700     108     713     580     63     1551     84     541     468 56
6.5-14          933     84     452    689 loo      534     56     350     445     17      400     28     558     901 199


r
ts   TABLE D.-Continued


                         Both @exe8                         Men                         Women
   Cigarette smoking                             -
   statue (by age)     N      n    Mean SD     SE      N      n    Mean SD     SE      N      n    Mean SD SE

Light smokers
25-74
25-34
35-44
45-54
55-64
65-74

Moderate smokers
25-74
25-34
35-44
4x4
55-64
65-74

Heavy smokers
25-74
25-34
35-44
45-54
55-6-t
65-74

2162     113
1261     72
1090     76
1043     57
304     21

4269     235
2413     130
2715     179
1281     82
464     44

2417     136
2146     116
1719     118
922     53
154     18

1049
1460
1122
837
706
660

970
1603
1134
711
643
373



882
1447
940
836
529
297'

679
534
4.31
540
1040

685
499
480
598
366

689
595
589
410
453

44
94      879     43
63      309     17
57      383     24
85      313     18
264      131     11

28
57     2534     123
52     1214     66
49     1145     15
12      690     45
68      261     ?a

47                 956
95     1363     72    1503
63     1505     15     995
57     1193     82     941
57      697     45     545
112      130     16    258'

1120
1641
1294'
840
931'
393'



1107
1755
1265
801
784
381

587

686
517
416
637
375

593
647

416

64                 985
113     1283     IO    1366
101     959     55    1067
131      707     52     836
182      730     39     609
231      172     10    864'

41                 846
82     1735     112    1362
78     1199     64    lOCKI
41     1570     104     656
119      597     37    481
85      203     16     363'

38                 815
101     1054     64    1374
85      643     41     811
73      586     36     620
62      224      8    479'
98      24      2     505'

703
531
388
450
1244

620
443
514
503
353

790
422
438
388
603

67
127
73
42
88
414

32
76
58
67
69
103

82
172
69
79
160
420

NOTJC N = weighted population estimate, in thousands; n = number of people in sample; SD = standard deviation; SE = standard error.
' Adjusted by the direct method to reflect the age distribution of the U.S. population at the midpoint of the survey.
`Does not meet standards of reliability.
SoUfKT National Center for Health Statisticsa. Unpublished data from the first National Health Nutrition and Examination Survey (NHANFS 1).


TABLE E.-FEVI/FVC ratio for white adults, by smoking status, sex, and age, United States, 1971-1975

                    Both sexes                          Men                          Women
Cigarette smoking
etatua Car age)     N      "    Mean SD     SE      N      n    Mean SD     SE      N      n    Mean SD SE

Never smokers
25-74
25-34
3.544
45-54
55-64
65-74

Ersmokem
25-74
25-34
35-u
45-54
55-64
65-14

Smokers
25-74
25-34
35-M
45-54
55-64
674

79.1'          0.21'
82.5    6.06    0.34
60.3    5.67    0.37
78.7    5.84    0.38
11.6    5.03    0.35
76.5    6.41    0.52

11.9 '          0.34 '
80.1    5.91     0.69
18.8    5.25    0.64
71.5    5.95    0.17
15.8    5.13    0.81
13.5    7.59    1.14

80.2 '         0.23 '
83.6    5.93   0.44
80.9    5.73   0.45
79.0    5.75   0.41
78.2    4.85   0.39
71.0    5.97   0.55

18.1         0.41
82.4    5.81   0.18
80.4    5.26   0.69
77.0    5.04   0.69
76.0    6.60   1.36
15.3    6.58   1.05

17 5         0.39
81.1    6.85   0.61
78.2    6 16   0.41
15.4    6.32   0.52
16.0    6.61   0.15
73.6    8.67   2.09

6733     394
5278    291
4942     353
3660    251
2875    235

24233     130
1669     81
1206     85
880     59
481     43

4039     264
3609     210
3736     268
2781     192
2394     152

77.1          0.30
81.7    5.92    0.53
79.5    6.26    0.56
76.2    6.58    0.50
73.7    7.79    0.70
11.5    9.34    1.05

76.6          0.44
80.9    5.94    0.94
78.8    6.78    0.83
75.9    1.10    0.66
12.1    8.07    0.19
10.0    9.83    120

2811     160
3086     171
3323    213
2669     181
1169     157

1359     66
1828     94
2345     143
1826     130
1270     121

1452     94
1258     77
918     10
843     51
499     36

75.9          0.26
80.3    6.78    0.38
76.7    7.28    0.46
74.2    7.05    0.41
73.1    8.13    0.59
69.8    9.40    1.44

14.0          036
19.2    6.50    0.52
75.3    1.92    071
13.0    1.55    059
10.6    9.59     1.03
67.0    8.94     1.54

8885
5849
5606
3251
933

487
320
374
192
84

4792
3027
2743
1700
534

239

4093     248
2822     162
2863     192
1551     84
400     28

156
182

108
56


z   TABLE E.-Continued
al

                     Both wxea                        Men                         Women
Cigarette smoking
statue (by age)      N      n     Mean SD     SE      N      n    Mean SD     SE      N      n    Mean SD SE

Light smokers
25-74
25-34
36-44
45-S
55-64
65-74

Moderate smoker8
25-74
25-34
3544
45.54
55-64
65-74

Heavy smokers
25-74
2x34
3544
45-54
5564
65-74

2162
1267
1090
1043
304

424%
2413
2715
1287
464

2417
2148
1779
922
154

     77.3          0.47
113    80.9    7.43 0.84
72    78.4    6.18    0.79
76    76.5    4.94    0.66
57    76.9    7.06    0.97
21    71.4    10.59    2.65

     75.8          0.36
235    80.4    6.36    0.53
130    77.9    6.18    0.65
179    73.6    7.48    0.69
82    73.2    7.46    0.81
44    69.3    8.30    1.46

     75.1          0.58
136    79.1 6.65    0.73
116    14.2    8.24    0.92
118    73.7    7.21    0.74
53    68.9    10.08    1.42
18    68.0'    9.18    2.66

879
308
383
313
131

2534
1214
1145
690
%I

     15.7
43    80.3
11    17.1'
24    75.1
18    74.8'
11    64.6'

     74.6
123    19.3
66    77.3
75    71.3
45    72.1
28    68.4

    72.8
72    78.0
75    73.3
82    74.0
45    67.1
16    66.9'

7.10
6.14
6.05
9.cQ
IO.84

6.29
6.61
7.87
8.00
7.63

6.33
8.68
7.34
10.09
8.75

0.76
1.11
1.54
1.58
2.25
4.17

0.48
0.70
0.85
0.96
1.38
1.56

0.57
0.89
1.21
0.86
1.81
2.42

1283
959
107
730
172

1735
1199

1054
643
586
224
24

     78.7         0.60
70    81.4    7.62   1.30
55    78.8    6.13   1.30
52    77.3    4.01   0.54
39    77.8    5.81   0.87
IO    76.5'    6.90   2.64

     76.9         0.47
112    81.9    6.16   0.13
64    18.6    5.64   0.71
104    75.3    6.67   0.80
37    14.3    6.58   1.07
16    70.4'    893   2.42

     77.2         1.06
64    81.9    6.90   1.16
41    76.2    6.64   1.15
36    73.2    6.91   1.30
8    74.6'    7.63   2.40
2    79.4'   6.66 4.63

NtX'Ez N = weighted population estimate. in thousands; n = number of people in sample; SD = standard deviation; SE = standard error.
`Adjusted by the direa method to reflect the age distribution of the U.S. population at the midpoit of the survey.
' Lhm not meet .stan&rds of reli.tbility.
SOURCE Natuxsd Center for Health St&tics. Unpublished data from the fii Natiaxal Health Nutrition and Examination Survey WGNES 1).


TABLE F.-MMEF for white adults, by smoking status, sex, and age, United States, 1971-1975

                    Both wxw                          Men                           Women
cigarette 8mokiLtg
atah (by age)      N      "    Mean SD     SE      N      "     Mean SD     SE      N      n     Mean SD SE

Never emokera
2s74
25-34
35-44
4564
5M4
65-74

Exsmokers
25-74
2.5-34
35-44
4554
5544
65-14

Smokem
25-74
25-34
35-M
4.554
55-64
65-14

3020'
3748
3140
2724
2301
1891

29'
64
58
50
43
51

3392'
4357
3501
3198
2734
2314

52'
106
106
113
104
130

2664'
3357
2973
2512
2164
1806

26'
58
58
48
51
56

51
103
104
102
180
115

41
77
63
66
18
220

1023
821
837

6733     394
5278    291
4942    353
3660    251
2815    236

2633     130
1669     81
1206     85
880     59
481     43

lCJJ3
911
1021
163
827

4199
3609
3736
n81
234

264
210
268
192
192

820
in
703
663
611

730
619

2910
3753
3500
2800
2318
1826

41
102
106
91
75
82

3324
4321
3882
3021
2463
1865

66
162
157
114
81
99

2537
3222
2944
2270
2005
1128

1066
1165
1111
948
873

2811     160
3086     171
3323    213
2669     181
1769     157

1359     66
1828     94
2345     143
18%     130
u-70     121

1014
1237
1171
953
922

1452     54
1258     77
978     70
843     51
499     36

809
165
714
857
123

2553
3512
2850
2283
1955
1474

31
66
65
54
67
118

2786
3857
3033
2511

49
93
107
18
106
104

2343
3109
2654
2065
1813
l&i5

4792
3027
2743

4093     248
2822     162
2863     192
1551     84
403     28

872
8lm
109
654
995

8835
5849
5636
3251
933

437
320
374
192
84

1069
970
8-96
854
831

239
158
182
109
56

1101
1073
1007

1700
534

985
677


TABLE F.--Continued

                      Both eerxa                         Men                          Women
cigarette smoking
8tatf.M (by age)     N      n     Mean SD     SE      N      n    Mean SD     SE      N      n    Mean SD SE

Light smokers
25-74
25-34
35-44
45-54
55-64
65-74

Moderate smokers
2b-74
25-34
3544
45-64
5E-64
65-14

Heavy smokers
25-14
25-34
35-44
4544
55-64
65-74

2162     113
1267     72
1090     76
1043     57
304     21

424%    235
2413     130
2715     179
1287     82
464     44

2417     136
2146     116
1779    118
922     53
154     18

2736
3457
2936
2334
2252
1667

2542
3605
2993
2169
1894
1395

2404
3389
26243
2421
1706
1313'

1034
839
641
894
102-3

1106
907
82.3
811
738

1018
1663
1087
764
591

57                2985
144      819     43    3923
110     308     17    3`uma
84      383     24    2521
124      313     18    2694'
257      131     11    1339'

41                2848
93     2534 123    3S60
99     1214     66    3257
14     1145     75    2245
103      690     45    2144
12.6      261     28    1535

53                2620
120     1363     72    3614
119     1505     75    n77
125     1193     82    2663
166      697     45    1754
151      130     16    12471

1044
760
806
1239
563

1132

968
891
848
746

1045
1144
1145
828
601

93                 2510
196     1283     70    3137
184      959     55    2787
173      707     52    2232
321      730     39    2063
238      172     10    1917'

64                2266
123     1735     112    3087
145     1199     64    2725
92     1570     104    2041
162     597     87    1604
159      203     16    1214*

72                2210
167     1054     64    3122
157     643     41    2280
150      536     36    1926
136      224      8    1557'
160      24      2    1665'

807
808
502
605
1206

828
752
744
655
687

911
135
766
439
369

17
153
124
68
87
404

40
98
92
95
106
157

87
187
123
185
169

NOTI? N = weighted population estimate. in thouann&; n = number of people in sample; SD = standard deviation: SE = standard ermr.
' Adjuted by the direct method to reflect theage distribution of the U.S. population at the midpoint of thesurvey.
*Does not meet standa& of reliability.
SOURCE: Natmnal Center for Health Statistics. Unpublished data from the first National Health Nutrition and Examination Survey (NHANlB 1).


TABLE G.-MEFR for white adults, by smoking status, sex, and age, United States, 1971-1975

                     Both sexen                          Men                         Women
Cigarett.e smoking
statue by age)      N      n    Mean SD     SE      N      "     Mean SD     SE      N      n    Mean SD SE

Never smokers
25-74
2544
36-44
45-54
lk5-64
65-74

Extlmokers
s-14
2544
35-44
45-54
5!%4
65-74

Smokers
%I4
25-34
35-44
45-54
66-64
65-74

6545'
7103
6144
5887
5260
4317

62'
123
144
110
98
112

7894'
8833
8519
7805
6722
6526

7809
9164
8789
7451
6532
5425

114'
167
223
268
226
269

5321'
5991
5923
5268
4824
3832

41'
94
103
86
98
118

83
167
131
191
245
220

55
101
94
113
171
263

5733     394
5278     291
4942     353
3660     251
2855     234

1895
1774
1625
1559
1776

2633     130
1669     81
1206     85
880     59
412     42

1551
1710
2106
1527
1863

4099     264
3609     210
3736     268
2781     192
2394     192

1081
1058
11%
1264
1394

5229

6453
7521
7664
6713
5644
4986

5914
7393
6712
5762
to30
3753

12
232
212
202
194
221

120
295
239
213
220
280

96
133
211
137
211
260

2311

160
171
213
181
157

2246
2241
2056
2002
2187

1359     66
1826     94
2345     143
1826     130
1270     121

1911
2006
1901
1997
2267

1452     94    5964    1153
1258     71    5759    1017
978     70    5146    1396
843     51    4671    1297
499     36    3867    1463

3086
3323

2669
1769

52
122
152
104
147
216

7041
8629
7780
5758
6834
4341

4691
5847
5566
4607
4149
2969

8885
5849
5606
3251
933

487
320
374
192
84

2019
1974
1864
1962
1662

4192     239
30!27     158
2743     182
1700     108
534     56

1728
1922
1819
2022
1961

4093     24.8
2.822     162
2863     192
1551     84
400     28

1216
1256
1332
1421
1373


z   TABLE G.-Continued

I-

                          Both aexea                           MelI                          Women
   Cigarette smoking
   8k3tu8 (by age)     N      "    Mean SD     SE      N n     Mm SD     SE      N n     Mean SD SE

Light smokers
25-74
2534
3544
45-54
5s64
65-74

Moderate smokers
25-74
25-34
35-44
4.5-54
55-64
65-74

Heavy smokers
25-14
2534
35-44
45.54
55-64
65-74

2162     113
1267     12
1090     76
1043     57
304     21

4269     235
2413     130
2715     179
1267     82
464     44

2417     136
2146     116
1119     118
922     53
154     18

6068          104                 7085
7006    1792 233      879     43    8347
6450    1784 275      308     17    8275'
%56    1632 232      383     24    6718
4979    1611 240      313     18    6142'
3535    1296 350      131      11    4054'

5921           76                 7165
7616    2146 154     2534     123    8755
6819    1992 230     1214     66    8112
5513    1755    137     1145     75    6633
5100    1996 243      690     45    6122
3701    m4    373      261     28    4495

5755           98                 6902
7356    1925 204     1363     12    8573
6751    x63 223     1505     75    7412
6167    2034    214     1193     82    6945
4989    2221 366      697     45    5410
41368   2060 496      130     16    4249'

1559
1918
1445
1903
1318

1864
1734
1799
1687
2122




1544
1996
1909

2187

177                 5150
2.46     1283     70    6088
530      959     55    5864
269      767     52    xl80
478      730     39    4462
451      172     10    3228'

120                 4798
176     1735     112    5952
264     1199     64    5511
181     1570     104    4769
261      591     37    3917
466      203     16    2681'

155                 4120
192     1054     64    5781
289     643     41    5205
239      586     36    4561
433      224      8    3679 2
571       24      2    3535'

1294
1270
1425
1154
1157

1263
1241
1286
1640
1512




1010
1164
1280
1327
964

114
193
192
249
m8
388

376

671

N(JITI: N = weighted population estimate, in thousands; n = number of people in sample; SD = standard deviatmn; SE = @amlard ermr
' Adjusted by the direct method to reflect the age distribution of the U.S. population et the midpoint of the survey.
' Ihe not meet standard9 of reliability.
SOURCE: Natmnal Center for Health Statistic-a Unpublished data from the first Natuxml Health Nutrition and Exammatlon Survey (NHANIB 1)


TABLE H.-Forced vital capacity for white adults, by smoking status, sex, and age, United States,
       1971-1975

                     Both aexea                         Men                           Women
Cigarette smoking                                                               ~-
Stahl8 (by age)      N      n    Mean SD     SE      N n    Mean SD     SE      N n     Mean SD SE

Never smokers
%I4
25-34
35-44
4544
55-54
65-74

Fzsmokere
25-14
25-34
3!%44
45-54
55-64
66-74

Smokers
2s74
25-34
35-44
45-54
55-64
65-74

3978'
4403
3972
3624
3252
2615

29'
67
65
45
47
46

      52'
759     89
159     98
795     92
758 123
774    127

24'
32
54
39
38
43

32
68
49
79
79
99

35
50
55
4.5
59
185

130    5480
81    4761
85    4506
59    4265
43    3867

3712
3607
3340

6733
5278
4942

394
291
353
251
235

1052
814
182
820
719

4099
3609
3736
2780
2394

264
210
268
192
192

464
so
522

526
462

30
101
91
78
94
86

4703
5335
5096
4499

      46
816    118
753     86
796     76
186     95
821     92

3357
3760
3633
3291
3044
2615

150
171
213
181
157

1043
972
915
898
864

1359     66
1826     94
2345     143
1826     130
1270     121

94
71
70
51
36

1256
978
843
499

1769

3793
4464
4146
3731
3316
2985

2%
55
59
49
66
118

4405
5111
4665
4264

      38
784     59
750     81
678     65
730     71
141    117

461
320
374
192
84

248    3707     539
162    3588     546
1%    3202     532
84    2712     467
28    7533     815

977
851
814
84.5
870

4792     239
3027     158
2743     182
1700     108
534     56


5   TABLE H.-Continued


                         Both aexea                         Men                           Women
   cigarette smoking
   statue by ege)     N      "    Mean SD     SE      N      n    Mean SD     SE      N      0    Mean SD SE

Light smokers
25-14
2x34
35-44
45-54
5564
65-74

Moderate smokers
25-74
25-34
35-44
4544
55-64
65-74

Heavy smoken,
25-14
25-34
35-44
4&54
554%
65-74

2162
1267

2417     136
2148     116
1779     118
922     53
154     18

113
72
76
57
21

235
130
179
82
44

3824
4260
3986
3521
3135
3042



3789
4584
4145
3658
3312
2928



3710

4244
3971
3524
3036'

857
875
680
704
917

1020
a46
852
854
820

988
a32
75-a
928
938

54
116      879     43
135      308     17
103      383     24
108      313     18
237      131     11

30                 4454
14     2534     123    5217
90     1214     66    4671
73     1145     75    4351
99      690     45    3881
149     261     28    3327

43
91
a2
81
151
240

1363     12
1505     75
1193     82
697     45
130     16

3866'
3470 q

4364
5055
4609
4304
3851
3189'

641
768
555
636
555

793
812
131
696
734

ala
679
638
798
925

ai
118
235
155
141
159

1283     70
959     55
707     52
730     39
172     10

50
a0     1735     112
125     1199     64
111     1570     104
a9      591     31
172      203     16

61
102     1054     64
94      643     41
a4     586     36
142      22-i      a
252      24      2

3342
3828
3686
3249
2822
2ll7 *



3190
3660
3612
3147
2651
2414'



3120
3644
3392

2%3'
2223'

     64
705   118
671   119
580 107
451 87
1001 347

     38
447 55
457 66
521 57
453 80
614   173

    54
404 69
440 73
480 95
438   143
472 328

No'I'Ez N = weighted population estimate. in thousands; n = number of people in sample; SD = standani deviation; SE = standard error.
' Adjusted by the direct method to reflect the age distribution of the U.S. population at the midpoint of the survey.
' Doee not meet standa& of reliability.
SOURCE: National Center for Health St&i&ice.. Unpublished data from the first National Health Nutrition and Examination Survey (NHANEZ 1).


TABLE I.-Recurring persistent cough attacks for adults, by sex, age, and smoking status, United
      states, 1971-1975

Never     Former

    Men
Smoking statue


Current    Light

Moderate

Never

Former

   Women
Smoking status

Current    Light

Moderate

2544
P
SE
ii

3.2       4.4       6.7       7.6       5.7       1.1          4.4       6.0      8.4       5.1       7.1      15.2
1.85      2.23      1.57      4.01      1.98      2.79         1.21      2.46      1.63      1.92      2.n     4.93
3319 168   1593 78  6608 321  1383 72  3335 160  1875 94    6416 399  1873 121  6304 367  2239 119  2642 164  1393 81

3.544
P      4.9       8.0      13.8      9.0       5.9      22.1         5.4       5.0      8.9       2.3       8.0      25.8
SE     2.59      3.47      3.17      6.39      2.69      6.40         1.60      2.46      1.89      1.21      2.85     7.37
ii  2114 101   2384 117  4412 226   614 33   1769 93  2029 100    5197 310  1771 107  4563 no  1776 103   1968 114  799 51

4554
P   "    4.3       9.2      10.3      6.4      12.0      10.6         4.9       3.0      11.5      7.8      9.9      21.8
  SE      1.61      2.28      2.07      2.13      3.65      3.53         1.55      1.97      2.16      2.61      2.99      4.04
i  1568 114   3290 204  4282 296   810 61   1705 122  1745 112    5989 435  1458 101  4&m 329   1497 18  2413 163  890 57

      55-64
       P      1.1       14.6      20.5      2.4      14.4      25.9          6.8       9.9      15.7      6.4      14.8     50.1
      SE      1.06      3.21      3.27      8.88      4.33      5.87         1.65      3.35      3.46      3.17      3.93     15.8
   F4  1320 94   2791 192  2990 205   708 50   1305 91   976 64    5599 394  1501 86  3014 178   1263 76   1369 a2  378 20

G
cn


ii   TABLE I.-Continued


                                Men                                             Women
                       Smoking status                              Smoking statue


            Never    Former    current    Light    Moderate   Heavy        Never    Former    Current    Light    Moderate   H-W

65-74
P      7.5      17.5      23.7      3.6      34.4      25.4          8.1       5.4      `2.31      17.2      24.8      59.9'
SE     3.16      3.44      4.55      2.31      6.96      10.1         1.52      2.85      4.93      6.06      8.02     22.31
E;   864 98   2232 232  1199 135   318 39   574 60   295 35    5467 461   958 61   952 a3   523 46   362 32   66 5

25-74
P'      3.9       9.6      13.4      10.2      12.0      16.7          5.7       5.8      12.4      7.1       11.6      31.1
SE'     0.92      1.51      1.30      2.22      1.66      2.31         0.66      1.25      1.19      1.32      1.84      5.63

NOTE: P = proportion; SE = standard error; n = number of people in sample; N = weighted population estimate. in thousands.
' Adjwted by direct method to reflect the age dintribution of the U.S. population at the midpoint of the survey.
* Dew not meet standards of reliability.
SOURCE NatIonal Center for Health Statistics. Unpublished data from the fust National Health Nutrition and Examiition Survey (NHANFS 1).


TABLE J.-Three-week periods of increased cough or phlegm for adults, by sex, age, and smoking
      status, united states, 1971-1975

Never    Former

    Men
Smoking et&u8

curre"t    Light

Moderate

Never

Former

   Women
Smoking statue


current    Light

Moderate

25-34
P      6.9      2.9       1.2       6.9       7.9       6.5
SE      2.39      1.67      1.83      4.04      2.63      2.33
ii  3319 168   1593 78  6608 321  1383 72  3335 160  1875 94


3.544
P      6.0       3.3       5.2       1.2       3.9       7.6
SE     2.43      1.98      1.68      1.20      2.06      2.86
ii  2114 101  2384 117  4412 226   614 33   1769 93  2229 100


4.544
P      1.7       3.9      6.3       0.3       5.5       9.8
SE     1.24      1.82      1.72      0.32      2.10      366
l  1568 114  3290 204  4282 298   810 61   1706 122   !745 112


5.5-64
P      1.2       2.9      11.4      6.8      10.2      16.2
SE      0.91      1.33      2.61      4.00      4.07      5.39
i   1320 94  2191 192  2990 205   708 50   1305 91   976 64

4.2       5.6      10.7      5.4      11.1      18.0
1.07      2.39      1.91      2.06      2.97     5.18
399      121      367      119      164      81
6416      1873      6304      2239      2642     1393

3.8       1.9       8.1       5.1      10.9      8.3
1.54      1.37      2.01      1.89      3.67      4.20
310      107      270      103      114      51
5197      1771      4563      1776      1968     799

3.5       6.1      10.8      8.4       a.4      21.6
1.00      2.39      2.14      2.93      2.12     6.49
435      101      329      109      163      57
5989      1458      4800      1497      2413      890

6.6      13.7      14.7      7.0      13.1     46.2
1.63      4.88      3.57      3.44      3.96     16.61
394       86       178       76       82       20
5599      1501      3014      1268      1369     378


TABLE J.--Continued

   Men                                           Women
Smoking statue                               Smoking status

65-14
P
SE
l

Never    Former    Current    Light    Moderate   Heavy        Never    Former    Current    Light    Mcderab   HMV




15       4.5      12.0      3.3       14.2      17 5          5.1       9.1      11.5      2.6      26.4      0.0 =

3.10      1.38      4.11      2.55      6.01      10.31         1.25      3.47      4.24      2.55      9.80      0.0
864 98   2232 232  1199 135   318 39   514 60   295 35    5487 461   958 81   952 a3   523 46   362 32   66 5

25-74
P'      4.6       3.4       79       3.8       7.6      10.5          4.5       6.9      11.0
SE'     1.04      0.93      102      1.43      1.31      2.04         0.63      1.34      1.26

NDl'E. P = proportion; SE _ standard rrror: n = number of people in sample. N = weighted population estimate. in thousands.
I Adjusted by direct method LO reflect the age dkibutmn of the U S population at the midpoint of the 8urvey.
* Ikea not meet standards of reliability
SOURC'E Natr.mnl Center for Health Statistca. Unpublished data fmm the timt National Health Nutrition and Examination Survey (NHANE 1).

5.9      12.9      19.5
1.18      1.84      3.86


TABLE K.Qhortness of breath for adults, by sex, age, and smoking status, United States, 1971-1975

Never    Former

    Men
smoking atatua


cumnt    Light

                                     Women
                            Smoking status

Moderate   H-V        Never    F0ITller    Current    Light    Moderate   H=V

25-34
P
SE
:

35-44
P
SE
i

`S-54
P
SE
ii

554
P
SE
it

5.6      15.2      23.3      10.0      23.1      33.6         14.4      17.9      31.0      30.9
1.99      4.97      3.20      3.61      4.01      7.21         1.92      4.94      3.17      5.65
168       78       321       72       160       94          399      121      367       119
3319      1593      6eQ8      1383      3336      1875         6416      1873      6304      223s

20.1
3.56
164
2642

51.5
1.43
61
1393

17.1      19.9      22.9      15.6      15.9      31.2         22.5      26.5      39.0      36.4      45.3     30.3
4.62      4.89      3.26      7.08      4.71      5.46         2.42      5.32      4.62      5.48      7.07      7.08
101      117      226       33       93       100         310      107      no      103      114      51
2114     2384      4412      614      1769      2029         5197      1771      4563      1776      1966     799

19.3      21.2      35.5      25.4      34.9      41.3         28.1      32.5      42.5      30.3      46.1      47.9
4.07      3.56      2.99      6.35      4.64      5.40         2.85      6.05      3.93      5.01      4.95     7.57
114      204      296       61       122      112          4.35      101      329      109      163      57
1568      3290      4232      610      1706      1745         5989      1456      4m      1497      2413     690

25.6      31.3      42.2      37.7      42.4      45.2         38.0      56.8      39.0      29.8      43.1     54.6
5.79      3.94      4.37      9.57      6.14      6.39         2.94      6.24      4.60      6.65      6.06     16.51
94       192      205       50       91       64          394       86       178       76       82      20
1320     2791      2sso      708      1305      9761         5599      1501      3014      1266      1369     370


E   TABLE K.-Continued


                             Men                                           Women
                       Smoking at&us                                 Smoking status


            Never    Former    Current    Light    Moderate   H@W        Never    Former    Current    Light    Moderate   H@W

65-74
P      27.0      45.8      41.7      26.7      42.4      54.4         41.6      32.3      43.2      48.6      40.0     17.4'
SE     5.46      4.06      4.59      7.87      6.86      9.12         2.92      5.63      6.70      9.64      10.66     16.12
i   664 98   2232 232  1199 136   318 39   574 60   296 35    5487 461   958 61   952 83   523 46   362 32   66 5

25-74
P'      17.1      25.2      31.4      21.5      29.9      39.2         27.0      31.8      38.2      34.1      38.2     42.4
SE'     1.69      2.38      1.75      2.64      2.31      2.74         1.27      2.82      2.03      2.59      2.88     5.07

NVl% P = prow'tion; SE = miandard error; n = number of people in sample: N = weighted population e&mate, in thouan&.
' Adjured by direct method to reflect the age distribution of the U.S. population at the midpoint of the survey
`Do% not meet standards of reliability.
XXIRCE National Center for Health Statistics. Unpublished dats from the first National Health Nutrition and Examicmtioo Survey (NHANE3 1).


TABLE L.-Wheezy chest sounds of adults, by sex, age, and smoking status, United States, 1971-1975

                         Men                                             Women
                 Smoking atatna                                 Smoking status

      Never     Former    Current    Light    Moderate   Hf=Y        Never    Former    Current    Light    Mcderate   HeaT


25.34
P      2.7       13.0      15.0      11.5      12.6      22.0          7.6      11.6      175      12.9      148      29.5
SE      1.17      4.67      2.42      4.43      2.72      6.14         1.46      3.54      2.33      3.13      2.94      6 13
:  3319 166   1593 70  6608 327   1363 72  3335 160   1876 94    6416 399   1873 121  6304 367  2239 119   2642 164  1393 RI


3iM-4
P      14.0       5.1      18.4      13.6      12.3      25.2         7.9       77      16.4      9.9      21.9      179
SE     4.72      2.12      3.28      6.14      4.03      5.61         1.83      2.98      2.56      3.77      4.53      4.89
it   2114 101   2384 117  4412 226   614 33   1769 93  2029 100    5197 310   1771 107  4563 no  1776 103  1968 114  799 51


45-54
P      4.3       12.3      18.8      10.2      23.2      18.7         8.5       5.3      22.7      12.9      24.1      35.7
SE      1.97      2.60      2.60      3.99      4.05      4.13         1.39      1 .a2      2.96      3.59      4.37     6.24
ii   1568 114   3290 204  4282 296   810 61   1706 122  1745 112    5969 435   1458 101  4800 329   1497 109   2413 163  890 57


6.544
P      12.0      13.6      26.9      29.9      26.6      22.1         12.7      22.0      27.3      19.5      31.0     40.0
SE      4.24      2.50      4.46      9.22      5.87      6.10         2.09      5.93      3.64      4.98      5.21     14.00
ii   1320 94   2791 192  2sso 205   708 50   1305 91   976 64    5599 394   1501 86   3014 178  1268 76  1369 A2  378 20


TABLE L..-Continued

   Men                                           Women
Smoking statue                               Smoking status

Never

Former

Current

Light

Moderate

Never

Former

current

Light

Moderate

65-74
P      5.0      20.7      33.1      34.7      31.6      35.6         15.1      21.5      28.6      34.6      18.1      39.02
SE     2.04      3.00      5.25      10.10      7.47      9.91         2.16      4.78      5.60      8.99      6.69     21.96
ii   864 98   2232 232  1199 135   316 39   574 60   295 35          461       81       03       46       32       5
                                                        5487      968      952      523      362      66

w74
P'      7.4      12.1      20.6      17.6      19.6      23.5
SE'     1.33      1.63      1.42      2.69      1.96      2.69

9.8      12.6      21.7      16.4      21.7     31.6
0.62      1.66      1.49      2.01      1.66     4.60

NOTE P : proportion; SE = standard error; n = number of people in sample; N = weighted population estimate. in thousandn.
' Adjusted by direct method to reflect the age distribution of the U.S.
`Doe not meet standards of reliability population at the midpoint of the survey.
SOURCE National Gnter for Health Statistics. Unpublished data from the first National Health Nutrition and Examination Survey (NHANES 1).


TABLE M.-Diminis hed or absent breath sounds of adults, by sex, age, and smoking status, United
      stat43, 1971-1975

Never    Former

    Men
Smoking etatus

Current    Light

Moderate

Never

Former

   Women
Smoking status

Current    Light

Moderate

25-34
P      1.8       0.0       0.3       0.4      0.0       0.7          0.1       0.0       0.6       0.3       0.0      2.2
SE      1.76      0.0      0.21      0.36      0.0      0.71         0.07      0.0      0.51      0.31      0.0      2.21
ii  3319 168   1593 78  6608 321  1383 72  3336 160  1875 94    6416 399  1873 121  6304 367  2239 119  2642 164  1393 61

3544
P      0.6       0.5       0.6      0.0       0.7       0.6          0.3       0.2       2.3       0.4       3.4      3.5
SE     0.61      0.47      0.55      0.0      0.73      0.57         0.26      0.22      1.56      0.44      3.33     3.39
Li  2114 101  2384 117  4412 2%   614 33   1769 93  2029 100    5197 310  1771 107   4563 270   1776 103   1968 114  799 51

45-54
P      0.7       1.0       5.9       0.4       9.8       4.7          0.8       2.4       14       1.0       1.6      1.5
SE     0.55      0.53      1.71      0.41      3.33      2.64         0.64      187      0.56      0.36      0.82      1.24
;   1568 114  3290 xl4  42.82 2%   810 61   1706 122   1745 112    5989 435  1458 101  4t?.w 329  1497 109   2413 163  890 57

      5.544
       P      2.5       5.7      12.4      8.4      13.0      14.4          0.8       4.1      3.36      2.7       3.9      3.5
      SE      2.12      1.66      3.15      4.75      4.57      4.99         0.53      2.51      1.44      1.82      2.40     3.55
   ii  1320 94  n9i 192  2sw 205   708 50   1305 91   976 64    5.599 394  1501 86  3014 176   1268 76  1369 82  376 20

E
w


z   TABLE M.-Continued

Never    Former

    Men
Smoking status

Current    Light

Moderate

Never

Former

   Women
Smoking status


Current    Light

Moderate

65-74
P      8.8       9.1      17.9      13.9      25.2      8.8          2.4       4.5       2.7       3.3       2.3      0.0'
SE     3.53      2.57      3.76      8.10      5.86      4.5         0.81      2.63      1.58      2.34      2.27      0.0
i   664 98   2232 232  1199 135   318 39   574 60   295 35    5487 461   958 81   952 83   523 46   362 32   66 5

s-74
P'      2.2      2.44      5.8      3.3       7.5       5.0          0.7       1.9       1.9       1.32      2.1      2.3
SE'     0.72      0.46      0.96      1.33      1.47      1.08         0.20      0.71      0.46      0.49      0.88      1.16

NW: P = proportion; SE = standard error; n = number of people in sample; N = weighted population estimate. in thouwand.%
' Adjusted by direct method to reflect the age distribution of the U.S. population at the midpoint of the survey.
' Doea not meet n&anti of reliabiiity.
SOURCE Natronal Center for Health Sk&&a. Unpublished data from the fti National Health Nutrition and Examination Survey (NW 1).


TABLE N.-Wheeze of adults, by sex, age, and smoking status, United States, 1971-1975

Never

Former

    Men
Smoking Btatua

Current    Light

Moderate

Never

Former

   Women
Smoking etatua


Current    Liiht

Moderate

2L3.4
P
SE
i

35-44
P
SE
i

4544
P
SE
ii

&64
P
SE
ii

0.0       1.2       1.7       1.1       1.6       2.2          0.4       0.0       0.7       0.0       13      0.0
0.0      1.24      0.77      1.06      1.25      1.28         0.29      00      0.37      0.0      0.79      0.0
166       78       327       72       160      94          399      121      367      119      164      81
3319      1593     8809      1363      3336      1875         6416      1873      6304      2239      2642     1393

0.0       1.0       1.3       0.0       0.9       2.1          0.3       0.0       3.2       0.0       3.6      9.6
0.0      0.75      0.67      0.0      0.89      1.22         0.26      0.0      126      0.0      1.50     4.97
101       117      226       33       93       100          310      107      no      103      114      51
2114      2384      4412      614      1769      2029         5197      1771      4563      1776      1968     799

0.0       1.2       2.5       0.0       4.5       1.8          0.3       0.0       2.4       0.8       3.3      2.5
0.0      1.02      0.93      0.0      2.13      1.27         0.33      0.0      0.94      0.76      1.40      1.76
114      204      296       61       122      112         435      101      329      109      163      57
1568      3290      4262      810      1706      1745         5989      1456      48al      1497      2413     890

0.0       0.4       5.6       2.3       3.3      10.9          0.1       0.0       1.7       0.8       1.4      5.8
0.0      0.37      1.76      1.95      1.69      4.48         0.05      0.0      0.95      0.77      1.18     5.76
94       192      m5       50       91       64         394       86       178       76       82      `20
1320      nsi      2990      708      1305      976         5599      1501      3014      1266      1369     378


z   TABLE N.-Continued


                                Men                                           Women
                      Smoking status                               Smoking status

           Never    Former    Current    Light    Moderate   H=V        NWW     Former    CutTent    Jight    Moderate   H=-Y

65-74
P      0.0       2.5      10.0      0.0      11.4      18.4          1.0       1.9       3.6       2.1       1.6      20.92
SE      0.0      1.11      3.75      0.0      5.27      10.98         0.56      1.85      2.14      2.66      1.64     18.53
i   864 96   2232 232  1199 135   318 39   574 60   295 35    5467 461   956 81   952 83   523 46   362 32   66 5

2%14
P'      0.0       1.2       3.4       0.7       3.5       5.5          0.4       0.2       2.1       0.7       2.3      6.3
SE'     0.0      0.46      0.71      0.46      0.92      1.65         0.14      0.25      0.45      0.41      0.46     2.79

NOTE P = proportion; SE = standard error; n = number of people in sample; N = weighted population estimate, m thousands.
' Adjusted by direct method to reflect the age distribution of the U.S. population at the midpoint of the survey.
`Does not meet 8tandania of reliability.
SOURCE Natwnal Center for Health Statiatva. Unpubliehed data from the first National Health Nutrition and Examination Survey (NHANES 1).


References

ABBOUD, R.T., MORTON, J.W. Comparison of maximal midexpiratory flow, flow
volume curves, and nitrogen closing volumes in patients with mild airway
obstruction. American Review of Respiratory Disease ill(4): 405-417, April 1975.
AMERICAN COLLEGE OF CHEST PHYSICIANSAMERICAN THORACIC SOCI-
ETY. Pulmonary terms and symbols. A report of the ACCP-ATS Joint Committee
on Pulmonary Nomenclature. Chest 67(5): 583-593, May 1975.
AMERICAN THORACIC SOCIETY. Chronic bronchitis, asthma and pulmonary
emphysema. A statement by the committee on diagnostic standards for nontuber-
culous respiratory disease. American Review of Respiratory Disease 85: 762-768,
May 1962.

ANDERSON, A.E., Jr., FORAKER, A.G. Centrilobular emphysema and panlobular
emphysema: Two different diseases. Thorax 28(5): 547550, September 1973.
ANDERSON, A.E., Jr., FURLANETG, J.A., FORAKER, A.G. Bronchopulmonary
derangements in nonsmokers. American Review of Respiratory Disease 101(4~: 51%
527, April 1970.

ANDERSON, A.E., Jr., HERNANDEZ, J.A., ECKERT, P., FORAKER, A.G. Emphyse-
ma in lung macrosections correlated with smoking habits. Science 144(3621): 1025
1026, May 22,1964.

ANDERSON, A.E., Jr., HERNANDEZ, J.A., HOLMES, W.L., FORAKER. A.G.
Pulmonary emphysema. Prevalence, severity and anatomical patterns in macrc-
sections, with respect to smoking habits. Archives of Environmental Health 12(5):
569-577, May 1966.

ANDERSON, D.O., FERRIS, B.G., Jr., ZICKMANTEL, R. The Chilliwack respiratory
survey, 1963: Part III. The prevalence of respiratory disease in a rural Canadian
town. Canadian Medical Association Journal 92(19): 1007-1016, May 8, 1965.
ANDERSON, H.R. Respiratory abnormalities and ventilatory capacity in a Papua
New Guinea island community. American Review of Respiratory Disease 114(3):
537548, September 1976.

ANDERSON, H.R. Chronic lung disease in the Papua New Quinea highlands. Thorax
34: 647-653,1979a.

ANDERSON, H.R. Respiratory abnormalities, smoking habits and ventilatory capaci-
ty in a highland community in Papua New Guinea: Prevalence and effect on
mortality. International Journal of Epidemiology 8(2): 127-135, June 1979b.
ANTHONISEN, N.R., BASS, H., ORIOL, A., PLACE, R.E.G.. BATES, D.V. Regional
lung function in patients with chronic bronchitis. Clinical Science 35(3): 495-511,
December 1968.

ASHLEY, F., KANNEL, W.B., SORLIE, P.D., MASSON, R. Pulmonary function:
Relation to aging, cigarette habit, and mortality. Annals of Internal Medicine
82(6): 739-745, June 1975.

A'ITINGER, E.O., GOLDSTEIN, M.M., SEGAL, MS. Effects of smoking upon the
mechanics of breathing. I. In normal subjects American Review of Tuberculosis
77(l): 1-9, January 1958.

AUERBACH, O., GARFINKEL, L., HAMMOND, E.C. Relation of smoking and age to
findings in lung parenchyma: A microscopic study. Chest 65(l): 29-35, January
  1974.

AUERBACH, O., HAMMOND, E.C., GARFINKEL, L., BENANTE, C. Relation of
smoking and age to emphysema: Whole-lung section study. New England Journal
of Medicine 286U6): 853-857, April 20.1972.
AUERBACH, O., HAMMOND, E.C., KIRMAN, D., GARFINKEL, L. Emphysema
produced in dogs by cigarette smoking. Journal of the American Medical
Association 199(4): 89-94, January 23,1967.
BAKE, B., OXHOJ, H., SIXT, R.. WILHELMSEN, L. Ventilatory lung function
following two years of tobacco abstinence. Scandinavian Journal of Respiratory
Diseases 58(6): 311-318, December 1977.

167


BALCHUM, O.J.. FELTON, J.S., JAMISON, J.N., GAINES, R.S., CLARKE, D.R.,
OWAN, T., The Industrial Health Committee, The Tuberculosis and Health
Association of Los Angeles County. A survey for chronic respiratory disease in an
industrial city. American Review of Respiratory Disease 86(5): 67-85, November
1962.

BANDE, J.. CLEMENT, J., VAN DE WOFSTIJNE, K.P. The influence of smoking
habits and body weight on vital capacity and FEVi in male air force personnel: A
longitudinal and cross-sectional analysis. American Review of Respiratory Disease
122(5): 781-790, November 1980.

BARTER, C.E., CAMPBELL, A.H. Relationship of constitutional factors and cigarette
smoking to decrease in l-second forced expiratory volume. American Review of
Respiratory Disease 113(3): 305-314, March 1976.
BARTER, C.E., CAMPBELL, A.H., TANDON, M.K. Factors affecting the decline of
FEVi in chronic bronchitis. Australian and New Zealand Journal of Medicine 4(4):
339-345, August 1974.

BATES, D.V. The fate of the chronic bronchitic: A report of the ten-year follow-up in
the Canadian Department of Veteran's Affairs Coordinated Study of Chronic
Bronchitis. American Review of Respimtory Disease 108(51: 1043-1065, November
1973.

BATES, D.V. Chronic bronchitis and emphysema. The search for their natural
history. In: Macklem, P.T., Permutt, S. (Editors). The Lung in the Transition
Between Health and Disease. New York, Marcel Dekker, Inc., 1979, pp. l-13.
BECK, G.J., DOYLE, C.A., SCHACHTER, E.N. Smoking and lung function. American
Review of Respiratory Disease 12X2): 149-155, February 1981.
BECK, G.J., DOYLE, CA., SCHACHTER, E.N. A longitudinal study of respiratory
health in a rural community. American Review of Respiratory Disease 12x41: 375
381, April 1982.

BEREND, N. The correlation of lung structure with function. Lang 160(3): 115130,
April 1982.

BEREND, N., SKCMX, C., THURLBECK, W.M. Exponential analysis of lobar
pressure-volume characteristics. 7'horu.r 36: 452-455, June 1981.
BEREND, N., SKOGG, C., WASZKIEWICZ, L., THURLBECK, W.M. Maximum
volumes in excised human lungs: Effects of age, emphysema, and formalin
inflation. Thorax 35tll): 859864, November 1980.
BEREND, N., THURLBECK, W.M. Exponential analysis of pressure-volume relation-
ship in excised human lungs. Journal of Applied Physiology 52(4): 838844, April
1982.

BEREND, N.. WOOLCOCK, A.J., MARLIN, G.E. Correlation between the function
and structure of the lung in smokers. American Review of Respiratory Disease
119(5): 695-705, May 1979.

BIGNON, J. Methods for quantitative pathology with special reference to emphysema
and chronic bronchitis. Bulletin Europeen de Physiopathologie Respiratoire 12(5):
675692, September-October 1976.

BLACK, L.F., KUEPPERS, F. Alphal-antitrypsin deficiency in nonsmokers, American
Review of Respiratory Disease 117(3): 421-428, March 1978.
BLAND, M., BEWLEY. B.R., POLLARD, V., BANKS, M.H. Effect of children's and
parents' smoking on respiratory symptoms. Archives of Disease in Childhood 53(2):
100-105, February 1978.

BODE, F.R.. DOSMAN, J., MARTIN, R.R., MACKLEM, P.T. Reversibility of pulmo-
nary function abnormalities in smokers. A prospective study of early diagnostic
tests of small airways disease. American Journal of Medicine 59(l): 43-52, July
  1975.

BOSSE, R., SPARROW, D., ROSE, CL., WEISS, ST. Longitudinal effect of age and
smoking cessation on pulmonary function. American Review of Respiratory Disease
123(41: 378-381, April 1981.

16G


LKIUHUYS, A. Lung Diseases in Ruml and Urban Communities. U.S. Department of
Health, Education, and Welfare, Public Health Service, National Institutes of
Health, National Heart, Lung, and Blood Institute, Division of Lung Diseases,
National Technical Information Service No. PB-267 974, June 10, 1977, 98 pp.
BOUHUYS, A., BECK, G.J., SCHOENBERG, J.B. Do present levels of air pollution
outdoors affect respiratory health? Nature 276&X7): 4fX-471, November 30.1978.
BOUHUYS, A., BECK, G.J., SCHOENBERG, J.B. Epidemiology of environmental
lung disease. Yak JournuL of Biology and Medicine 52(2): 191-210, March-April
  1979.

BOUSHY, SF., ABGUMRAD, M.H., NORTH, L.B., HELGASON, A.H. Lung recoil
pressure, airway resistance, and forced flows related to morphologic emphysema.
American Review of Respimtory LXsease 104t4): 551-561, October 1971.
BRITI'. E.J., COHEN. B., MENKES, H., BLEECKER, E., PERMUTT, S., ROSEN-
THAL, R., NORMAL, P. Airways reactivity and functional deterioration in
relatives of COPD patients. Chest 77(2): 260-261. February 3980, Supplement.
BROWN, P., GAJDUSEK, D.C. Acute and chronic pulmonary airway disease in
Pacific Island Micronesians. American Journal of Epidemiology 108t4): 266273,
October 1978.

BROWN, R., WOOLCOCK, A.J., VINCENT, N.J., MACKLEM, P.T. Physiological
effects of experimental airway obstruction with beads. JournaZ of Applied
PAysiologv 27(3): 328335, September 1969.
BUIST, A.S., ADAMS, B.E., AZZAM, A.H., SEXTON, G.J. Pulmonary function in
young children with alphai-antitrypsin deficiency: Comparison with matched
control subjects. American Review of Respimtory Disease 122(6): 817-822, Decem-
ber 1980.

BUIST, A.S., BURROWS, B., ERIKSSON, S., MITI'MAN, C., WU, M. The natural
history of air-flow obstruction in PiZ emphysema. American Ret&w of Respimtory
Disease 127(2): S43-S45, February 1983.

BUIST, A.S., DUCIC, S. Smoking. Evaluation of studies which have demonstrated
pulmonary function changes. In: Macklem, P.T., Per-mutt, S. (Editors). The Lung in
the Tmnsition Between Health and Disease. New York, Marcel Dekker, Inc., 1979,
pp. 271-286.

BURST, A.S., GHEZZO, H., ANTHONISEN, N.R., CHERNIACK, R.M.. DUCIC, S.,
MACKLEM, P.T., MANFREDA, J., MARTIN, R.R., McCARTHY, D., ROSS, B.B.
Relationship between the single-breath Nz test and age, sex, and smoking habit in
three North American cities. American Review of Respimtory Disease 120(2): 305-
318, August 1979a.

BUIST, A.S., ROSS, B.B. Predicted values for closing volumes using a modified single
breath nitrogen test. American Review of Respimtory Disease 107(5): 744-752, May
  1973a.

BUIST, A.S., ROSS, B.B. Quantitative analysis of the alveolar plateau in the diagnosis
of early airway obstruction. American Review of Respimtory Disease 108(5): 107%
1087, November 1973b.

BUIST, A.S., SEXTON, G.J., AZZAM, A.M.H., ADAMS, B.E. Pulmonary function in
heteroxygotes for alphai-antitrypsin deficiency: a casecontrol study. American
Review of Respiratory Disease 12Of4): 759-766, October 1979b.
XJIST, AS., SEXTON, G.J., NAGY, J.M., ROSS, B.B. The effect of smoking cessation
and modification on lung function. American Review of &pimtory Dkaz,w 114(l):
116122, July 1976.

iUIST, A.S., VAN FLEET, D.L., ROSS, B.B. A comparison of conventional spirome
tric tests and the test of closing volume in an emphysema screening center.
American Review of Respimtory Disease 107(5): 735-743, May 1973.
XJIST, AS., VOLLMER, W.M., JOHNSON, L.R. Does the single breath Nx test
identify the susceptible individual? Chest 85(6, Supplement): lOS, June 1984.

169

400-144 0 - 85 - 7


BURGHARD, G., COOREMAN. J., PERDRIZET, S., MET%MARCY, G., WELSCH, M
The tobacco habit and respiratory symptoms amongst the adolescents of a French
department. Bulletin of the bakrnationa~ Union Against i%bemuhsis 54(l): 83-86.
March 1979.

BURROWS, B. An over%v of obstructive lung d&eases. Medical Clinics of North
America 65(3): 455-471, May 1981.

BURROWS, B., EARLE, =R.H. Course and prognosis of chronic obstructive lung
disease. A prospectivt%tudy of 209 patienta. New England Journal of Medicine
280(B): 39'7404, February 29,1969.

BURROWS, B., KNUDSON, R.J., CLINE, M.G., LEBOWITZ. M.D. Quantitative
relationships between cigarette smoking and ventilatory function. American
Review of Respimtoty Dieease 115f2): 195-205, February 1977a
BURROWS, B., KNUDSON, R.J., LEBOWITZ, M.D. The relationship of childhood
respiratory illness to adult obstructive airway disease. American Review of
Respiratory Disease 115f5): 751-769, May 1977b.
BURROWS, B., LEBOWITZ, M.D., BARBEE, R.A. Respiratory disorders and allergy
skin-test reactions. Annals of hkrnal Medicine &L(2): 134-139, February 1976.
BURROWS, B., HALONEN, M., BARBEE, R.A., LEBOWITZ, M.D. The relationship of
serum immunoglobulin E to cigarette smoking. American Review of Respimtory
Llisa8e 124: 52&525,1981.

BURROWS, B., LEBOWITZ, M.D., BARBEE, R.A., KNUDSON, R.J., HALGNEN, M.
Interactions of smoking and immunologic factors in relation to airways ohstruc-
tion. Chest 84(6): 657-661. December 1983.

BURROWS, B., TAUSSIG, L.M. As the twig is bent, the tree inclines (perhaps).
American Review of Respiratory Disease 1220: 813-816, December 1989.
CAMPBELL, E.J., LEFRAK, S.S. Physiologic pn of aging in the respiratory
system. In: Kretchel, S.W. (Editor.1 Anehesia and the Geriatric Patient. New
York, Grune and Stratton, Inc., 1983, pp. 23-43.
CHIANG, S.T., WANG, B.C. Acute effecta of cigarette smoking on pulmonary
function. American Review of Respimtoty L&ease lOl(6): 869-868, June 1970.
CIBA FOUNDATION GUEST SYMPOSIUM. Terminology, definitions and classiflca-
tion of chronic pulmonary emphysema and related conditions. Tbomx 14(4): 286
299, December 1959.

CLARKE.B.G., GUYA'IT, A.R.,ALPERS, J.H., -,C.M., HILL, I.D. Changes
in airways conductance on smoking a cigarette. Thorru 25(4): 418422, July 1970.
CLEMENT, J., VAN DE WOESTIJNE, K.P. Rapidly decreasing forced expiratory
volume in one second or vital capacity and development of chronic airflow
obstruction. American Review of Respimtory L&ease 125f5): 553-558. May 1982.
COATES, E.O., Jr., BOWER, G.C., REINSTEIN, N. Chronic respiratory disease in
postal employees. Journal of the American Medical Association 191(3): 161-165,
January 18,1965.

COCHRANE, A.L., CHAPMAN, P.J., OLDHAM, P.D. Observers' errors in taking
medical histories. Lancet l(6662): 1607-1009, May 5,195l.
CGCHRANE, G.M. PRIETG, F., HICKEY, B., BENATAR, S.R.. CLARK. T.J.H. Early
diagnosis of airways obstruction. Thomx 29f4): 389393, July 1974.
COHEN, B.H. Chronic obstructive pulmonary disease: A challenge in genetic
epidemiology. American Journal of Epidemiology 112(2): 274-288, August 1980.
COHEN, B.H., BIAS, W.B., CHASE, G.A., DIAMOND, E.L., GRAVES, CC., LEVY,
D.A., MENKES, H., MEYER, M.B., PERMUTT, S., TGCKMAN, MS. Is ABH
nonsecretor status a risk factor for obstructive lung dii? American Journal of
Epidemiology ill(3): 265291, March 1980a.

COHEN, B.H., CELENTANO, D.D., CHASE, G.A., DIAMOND, E.L., GRAVES, C.G.,
LEVY, D.A., MENKES, H.A., MEYER, M.B., PERMUTT, S., TGCKMAN, MS.
Alcohol consumption and airways obstruction. American Review of Respimtory
Disease 121(2): 205-215, February 198Ob.

170


THE COLLEGE OF GENERAL PRACTITIONERS. Chronic bronchitis in Great
Britain. A national survey carried out by the respiratory diseases study group of
the College of General Practitioners. British Medical Journal Z5258): 973-979,
October 14.1961.

COLLINS, J.V., CLARK, T.J.H., McHARDY-YOUNG. S., COCHRANE, G.M., CRAW-
LEY, J. Closing volume in healthy non-smokers. British Journal of Diseases of the
Chest 67: 19-27, January 1973.

COMSTOCK, G.W., BROWNLOW. W.J., STONE, R.W., SARTWELL, P.E. Cigarette
smoking and changes in respiratory findings. Archives of Environmental Health
21(l): 50-57, July 1970.

COMSTCCK, G.W., STONE, R.W., SAKAI, Y., MATSUYA, T., TONASCIA, J.A.
Respiratory findings and urban living. Archives of Environmental Health 27(3):
14%150, September 1973.

COSIO, M., GHEZO, H., HOGG, J.C., CORBIN, R., LOVELAND, M., DOSMAN, J.,
MACKLEM, P.T. The relations between structural changes in small airways and
pulmonary function tests. New England Journal of Medicine 29823): 1277-1281,
June 8.1978.

COSIO, M.G., HALE, K.A., NIEWOEHNER. D.E. Morphologic and morphometric
effects of prolonged cigarette smoking on the small airways. American Review of
Respiratory Disease 122(2): 265-271, August 1980.
COTES, J.E. Lung Function. (Fourth Edition). Oxford, Blackwell Scientific Publica-
tions, 1979.

CRAPO, R.O., MORRIS, A.H., GARDNER, R.M. Reference spirometric values using
techniques and equipment that meet ATS recommendations. American Review of
Respiratory Disease 123(6): 659-664, June 1981.
DA SILVA, A.M.T., HAMOSH, P. Effect of smoking a single cigarette on the "small
airways." Journal ofApplied Physiology 34(3): 361-365, March 1973.
DEAN, G., LEE, P.N., TODD, G.F., WICKEN, A.J. Report on a Second Retrospective
Mortality Study in North-East England. Part I. Factors Related to Mortality From
Lung Cancer, Bronchitis, Heart Disease and Stroke in Cleveland County, With a
Particular Emphasis on the Relative Risks Associated With Smoking Filter and
Plain Cigarettes. Research Paper 14. London, England, Tobacco Research Council,
1978.115 pp.

DEAN, G., LEE, P.N., TODD, G.F., WICKEN, A.J., SPARKS, D.N. Factors related to
respiratory and cardiovascular symptoms in the United Kingdom. Journal of
Epidemiology and Community Health 32: 86-96, June 1978.

DE HAMEL, F.A., CARRELL, R.W. Heterozygous a,-antitrypsin deficiency: A
longitudinal lung function study. New Galand Medical Journal 94(697): 407410,
December 9,1981.

DeMEYERE, M., VUYLSTEEK, K. Influence of smoking habits and respiratory
symptoms on the ventilatory function: A longitudinal study of a selected
population. Results of the first two and a half years. Department of Health,
Education, and Welfare, Public Health Service, Health Services and Mental
Health Administration, National Clearinghouse for Smoking and Health. Transla-
tion No. 34. Translated from Archives Beiges o!e Medicine So&ale, Hygiene,
Medicine du Travail et Medecine Legale 29(9-10): 581-4, November-December
  1971.

DENSEN, P.M., JONES, E.W., BASS, H.E., BREUER, J., REED, E. A survey of
respiratory disease among New York City postal and transit workers. 2. Ventilato-
ry function test results. Environmental Research 2(4): 277-296, July 1969.
DETELS, R., ROKAW, S.N., COULSON, A.H., TASHKIN, D.P.. SAYRE, J.W.,
MASSEY, F.J., Jr. The UCLA population studies of chronic obstructive respiratory
disease. I. Methodology and comparison of lung function in areas of high and low
pollution. American Journal of Epidemiology 109(l): 33-58, 1979.

171


DETELS, R., TASHIUN, D.P., SIMMONS, M.S., CARMICHAEL, H.E., Jr., SAYRE,
J.W., RORAW, S.N., COUISON, A.H. Clinical significance of pulmonary function
tests. 5. Agreement and disegmement of testa in identifying abnormal lung
function. Chest 82(5): 636638, November 1982.
DICRMAN, M.L., SCHMIDT,C.D.,GARDNER.R.M., MARBHALL,H.W., DAY, W.C.,
WARNER, H.R. On-line computerized spirometry in 738 normal adults. American
Review ofRespimtwy Llimme 16tX6): 78&796, December 1969.
DIEM, J.E., JONES, R.N., HENDRICK, D.J., G-MEYER, H.W., SALVAGGIO,
J.E., WEILL, H. Fiveyear longitudinal study of workers employed in a new
diisocyanate manufacturing plant. American Review of Reapimtory L&use 126:
420-428,1982.

DOSMAN, J., BODE, F., GHEZZG, R.H., MARTIN, R., MACRLEM, P.T. The
relationship between symptoms and functional abnormalities in clinically healthy
cigarette smokers. American Review of Respimtory LXseae 1142): 297-364, August
  1976.

DOSMAN, J.A., CVlTGN, D.J., GRAHAM, B.L., HALL, D.L., LI, R., FROH, F.,
BARNEll', G.D. Sensitivity and specificity of early diagnostic tests of lung
function in smokers. Chest 79(l): 6-11, January 1981.
EDELMAN, N.H., MITTMAN, C., NORRIS, A.H., COHEN, B.H.. SHOCK, N.W. The
effecta of cigarette smoking upon spirometric performance of community dwelling
men. American Review of Respiratory Diseuse 94(3): 421429, September 1966.
EMIRGIL, C., SOBOL, B.J. Pulmonary function in former alcoholics. Chest 72(l) :45-
51, July 1977.

EMIRGIL, C., SOBOL, B.J., VARBLE, A., WALDIE, J., w B. Long-term
course of chronic obstruction pulmonary disease. A new view of the mode of
functional deterioration. American Journal of Medicine 51(4): 594-512, October
  1971.

ENJEl'I, S., HAZELWOOD, B., PERMUTT, S., MENKES, H., TERRY, P. Pulmonary
function in young smokers: Male-female differences. American Review of Respim-
tory Diuawe 118(4): 667676, October 1978.

ERKSSON, S. Studies in a,-antitrypsin deficiency. Acta Medico Scandinavica
117(Supplement 432): l-185,1965.

ERKSS~N, s., MOJ~~-RUP, T., HAGERSTRAND, I. Liver, lung and malignant
disease in heterosygous (PiME) al-antitwin deficiency. A& Medico Scondinavi-
co 19EK4): 243-247, October 1975.

FERRIS, B.C., Jr. Epidemiology standardization project. American Review of Respim-
tory Disuse 118f6, Part 2): l-126, December 1978.
FERRIS, B.C., Jr., ANDERSON, D.O. The prevalence of chronic respiratory disease in
a New Hampshire town. American Review of Respiratory Disease 86(l): 165-177,
July 1962.

FERRIS, B.G., Jr., CHEN, H., PULEO, S., MURPHY, R.L., Jr. Chronic nonspecific
respiratory disease in Berlin, New Hampshire, 1967 to 1973. A further follow-up
study. American Review of Reapimtov L&ease 11x4): 475486, April 1976.
FERRIS, B.G., Jr., HIGGINS, I.T.T., HIGGINS, M.W., PElERS, J.M. Chronic
nonspecific respiratory disease in Berlin, New Ham&ire, 1961 to 1967. A follow-
up study. American Review of Respimtory Diacasc 107(l): 116-122, January 1973.
FERRIS, B.G., Jr., SPEIZER, F.E., SPENGLER, J.D., DOCRERY, D., BISHOP,
Y.M.M., WOLFSON, M., HUMBLE, C. Effecta of sulfur oxides and respirable
particles on human health. Methodology and demography of populations in study.
American Review of Respiratory Dkase 12CK4): 767-779, October 1979.
FISHMAN, A.P. The lungs in later life. In: Fishman, A.P. (Editor). Update: Pulmcnoly
Diseases and Disoro!ers. New York, McGraw-Hill, 1962, pp. 123-136.
FLEICHER, C.M. An 8-year follow-up of FEV and respiratory symptoms in middle
aged men. Scandinovinn Journal of Respimtoty Diseases 57(6): 318-319,1976.

172


FLETCHER, C.M. Terminology in chronic obstruction lung diseases. Journal of
Epidemiology and Community Health 32: 262-266, 1978.
FLETCHER, C.M., PETO, R. The natural history of chronic airflow obstruction.
British Medical Journal l(6077): 16451648, June 25,1977.
FLETCHER, C.M., PESO, R., TINKER, C., SPEIZER, F.E. The Natural History of
Chronic Bronchitis and Emphysema. An Eight-Year Study of Early Chronic
Obstructive Lung Disease in Working Men in London. New York, Oxford
University Press, 1976,272 pp.

FRIEDMAN, G.D., SIEGELAUB, A.B. Changes after quitting cigarette smoking.
Circulation 61(4): 716-723, April 1980.

FULMER, J.D., ROBERTS, W.C., VON GAL, E.R., CRYSTAL, R. Small airways in
idiopathic pulmonary fibrosis. Comparison of morphologic and physiologic observa-
tions. Journal of Clinical Invesligation 60(3): 595-610, September 1977.
GELB, A.F., ZAMEL, N. Simplified diagnosis of small-airway obstruction. New
England Journal of Medicine 288(a): 39&398, February 22,1973.
GELB, A.F., ZAMEL, N. Lung recoil and density dependence of maximum expiratory
flow in emphysema. Bulletin Europeen de Physiopulhologie Respimtoire 17(5): 791
798, Septemberatober 1981.

GOLDSMITH, J.R., HECHTER, H.H., PERKINS, N.M.. BORHANI, N.O. Pulmonary
function and respiratory findings among longshoremen. American Review of
Respimtoty Disease 86(6): 667-674, December 1962.
GREAVES, I.A., COLEBATCH. H.J.H. Elastic behavior and structure of normal and
emphysematous lungs post mortem. American Review of Respimtory Diseclse
121(l): 127-136, January 1980.

GRIMES, C.A.. HANES, B. Influence of cigarette smoking on the spirometric
evaluation of employees of a large insurance company. American Review of
Respimtory Disease 108(2): 273-282, August 1973.
GUENTER, C.A., COALSON, J.J., JAQUES, J. Emphysema associated with intravas-
cular leukocyte sequestration. American Review of Respiratory Disease 123: 79-64,
  1981.

GULSVIK, A. Prevalence of respiratory symptoms in the city of Oslo. Scandinavian
Journal of Respiratory Diseases 60(5): 275-285,1979.
HAINES, A.P., IMESON, J.D., MEADE, T.W. ABH secretor status and pulmonary
function. American Journnl of Epidemiology 115(3): 367370, March 1982.
HANKINS, D., DRAGE, C., ZAMEL, N.. KRONENBERG, R. Pulmonary function in
identical twins raised apart. American Review of Respimtory Disease 125(l): 119-
121, January 1982.

HASLETON, P.S. The internal surface area of the adult human lung. Journal of
Anatomy 112(3): 391-400, September 1972.

HEARD, B.E., KHATCHATOUROV, V., Ol'TO, H., PUTOV, N.V., SOBIN, L. The
morphology of emphysema, chronic bronchitis and bronchiectasis: Definition,
nomenclature and classification. Journal of Clinical Pathology 32(g): 662-892,
September 1979.

HEPPLESTON, A.G., LEOPOLD, J.G. Chronic pulmonary emphysema. Anatomy and
pathogenesis. American Journal of Medicine 31: 279-291, August 1961.
HERNANDEZ, J.A., ANDERSON, A.E., Jr., HOLMES, W.L., FORAKER, A.G.
Pulmonary parenchymal defects in dogs following prolonged cigarette smoke
exposure. American Review of Respimtory Disease 93(l): 7883, January 1966.
HIGENBO'ITAM. T., SHIPLEY, M.J., CLARK, T.J.H., ROSE, G. Lung function and
symptoms of cigarette smokers related to tar yield and number of cigarettes
smoked. Lund l(8165): 409-412, February 23,198O.
HIGGINS, I.T.T. Respiratory symptoms, bronchitis, and ventilatory capacity in a
random sample of an agricultural population. British Medical Journal 2(5055):
1198-1203, November 23.1957.

173


HIGGINS, I.T.T. Epidemiology of Chronic Respiratory Disease: A Literature Review.-
Environmental Health Effects Research Series. US. Environmental Protection
Agency. Office of Research and Development, EPA-650/i-74007, August 1974,
129 pp.

HIGGINS, I.T.T., COCHRANE, A.L. Chronic respiratory disease in a random sample
of men and women in the Rhondda Fach in 1958. British Journal of Industrial
Medicine 18(2): 93-102, April 1961.

HIGGINS, I.T.T., COCHRANE, A.L., GILSON, J.C., WOOD, C.H. Population studies of
chronic respiratory disease. A comparison of miners, foundryworkers, and others
in Staveley, Derbyshire. British Journal of Industrial Medicine 16(4): 25&268,
October 1959.

HIGGINS, I.T.T., GILSON, J.G., FERRIS, B.G., Jr., WATERS, M.E., CAMPBELL, H.,
HIGGINS, M.W. Chronic respiratory disease in an industrial town: A nine-year
follow-up study. Preliminary Report. American Journal of Public Health and the
Nation S Health 58(g): 1667-1676, September 1968b.
HIGGINS, I.T.T., HIGGINS, M.W., LOCKSHIN, M.D., CANALE, N. Chronic respira-
tory disease in mining communities in Marion County, West Virginia. British
Journal of Industrial Medicine 25(3): 165-175, July 1968a.
HIGGINS, I.T.T., OLDHAM, P.D. Ventilatory capacity in miners. A five-year follow-
up study. British Journal of Industrial Medicine 19(l): 65-76, January 1962.
HIGGINS, M.W. Epidemiology of COPD: State of the art. Chest W6): 3s-%, June
1984, Supplement.

HIGGINS, M.W., KELLER, J.B. Familial occurrence of chronic respiratory disease
and familial resemblance in ventilatory capacity. Journal of Chronic Disease 2&X4):
239-251, April 1975.

HIGGINS, M.W., KELLER, J.B., BECKER, M.. HOWATT, W., LANDIS, J.R.,
ROTMAN, H., WEG, J.G., HIGGINS, I. An index of risk for obstructive airways
disease. American Review of Respiratory Disease 125(2): 144-151, February 1982.
HIGGINS, M.W., KELLER, J.B., METZNER, H.L. Smoking, socioeconomic status and
chronic respiratory disease. American Revieul of Respiratory Disease 116(3): 403
410, September 1977.

HIGGINS, M.W., KJELSBERG, M. Characteristics of smokers and nonsmokers in
Tecumseh, Michigan. Il. The distribution of selected physical measurements and
physiologic variables and the prevalence of certain diseases in smokers and
nonsmokers. American Journal of Epidemiology 86(l): -77, July 1967.
HOGG, J.C.. MACKLEM, P.T., THURLBECK, W.M. Site and nature of airway
obstruction in chronic lung disease. New England Journal of Medicine 278(251:
1355-1360, June 20,1968.

HOIDAL, J.R., NIEWOEHNER, D.E. Cigarette smoke inhalation potentiates elastase-

mduced emphysema in hamsters. American Review of Respiratory Disease 127(4):
478-481, April 1983.

HOWARD, P. A long-term follow-up of respiratory symptoms and ventilatory function
in a group of working men. British Journal of Zndvstrial Medicine 27(4): 326333,
October 1970.

HOWARD, P. The changing face of chronic bronchitis with airways obstruction.
British Medical Journal 2(5910): 89-93, April 13, 1974.
HOWARD, P., ASTIN, T.W. Precipitous fall of the forced expiratory volume. Thorax
24(4): 492495, July 1969.

HUBERT, H.B., FABSITZ, R.R., FEINLEIB, M., GWINN, C. Genetic and environmen-
tal influences on pulmonary function in adult twins. American Review of
Respiratory Disease 125(4): 409415, April 1982.
HUGHES, J.A., HUTCHISON, D.C.S., BELLAMY, D., DOWD, D.E., RYAN, KC.,
HUGH-JONES, P. The influence of cigarette smoking and its withdrawal on the
annua! change of lung function in pulmonary emphysema. Quarterly Journal of
Medicine 51(202): 115124, Spring 1982.

174


HUHTI, E. Ventilatory function in healthy nonsmokers and smokers. Scandrnartan
Journal of Respirator-y Diseases 48(2): 149-155,1967.
HUHTI, E., IKKALA, J. A lo-year follow-up study of respiratory symptoms and
ventilatory function in a middle-aged rural population. European Journal of
Respiratory Diseases 61(l): 3345, February 1980.
HUHTI, E., TAKALA, J., NUUTINEN, J., POUKKULA, A. Chronic respiratory
disease in rural men. An epidemiological survey at Hankasalmi. Finland. Annals
of Clinical Research lo(2): 87-94, April 1978.
IDELL, S., COHEN, A.B. Alpha,-antitrypsin deficiency. Cbnics in Chest Medrcine 4(31:
359-375, September 1983.

INGRAM, R.H., SCHILDER, D.P. Association or a decrease in dynamic compliance
with a change in gas distribution. Journal of Applied Physsrology 23~61: 911-916.
  1967.

INGRAM, R.H., O'CAIN. C.F. Frequency dependence of compliance in apparently
healthy smokers vs. non-smokers. Bulletin of Ph.wLologic and Pathologic Respira-
tion 7. 195210, 1971.

JEDRYCHOWSKI. W. A consideration of risk factors and development of chronic
bronchitis in a five-year follow-up study of an industrial population. Journal of
Epidemiology and Community Health 33(3): 21C-214, September 1979.
JOHNSTON, R.N., McNEILL. R.S.. SMITH, D.H., LEGGE, J.S.. FLETCHER, F.
Chronic bronchitis: Measurements and observations over 10 years. Thorax 31(11:
25-29, February 1976.

KANNER, R.E., RENZETTI, A.D.. Jr., KLAUBER, M.R., SMITH. C.B.. GOLDEN, C.A.
Variables associated with changes in spirometry in patients with obstructive lung
diseases. American Journal of Medicine 67: 44-50. July 1979.
KAUFFMANN, F., DROUET, D., LELLOUCH, J.. BRILLE. D. Twelve-year spirome-
tric changes among Paris area workers. International Journal of Epidemlolog>
8(3): 201-212, September 1979.

KAUFFMANN, F., DROUET, D., LELLOUCH, J., BRILLE, D. Occupational exposure
and 12-year spirometric changes among Paris area workers. Britah Journal of
Industrial Medicine 3%3): 221-232, August 1982b.
KAUFFMANN, F., KLEISBAUER, J.P., CAMBON-DE MOUZON. A., MERCIER, P.,
CONSTANS, J., BLANC, M., ROUCH, Y., FEINGOLD, N. Genetic markers in
chronic air-flow limitation. A genetic epidemiologic study. Amerzcan Review of
Respiratory Disease 127(3): 263-269, March 1983.
KAUFFMANN, F., MARTY, Y., KLEISBAUER, J.P., CAMBON-DE MOUZON, A.,
ROUCH, Y., DUCOS, J., FEINGOLD, J. ABH non-secretor status, blood group 0,
and chronic air-flow limitation. (Letter). Lancet 1: 513-514, February 27, 1982a.
KESTELOOT, H., VUYLSTEKE, M., VAN HOUTE, 0. Distribution and consequences
of smoking habits in a cross-sectional epidemiological survey. Journal of Chronic
Diseases 29(5): 301310, May 1976.

KHOSLA. T. Indices of ventilatory measurements. British Journal of PreuentiLv and
Social Medicine 25(4): 203-209, November 1971.
KIDOKORO, Y., KRAVIS, T.C., MOSER, K.M., TAYLOR, J.C., CRAWFORD, I.P.
Relationship of leukocyte elastase concentration to severity of emphysema in
homozygous alpha,-antitrypsindeficient persons. American Reuieul of Respiratory
Disease 115(5): 793-803, May 1977.

KIERNAN, K.E., COLLEY, J.R.T., DOUGLAS, J.W.B., RIED, D.D. Chronic cough in
young adults in relation to smoking habits, childhood environment and chest
illness. Respiration 33(3): 236-244, 1976.

KJUUS, H., ISTAD, H., LANGARD, S. Emphysema and occupational exposure to
industrial pollutants. Scandinavian Journal of Work, Enuironment and Health
7(4): 29C-297, December 1981.

175


KNUDSON, R.J., BURROWS, B., LEBOWITZ, M.D. The maximal expiratory flow-
volume curve: Its use in the detection of ventilatory abnormalities in a population
study. American Review of Respiratory Disease 114(3): 871-879, November 1976.
KNUDSON, R.J., CLARK, D.F., KENNEDY, T.C., KNUDSON, D.W. Effect of aging
alone on mechanical properties of the normal adult human lung. Journal of-
Applied Physiology: Respiratory, Environmental and Exercise Physiology 43(6):
1054-1062, December 1977.

KNUDSON, R.J., LEBOWITZ, M.D. Comparison of flow-volume and closing volume
variables in a random population. American Review of Respiratory Disease llq6):
1039-1045, December 1977.

KNUDSON, R.J., KALTENBORN, W.T. Evaluation of lung elastic recoil by exponen-
tial curve analysis. Respiratory Physiology 46: 29-42,1981.
KNUDSON, R.J., LEBOWITZ, M.D., HOLBERG, C.J., BURROWS, B. Changes in the
normal maximal expiratory flow-volume curve with growth and aging. American
Review of Respimtory Disease 127(61: 725-734, June 1983.
KRUMHOLZ, R.A., HEDRICK, E.C. Pulmonary function differences in normal
smoking and nonsmoking, middle-aged, white-collar workers. American Review of
Respiratory Disease 107(2): 225-230, February 1973.
KRZYZANOWSKI, M. Changes of ventilatory capacity in an adult population during
a five-year period. Bulletin Europeen de Physiopathologie Respimtoire 16(2): 155
170,198o.

KUEPPERS, F., BLACK, L.F. Alphai-antitrypsin and its deficiency. American Review
of Respimtoy Disease llo(2): 176194, August 1974.
KUEPPERS, F., MILLER, R.D., GORDON, H., HEPPER, N.G., OFFORD, K. Familial
prevalence of chronic obstructive pulmonary disease in a matched pair study.
American Journal of Medicine 63: 336-342, September 1977.
LAM, S., ABBOUD, R.T., CHAN-YEUNG, M., TAN, F. Use of maximal expiratory
flow-volume curves with air and helium-oxygen in the detection of ventilatory
abnormalities in population surveys. American Review of Respimtory Disease
123(2): 234-237, February 1981.

LARSSON, C. Natural history and life expectancy in severe alphai-antitrypsin
deficiency, PiZ. Acta Medica Bcandinavica 204(5): 345-351, May 1978.
LARSSGN, C., ERIKSSON, S., DIRKSEN, H. Smoking and intermediate alpha-l-
antitrypsin deficiency and lung function in middle-aged men. British Medical
Journal 2(6092): 922-925, October 8,1977.
LEBOWITZ, M.D. Occupational exposures in relation to symptomatology and lung
function in a community population. Environmental Research 14(l): 59-67, August
  1977a.

LEBOWITZ, M.D. The relationship of so&-environmental factors to the prevalence of
obstructive lung diseases and other chronic conditions. Journal of Chronic Diseases
30(g): 599-611, September 1977b.

LEBOWITZ, M.D. Respiratory symptoms and disease related to alcohol consumption.
American Review of Respimtory Disease 123(l): 1618, January 1981.
LEBOWITZ, M.D., BURROWS, B. Q uantitative relationships between cigarette
smoking and chronic productive cough. International Journal of Epidemiologv6(2):
107-113, June 1977.

LEBOWITZ, M.D., KNUDSON, R.J., BURROWS, B. Tucson Epidemiologic study of
obstructive lung diseases. I: Methodology and prevalence of disease. American
Journal of EpidemialogV 102(2): 137-152, August 1975.
LEBOWITZ, M.D., KNUDSON, R.J., BURROWS, B. Family aggregation of pulmonary
function measurements American Review of Respiratory Disease 129(l): 8-11,
  1984.

LEBOWITZ, M.D, KNUDSON, R.J., BURROWS, B. Risk factors for airways obstruc-
tive diseases: A multiple logistics approach. Chest 85(6): 11~12s June 1984,
Supplement.

176


LEEDER, S.R., COLLEY. J.R.T., CORKHILL, R.. HOLLAND, W.W. Change in
respiratory symptom prevalence in adults who alter their smoking habits.
American Journal of Epidemiology 105(6): 522-529,1977.
LEFCOE, N.M., ASHLEY, M.J., PEDERSON, L.L., KEAYS, J.J. The health risks of
passive smoking. The growing case for control measures in enclosed environments.
Chest 84(l): 9&95,1983.

LEFCOE, N.M.. WONNACO'IT, T.H. Chronic respiratory disease in four occupational
groups. Archives ofEnvironmental Health 29(3): 143-146, September 1974.
LIANG, A., MACFIE, A.E., HARRIS, E.A., WHITLOCK, R.M.L. Transit-time analysis
of the forced expiratory spirogram during clinical remission in juvenile asthma.
Thorax 34(2): 194-199, April 1979.

LIARD, R., PEDRIZET. S., COOREMAN, J., BIDOU, S. Smoking and chronic
respiratory symptoms: Prevalence in male and female smokers. American Journal
of Public Health 70(3): 271-273, March 1980.
LINN, W.W., HACKNEY, J.D., PEDERSEN, E.E., BREISACHER, P., PATTERSON,
J.V., MULRY, C.A., COYLE, J.F. Respiratory function and symptoms in urban
office workers in relation to oxidant air pollution exposure. American Review of
Respimtory Disease 114(3): 477-483, September 1976.
LOVE, R.G., MILLER, B.G., Longitudinal study of lung function in coal-miners.
Thorax 37(3): 193-197, March 1982.

MACFIE, A.E., HARRIS, E.A., WHITLOCK, R.M.L. Transit-time analysis of the
forced spirogram in healthy children and adults. Journal of Applied Physiology:
Respimtory, Environmental and Exercise Physiology 46(2): 263267, February 1979.
MACKLEM, P.T., MEAD, J. Resistance of central and peripheral airways measured
by retrograde catheter. Journal of Applied Physiology 22(3): 395-401, March 1967.
MACNEE, W., POWER, J., INNES, A., DOUGLAS, N.J., SUDLOW, M.F. The
dependence of maximal flow in man on the airway gas physical properties. Clinical
Science 65(3): 273-279, September 1983.
MADISON, R., MITTMAN, C., AFIFI, A.A., ZELMAN, R. Risk factors for obstructive
lung disease. American Review of Respiratory Disease 124: 149153, August 1981.
MANFREDA, J., NELSON, N., CHERNIACK, R.M. Prevalence of respiratory
abnormalities in a rural and an urban community. American Review of Respim-
tory Disease 117(2): 215-226, February 1978.

MARAZZINI, L., PELOSI, V., VEZZOLI, F., PENNASI, R., LGNGHINI, E. Prospec-
tive study of airway obstruction in a population with small airway disease.
Bulletin Europeen & Physiopathologie Respimtoire 13(2): 219-229, March-April
  1977.

MARAZZINI, L. VEZZOLI, F., LONGHINI, E. Respiratory function 8 years after a
diagnosis of peripheral airways disease. Respiration 42(2): 88-97,1981.
MARCQ, M., MINE'ITE, A. Lung function changes in smokers with normal
conventional spirometry. American Review of Respiratory Disease 114(4): 723-738,
October 1976.

McCARTHY, D.S., CRAIG, D.B., CHERNIACK, R.M. Effect of modification of the
smoking habit on lung function. American Review of Respiratory Disease 114(l):
103-113, July 1976.

McCARTHY, D.S., SPENCER, R., GREENE, R., MICLICEMILI, J. Measurement of
"closing volume" as a simple and sensitive test for early detection of small airway
dise~~. American Journal of Medicine 52: 747-753, June 1972.
MEAD, J. Problems in interpreting common tests of pulmonary mechanical function.
In: Macklem, P.T., Permutt, S. (Editors). The Lung in the Transition Between
Health and Disease. New York, Marcel Dekker, Inc., 1979, pp. 43-51.
MEDICAL RESEARCH COUNCIL COMMITTEE ON THE AETIOLOGY OF CHRON-
IC BRONCHITIS. Standardized questionnaires on respiratory symptoms. British
Medical Journal 2(5213): 1665, December 3.1960.

177


MENDELSSOHN, A Journal of the Russian National Health Society, September
1897. Lanwf 2~38671: 952-953, 1897.

MICHAEL% R.. SIGLTRDSON. M.. THURLBECK, S., CHERNIACK, R. Elastic recoil
of the lung in cigarette smokers: the effect of nebulized bronchodilator and
cessation of smoking. American ReLliew of Respirator?, Disease 119(5): 707-716, May
  1979

MILLER, A., THORNTON, J.C.. WARSHAW, R., ANDERSON, H., TEIRSTEIN, A.S.,
SELIKOFF. I.J. Single breath diffusing capacity in a representative sample of the
population of Michigan, a large industrial state. Predicted values, lower limits of
normal, and frequencies of abnormality by smoking history. American Review of
Respiratop Dispase 127(3): 270-277, March 1983.
MILNE, J.S. Longitudinal respiratory studies in older people. Thorax 33: 547-554.
  1978.

MIMICA. M. Stud-v of Regional Prevalence and Incidence of Chronic Bronchitis and
Asthma in Adults. Final Report. US. Department of Health, Education, and
Welfare. Public Health Service, National Institutes of Health, January 1975.
MINK, S.N., WOOD, L.D.H. How does HeOzincrease maximum expiratory flow in
human lungs? Journal of Clinical Investigation 66(4): 720-729, October 1980.
MITCHELL, R.S., STANFORD. R.E., JOHNSON, J.M., SILVERS, G.W., DART, G.,
GEORGE, MS. The morphologic features of the bronchi, bronchioles and alveoli in
chronic airway obstruction: A clinicopathologic study. American Review of
Respzratorq. Disease 114: 137-145, July 1976.
MI'ITMANN, C. The PiMZ phenotype: Is it a significant risk factor for the
development of chronic obstructive lung disease? American Review of Respiratory
Disease 118(4): 649-652, October 1978.

MONSON. R.R. Occupational EpidemLology. Boca Raton, Florida, CRC Press, Inc.,
  1980.

MORRIS, J.F., KOSKI, A., JOHNSON, L.C. Spirometric standards for healthy
nonsmoking adults. American Reoiew of Respiratory Disease 103(l): 5747,
January 1971.

MORSE, J.O. Alphal-antitrypsin deficiency. New England Journal of Medicine
29%19): 104%1048, November 9, 1978 and 299(20): 1099-1105, November 16,197s.
MUELLER, R.E.. KEBLE, D.L., PLUMMER, J., WALKER, S.H. The prevalence of
chronic bronchitis, chronic airway obstruction, and respiratory symptoms in a
Colorado city. American Review of Respiratory Disease 103(2): 209-228, February
  1971.

MUELLER, W.H., CHAKRABORTY, R., BARTON, S.A., ROTHHAMMER, F.,
SCHULL, W.J. Genes and epidemiology in anthropological adaptation studies:
Familial correlations in lung function in populations residing at different altitudes
in Chile. Medical Anthropo1og.v 4(3): 367-384, Summer 1980.
MULTIPLE RISK FACTOR INTERVENTION TRIAL RESEARCH GROUP. Risk
factor changes and mortality results. Journal of the American Medical Association
248(12): 14651477, September 24. 1982.

NADEL. J.A.. COMROE, J.H.. Jr. Acute effects of inhalation of cigarette smoke on
airway conductance. Journal ofApplied Phvsiolom 16(4): 713-716, July 1961.
NATIONAL CENTER FOR HEALTH STATISTICS. Vital and Health Statistics Serves
:Vo. 136. DHHS Publication No. (PHS) 81-1564, 1981.
NATIONAL CENTER FOR HEALTH STATISTICS. Unpublished data.
NEMERY, B., MOAVERO, N.E., BRASSEUR, L., STANESCU, D.C. Significance of
small airway tests in middle-aged smokers. American Review of Respiratop
Disease 124131: 232-238, September 1981.

NERI, L.C.. MANDEL. J.S., HEWITT. D., JURKOWSKI. D. Chronic obstructive
pulmonary disease in two cities of contrasting air quality. Canadian Medical
Assoclatzon Journal 113tlli: 104>1046, December 13, 1975

178


NEUBURGER, N., LEVISON. H., KRUGER, K. Transit time analysis of the forced
expiratory vital capacity in cystic fibrosis. American Reuiew of Respirutop Disease
114(4): 753-759, October 1976.

NEUKIRCH, F., LIARD, R., COOREMAN, J., PERDRIZET, S. Prevalence of respira-
tory symptoms in Parisian teenagers according to smoking habits. Journal of
Epidemiology and Community Health 36(31: 202-204, September 1982.
O'DONNELL, T.V., DE HAMEL, F. Objective respiratory screening among Dunedm
public servants. New Zealand Medical Journal 84: 99-103, August 11,1976.
OGILVIE, A.G., STRANG. C., LEGGAT, P.O., NEWELL, D.J. A Ten-Year Pro.spectrLre
Study of Chronic Bronchitis in the North-East of England. Edinburgh, Churchill
Living&me, 1973.

ORELL, S.R., MAZODIER, P. Pathological findings in a,-antitrypsin deficiency. In:
Mittman, C. (Editor). Pulmonary Emphysema and Pmteolysis. New York, Academic
Press, 1972, pp. 69-88.

ORIE, N.G., SLUITER, H.J., DeVRIES, K., TAMMELING. G.J., WITKOP. J. The host
factor in bronchitis. In: Orie, N.G.M., Sluiter, H.J. (EditorsI. Bronchitis, An
International Symposium, April 27-29. 1960. Assen. Netherlands, Charles C
Thomas, Royal Vangorcum, 1961, pp. 43-59.
OSMAN, M., CANTOR, J., ROFFMAN, S.. TURINO, G.M., MANDL, I. Tobacco smoke
exposure retards elastin repair in experimental emphysema. American Review of
Respiratory Disease 125(4): 213A, April 1982.
OXHOJ. H., BAKE, B., WILHELMSEN, L. Spirometry and flow-volume curves in 1&
year follow-up in men born 1913. Scandinavian Journal of Respiratory Diseases
57(6): 310-312, 1976.

PARE, P.D., BROOKS, L.A.. BATES, J., LAWSON, L.M., NELEMS, J.M.B., WRIGHT,
J.L., HOGG, J.C. Exponential analysis of the lung pressure-volume curve as a
predictor of pulmonary emphysema. American Revieu: of Respirato? Disease
1260): 54-61, July 1982.

PARK, S.S., JANIS, M., SHIM, C.S., WILLIAMS, M.H., Jr. Relationship of bronchitis
and emphysema to altered pulmonary function. American Review of Respiratoo
Disease 102(6): 927-936, December 1970.

PARK, S.S., KIKKAWA, Y., GOLDRING, I.P., DALY, M.M., ZELEFSKY, M., SHIM,
C., SPIERER. M., MORITA, T. An animal model of cigarette smoking in beagle
dogs: Correlative evaluation of effects on pulmonary function, defense, and
morphology. American Review of Respimtory Disease 115(61: 971-979, June 1977.
PARK, T.K. Cigarette smoking patterns among students attending a Christian
university in Seoul, Korea. Yonsei Medical Journal 2'32): 145154,198l.
PERMU'IT, S., MENKES, H.A. Spirometry. Analysis of forced expiration within the
time domain. In: Macklem, P.T., Permutt, S. fRditors). The Lung in the Transition
Between Health and Disease. New York, Marcel Dekker, 1979, pp. 113-152.
PE'IQ R., SPEIZER, F.E., COCHRANE, A.L., MOORE, F., FLETCHER, C.M.,
TINKER, CM., HIGGINS, I.T.T., GRAY, R.G., RICHARDS, S.M., GILLILAND, J.,
NORMAN-SMITH, B. The relevance in adults of air-flow obstruction, but not of
mucus hypersecretion, to mortality from chronic lung disease: Results from 20
years of prospective observation. American Review of Respiratov Disease 128(3):
491-500, September 1983.

PETTY, T.L., PIERSON, D.J., DICK, N.P., HUDSON, L.P., WALKER, S.H. Follow-up
evaluation of a prevalence study for chronic bronchitis and chronic airway
obstruction. American Review of Respiratory Disease 114(3): 881-890, November
  1976.                                   I

PITY, T.L., RYAN, S.F., MITCHELL, R.S. Cigarette smoking and the lungs:
Relation to postmortem evidence of emphysema, chronic bronchitis and black lung
pigmentation. Archives of Environmental Health 14: 172-177, January 1967.

179


PETTY, T.L., SILVERS, G.W., STANFORD, R.E. Functional correlations with mild
and moderate emphysema in excised human lungs. American Review of Respim-
tory Disease 12X6): 700-764, December 1981.
POUKKULA. A., HUHTI, E., MAKARAINEN, M. Chronic respiratory disease among
workers in a pulp mill. A ten-year follow-up study. Chest 81(3): 285-289, March 3,
  1982.
QIZILBASH, A., YOUNG-PONG, 0. Alphal-antitrypsin liver disease in differential
diagnosis of PASpositive, diastaseresistant globules in liver cells. American
Journal of Clinical Pathology 7%6): 697-702, June 1983.
RAWBONE, R.G., KEELING, C.A., JENKINS, A., GUZ, A. Cigarette smoking among
secondary school children in 1975. Prevalence of respiratory symptoms, knowledge
of health haxards, and attitudes to smoking and health. Journal of Epidemiology
and Community Health 32(l): 53-58, March 1978.
REID, L.M. Pathology of chronic bronchitis. Luncet l(6806): 275-278, February 6,
  1954.
ROBERTSON, D.G., WARREL, D.A., NEWTON-HOWE& J.S., FLETCHER, C.M.
Bronchial reactivity to cigarette and cigar smoke. British Medical Journal 3(5665):
269-271, August 2,1969.
ROKAW, S.N., DETELS, R., COULSON, A.H., SAYRE, J.W., TASHKIN, D.P.,
ALLWRIGHT, S.S., MASSEY, F.J., Jr. The UCLA population studies of chronic
obstructive respiratory disease. 3. Comparison of pulmonary function in three
communities exposed to photochemical oxidants, multiple primary pollutants, or
minimal pollutants. Chest 78: 252-262, August 1980.
RYAN, S.F., VINCENT, T.N., MITCHELL, R.S., FILLEY, G.F., DART, G. Ductectasia:
An asymptomatic pulmonary change related to age. Medicinu Thomcalis 22(2):
181-187,1%X.
RYDER, R.C., DUNNILL, M.S., ANDERSON, J.A. A quantitative study of bronchial
mucous gland volume emphysema and smoking in a necropsy population. Journal
ofpathology 104(l): 59-71, May 1971.
RYDER, R.C., THURLBECK, W.M., GOUGH, J. A study of the interobserver
  variation in the assessment of the amount of pulmonary emphysema in paper-
mounted whole lung sections. American Review of Respiratory Disease 99: 354-364,
  March 1969.
SALMON, R.B., SAIDEL, G.M., INKLEY, S.R., NIEWOEHNER, D.E. Relationship of
ventilation inhomogeneity to morphologic variables in excised human lungs.
American Review of Respimtory Disease 126(4): 686690, October 1982.
SAMEI', J.M. A historical and epidemiologic perspective on respiratory symptoms
questionnaires. American Journal of Epidemiology 108f61: 435446, December
  1978.
SAMEX', J.M., SCHRAG, S.D., HOWARD, CA., KEY, CR., PATHAK, D.R. Respira-
tory disease in a New Mexico population sample of Hispanic and non-Hispanic
whites. American Review of Respimtoy Disease X%(2): 152-157, February 1982.
SAMET, J.M., TAGER, LB., SPEIZER, F.E. The relationship between respiratory
illness in childhood and chronic air-flow obstruction in adulthood. American
Review of Rtxpimtory Disease 127(41: 508-523, April 1983.
SARIC, M., LUCICPALAIC, S., HORTON, R.J.M. Chronic nonspecific lung disease
and alcohol consumption. Environmental Research 14(l): 14-21, August 1977.
SAWICKI, F. Regression Persistence and Incidence of Chronic Bronchitis in a Sample
of an Urban Population Followed Up for 5 Years Presented at the 8th
International Scientific Meeting of the International Epidemiological Association,
Puerto Rico, September 1977.
SCHENKER, M.B., SAMET, J.M., SPEIZER, F.E. Effect of cigarette tar content and
smoking habits on respiratory symptoms in women. American Review of Respim-
tory Diseclse 125(6): 684-690, June 1982.
SCHILLING, R.S.F., LETAI, A.D., HUI, S.L., BECK, G.J., SCHOENBERG, J.B.,
BOUHUYS, A. Lung function, respiratory disease, and smoking in families.
American Journal of Epidemiology 106(4): 274-283, October 1977.


SCHLESINGER, Z., GOLDBOURT, U., MEDALIE, J.H., RISS, E., NEUFELD, H.N.,
ORON, D. Pulmonary function and respiratory disease among adult male Israelis.
Variations by age and birth place. Israel Journal of Medical Sciences 8(7): 957-964,
July 1972.

SCHUYLER, M.R., RYNBRANDT, D.J., KLEINERMAN, J. Physiologic and morph*
logic observations of the effects of intravenous elastase on the lung. American
Review of Respimtory Disease 117(l): 97-102, January 1978.
SEELY, J.E., ZUSKIN, E., BOUHUYS, A. Cigarette smoking: Objective evidence for
lung damage in teenagers. Science 172(3963): 741-743, May 14.1971.
SHARP, J.T., PAUL, O., LEPPER, M.H., McKEAN, H.. SAXON, G.A., Jr. Prevalence
of chronic bronchitis in an American male urban industrial population. American
Review of Respimtory Disease 91(4): 510-520, April 1965.
SHARP, J.T., PAUL, 0.. McKEAN, H., BEST, W.R. A longitudinal study of bronchitic
symptoms and spirometry in a middle-aged, male, industrial population. American
Review of Respimtory Disease 108(5): 1066-1077, November 1973.
SILVERS, G.W., PETTY, T.L., STANFORD, R.E. Elastic recoil changes in early
emphysema. Thorox 35: 490-495. July 1960.
SIMONSSON, B. Effect of cigarette smoking in the forced expiratory flow rate.
American Review of Respiratory Disease 85: 543-539.1962.
SLUIS-CREMER, G.K., SICHEL, H.S. Ventilatory function in males in a Witwaters-
rand town. Comparison between smokers and nonsmokers. American Review of
Respimtory Diseoae g&2): 229-239, August 1966.
SOBOL, B.J., VAN VOORHIES, L., EMIRGIL, C. Detection of acute effects of
cigarette smoking on airway dynamics: A critical and comparative study of
pulmonary function tests Thorax 32(3): 312-216, June 1977.
SPAIN, D.M., SIEGEL, H., BRADESS, V.A. Emphysema in apparently healthy adults.
Smoking, age, and sex. Journal of the American Medical Association 224(3): 322-
325, April 16,1973.

SPARROW, D., ROSNER, B., COHEN, M., WEISS, ST. Alcohol consumption and
pulmonary function. A croes-sec tionai and longitudinal study. American Review of
Respiratory Disease 127(6): 735733, June 1963a.
SPARROW, D., STEFOS, T., BOSSE, R.. WEISS, S.T. The relationship of tar content
to decline in pulmonary function in cigarette smokers. American Review of
Respiratory Disease 127(l): 5656, January 198313.
SPEIZER, F.E., TAGER, I.B. Epidemiology of chronic mucus hypersection and
obstructive airways disease. Epidemiologic Reviews 1: 124-142.1979.
STANESCU, D.C., VERITER, C., FRANS, A., BRASSEUR, L. Maximal expiratory
flow rates and "closing volume" in asymptomatic healthy smokers. Scandinavian
Journal of Respimtoty Disease 54(4): 264-271.1973.
STEBBINGS, J.H., Jr. Chronic respiratory disease among nonsmokers in Hager&own,
Maryland. III. Social class and chronic respiratory disease. Environmental
Researrh 4(3): 213-232, August 1971.

STERLING, G.M. Mechanism of bronchoconstriction caused by cigarette smoking.
British Medical Journal 3(5560): 275277, July 29,1967.
STUART-HARRIS, C.H. Chronic bronchitis (Part I). Abstracts of World Medicine
42(g): 64-9, September 1966a.

STUART-HARRIS, C.H. Chronic bronchitis (Part II). Abstracts of World Medicine
42(10): 737-751, October 1966b.

SUTINEN, S., VAAJALAHTI, P., PAAKKO, P. Prevalence, severity, and types of
pulmonary emphysema in a population of deaths in a Finnish city. Correlation
with age, sex and smoking. Scandinavian Journal of Respimtory Disease 59(2):
101-115, April 1978.

SYMONDS, G., RENZE'PTI, A.D., Jr., MITCHELL, M.M. The diffusing capacity in
pulmonary emphysema. American Review of Respiratory Disease 109(3): 391-393,
March 1974.

181


TAGER, LB., ROSNER, B., TISHLER, P.V., SPEIZER, F.E., KASS, E.H. Household
aggregation of pulmonary function and chronic bronchitis. American Review of
Respiratory Disease 114(3): 485492, September 1976.
TAGER, I.B., SPEIZER, F.E. Risk estimates for chronic bronchitis in smokers: A study
of male-female differences. American Review of Respiratory Disease 113(5): 619
625, May 1976.

TAGER, I., TISHLER, P.V., ROSNER, B., SPEIZER, F.E., LI'll', M. Studies of the
familial aggregation of chronic bronchitis and obstructive airways disease.
International Journal of Epidemiology 7(l): 55-62, March 1978.
TATTERSALL, S.F., BENSON, M.K., HUNTER, D., MANSELL, A., PRIDE, N.B.,
FLETCHER, C.M. The use of tests of peripheral lung function for predicting future
disability from airflow obstruction in middle-aged smokers. American Review of
Respiratory Disease 118(6): 10351050, December 1978.
TATTERSALL, S.F., PEREIRA, R.P., HUNTER, D., BLUNDELL, G., PRIDE, N.B.
Lung distensibility and airway function in intermediate alphal-antritrypsin
deficiency (PiMZ). Thorax 34(5): 637-646, October 1979.
THURLBECK, W.M. A clinicopathological study of emphysema in an American
hospital. Thorax 18(l): 59-67, March 1963.
THURLBECK, W.M. The diagnosis of emphysema. Thorax 19(6): 571-574, November
  1964.

THURLBECK, W.M. Internal surface area and other measurements in emphysema.
Thorax 22(6): 483-496, November 1967a.

THURLBECK, W.M. The internal surface area of nonemphysematous lungs. Ameri-
can Review of Respiratory Disease 9X5): 765-773, May 1967b.
THURLBECK, W.M. Chronic Airflow Obstruction in Lung Disease. Major Problems in
Pathology, Volume 5. Philadelphia, W.B. Saunders Company, 1976,456 pp.
THURLBECK, W.M. Aspects of chronic airflow obstruction. Chest 72(3): 341-349,
September 1977.

THURLBECK, W.M. Post-mortem lung volumes. `2Xoro.z 34(6): 735-739, December
  1979.

THURLBECK, W.M. Overview of the pathology of pulmonary emphysema in the
human. Clinics in Chest Medicine 4(3): 337350, September 1983.
THURLBECK, W.M., DUNNILL, M.S., HARTUNG, W., HEARD, B.E., HEPPLE-
STON, A.G., RYDER, R.C. A comparison of three methods of measuring emphyse-
ma. Human Pathology l(2): 215226, June 1970.
THURLBECK, W.M., RYDER, R.C., STERNBY, N. A comparative study of the
severity of emphysema in necropsy populations in three different countries.
American Review of Respiratory Disease 109(2): 239248, February 1974.
TOBIN, M.J., COOK, P.J.L., HUTCHISON, D.C.S. Alphal-antitrypsin deficiency: The
clinical features and physiological features of pulmonary emphysema in subjects
homozygous for Pi type Z. A survey by the British Thoracic Association. British
Journal of Diseases of the Chest 77: 14-27, January 1983.
TGCKMAN, M.S. Follow-up Study of Pulmonary Function in Nonsmokers. Doctoral
Dissertation, The Johns Hopkins University, Baltimore. Ann Arbor, University
Microfilms International, Thesis No. 79-24643,1979,650 pp.
TOCKMAN, M., MENKES, H., COHEN, B., PERMUTT. S., BENJAMIN, J., BALL,
W.C., Jr., TONASCIA, J. A comparison of pulmonary function in male smokers
and nonsmokers. American Review of Respiratory Disease 114(4): 711-720, October
  1976.

U.S. DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE. Smoking and
Health: A Report of the Surgeon Ceneml. US. Department of Health, Education,
and Welfare, Public Health Service, Office of the Assistant Secretary for Health,
Office on Smoking and Health, DHEW Publication No. (PHQ79-50066, 1979, 1136
  PP.

182


U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES, The Health Conse-
quences of Smoking for Women: A Report of the Surgeon General. U.S. Department
of Health and Human Services, Public Health Service, Office of the Assistant
Secretary for Health, Office on Smoking and Health, 1980a. 359 pp.
U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES. Report of Task Force
on Epidemiology of Respiratory Disease. State of Knowledge, Problems, Needs. July
1979. Public Health Service, National Institutes of Health, NIH Publication No.
81-2019, October 1980b.

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES. The Health Conse-
quences of Smoking. The Changing Cigarette: A Report of the Surgeon General. U.S.
Department of Health and Human Services, Public Health Service, Office of the
Assistant Secretary for Health, Office on Smoking and Health, DHHS Publication
No. (PHS)81-50156,1981,269 pp.

US. PUBLIC HEALTH SERVICE. Smoking and Health. Report of the Advisory
Committee to the Surgeon General of the Public Health Service. U.S. Department of
Health, Education, and Welfare, Public Health Service, Center for Disease Control,
PHS Publication No. 1103, 1964,387 pp.

U.S. PUBLIC HEALTH SERVICE. The Health Consequences of Smoking. A Report of
the Surgeon Geneml, 1971. U.S. Department of Health, Education, and Welfare,
Public Health Service, Health Services and Mental Health Administration. DHEW
Publication No. (HSM)71-7513,1971,458 pp.
U.S. PUBLIC HEALTH SERVICE. Prevalence of Selected Chronic Respiratory
Conditions, United States, 1970. Vital and Health Statistics data from the National
Health Survey, Series 10, Number 84, September 1973.
VAN DER LENDE, R., KOK, T.J., PESET REIG, R., QUANJER, Ph.H., SCHOUTEN,
J.P., ORIE, N.G.M. Decreases in VC and FEVI, with time: Indicators for effects of
smoking and air pollution. Bulletin Europeen d.e Physiopathologie Respiratoire
17(5): 775-792, September-October 1981.

WALTER, S., NANCY, N.R., COLLIER, C.R. Changes in the forced expiratory
spirogram in young male smokers. American Review of Respiratory Disease 11%5):
717-724, May 1979.

WEBSTER, P.M., LORIMER, E.G., MAN, S.F.P., WOOLF, C.R., ZAMEL, N. Pulmo
nary function in identical twins: Comparison of nonsmokers and smokers.
American Review of Respiratory Disease 119t2): 223-228, February 1979.
WEISS, S.T., TAGER, I.B., SCHENKER, M., SPEIZER, F.E. The health effects of
involuntary smoking. American Review of Respiratory Disease 123(5): 933942,
November 1983.

WILHELMSEN, L., ORHA. I., TIBBLIN, G. Decrease in ventilatory capacity between
ages 50 and 54 in a representative sample of Swedish men. British Medical Journal
3(5670): 553-556, September 6,1969.

WOOLCGCK, A.J., COLMAN, M.H., BLACKBURN, C.R.B. Chronic lung disease in
Papua New Guinea and Australian populations. Papua New Guinea Medical
Journal l&l): 29-35, March 1973.

WOOLCOCK, A.J., VINCENT, N.J., MACKLEM, P.T. Frequency dependence of
compliance as a test for obstruction in the small airways. Journal of Clinical
Investigation 48(6): 1097-1106, June 1969.

WOOLF, CR.. SUERO, J.T. The respiratory effects of regular cigarette smoking in
women. American Review ofRespimtory Disease 103(l): 26-37, January 1971.
WOOLF, C.R., ZAMEL, N. The respiratory effects of regular cigarette smoking in
women. A five-year prospective study. Chest 78(5): 707-713, November 1980.
ZAMEL, N., YOUSSEF, H.H., PRIME, F.J. Airway resistance and peak expiratory
flow rate in smokers and nonsmokers. Lancet 1: 1237-1238,1963.

183


CHAPTER 3. MORTALITY FROM
         CHRONIC
         OBSTRUCTIVE LUNG
         DISEASE DUE TO
         CIGARETTE SMOKING

185


CONTENTS

Introduction

COLD Mortality Patterns in the United States

Prospective Studies

The British Doctors Study
The American Cancer Society 25-&&e Study
The U.S. Veterans Study
The Canadian Veterans Study
The American Cancer Society g-State Study
California Men in Various Occupations
The Swedish Study
The Japanese Study of 29 Health Districts

Cigarette Smoking and Overall COLD Mortality

Retrospective Studies

Male and Female Differences in COLD Mortality

Amount Smoked and Mortality From COLD

Inhalational Practice and Mortality From COLD

Age of Initiation and COLD Mortality

Smoking Cessation and COLD Mortality

Pipe and Cigar Smoking Mortality From COLD

International Comparison of COLD Death Rates a
Smoking Habits: The Emigrant Studies

COLD Mortality Among Populations With Low SI
Rates

Summary and Conclusions

References


Introduction

The chronic obstructive lung diseases (COLD) that are causally
related to cigarette smoking are chronic bronchitis, emphysema, and
chronic obstructive pulmonary disease and allied conditions without
mention of asthma, bronchitis, or emphysema. The last classification
was introduced by the National Center for Health Statistics in
response to the changes that occurred in the late 1960s in patterns of
reporting causes of death on death certificates. During this period,
physicians increasingly recorded deaths as due to "chronic obstruc-
tive lung disease" rather than the more specific categories of
"emphysema" or "chronic bronchitis" (NCHS 1982). Because of this
shift in patterns of reporting, and in recognition of the difficulty of
clinically separating these categories from one another as a cause of
death, the discussion in this chapter combines all of these categories
for analysis, where possible, which should result in a more complete
description of death rates from COLD.

COLD Mortality Patterns in the United States

The three chronic obstructive lung diseases related to smoking
may account for almost 62,000 deaths in 1983, compared with 56,920
deaths in 1982, according to provisional mortality data recently
published by the National Center for Health Statistics. This data is
based on a 10 percent sample of all deat.h certificates for the 12-
month period ending in November (NCHS 1984). This is a dramatic
increase from 1970, when slightly over 33,000 deaths were attributed
to COLD.

Complete mortality data are available through 1980, and Table 1
presents the numbers of male and female deaths from COLD for
1970,1975, and 1980. In addition to the relatively rapid rise in COLD
deaths during these years, there was also a shift in the male to
female ratio of these deaths. In 1970 male deaths outnumbered
female deaths by a ratio of 4.3 to 1. By 1980 this ratio had declined to
2.36.

The ageadjusted death rates for COLD during the years 1960
through 1980 are presented in Figure 1 for white men, white women,
and men and women of other races. As described in the previous
chapter, however, COLD is a slowly progressive disease, and death
from COLD usually occurs only after extensive damage has devel-
oped in the diseased lungs. Many individuals with COLD will die
with their disease rather than because of it, and even those who do
die of COLD are usually symptomatic for an extended period of time
prior to death.

Therefore, death rate data may not accurately reflect the true
prevalence or incidence of COLD in the U.S. population. In addition,
COLD is often not recorded as a cause of death in hospital records

189


TABLE l.-Number of and ratio of male to female chronic
      obstructive lung disease (COLD) deaths for
      three time periods, United States

Cause of death

   1970              1975             1980

Men    Women      Men    Women      Men   Women

Chronic bronchitis

Emphysema

COLD and
allied conditions

4,262    1,564      3,260    1,452      2,380   1,348

18,901    3,820     14,649    3,946     10,133   3,744


3,601     848     13,411    4,182     24,820   10,734

Total COLD deaths      26,764    6,227     31,520    9,580      37,333   15,826

M:F ratio                 4.30              3.29             2.36

SOURCE: National Center for Health Statistics (1982, and unpublished mortality data)

                       OTHERd
15

10                           WHITE?

5                           OTHER?

1960       1965        1970        1975        1980
             YEAR

FIGURE l.-Age-adjusted COLD mortality rates for whites
       and nonwhites in the United States, 1960-1980
SOURCE National Center for Health Statistics (1962, and unpublisheddata).

(Moriyama et al. 1966) or on death certificates (Mitchell et al. 1968),
even though it may have played an important role in a person's
death. In a recent prospective study, nearly half of the excess
mortality associated with significantly lowered FEV, was attributed
to other causes (Pete et al. 1983). Relatively advanced lung disease
(as judged by pathologic examination) may also exist without clinical

190


recognition because of the lung's large ventilatory reserve (Mitchell
et al. 1968; Hepper et al. 1969). A joint committee of the American
College of Chest Physicians and the American Thoracic Society
(ACCP-ATS 1975) has developed standardized definitions of these
conditions that may improve the accuracy of mortality reporting in
the future.

As discussed in the chapter on morbidity in this Report, COLD in
an individual is usually a combination of mucus hypersecretion,
airway narrowing, and emphysema. The extent of damage represent-
ed by each of these three processes can vary substantially from
individual to individual, both in the absolute magnitude of the
damage and in the proportional contribution of each of these three
components. The majority of those with smoking-induced lung
damage do not have enough damage to result in clinically significant
disease, and only some of those with clinically significant disease
have damage to the lung that results in death from COLD. The
progressive loss of FEV, in smokers described in the preceding
chapter is one measure of the extent and progression of lung
damage, and individuals with a markedly reduced FEV, are far more
likely to die of COLD (Peto et al. 1983). These deaths commonly occur
secondary to the failure of these severely damaged lungs to carry out
the gas exchange required for survival.

Because death from COLD is the end result of lung damage
accumulated over many years, these deaths would be expected to
occur disproportionately in the older age groups; therefore, the
presentation of a single age-adjusted death rate might not reflect a
true picture of the changes in this disease with time. Figure 2
presents the age-specific death rates in 1977 for COLD in the
different sexes and racial groups. Death rates increase rapidly over
the age of 45, and this increase is particularly dramatic over the age
of 65. In addition, the bulk of the difference between white men and
men of other races, evident in Figure 2, occurs in those over age 65.
Indeed, the COLD death rates for nonwhite men are actually higher
than that for white men under age 55.

The examination of age-specific death rates over time also presents
a somewhat different picture from that presented by the age-
adjusted numbers in Figure 1. The age-adjusted rates for white men
in Figure 1 seem to have changed only slightly between 1968 and
1980. However, when the age-specific rates for the years 1968 and
1977 are examined (Figure 31, this apparent stability can be seen to
be a product of counterbalancing trends in those under and over 65
years of age. The death rates from COLD declined in white men
under age 65 between 1968 and 1977, but COLD death rates
increased in white men over age 65 during the same years; this
increase was particularly dramatic in those over age 75.

191


I
25-34

AGE

FIGURE 2.-Age-specific COLD mortality rates for whites
       and nonwhites in the United States, 1977
SOURCE: National Center for Health Statida, (1982).

Figure 4 presents the age-specific COLD mortality rates for white
women in 1960, 1968, and 1977. As with the male rates, the female
COLD death rates rise rapidly with age, but they are substantially
lower than the male rates. In contrast with the male rates, however,
the white female death rates increased steadily with time from 1960
through 1977 both above and below age 65. In each of the age groups
over the age of 45, where significant numbers of COLD deaths would
be expected, there was a steady increase in rates from 1960 to 1968
and from 1966 to 1977. As is discussed later in this chapter, these
differences between men and women over time are consistent with
their differences in smoking behavior.

The effect of the normal aging process on the lung is small, rarely
limits maximal exercise, and never results in ventilator-y failure.
Therefore, death from chronic obstructive lung disease is never a
natural part of the aging process; it is the result of an infectious or
other disease process or of the cumulative damage of environmental
respiratory toxins. The most important of these toxins in the United
States is cigarette smoke.

192


25-34 35-44 45-54   55-64 65-74   75-84   85+

FIGURE 3.-Age-specific COLD mortality rates for white
      men in the United States, 1960, 1968, and 1977
SOURCE: National Center for Health Statistics (1982).

In spite of the large ventilator-y reserve possessed by the lung,
death from COLD is a major cause of U.S. mortality. This mortality
is closely linked to cigarette smoking and has been examined
extensively. Figure 5 shows the differences in COLD death rates for
smokers and nonsmokers at different ages. From the rarity of COLD
death in nonsmokers and the magnitude of the increased risk
associated with smoking, it is clear that the overwhelming impor-
tance of cigarette smoking as a determinant of abnormal lung
function demonstrated in the previous chapter is matched by the
importance of cigarette smoking as a determinant of death from
COLD. Examination of the death rates from COLD in smokers and
nonsmokers suggests that from 85 to 90 percent of the COLD deaths
in the United States can be attributed to cigarette smoking.

Prospective Studies

The relationship between smoking and death from COLD has been
evaluated in a large number of prospective mortality studies. There
are eight major prospective studies of the disease consequences of
smoking. They involve large numbers of smokers and nonsmokers

193


AGE

FIGURE 4.-Age-specific COLD mortality rates for white
       women in the United States, 1960, 1968, and
         1977

SOURCE Natmnal Center for Health Statmtics / 19H2 I

and have examined the death rates from COLD in both groups.
These studies cumulatively represent more than 17 million person-
years of observation and over 330,000 deaths. The size of the
populations studied allows a detailed examination of the relationship
between smoking and death rates. The characteristics of the
populations studied are summarized in Table 2 and are briefly
reviewed here.

The British Doctors Study

The British doctors study (Doll and Hill 1954, 1956, 1964a, 1964b,
1966; Doll and Peto 1976, 1977; Doll and Pike 1972; Doll et al. 1980)
of 40,000 male and female physicians in Britain was the first
prospective study and is the longest running. Deaths from chronic
bronchitis and emphysema were combined. Deaths from car pulmo-
nale (i.e., heart failure secondary to lung disease) were separately
analyzed by smoking category and probably include some deaths
from chronic bronchitis and emphysema.

194


450



400

100

FIGURE

                    -                    -1
                                           !

                               I





,
._


I
!
I

Z-Death rate for bronchitis, emphysema, or both,
per 100,000 population, by age and smoking

      status I, U.S. veterans study, 16-year followup
`Smoker LS defined as all people who smoke agarettes and those who have ever smoked other tohocco products
SOURCE- Adapted fmm Fbgot and Murray / 19801

The American Cancer Society 25State Study

The American Cancer Society 25-State study (Hammond 1965,
1966; Hammond and Garfinkel 1969; Hammond et al. 1976; Lee and
Garfinkel 1981) represents the largest investigation. Deaths from
emphysema were separately analyzed by smoking habit; deaths from
car pulmonale were also separately recorded.

The U.S. Veterans Study

The mortality experience of approximately 294,000 U.S. veterans
who held U.S. Government life insurance policies in December 1953
was examined in the U.S. veterans study (Darn 1959; Kahn 1966;
Rogot 1974a, b; Rogot and Murray 1980). Deaths from COLD were
recorded as "bronchitis and/or emphysema"; "bronchitis, underlying
or contributory"; and "emphysema without bronchitis."

The Canadian Veterans Study
Initiated in 1955 by the Canadian Department of National Health
and Welfare, the Canadian veterans study (Best 1966; Best et al.
1961) included 78,000 men and 14,000 women. Over the next 6 years
of followup, there were 9,491 male and 1,794 female deaths. The
cause of death in most of these cases was confirmed by autopsy.

195


z - TABLE 2 .-Outline of eight major prospective studies

                      Doll                    Darn                     kat                    Weir        GxiwkJf

        Aulhon         Hill        Hammond       Krhn       H~nyama        JOUC        ltammmd        Dunn      fibsy
                     Pet0                Roaol                    Walker        HW!l        laden        HNbc
                     Rke                                                                BraloW        Lonch



                               Melee and             Total population                          Ghfomu     ProtaMity

                    Bntinh        femalea        US          of         Gnadlan     while m&a             rmple of
      Sub@a                     I"                    29hdth                             nuke I"
                     do2lon                                                       I"
                                           votorura                                                      the
                                 25                    dmtncLs I"                             "UWU
                                                                 peMlolW"     nme stata                 SW&h
                                SlAkB               JW                           mupllom     pophtion

     Population aize      wm       l.~.~      mw     266.ooo ' 9zoal       187,oal       wax)        mm
        FellUka        WQ       562.671        (1%        lw?57        14,ma                           n.700


      AIF nn%       B435+        3M.4         3544          40          3cao
                                          d up                   504         D-64         18.4



        Year of         1961          1960         1W          1966          1966
        cnrdlment                               1967                                1962         1954         1969



        Yeem of
      fdlowup         20-22       UY-      16 YAM      13 y-      6y-      4 Y-         54

                     Y-                                                             10 yean
                                                                           Y-



         Number
          Of         ll.166       150,ooO      ICnJoo        39.100        11,oal       I2m        4.700        4aO
         death

     Person y-
          of         woo0      J%~.~      35Qo.w      3.W~      WoaJ       670,ooO       @A~       We
      cxpricmx


The American Cancer Society S-State Study

In the American Cancer Society g-State study (Hammond and
Horn 1958a, b), 187,783 white men were followed for an average of 44
months by 22,000 American Cancer Society volunteers. All deaths
from pulmonary disease (except pulmonary neoplasms) were consid-
ered as one group and included deaths from pneumonia, asthma,
tuberculosis, lung abscess, pneumoconiosis, bronchiectasis, and em-
physema.

California Men in Various Occupations

The study of California men in various occupations (Dunn et al
1960; Weir and Dunn 1970) examined the mortality experience of
68,153 men, aged 35 to 64, drawn from labor union rolls in specified
occupations. Deaths from emphysema were separately categorized.

The Swedish Study

The study of a probability sample of 55,000 Swedish men and
women (Cederlof et al. 19751, aged 18 to 69, represents a detailed
analysis of mortality by smoking status over a period of 10 years.
The cause of death was ascertained by death certificates collected by
the Central Bureau of Statistics for all of Sweden.

The Japanese Study of 29 Health Districts

In the fall of 1965, a total of 265,118 men and women in 29 health
districts in Japan were enrolled in a prospective study (Hirayama
1967,1970,1972,1975a, 1975b, 1977, 1981). Mortality data regarding
deaths from asthma and emphysema have recently been reported.

Cigarette Smoking and Overall COLD Mortality

The data from the major prospective studies relating smoking to
mortality from COLD in men and women are presented in Table 3.
These data demonstrate a uniform increase in death rates from
COLD among male and female smokers when compared with
nonsmokers of either sex. The mortality ratios for smokers compared
with nonsmokers vary markedly, however, from 2.2 in the Japanese
study to 24.7 in the study of British doctors. Some of this variability
can be attributed to different patterns of certification of cause of
death in different countries, but a number of other factors are also
important. Perhaps the most important other factor is the age range
of the population studied. As described earlier in this chapter, death
rates from COLD rise steeply with age, particularly over the age of
65. Studies of populations under age 65 may significantly underesti-
mate the impact of cigarette smoking on COLD because of the long
duration of smoking required to damage enough lung to result in

197


death from COLD. The population under 65 contains large numbers
of individuals who have significant airflow obstruction and who will
die of COLD, but who have not done so prior to age 65. This effect is
demonstrated in the American Cancer Society 25-State study, in
which the COLD mortality ratio for male smokers aged 45 to 64 was
6.55, but increased to 11.41 in male smokers aged 65 to 79.

A second reason for differences in mortality ratios is the selection
of study populations who are currently employed, particularly if the
duration of followup is relatively short. The incremental nature of
the lung injury in COLD often results in a prolonged period of
disability prior to resulting in death. This disability is usually
incompatible with full-time work, particularly in those occupations
requiring substantial exertion. Therefore, the study of a working
population excludes those with significant existing disability from
COLD and underestimates the COLD death rates in the general
population. Unless the followup period is long enough to observe the
progression of COLD from its asymptomatic stages through the
development of disability and finally death, the impact of cigarette
smoking on COLD death rates will be underestimated. This effect is
particularly important because cigarette smoking is overwhelmingly
the major determinant of COLD risk, and therefore an underestima-
tion of the true COLD prevalence leads to an underestimation of the
relative risk of smoking. As the followup period is extended for a
duration sufficient to allow the full time course of COLD to be
observed, the impact of cigarette smoking on COLD death rates also
emerges from the small background rate of COLD death certification
in nonsmokers (which includes those classified in error and those
with disease induced by agents that results in a more rapid
progression to death).

This "healthy worker" effect is present to varying extents in all of
the prospective studies and is one of the reasons the studies with the
longest followup periods also tend to have the largest COLD
mortality ratios. This is particularly evident in the study with the
longest followup. The British doctors study, with a followup of 20
years, revealed a mortality ratio for male smokers of 24.7.

A final reason for the differences in mortality ratios is the
differences in the smoking habits of the various populations. As was
discussed in the previous chapter, the extent of lung injury is
influenced by both the number of cigarettes smoked per day and the
duration of the smoking habit. As is shown in Table 4, some of the
variability in mortality ratios among the studies disappears when
the mortality ratios are reported by number of cigarettes smoked per
day. However, there are also substantial differences in the pattern of
cigarette use in different countries, particularly in the use of the
milder types of tobacco cigarettes that are more likely to be inhaled
and are smoked in the United States. For example, these cigarettes

198


TABLE 3.-COLD mortality ratios by disease category, eight prospective studies

Study

size of
population

Nonsmoker

Emphysema

Bronchitis

Both

Other

Cfimments

Brltlsh physicians
  Men
  Women

34.ooo         1.00
6.195         loo

24 7

Ratio for women by
amount smoked
only.
see Table 4

Cahforma men m
Yar\ous occupations

Canadian veterans
  Men

American Cancer Society
25-state
  Men
  Women

US veterans
  Men

Amcrlran Cancer Society
9.Stale
  Men

66.00(1



78.ooo

440.500
562.7llu

290K1.000

100



100

1.00
1.00

100

100

12 33

5 85             11.42

45-64'      6S79 '
6 55       11.41
4 89        750

1482

5 II

`Age range

1207

2.85

All pulmonary
&eases uLher than
cancer ipneumoma.
mfluen~~. TB.
asthma, bronchitis.
lung abscess. etc.1


8   TABLE 3.-Continued


                         SW.. of

Study              population     Nonsmoker      Emphysema         Bronchltls      Both      Other      Comments

Swedish
  Men
  Women

27,0(x)
28.ooo

100
100

.

2.20

' Number of deaths
too small for
statistical analysw
Includes deaths due
to asthma

Japanese
  Men


  Women

12w.M

143,GGo

loo


1.00

Data by amount
smoked
only; see Table 4


were not introduced into Japan in large numbers until after the
Second World War. The chronicity of tobacco use, particularly of
those forms of tobacco that are commonly inhaled, is probably more
important than age per se in producing COLD death. The chronicity
of tobacco use differs in different countries and between men and
women in the same country; these differences would be expected to
result in different COLD mortality ratios.

In several of these prospective mortality studies, the mortality
ratio for COLD deaths in smokers compared with nonsmokers was
even larger than that found for lung cancer. This is consistent with
the data in the previous chapter showing that cigarette smoking is
the major predictor of decline in lung function and is also consistent
with the clinical observation that clinically significant airflow
obstruction is rare in the absence of a history of smoking.

Retrospective Studies

The relationship between smoking and mortality from COLD was
also examined in several large retrospective studies. Wicken (1966)
conducted a study of 1,189 men living in Ireland who died from
chronic bronchitis. Smoking habits were determined through person-
al interviews with relatives of the decedents. The relative risk for
mortality from COLD was increased in smokers as compared with
nonsmokers. Smokers of as few as 1 to 10 cigarettes per day had a
2.95fold higher risk for mortality from COLD as compared with
nonsmokers.

Dean and associates conducted two retrospective studies of the
relationship between changes in smoking patterns and changes in
mortality from bronchitis among a sample of the population in
urban areas and in rural areas of northeast England. The periods of
observation in the two studies were 1952 to 1962 (Wicken and Buck
1964; Wicken 1966) and 1963 to 1972 (Dean et al. 1977, 1978),
respectively. Smoking status classifications in the two studies were
similar, and were based upon questions relevant to the last 2 years
before death or interview. In both studies, the relative risk for
mortality from chronic bronchitis was substantially increased for
smokers as compared with nonsmokers.

In summary, data from both the prospective and the retrospective
studies consistently demonstrate an increase in mortality from
COLD for smokers as compared with nonsmokers. These studies
include populations of widely different ages, social and ethnic
groups, geographic locations, and occupations; nevertheless, they
strongly support a causal relationship between smoking and COLD.

201

480-144 0 - 85 - 8


TABLE I.-COLD mortality rates for men and women, by
      number of cigarettes smoked per day,
      prospective studies

Study

      MelI                Women

Cigarettes   Mortality     Cigarettes   Mortality    COLD disease
per day      ratios      per day      ratios      classification

British
physicians

Nonsmoker
  1-14
1524
25+

U.S. veterans

Nonsmoker
  1-9
10-20
2139
40+

1.03
17.00
26.00
36.00


1.00
3.63
4.51
4.57
8.31

Nonsmoker     1.00
1-14       10.50
l&224      28.50
25+       32.00

Nonsmoker      1.M)
  l-9        5.33
l&19       14.04
2139      17.04
40+       25.34

Emphysema

Nonsmoker
  1-9
l&19
2139
40+

1.00
4.84
11.23
17.45
21.98

Chronic bronchitir
and emphysema

Canadian
veterans

Nonsmoker      l.cMl
  l-9        7.02
10-20       13.65
2lf       14.63

Chronic bronchitis

Nonsmoker     Loo
  l-9        4.81
l&20       6.12
21-t        6.93

Emphysema

Japanese

Nonsmoker      1.00      Nonsmoker     1.00
< 100,m'      0.51       < 100,ooo      2.28
< 200,oGfl      2.57       <2CQOOO      3.14
> 3oo.ooo      1.93       > 300,oca     10.93

California men  Nonsmoker2     1.00
in various   About `12 pk     8.18
occupations   About 1 pk     11.80
        About 1'1, pk    20.66

Emphysema

American Cancer Nonsmoker     1.00
Society         l-9        1.67
sstate        i&20       3.00
            20-        3.64

All pulmonary
diseases other
than cancer3

Chronic bronchitb
emphysema: or
both



Chronic bronchith

Emphysema

' Data for the Japanese study are for lifetime exposure by > total number of crgarettea consumed
`Nonsmoker m the Cabfornia occupations study aleo includes > smokers of pipes and cigars.
a Pneumoma. mfluenza. TB. asthma, bronchitis, lung abscess. etc.

202


Male and Female Differences in COLD Mortality

Mortality data presented by the National Center for Health
Statistics indicate that in 1980 the number of deaths from COLD was
2.36 times higher among men than among women (9th ICDA nos.
490, 491, 492, and 494496). In the prospective studies reviewed
above, it is also apparent that the relative risk for death from COLD
was greater for male smokers than for female smokers, although
both male and female smokers exhibited a greater risk than
nonsmokers for death from COLD. These differences are most likely
a consequence of differences in male and female smoking patterns.
The women in these studies tended to smoke fewer cigarettes, inhale
less deeply, and begin smoking later in life than the men. They more
frequently smoked filtered and low tar and nicotine cigarettes and
had less occupational exposure to pulmonary irritants than men.
These differences in mortality from COLD are narrowing because of
a more rapid rise in female mortality from COLD (see Table 1).

Figures 6 and 7 help to explain the male-female differences in
COLD mortality ratios in the prospective mortality studies and in
U.S. COLD death rates. The figures are descriptions of the preva-
lence of cigarette smoking in successive lO-year birth cohorts of men
and women as those cohorts progressed through the years 1900-1980
(Harris 1983). Examination of these figures revealed several impor-
tant findings. Relatively few women took up smoking prior to 1930.
The heaviest smoking cohorts of men have a prevalence of over 70
percent compared with 45 percent of women, and the male cohorts
with these peak prevalences are older than the female cohorts.
However, as discussed earlier, the incremental and progressive
nature of cigarette-induced lung injury results in both prevalence
and duration of cigarette smoking having an impact on COLD death
rates. Therefore, in examining Figures 6 and 7 it is important to
consider the span of years of a given prevalence of smoking
maintained by a given birth cohort as well as the peak prevalence
achieved by that cohort. The COLD death rates should then be
proportional to the area under the prevalence curve described by
each cohort, rather than to the peak of that curve.

A careful examination of Figure 6 reveals that the area under the
prevalence curve for the cohort born between 1921 and 1930 is less
than the area under the curve for the cohort born between 1911 and
1920, in spite of their similar peak prevalences. This difference is due
to the more rapid decline in prevalence with age in the 1921 to 1930
cohort. Similarly, the cohort born between 1901 and 1910 partially
compensates for a peak prevalence that is lower than the 1911 to
1920 cohort by having a somewhat a broader base. Each of the
cohorts born prior to 1900 have substantially smaller areas under
their curves than those born during the first three decades of this
century. These differences in prevalence are reflected in the changes

203


     1910   1920    1930
.R                      1940   1950    1960    1970
      I      I      1      I

    Men

i                           1921-30
.7

.6 .





.5 -





.4 -

1891

1900   1910  -1920  1930 1940 1950 1960   1970 l!

FIGURE &-Prevalence of cigarette smoking among
      successive birth cohorts of men, 1999-1999,
      derived from smoking histories in the National
      Health Interview Survey (HIS)
SOURCE: Harris 1983.

in age-specific death rates portrayed in Figure 8 and Table 5. The
oldest age group (7584) continues to show a rapid rise in COLD
death rates as those birth cohorts with increasing prevalence and
duration of smoking move into this age range. In the age range 65-74
the rates rose rapidly from 1960 through the mid 19708, but seem to
be leveling off, consistent with the fact that this age group is now
made up entirely of men born after 1900. In the age range S5-64 the
rates suggest a slight downturn beginning in the mid 197Os,
coincident with the entry of the 1921 to 1930 birth cohort into this
age group. The numbers for the age range 45-54 are too small to

204


2                                             2





1                                             1





0                                             0
1900   1910    1920   1930   1940   1950    1960    1970   1980

FIGURE 7.-Prevalence of cigarette smoking among
      successive birth cohorts of women, 1900-1980,
      derived from smoking histories in the National
      Health Interview Survey (HIS)
SOURCE: Hmie 1983

permit firm conclusions, but also suggest that a downturn in rates
occurred in this group in the late 1960s.

A close examination of Figures 6 and 7 also offers an explanation
of the differences in mortality ratios for men and women observed in
the prospective studies. COLD is a slow, progressive disease, and
death from COLD usually results only after extensive lung damage
has occurred. The fact that death from COLD is unusual prior to age
45 reflects, in part, the 30 or more years required for cigarette smoke
to damage enough lung to result in death. The substantial ventilato-
ry reserve of the lung allows a significant amount of damage to exist
in a person without symptomatic limitation or risk of death from
COLD. The prospective mortality studies were conducted in the
1950s and 1960s a point in time approximately 30 years after the
beginning of the rise in smoking prevalence among women demon-
strated in Figure 7. Even the older cohorts, where significant
mortality might be expected, had begun smoking largely after 1930,
and therefore had a shorter duration of smoke exposure than the
men born in the same years. This shorter duration of the smoking
habit, together with the previously described tendency of women to


1960        1965         1970         1975

YEAR

FIGURE 8.-Age-specific COLD mortality rates for white

     men in the United States, 1960-1977
NOTE ICDA Nc.s 49@492 and 519.3
SOURCE Nat,onal Center for Health Statlstux 119821.

smoke fewer cigarettes per day and to inhale less deeply, would be
expected to result in less cumulative lung damage at any given age.
This difference in extent of lung damage could explain the difference
in COLD mortality ratios between men and women observed in the
prospective mortality studies.

The British doctors study examined the risk of COLD death for
male and female physicians who smoked similar numbers of
cigarettes per day (Table 41, and the mortality ratios were similar for
similar numbers of cigarettes smoked per day.

In summary, data from the prospective studies indicate that the:
relative risk of death from COLD is greater for male smokers than
for female smokers. These differences are most likely a consequence
of differences in female smoking patterns. Women tend to smoke-
fewer cigarettes, inhale less deeply, and begin to smoke later in life-
than men. These differences in mortality from COLD are narrowing-
because of a more rapid rise in female mortality from COLD than in
male COLD mortality. This reflects the narrowing in differences
between male and female smoking patterns and the rising preva-
lence of female smokers in successive cohorts born between 1920 and

206


TABLE 5.-Age-specific COLD death rates per 100,000
      population

Year            45-54           55-65           65-74         75-a

1960              8.6            361
1961              7.6            38.7
1962              9.6            44.2
1963              11.7            52.3
1964              12.1            518
1965              12.4            57 8
1966              12.4            61.9
1967              12.4            61.2
1968              13.1            67.4
1969              13.9            67.5
1970             13.6            66.1
1971              13.5            67.4
1972              13.0            67.7
1973             12.7            69.9
1974              12.8            64.8
1975              11.9            64.7
1976              12.2            64.0
1977              11.4            60.1


SOURCE: Natmnal Center for Health Statimcs (1982)

82.9         101.8
87.9         111.8
107.2         136.7
131.2         169.6
131.6         181.9
153.6         216.6
161.9         244 8
164.8         248 6
1867         266.5
189.5         294.3
196.5         311.5
105 6         327 4
204.8         351.4
210.1         378.4
2048         3804
207.6         399.7
210.7         419 7
2061         4315

1950. These data are ominous for women, portending a rising
mortality from COLD over the next decades.

Amount Smoked and Mortality From COLD

Six of the major prospective studies evaluated the influence of
different smoking levels on mortality from COLD. These studies
employed a variety of measures of tobacco exposure, including
number of cigarettes smoked per day, grams of tobacco smoked, and
total number of cigarettes smoked in a lifetime. The data, presented
in Table 4, show a gradient in risk for mortality from COLD as the
number of cigarettes smoked per day increases and as the cumula-
tive number of lifetime cigarettes smoked increases. In the U.S.
veterans study, smokers of two packs or more per day had 22 times
the risk of COLD death of nonsmokers. Furthermore, mortality
ratios between the two followup periods for bronchitis and emphyse-
ma actually increased overall and by the amount smoked (Figure 9).
The authors noted that this was the only major disease of those
associated with cigarette smoking that showed such an increase,
suggesting that mortality ratios have been increasing over time at
all levels of smoking. In the British and Japanese studies, women
smokers at the highest levels exhibited a 32- and an 11-fold higher
risk for death from COLD (respectively) than their nonsmoking
counterparts. The variability in COLD mortality ratios noted in

207


  20







  15
9
F
f
fi
=  10






  5






  0

3 0112years

m 16 years                         17.45

12.07

.65
1

   4.84
4.14
Ia

11.23

a.73
I

Nmsmdtw All cigarette     l-9      lo-20     2139
       smokers
            Clgerenessmokedpwday

21.90







02

240

FIGURE O.-Bronchitis and emphysema for male smokers
      number of cigarettes smoked per day, U.S.
      veterans study, W/,-year and H-year followup

Table 3 is much less evident when the mortality ratios are presented
by amount smoked.

In summary, the degree of tobacco exposure strongly affects the
risk for death from COLD in men and in women. This clearcut dose-
response relationship enhances the strength of the causal relation-
ship between smoking and COLD.

Inhalational Practice and Mortality From COLD

The inhalation of tobacco smoke is the major mechanism whereby-
bronchial and alveolar tissues are exposed to the potentially
damaging effects of tobacco smoke. In the British doctors study,
subjects who acknowledged inhaling exhibited a 1.53-fold higher risk-
for COLD death as compared with those who stated they did not-
inhale (see Table 6). However, all smokers, regardless of their
inhalational practice, exhibited higher risk for COLD mortality than
did nonsmokers.

In the retrospective study from northeast England (Dean et al.
1977, 19781, the risk among men for mortality from chronic
bronchitis steadily declined with a decrease in the depth of inhala-
tion (Table 7). Among women, the risk for mortality from chronic
bronchitis was lower for all other groups than for those who stated-
they "inhaled a lot."


TABLE 6.-COLD mortality by inhalation practice, British
      doctors study, men

Cause of death

Number of
deaths

Annualized death rate per     Risk in Inhalers
100,ooO men responding    compared wth unity
to question: do you inhale?      in noninhalers

Chronic bronchitis
and emphysema end
pulmonary heart dieease

         Yes         No
71         89          58           1.53

Table 7.-Relative risk for mortality by depth of
     inhalation, 1963-1972, second retrospective
     mortality study in northeast England

Relative risk for
chronic bronchitis

Depth of inhalation

Men      Women

A lot (baee~               1.00        1.00
A fair emount              0.98       0.54
A little                  062       0.41
None                   0.58       0.58

SOURCE, Dean &al. 11977.19781

Results from prospective mortality studies comparing COLD death
rates by inhalation are identical to those observed in the morbidity
studies, which have consistently shown that COLD is more prevalent
among inhalers than noninhalers (Ferris et al. 1972; Comstock et al.
1970; Rimington 1974).
These data suggest that inhalational practice affects the risk of
mortality from COLD. People who inhale deeply experience a higher
risk for mortality from COLD than people who do not inhale.
Regardless of their inhalational practice, however, smokers still
experience higher rates of death from COLD than nonsmokers.

Age of Initiation and COLD Mortality

Another indicator of exposure to tobacco smoke that may influ-
ence risk for mortality from COLD is the age of initiation of smoking.
If their smoking habits are otherwise similar, people who take up
smoking at a younger age have a greater total exposure to tobacco
smoke than those who take up smoking later in life, and might be
expected to experience greater adverse consequences from smoking.
In the Japanese prospective study (Hirayama 19811, men who began
to smoke before the age of 19 exhibited slightly higher mortality
ratios for emphysema than did men who began to smoke after the


TABLE S.-Number of deaths from chronic bronchitis,
     emphysema, and pulmonary heart disease in ex-
      cigarette smokers, by years of cessation, versus
      number of deaths in lifelong nonsmokers,
      British doctors study

Number of deaths in ex-smokers, divided by        Number of deaths
number expected in lifelong smokers           in nonsmokers

Years of
cessation          0'     <5     69    lo-14    >14

35.6    34.2    47.7     7.3     8.1              2

age of 20. In the retrospective study from northeast England (Dean
et al. 1977, 19781, the relative risk for death from chronic bronchitis
among men who began to smoke after the age of 25 was 60 percent of
that of men who began to smoke between the ages of 15 and 19.
Among women in the same study who began to smoke between the
ages of 15 and 19, the relative risk for death from chronic bronchitis
was 1.28fold higher than for women who began to smoke after age
25; however, the number of deaths was small.

Smoking Cessation and COLD Mortality

The effects of smoking cessation on mortality from COLD were
examined in the British doctors study and the U.S. veterans study.
In the British doctors study, men who quit smoking experienced no
change in mortality from COLD in the first 4 years and a rise in the
next 5 years; presumably, this is related to the presence of many
people in this group who quit smoking for health reasons (Table 8).
Thereafter, ex-smokers experienced lower death rates from COLD,
although their rates were still higher than those of the nonsmokers.
Female ex-smokers also experienced lower mortality rates than
current smokers, but the rates in ex-smokers were still higher than
those in nonsmokers.

In the U.S. veterans study, ex-smokers who had quit for reasons
other than ill health experienced lower mortality rates for COLD
than did current smokers. However, the benefit of cessation upon
risk for mortality was heavily dependent upon the prior level of
smoking and the length of time of cessation. These data are
presented in Table 9. Ex-smokers who had smoked less than 10
cigarettes per day had a 1.64-fold higher risk for mortality from
COLD than nonsmokers; in contrast, ex-smokers who smoked more
than 39 cigarettes per day had a 9.91-fold higher rate of death from
COLD than nonsmokers. For any given number of cigarettes smoked

210


TABLE O.-Mortality ratios for bronchitis and emphysema
       in nonsmokers and in ex-smokers and current
     smokers by number of cigarettes smoked daily
     and number of years of cessation, U.S. veterans
      study

Cigarettes/day

Smoking status     0        < 10         1620       21-39        >39

Nonsmoker       1.00                             -
Ex-smoker                 1.64         5.35        7.68        9.91
Current smoker             4.84         11.23        17.45        21.98

Years of cessation

         CUTC3d
Nonsmoker    smoker       <5        5-9       l&14      15-20      >20

  1.00      12.07       11.66       14.35       10 19       5.66      2.64

per day, however, ex-smokers had a lower risk than current smokers.
As in the British study, mortality ratios initially increased over the
first 9 years of cessation. After the first 9 years, mortality ratios for
ex-smokers fell, but never reached the level of the nonsmoker.

Two studies have evaluated mortality rates from COLD among
physicians, a group among whom many quit smoking to protect their
health. Fletcher and Horn (1970) assessed the mortality rates from
bronchitis among physicians in England and Wales. Among doctors
aged 35 to 64, there was a 24 percent reduction in bronchitis
mortality between 1953-1957 and 1961-1965, as compared with a
reduction of only 4 percent in the national bronchitis mortality rates
for men of the same age in England and Wales. Enstrom (1983)
assessed mortality trends from COLD in a cohort of 10,130 physi-
cians in California. The standardized mortality ratio for bronchitis,
emphysema, and asthma among male California physicians relative
to American white men declined from 62 during the period 1950 to
1959 to 35 during the period 1970 to 1979.

In summary, cessation of smoking leads to a decreased risk for
mortality from COLD as compared with that of current smokers. The
residual risk of death for the ex-smoker is determined by the
person's prior smoking status and the number of years of cessation.
However, the residual risk remains larger than that of the nonsmok-
er, presumably because of the presence of irreversible lung damage
acquired during prior smoking.

Pipe and Cigar Smoking Mortality From COLD
Several of the prospective epidemiological studies examined the
relationship between pipe and cigar smoking and mortality from
COLD. The data from these studies indicate that pipe smokers and

211


TABLE lO.-COLD mortality ratios in male pipe and cigar
       smokers, prospective studies

Type of smoking

Study          Catwry

                 Total
NOtI-   Cigar   pipe   pipe and  Cigarette
smoker  only   only    cigar    tdy    Mixed

American Cancer
Society 9-State

COLD total
Emphysema
Bronchitis

1.00    1.29    1.77             2.85

British doctors




Canadian veterans




American Cancer
Society 25-State

COLD total
Emphysema
Bronchitis

COLD total
Emphysema
Bronchitis

COLD total
Emphysema
Bronchitis

1.00                9.33      24.67    11.33


1.00                4.00      7.oil    6.67



1.00    3.33     .75             5.65
1.00    3.57    2.11            11.42



1.00                1.37      6.55 '

U.S. veterans       COLD total
(E&year       Emphysema
followup~        Bronchitis

U.S. veterans       COLD total
!&year        Bmnchitis,
followup)        emphysema

1.00     .79    2.36      39      10.08
1.00    1.24    2.13     1.31      14.17
1.00    1.17    1.28     1.17      4.49

1.00    0.84 2   1.44'            4.75 '


1.00         2.535            13.13'

' Mortality rake for agea 55 to 64 only BIT presented.
' Pure ctgar.
' Pure pipe

cigar smokers also experience higher mortality from COLD as
compared with nonsmokers. However, the risk of dying from COLD
is less than that of current cigarette smokers (Table 10).

International Comparison of COLD Death Rates and Smoking
Habits: The Emigrant Studies

Reid (1971) reported that age-adjusted mortality rates from
chronic nonspecific lung disease among British citizens varied with
migration patterns. British men living in the United Kingdom had a-
chronic, nonspecific lung disease death rate of 125 per 100,000,
whereas migrants to the United States experienced a mortality rate
of only 24 per 100,000, which is similar to the rate found in the U.S.
population. Differences in cigarette smoking and air pollution were
identified as the major factors contributing to the real excess in
bronchitis morbidity experienced by the British in the United
Kingdom. Rogot (1978) conducted a study of British and Norwegian
emigrants to the United States. The mortality rate from chronic
nonspecific lung disease (CNSLD) in Great Britain is about fivefold

212


that in the United States, whereas the mortality rate from CNSLD
in Norway is slightly lower than that in the United States. In
contrast, the British migrant rates were about equal to those of
native-born Americans and the Norwegian migrant rates were the
lowest. Mortality rates for CNSLD were higher for smokers than for
nonsmokers in all groups. These data suggest that ethnic origin
plays a minor role, if any, in determining COLD risk. Regardless of
country of origin, these studies indicate that tobacco smokers
experience higher mortality rates for COLD than do nonsmokers.

COLD Mortality Among Populations With Low Smoking Rates

Numerous studies have reported that certain population groups
who traditionally abstain from cigarette smoking for religious or
other reasons have lower mortality rates from those diseases
traditionally related to tobacco use. The 1982 and 1983 Reports of
the Surgeon General, The Health Consequences of Smoking
(USDHHS 1982, 19831, extensively reviewed this phenomenon as it
relates to cancer and cardiovascular diseases among Mormons,
Seventh Day Adventists, and others. Because Amish are seen as
strict and fundamentalist in outlook, it is assumed that their use of
tobacco is severely restricted. While cigarettes are largely considered
taboo, pipe and cigar smoking and tobacco chewing are widespread
(Hostetler 1968). Hamman et al. (1981) examined the major causes of
death in Old Order Amish people in three settlements in Indiana,
Ohio, and Pennsylvania to determine if their lifestyle altered their
mortality risk compared with neighboring non-Amish. Mortality
ratios from all respiratory diseases were significantly lower by over
80 percent in Amish men 40 to 69 years old, and by 50 percent in
those 70 and older. In the chronic pulmonary disease categories
including emphysema, bronchitis, and asthma, only one Amish male
death occurred, whereas approximately 23 were expected. The
pattern of mortality "om chronic respiratory diseases was similar
for Amish women.

Summary and Conclusions

1. Data from both prospective and retrospective studies consis-
tently demonstrate a uniform increase in mortality from COLD
for cigarette smokers compared with nonsmokers. Cigarette
smoking is the major cause of COLD mortality for both men
and women in the United States.

2. The death rate from COLD is greater for men than for women,
most likely reflecting the differences in lifetime smoking
patterns, such as a smaller percentage of women smoking in

213


past decades, and their smoking fewer cigarettes, inhaling less
deeply, and beginning to smoke later in life.

3. Differences in lifetime smoking behavior are less marked for
younger age cohorts of smokers. The ratio of male to female
mortality from COLD is decreasing because of a more rapid rise
in mortality from COLD among women.

4. The dose of tobacco exposure as measured by number of
cigarettes or duration of habit strongly affects the risk for
death from COLD in both men and women. Similarly, people
who inhale deeply experience an even higher risk for mortality
from COLD than those who do not inhale.

5. Cessation of smoking eventually leads to a decreased risk of
mortality from COLD compared with that of continuing
smokers. The residual excess risk of death for the ex-smoker is
directly proportional to the overall lifetime exposure to ciga-
rette smoke and to the total number of years since one quit
smoking. However, the risk of COLD mortality among former
smokers does not decline to equal that of the never smoker
even after 20 years of cessation.

6. Several prospective epidemiologic studies examined the rela-
tionship between pipe and cigar smoking and mortality from
COLD. Pipe smokers and cigar smokers also experience higher
mortality from COLD compared with nonsmokers; however,
the risk is less than that for cigarette smokers.

7. There are substantial worldwide differences in mortality from
COLD. Some of these differences are due to variations in
terminology and in death certification in various countries.
Emigrant studies suggest that ethnic background is not the
major determinant for mortality risk due to COLD.

214


References

AMERICAN COLLEGE OF CHEST PHYSICIANS and THE AMERICAN THORAC-
IC SOCIETY. Pulmonary terms and symbols. A report of the ACCP-ATS Joint
Committee on Pulmonary Nomenclature. Chest 67(5): 583593, May 1975.
BEST, E.W.R. A Canadian Srudy of Smoking and Health. Department of National
Health and Welfare, Epidemiology Division, Health Services Branch, Biostatistics
Division, Research and Statistics Directorate, Ottawa, 1966, 137 pp.
BEST, E.W.R., JOSIE, G.H., WALKER, C.B. AC anadian study of mortality in relation
to smoking habits. A preliminary report. Canadian Journal of Public Health 52(3):
99-106, March 1961.

CEDERLOF, R., FRIBERG, L., HRUBEC, Z.. LORICH, U. The Relationship of
Smoking and Some Social Covariables to Mortality and Cancer Morbidity. A Ten-
Year Follow-up in a Probability Sample of 55.000 Swedish Subjects. Age lfG9.
Part 1 and Part 2. Stockholm, Karolinska Institute, Department of Environmental
Hygiene, 1975,91 pp.

COMSTOCK, G.W., BROWNLOW, W.J., STONE, R.W., SARTWELL. P.E. Cigarette
smoking and changes in respiratory findings. Archives of Encironmental Health
21(l): 50-57,1970.

DEAN, G., LEE, P.N., TODD, G.F., WICKEN, A.J. Report on a Second Retrospective
Mortality Study in North-East England. Part I: Factors Related to Mortality From
Lung Cancer, Bronchitis, Heart Disease and Stroke in Cleveland County, With a
Particular Emphasis on the Relative Risks Associated With Smoking Filter and
Plain Cigarettes. Research Paper 14, Part 1. London, England, Tobacco Research
Council, 1977, 95 pp.

DEAN, G., LEE, P.N., TODD, G.F.. WICKEN, A.J. Report on a Second Retrospective
Mortality Study in North-East England. Part ZZ: Changes in Lung Cancer and
Bronchitis Mortality and in Other Relevant Factors Occurring in Areas of North-
East England, 1963-1972. Research Paper 14, Part 2. London, England, Tobacco
Research Council, 1978. 115 pp.

DOLL, R., GRAY, R., HAFNER, B.. PETO, R. Mortality in relation to smoking: 22
years' observations on female British doctors. British Medical Journal 280(62191:
967-971, April 5, 1980.

DOLL, R., HILL, A.B. The mortality of doctors in relation to their smoking habits. A
preliminary report. British Medical Journal (4877): 1451-1455, June 26.1954.
DOLL, R., HILL, A.B. Lung cancer and other causes of death in relation to smoking. A
second report on the mortality of British doctors. British Medical Journal 2(5001):
1071-1081, November 10,1956.

DOLL, R., HILL, A.B. Mortality in relation to smoking: Ten years' observations of
British doctors. British Medical Journal l(53951: 139%1410, May 30.1964a.
DOLL, R., HILL, A.B. Mortality in relation to smoking: Ten years' observations of
British doctors. British Medical Journal l(53961: 14-1467, June 6,1964b.
DOLL, R., HILL, A.B. Mortality of British doctors in relation to smoking: Observa-
tions on coronary thrombosis. In: Haenrel, W. (Editor). Epidemiological Ap-
proaches to the Study of Cancer and Other Chronic Diseases. National Cancer
Institute Monograph No. 19. U.S. Department of Health, Education, and Welfare,
Public Health Service, National Institutes of Health, National Cancer Institute,
January 1966, pp. 205-268.

DOLL, R., PETO, R. Mortality in relation to smoking: 20 years' observations on male
British doctors. British Medical Journal 2(60511: 15251536, December 25, 1976.
DOLL, R., PETO, R. Mortality among doctors in different occupations. British Medical
Journal l(60741: 143%1436, June 4,1977.
DOLL, R., PIKE, M.C. Trends in mortality among British doctors in relation to their
smoking habits. Journal of the Royal College of Physicians of London 6(2): 216222,
January 1972.

215


DORN, H.F. The Mortality of Smokers and Nonsmokers. Proceedings of the Social
Statistics Section of the American Statistical Association. Washington, D.C.,
American Statistical Association, 1959, pp. 34-71.
DUNN, J.E., LINDEN, G., BRESLOW, L. Lung cancer mortality experience of men in
certain occupations in California. American Journal of Public Health 50(10): 147%
1487, October 1960.

ENSTROM, J.E. Trends in mortality among California physicians after giving up
smoking: 1950-79. British Medical JournaZ(286): 1101-1105, April 2,1983.
FERRIS, B.G., Jr., HIGGINS, I.T.T., HIGGINS, M.W., PETERS, J.M., VanGANSE,
W.F., GOLDMAN, M.D. Chronic non-specific respiratory disease, Berlin, New
Hampshire, 1961-1967: A cross-sectional study. American Review of Respiratory
Disease 104: 232-244,1972.

FLETCHER, C.M., HORN, D. Smoking and health. WHO Chronicle 24(8): 345370,
August 1970.

HAMMAN, R.F., BARANCIK, J.I., LILIENFELD, A.M. Patterns of mortality in the
Old Order Amish. I. Background and major causes of death. American Journal of
Epidemiology 114(6): 845861, December 1981.
HAMMOND, E.C. Evidence on the effects of giving up cigarette smoking. American
Journal of Public Health 535): 682-691, May 1965.
HAMMOND, E.C. Smoking in relation to the death rates of one million men and
women. In: Haensxel, W. (Editor). Epidemiological Approaches to the Study of
Cancer and Other Chronic Diseases. National Cancer Institute Monograph No. 19,
U.S. Department of Health, Education, and Welfare, Public Health Service,
National Institutes of Health, National Cancer Institute, January 1966, pp. 127-
  204.

HAMMOND, EC., GARFINKEL, L. Coronary heart disease, stroke, and aortic
aneurysm. Factors in the etiology. Archives of Environmental Health 19f2): 167-
182, August 1969.

HAMMOND, E.C., GARFINKEL, L., SEIDMAN, H., LEW, E.A. "Tar" and nicotine
content of cigarette smoke in relation to death rates. Environmental Research
12(31: 263-274, December 1976.

HAMMOND, E.C., HORN, D. Smoking and death rates-Report on forty-four months
of follow-up on 187,783 men. I. Total mortality. Journal of the American Medical
Association 166(10): 1159-1172, March 8,1958a.
HAMMOND, E.C., HORN, D. Smoking and death rates-Report on forty-four months
of follow-up of 187,783 men. II. Death rates by cause. Journal of the American
Medical Association 166tll): 1294-1308, March 15,1958b.
HARRIS, J.E. Cigarette smoking among successive birth cohorts of men and women in
the United States during 1900-80. Journal of the National Cancer Znstitute.71(3):
473-479, September 1983.

HEPPER, N.G., HYATT, R.E., FOWLER, W.S. Detection of chronic obstructive lung
disease. An evaluation of the medical history and physical examination. Archives
of Environmental Health 19f6): 806-813, December 1969.
HIRAYAMA, T. Smoking in Relation to the Death Rates of 26X,118 Men and Women
in Japan. Tokyo, National Cancer Center, Research Institute, Epidemiology
Division, September 1967.

HIRAYAMA, T. Smoking and drinking-Is there a connection? Smoke Signals 16(7):
l-8, July 1970.

HIRAYAMA, T. Smoking in Relation to the Death Rates of 265,118 Men and Women
in Japan. A Report on 5 Years of Follow-Up. Paper presented at the American
Cancer Society's 14th Science Writers' Seminar, Clearwater Beach, Florida, March
24-29.1972.

216


HIRAYAMA, T. Prospective studies on cancer epidemiology based on census
population in Japan. In: Bucalossi, P., Veronesi, U., Cascinelli, N. Editors). Cancer
Epidemiology, Environmental Factors. Volume 3. Proceedings of the 11th Interna-
tional Cancer Congress, Florence, Italy, October 20-26, 1974. Amsterdam, Excerg
ta Medica, 1975a, pp. 26-35.

HIRAYAMA, T. Operational aspects of cancer public education in Japan. In:
Summary Proceedings of the International Conference on Public Education About
Cancer. UICC Technical Report Series. Volume 18, Geneva, 1975b, pp. 85-90.
HIRAYAMA, T. Changing patterns of cancer in Japan with special reference to the
decrease in stomach cancer mortality. In: Hiatt, H.H., Watson, J.D., Winsten, J.A.
(Editorsl. Origins of Human Cancer. Book A. Incidence of Cancer in Humans. Cold
Spring Harbor Conferences on Cell Proliferation, Volume 4. Cold Spring Harbor,
New York, Cold Spring Harbor Laboratory, 1977, pp. 55-75.
HIRAYAMA, T. Smoking and cancer in Japan. A prospective study on cancer
epidemiology based on census population in Japan. Results of 13 years followup.
In: Tominaga, S., Aoki, K. (Editors). The UZCC Smoking Control Workshop. Japan,
August 24-25, 1981. Nagoya, Japan, University of Nagoya Press, 1981, pp. 2-8
HOSTETLER, J.A. Amish Society. Baltimore, Johns Hopkins Press, 1968.
KAHN, H.A. The Dorn study of smoking and mortality among U.S. veterans: Report
on 8 and one-half years of observation. In: Haensxel, W. (Editor). Epidemiological
Approclches to the Study of Cancer and Other Chronic Diseases. National Cancer
Institute Monograph No. 19. U.S. Department of Health, Education, and Welfare,
Public Health Service, National Institutes of Health, National Cancer Institute,
January 1966, pp. 1-125.

LEE, P.N., GARFINKEL, L. Mortality and type of cigarette smoked. Journal of
Epidemiology and Community Health 35(l): 16-22. March 1981.
MITCHELL, R.S., SILVERS, G.W., DART, G.A., PElTY, T.L., VINCENT, T.N.,
RYAN, S.F., FILLEY, G.F. Clinical and morphologic correlations in chronic airway
obstruction. American Review: of Respimtory Disease 97(l): 5462, January 1968.
MORIYAMA, I.M., DAWBER, T.R., KANNEL, W.B. Evaluation of diagnostic informa-
tion supporting medical certification of deaths from cardiovascular disease. In:
Haensxel, W. (Editor). Epidemiological Approaches to the Study of Cancer and
Other Chronic Dz&a.ws. National Cancer Institute Monograph No. 19. U.S.
Department of Health, Education, and Welfare, Public Health Service, National
Institutes of Health, National Cancer Institute, January 1966, pp. 405-419.
NATIONAL CENTER FOR HEALTH STATISTICS. Mortality from Diseases Associ-
ated With Smoking. United States, 196&1977. DHHS Publication No. (PHS)81-
1854. US. Department of Health and Human Services, Public Health Service,
Oftice of Health Research, Statistics, and Technology, 1982.
NATIONAL CENTER FOR HEALTH STATISTICS, Annual summary of births,
deaths, marriages, and divorces: United States, 1983. Monthly Vital Statistics
Report. Volume 32, No. 12. U.S. Department of Health and Human Services, Public
Health Service, Office of Health Research. Statistics, and Technology. March 26,
1984, pp. 1-12.

PETO, R., SPEIZER, F.E., COCHRANE. A.L., MOORE, F., FLETCHER, CM..
TINKER, CM., HIGGINS, I.T.T., GRAY, R.G., RICHARDS, S.M., GILLILAND, J.,
NORMANSMITH, B. The relevance in adults of air-flow obstruction, but not
hypersecretion, to mortality from chronic lung disease. American Review of
Respimtory Disease 12&3): 491-500.1983.

REID, D.D. Bronchitis among the British. Israel Journal and Medical Sciences 7( 12):
1569-1572, December 1971.

RIMINGTON, J. Cigarette smokers' chronic bronchitis: Inhalers and non-inhalers
compared. British Journal of Diseases ofthe Chest 68: 161-165.1974.

217


ROGOT, E. Smoking and General Mortality Among U.S. Veterans, 1954-1969. DHEW
Publication No. (NIHj74-544. U.S. Department of Health, Education and Welfare,
Public Health Service, National Institutes of Health, National Heart and Lung
Institute, Epidemiology Branch, 1974a, pp 65.
RCGOT, E. Smoking and mortality among U.S. veterans. Journal of Chronic Diseases
27(4/5): 189-203, July 1974b.

ROGOT, E. Cardiorespiratory disease mortality among British and Norwegian
migrants to the United States. American Journal of Epidemiology 108(3): 181-191,
September 1978.

ROGOT, E., MURRAY, J.L. Smoking and causes of death among U.S. veterans: 16-
years of observation. Public Health Reports 9x3): 213-222, May-June 1980.
U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES. The Health Conse-
quences of Smoking: Cancer. A Report of the Surgeon Geneml. DHHS Publication
No. (PHSl82-50179. U.S. Department of Health and Human Services, Public-
Health Service, Office of the Assistant Secretary for Health, Office on Smoking
and Health, 1982,322 pp.

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES. The Health Conse-
quences of Smoking: Cardiovascular Disease. A Report of the Surgeon General.
DHHS Publication No. (PHS184-50204. U.S. Department of Health and Human
Services, Public Health Service, Office of the Assistant Secretary for Health, Office
on Smoking and Health, 1983.

WEIR, J.M., DUNN, J.E., Jr. Smoking and mortality: A prospective study. Cancer
25(l): 105-112, January 1970.

WICKEN, A.J. Environmental Personal Factors in Lung Cancer and Bronchitis
Mortality in Northern Ireland, 1960-62. Research Paper No. 9. London, England,
Tobacco Research Council, 1966,84 pp.

WICKEN, A.J., BUCK, SF. Report on a Study of Environmental Factors Associated
with Lung Cancer and Bronchitis Mortality in Areas of Northeast England.
Research Paper No. 8. London, England, Tobacco Research Council, 1964.

218


CHAPTER 4. PATHOLOGY OF LUNG
         DISEASE RELATED TO
         SMOKING

219


CONTENTS

Introduction

Lesions Associated With Chronic Airflow Obstruction
  Central Airways
      Mucus

  Other Abnormalities of Central Airways
Peripheral (Small) Airways
   General Review
  Smoking and Lesions of Peripheral (Small)
   Airways

  Vascular Lesions Related to Smoking
Emphysema
   Definition
   Classification
   Proximal Acinar Emphysema
   Panacinar (Panlobular) Emphysema
   Distal (Paraseptal) Acinar Emphysema
   Irregular Emphysema

Tobacco Smoking and Emphysema

Summary and Conclusions

References

221


introduction

It is usual to think of chronic airflow obstruction as being caused
by airway narrowing or loss of airflow driving pressure-the elastic
recoil of the lung (Macklem 1971J-or both. Lesions of the airways
are often divided into those of the "large airways" and those of the
"small airways." The reasons for this division are both historical and
conceptual. Hogg et al. (1968) showed that in patients with chronic
obstructive lung disease (COLD) the major site of airway obstruction
lay in airways that were peripheral to the wedged catheter that the
researchers used to partition airway resistance. The catheter was
wedged in airways 2 or 3 mm in diameter, and thus the airways
peripheral to the catheter included the smallest bronchi (airways
with cartilage in their walls) and bronchioles (conducting airways
without cartilage in their walls). Since both bronchi and bronchioles
were involved, Hogg and associates used the term "small airways" to
describe them, which has since become a popular term. Conceptual-
ly, lesions of airways may consist of an intraluminal component
(mucus) or a mural component. Most of the mucus in the airways is
thought to be secreted by the tracheobronchial submucosal glands
(Reid 1960); these are mainly confined to airways more than 2 or 3
mm in diameter, or large airways. Because of the documented
association between chronic productive cough and airflow obstruc-
tion (Fletcher et al. 1959), for a long time it was thought by many
that intraluminal mucus was a major source of chronic airflow
obstruction. Thus, the notion developed, without proper substantia-
tion, that central airways obstruction was due to intraluminal
mucus and peripheral airway obstruction was due to inflammation
and narrowing. It is also true that many have equated emphysema
with loss of elastic recoil, but when this has been examined in vivo
(Park et al. 1970; Boushy et al. 1970; Gelb et al. 1973; Berend et al.
1979; Pare et al. 1982) or in excised lungs (Berend et al. 1980; Silvers
et al. 1980), the association has not been close, with some notable
exceptions (Niewoehner et al. 1975; Greaves and Colebatch 1980).
Thurlbeck (1983) reviewed the evidence and argued that loss of recoil
in emphysematous lungs may not be due to the lesions of emphyse-
ma per se but to defects in apparently morphologically normal
intervening lung tissue.

The classical approach to considering the different sites of flow
obstruction is used in this chapter to analyze the relationship
between smoking and the morphologic lesions associated with
chronic airflow obstruction in humans. Lesions of the large airways
(bronchi) are discussed first, followed by small airways, and then by
alveolated structures. It has very recently become apparent that it is
important to include respiratory bronchiolitis as well as emphysema
in the last category (Wright et al., in press); this issue is discussed in
the paragraphs on peripheral (small) airways. Definitions and a brief

223


review of the diseases involved are provided. This chapter attempts
to present the morphologic changes associated with chronic obstruc-
tive lung disease. The detailed epidemiologic and experimental
evidence relating cigarette smoking and COLD are presented
elsewhere in this Report.

Lesions Associated With Chronic Airflow Obstruction
Central Airways
MUCUS

It is convenient to discuss intraluminal mucus and increased
tracheobronchial mucus gland size together, because they are
thought to be related (Reid 1960). Chronic bronchitis is defined as
"the condition of subjects with chronic or recurrent excess mucus
secretion into the bronchial tree" (Ciba Foundation Guest Sympo-
sium 1959). Because there is no way to accurately measure the
amount of mucus secreted into the bronchi, the empirical approach
was taken that production of any sputum was abnormal. Chronic
was defined as "occurring on most days for at least 3 months of the
year for at least 2 successive years" (Ciba Foundation Guest
Symposium 1959). A further qualification was that such sputum
production should not be on the basis of specific diseases such as
tuberculosis, bronchiectasis, or lung cancer.

The initial step was to correlate chronic bronchitis, as defined
above, with lesions in the central airways. This was first done by
Reid (19601, who assessed gland size by comparing the thickness of
the submucosal bronchial mucus glands in histologic sections to the
thickness of the bronchial wall. The latter was defined as the
distance from the basement membrane of the epithelium to the-
inner periochondrium. This measurement is now known as the Reid
Index. This increase has been confirmed by several observers
(Thurlbeck et al. 1963; Thurlbeck and Angus 1964; Mitchell et al.
1966; MacKenzie et al. 1969; Scott 1973), but not by all (Bath and
Yates 1968; Karpick et al. 1970). An important observation was that
there was a distinct overlap in the value of the Reid Index between
bronchitics and nonbronchitics (Thurlbeck and Angus 1964) as
opposed to Reid's 1960 finding that there were two completely
separate groups. In practical terms, this meant that the Reid Index
had limitations in predicting the presence or absence of chronic
bronchitis. More important, it suggested a broad border between-
health (nonbronchitis) and disease (bronchitis). For a variety of
technical reasons (Jamal et al., in press), the Reid Index is a difficult
measurement to use; thus, other measurements of mucus gland size-
were developed. The most popular was the volume density of mucus
glands, i.e., the ratio of area of mucus glands to area of the entire
bronchial wall as seen on histologic slides (Hale et al. 1968; Dunnill

224


et al. 1969; Takizawa and Thurlbeck 1971; Oberholzer et al. 1978).
Other methods included absolute gland size (Restrepo and Heard
1963; Bedrossian et al. 1971) and a radial intercept method (Alli
1975). The size of the acini (tubules) of mucus glands, the number per
unit area, and the ratio of mucus to serous tubules have also been
used (Reid 1960).

The Reid Index, the volume density of mucus glands, and the ratio
of mucus to serous acini have been examined in smokers and
nonsmokers; the results are shown in Table 1. When one considers
the overwhelming association between smoking and chronic bronchi-
tis in living subjects, differences in mucus gland size are insignifi-
cant. For example, three laboratories (Reid 1960; Thurlbeck et al.
1963; Thurlbeck and Angus 1964; Scott 1973) have found a difference
in Reid Index between smokers and nonsmokers; two have not (Bath
and Yates 1968; Hayes 1969). The results from volume density of
mucus glands are clearer-Ryder et al. (1971) found a higher volume
density of mucus glands in both male and female subjects. In
populations of mixed sex, Cosio et al. (1980) and Pratt et al. (1980)
found a higher volume density of glands, but Sobonya and Kleiner-
man (1972) and Scott (1973) did not. When observers have expressed
their morphologic findings as either "normal" or "abnormal" (using
different criteria), the smokers have been significantly abnormal in
all the studies (Field et al. 1966; Megahed et al. 1967; Petty et al.
1967; Vargha 1969). The balance of the evidence is that there is an
increase in mucus gland size in smokers. The discrepancy between
the clinical and the morphologic findings may reflect several factors:
the wide variation in mucus gland size in normal subjects, the
difficulties in measuring the Reid Index and volume density of
mucus glands, the different ways in which the cases have been
collected, and the errors inherent in assessing smoking histories-
from analysis of charts; also, the fact that mucus glands can enlarge
terminally (Helgason et al. 1970) might obscure true differences
between the two groups. In addition, submucosal gland enlargement
is a nonspecific change that can also occur in pneumoconiosis and
cystic fibrosis.

Mucus is also secreted by goblet cells, most of which are in the
major airways. Pratt et al. (1980) showed that goblet cells constituted
10.7 percent of the cells in the central airways of nonsmoking
nontextile workers and 20.4 percent in smoking nontextile workers.
Interestingly, they found an 18 percent frequency of goblet cells in
nonsmoking textile workers; the frequency was about the same in
smokers, whether or not they were textile workers.

Other Abnormalities of Central Airways
A variety of other changes have been described in the central
airways in patients with chronic airflow obstruction, including

225


TABLE L-Comparison of mucus gland size in smokers
       and nonsmokers

Findings in smoking category

Assessment of
mucus gland
enlargement

Author

          Light and
NOW         moderate  Heavy
smokers Smokers   smokers  smokers

Reid index        Reid (1960)                            0.46     0.43
            Thurlbeck et al. (19631          0.43    0.50   0.45     0.53
           Thurlbeck and Angus 11964)       0.44    0.49
             Bath and Yates 119681          0.45    0.49
           Hayes (19691                0.32    0.33
            Scott (1973)                 0.41    0.46

Mucus gland
proportion

Ryder et al. (1971) (men)        14.5%   17.8%
Ryder et al. (1971) women)      14.5%   17.1%
Sobonya and Kleinerman (1972)    11.2%   10.7%
Scott 119731               14.1%   14.4%
C&o et al. (1980)                Increased
Pratt et al. 11980~            9.3%   12.6%

Frequency of cases    Field et al. 119661 (men)
with MGH ' expressedField et al. (1966) lwomenl
as a percentage of  Megahed et al. (1967)
cases m the group  Petty et al. (19671
           Vargha 11969)

12%    37%
18%    26%
14%    61%
8.8%    37%
18%    44%

1 MGH = Mucus gland hypertrophy

inflammation and edema of the wall (Reid 1954), increase in
bronchial smooth muscle (Hossain and Heard 1970; Takizawa and
Thurlbeck 19711, and diminished cartilage, which is related more to
emphysema than to chronic bronchitis (Thurlbeck et al. 1974a).

Peripheral (Small) Airways
General Review

As indicated, it was as recent as 1968 that the obstruction in
patients with chronic airflow obstruction was conclusively shown to
be due mainly to lesions in airways less than 2 or 3 mm in diameter.
However, abnormalities in these airways had long been recognized.
Indeed, Laennec (1962) pointed out in 1826 that air remained
trapped in emphysematous lungs even when the major bronchi had
been opened, and he reasoned that the source of the air-trapping was
obstruction in the airways peripheral to the opened ones Since then,
numerous descriptions have been made of the peripheral airways in
severe chronic airflow obstruction (see Table 2). Smokers were not
compared with nonsmokers in any of these series. The probable
reason is that for a long time it was thought that bronchiolitis was
an infective complication of chronic bronchitis. Only very recently,
and from studies in patients with mild chronic airflow obstruction,

226


has the link between smoking and peripheral airway lesions become
established.

Hogg et al. (1968) not only found that the peripheral airways were
the site of airflow obstruction in patients with severe disease, but
also observed that peripheral airways contributed only about 15
percent of resistance to flow in normal lungs. It followed that
considerable disease could be present in these peripheral airways
without airway resistance being measurably increased. It was
reasoned also that standard tests of expiratory function, such as the
FEVl and the FEFww, might not be abnormal in the presence of
significant disease. Thus a variety of "tests of small airway function"
were devised; these evolved to the single breath nitrogen washout
test and to flow volume studies, in some instances comparing the
effect of breathing helium mixtures with the effect of breathing
room air. It soon became apparent that these tests could be abnormal
when the FEVl was greater than the 80 percent predicted and that
tests of small airway function could return to normal after cessation
of smoking (Buist et al. 1976, 1979; Beck et al. 1981; Bouse et al.
1981). The term "small airways disease" was and is often applied to
these abnormalities. It then became of interest to determine what
the lesions in the airways were. Long before this, Reid (1955) had
studied nine lungs resected from patients with chronic bronchitis
and two lungs from chronic bronchitics obtained at autopsy. She
found excess intraluminal mucus and narrowing and obliteration of
airways, as assessed subjectively. Because the surgical patients also
had lung cancer, most likely they were chronic smokers. Matsuba
and Thurlbeck (1973) compared the airways of chronic bronchitics to
those of nonbronchitics in nonemphysematous lungs. All the bron-
chitics were smokers and two nonbronchitics were smokers. Morpho-
metrically, they found obvious narrowing of airways less than 2 mm
in diameter, which also contained excess mucus.

The important study by Cosio et al. (19781, using surgically
resected lungs, showed for the first time that abnormal tests of small
airway function were related to abnormal morphology. There were
34 smokers and 2 nonsmokers in their group. A variety of abnormali-
ties were observed, including inflammation, squamous cell metapla-
sia, ulceration, fibrosis, pigmentation, and increased muscle. They
developed a score that summed the observed lesions (the total
pathology score), and divided their patients into four groups on the
basis of this score. They showed that as the total pathology score
increased, tests of small airway function (single breath nitrogen test
and flows on air and helium mixtures) deteriorated, as did standard
tests of pulmonary function such as the FEVl and FEFzsx. The data
concerning smoking are hard to interpret, but the smoking index
(number of cigarettes smoked per day times number of years
smoked) increased from groups I to III and was similar in groups III

227


TABLE 2.-Occurrence of lesions of peripheral airways in
     patients with severe chronic airflow obstruction

Authors

Disease invest:gated

Abnormalities found

Laennec (1962)

Spain and Kaufman
( 1953)

Reid (1954)

Emphysema

Chronic bronchitis

Leopold and Gough
(1957)

Centrilobular emphysema

McLean (1958)         Emphysema

Anderson and Foraker
(1962)

Pratt et al. (1965)

Anderson and Foraker
(1967)

Hogg et al. (1968)

Mitchell et al. (1968)

Bqnon et al
(1969. 1970)

Karpick et al. 119701

Linhartova et al.
(19711

Matauba and Thurlbeck
(1972)

Linhartova et al.
11973, 1974, 19771

Scott and Steiner
(1975)

Scott c 19761

Mitchell et al.
(1976)

Emphysema

Emphysema

Centrilobular emphysema

Emphysema

Emphysema with severe
chronic airflow obstruction

Chronic airflow
obstruction and severe
emphysema

Cm pulmonale and
centrilobular emphysema

Respiratory failure

Emphysema

Severe emphysema and
chronic airflow limitation

Emphysema

Car pulmonale

Chronic airflow obstruction

Chronic airflow obstruction
obstruction

Obstruction to flow in peripheral
airways

Mural inflammation and fibrosis
of bronchioles

Bronchiolitia, broncbiolar oblit-
eration, and mxus plugging

Inflammation, fibrosis with
narrowing of 60% of bronchioles
supplying centrilobular space
Inflammation of proximal rea-
piratory bronchioles, mucus
plugging, and loss of bronchioles

Collapse of bronchioles due to
loss of alveolar attachments

Loss or distortion of the
radial support of bronchioles
Loss of bronchioles in patients
under age 70

Inflammation and fibrosis of
bronchi and bronchioles and
nNKus plugging

Inflammation, atrophy, goblet
cell metaplasia, squamous
metaplasia, and mucus plugs
in bronchioles

Inflammatory narrowing and
fibrosis, loss of bronchioles.
and mucus plugging
Goblet cell metaplasia
Plugging of bronchioles with
inflammatory cells and mucus
Loss of lumen of airways less
than 2 mm in diameter due
primarily to narrowing and
InUCus plugs

Distortion, tortucsity, and
irregular narrowing of bronchioles
Lack of tilling bronchioles of
less than 1 mm

Loss of airway lumen

Chronic inflammation (r=0.48),
narrowing (OB), fibrosis (0.27).
goblet cell metaplasia (0.241,
and fewer small airways (-0.18)

228


and IV. The lesions that were different in group II from lesions in
group I were squamous cell metaplasia, inflammation, and fibrosis.
Fibrosis and squamous cell metaplasia increased steadily from
groups I to III. Increased muscle and goblet cell metaplasia occurred
only in group IV. One extrapolation of these data is that inflamma-
tion in the peripheral airways is the initial event produced in
response to cigarette smoke. This inflammation leads to, or is
associated with, squamous metaplasia and mural fibrosis. Goblet cell
metaplasia and increase in muscle subsequently occur and are
associated with decrements of function.
Berend et al. (1979) did a similar study on 21 smokers and 1
nonsmoker, and added the important information that airway
narrowing occurred and was associated with abnormalities of the
single breath nitrogen washout test and the FEFs75. The data were
reanalyzed subsequently (E&end et al. 1981b) and showed that
inflammation was the lesion associated with the most abnormalities
in tests of expiratory function. Airway inflammation was significant-
ly related to abnormalities of the FEV1, FEFzF~x, slope of phase III of
the single breath nitrogen test, and closing volume expressed as a
percentage of vital capacity. The authors also noted that as the total
pathology score got worse, the airways diminished in caliber in
surgically derived lungs, but not in autopsy lungs. They noted that
airway caliber was larger in autopsy lungs than surgical lungs, and
suggested that this represented functional narrowing due to in-
creased muscle tone, which was caused by release of mediators
affecting the muscle directly or reflexly.
Studies of lungs at autopsy have shown correlations between
airway lesions and abnormal tests of function. Petty et al. (1980,
1982) have shown that correlations exist between inflammation, and
increased muscle and elevations in the closing capacity; that
occlusion of airways by cells and mucus, inflammation, and in-
creased airway muscle are related to abnormalities of the slope of
phase III of the nitrogen washout; that airway narrowing is closely
related to the FEVi, FEFs75, and slightly less well related to closing
capacity. Similarly, Berend et al. (1981a) showed an association
between post-mortem closing capacity and both peripheral airways
inflammation and a total pathology score. Decrease in maximum
flow at a transpulmonary pressure of 5 cm HzO was related to
inflammation and the total pathology score, but not as well related
to airway narrowing (Berend and Thurlbeck 1982). Morphologic
abnormalities similar to those found in autopsy lungs have been
found in surgically excised lungs derive* almost entirely from
smokers, and these in turn have been related to abnormal tests of
small airway function.


Smoking and Lesions of Peripheral (Small) Airways

An increase in goblet cells was the first abnormality of peripheral
airways noted in smokers. The observation was made in bituminous
coal workers. In nonsmokers, about 0.66 percent of peripheral
airway cells were found to be goblet cells; in smokers, this rose to
about 1.0 percent (Naeye et al 1971).

The critical observation, both factually and conceptually, was that
of Niewoehner et al. (1974). In an autopsy study of men under the
age of 40 who died suddenly elsewhere than in the hospital, they
compared lesions of bronchioles and respiratory bronchioles (airways
with both nonrespiratory epithelium and alveoli in their walls) in
smokers and nonsmokers. Emphysematous lungs were excluded, and
the smoking history was obtained by personal interview with close
relatives, using a standard questionnaire. The researchers found
that intraluminal mucus, mural edema, peribronchiolar pigment,
peribronchiolar fibrosis, denuded epithelium, mural inflammatory
cells, and respiratory bronchiolitis were more severe in the smokers.
The last three were significantly different statistically. They empha-
sized the importance of respiratory bronchiolitis, which consisted of
aggregates of brown macrophages in and around the first and second
order respiratory bronchioles and was associated with edema,
fibrosis, and epithelial hyperplasia in adjacent bronchioles and
alveolar walls. Bronchiolitis was found in all of the smokers, but in
only 5 of the 20 nonsmokers, and it was the lesion that showed the
greatest difference between smokers and nonsmokers. Since respira-
tory bronchiolitis was found in precisely the same regions where
centrilobular emphysema is found in subjects 20 years older, the
researchers suggested that this lesion might evolve into emphysema.
This observation fits well the proteolytic-antiproteolytic hypothesis
of the pathogenesis of emphysema.

Ebert and Terracio (1975) compared the peripheral airways in
resected lungs of 22 smokers and 3 nonsmokers and found that the
number of Clara cells (the tall nonciliated airway cells thought to be
secretory, although the nature of their secretion is not completely
certain) was diminished, as assessed subjectively, and the number of
goblet cells was increased, as assessed quantitatively.

Two laboratories have concentrated on the association between
smoking and lesions of vessels as well as of airways. One has used
autopsy-derived lungs (Casio et al. 1980; Hale et al 1980); the other,
surgically excised lungs (Wright et al. 1983a, b, in press). The first
material has the advantage that the entire lung can be examined,
but has the disadvantage that agonal changes may affect the airway;
the second has the advantage that agonal changes are absent and
structure-functional studies can be done, but has the serious
disadvantage that usually only a part of the lung is examined.
Because of the wide variation in severity of emphysema from lobe to

230


lobe, emphysema in the whole lung cannot be assessed from a single
lobe. Also, airway inflammation may not be evenly distributed
through the airways (Berend 1981; Hale et al. 1980).
Cosio et al. (1980) studied 14 nonsmokers with an average age of
71.6 years and 25 long-term smokers with an average age of 58.4
years. The total pathology score was significantly higher in the
smokers; in them, but not in the nonsmokers, the total pathology
score was significantly related to age. Respiratory bronchiolitis was
more common in the smokers, and of the components of the total
pathology score, goblet cell metaplasia (p <O.OOl), inflammation of
the bronchiolar wall (p <O.Ol), and smooth muscle hypertrophy (p
~0.05) were significantly more abnormal in the smokers. Smokers
had an excess of airways less than 400 p in diameter, also related to
the total pathology score. Because goblet cell metaplasia and
increased smooth muscle were not significantly increased in the
researchers' previous study of young smokers (Niewoehner et al.
19741, they concluded that these lesions were a late complication of
cigarette smoking. They noted that there was a considerable
similarity of all lesions of both smokers and nonsmokers, and felt
that this indicated the existence of other causes of small airway
lesions. They also made the interesting suggestion that the relation-
ship between the total pathology score and the proportion of airways
less than 400 ~1 in diameter might indicate a predisposition of
subjects with small airways to develop peripheral airway lesions.
Wright et al. (1983b) studied 9 nonsmokers, 51 current smokers, 18
ex-smokers who had quit less than 2 years, and 19 ex-smokers who
had quit more than 2 years. The only lesion of the bronchioles that
distinguished the nonsmokers from the smokers and the long-term
ex-smokers was goblet cell metaplasia, although there were obvious
differences in pulmonary function among these groups. The signifi-
cance of goblet cell metaplasia may be related to mucus production
in airways not usually lined by mucus. There is evidence that they
are lined by surfactant. If this is displaced by mucus with a higher
surface tension it will produce narrowing difficult to detect by
standard morphological methods. Respiratory bronchiolitis was
more severe in the smokers and ex-smokers than in the nonsmokers.
No differences were noted between the ex-smokers and smokers.
This study has recently been extended (Wright et al., in press), and
correlations between both bronchiolar inflammation and respiratory
bronchiolitis and the FEVl were evident. When the FEVl was greater
than the 80 percent predicted, the most important determinant of
abnormalities of tests of small airway function was respiratory
bronchiolitis. Thus, respiratory bronchiolitis may not only represent
a stage in the pathogenesis of centrilobular emphysema, but also
result in abnormalities of the single breath nitrogen test and other
tests of small airway function.

231


It is not certain why cessation of smoking results in improvement
of lung function. The most likely reversible parameter is inflamma-
tion; the lack of difference between nonsmokers and the other groups
in the study by Wright et al. (1983b) is very surprising in view of the
observations of Niewohner et al. (1974) and Cosio et al. (1980), but
may be due to the very small number of nonsmokers studied and the
fact that the nonsmokers had lung lesions for which resection was
performed. An additional factor is the use of lobes in the study,
which in the small group of normals may produce distortions in the
data because of lobar variations in the total pathology score.

Vascular Lesions Related to Smoking

At first sight it may appear surprising that vascular lesions are
detectable in asymptomatic smokers or those with only mild or
moderate chronic airflow obstruction. On reflection, this could be
anticipated. Severe chronic airflow obstruction, usually related to
smoking, is often accompanied by pulmonary artery hypertension;
mild chronic airflow obstruction might be associated with mild
pulmonary artery hypertension and vascular lesions. The first study
(Hale et al. 1980) involved the same cases reported by Cosio et al.
(1980). They found that the smokers had an increased number of
arteries less than 200 p in diameter and also an increased medial
and intimal thickness of the pulmonary arteries. The intimal
thickness was increased more in those vessels of less than 200 p in
diameter. Both intimal and medial thickness were directly related to
the total pathology score. Wright et al. (1983a) found an increase in
the vessel area from an average of 0.12 mm2 in nonsmokers to
approximately 0.3 mm* in smokers. Intimal area expressed as a
proportion of vessel area increased; there was an absolute increase of
the medial area, but no proportional change. The adventitial area
also increased in absolute terms, but the adventitial proportional
area was decreased and was related to the pulmonary wedge
pressure. Pulmonary artery pressures were normal at rest, but
abnormal and reversible by oxygen on exercise in the smokers with
the worst airway inflammation and emphysema.

Emphysema

Of the lesions associated with chronic airflow obstruction, em-
physema has been the one most clearly associated with tobacco
smoking. There are several different types of emphysema, however,
and cigarette smoking has not been clearly linked to, or examined in,
all forms of the disorder. Therefore, the definition and classification
of emphysema are reviewed before discussing the association be-
tween smoking and emphysema.

232


FIGURE I.-Components of the acinus

NOTE `IT- tmmina, bmnchmle: RB,. RB2. RBI the three orders of resp,ramry bronchmles. AD alveolar duct.
As alveolar sac
SOURCE Thurlbeck (19761

Definition

Emphysema is defined as an abnormal enlargement of the air
spaces of the lung accompanied by destruction of alveolar walls
(World Health Organization 1961; American Thoracic Society 1962).
Thus, emphysema is a disorder of anatomy, and one must know the
appropriate normal anatomy in order to understand the pathology of
emphysema. The structure involved is the acinus, the unit gas-
exchanging structure of that part of the lung containing alveoli. The
last purely conducting airway is the terminal bronchiole; structures
distal to it constitute the acinus. The acinus is a complex unit, but a
simplified model will suffice (Figure 1). The structures immediately
before the terminal bronchiole are the respiratory bronchioles,
which, as indicated previously, have both alveoli and nonalveolated
epithelium forming their walls; thus, respiratory bronchioles both
conduct and exchange gas. Proceeding distally, progressively more
alveoli appear in the walls of respiratory bronchioles, of which there
are three orders in the usual model of the acinus. Alveolar ducts
succeed respiratory bronchioles, and their walls are entirely alveo-
lated. Alveolar ducts lead into alveolar sacs, the terminal respiratory
structures, which are likewise completely alveolated.

Classification

Emphysema is classified by the way it involves the acinus, and
four forms of emphysema are usually recognized (Thurlbeck 1976):
(1) proximal acinar emphysema, (2) panacinar (panlobular) emphyse-

233

480-144 0 - 85 - 9


ma, (3) distal (paraseptal) acinar emphysema, and (4) irregular
emphysema.

Proximal Acinar Emphysema

In proximal acinar emphysema, the respiratory bronchioles are
selectively or dominantly involved. Emphysema involving the proxi-
mal part of the acinus is found in two different circumstances-
centrilobular emphysema and focal emphysema.

Proximal acinar emphysema is the common form of nonindustrial
emphysema and is associated with inflammation of the distal
airways (Leopold and Gough 1957) and of the walls of emphysema-
tous spaces. This form of emphysema is usually referred to as
centrilobular emphysema (Figure 2) because the lesions lie close to
the center of the secondary lobules. The emphysematous spaces are
found more frequently in the upper zones of the lungs, and
centrilobular emphysema is usually more severe there (Thurlbeck
1963a). Involvement of the lung is characteristically quite uneven;
some respiratory bronchioles are spared or slightly involved,
whereas others close by may be severely affected, producing large
emphysematous spaces. Centrilobular emphysema is frequently
associated with chronic bronchitis, and is the form of emphysema
most commonly encountered in patiepts with symptomatic chronic
airflow obstruction.

Focal emphysema, or simple pneumoconiosis of coalworkers, also
involves the proximal part of the acinus. It can be distinguished from
centrilobular emphysema in that there is always a heavy deposit of
coal around the emphysematous spaces, the enlargement of respira-
tory bronchioles is usually moderate, and the process is more
uniform through the lung. Simple pneumoconiosis is usually associ-
ated with only mild impairment of function, producing only minor
abnormalities of gas exchange (Morgan and Seaton 1975).

Panacinar (Panlobular) Emphysema

In panacinar or panlobular emphysema, there is more or less
uniform involvement of the acinus (Figure 3). Controversy exists
concerning the distinction between centrilobular and panacinar
emphysema; some believe them to be different conditions (Anderson
and Foraker 1973), but others believe them to have the same clinical
and functional associations (Mitchell et al. 1970). The reason for this
disagreement is discussed below. Four different associations of
panacinar emphysema are described (Thurlbeck 1976), each with its
specific clinicopathologic associations. This view is not shared by all,
however.
The classical association of panacinar emphysema is with aI-
antitrypsin deficiency (Eriksson 1965), most commonly with the PiZ

234


FIGURE 2.-Centrilobular emphysema
NOTE See footnote to Figure 1 for definitmns
SOURCE: Thurlbeck (1976)

FIGURE 3.-Panlobular emphysema
NOTE: See footnote to Figure 1 for definhons
SOURCE: Thurlbeck (1976).

235


phenotype. It is probable that other forms of Pi-associated emphyse-
ma, such as PiSZ, are also panacinar in type. Familial emphysema
unassociated with a,-antiprotease deficiency has been shown to be
panacinar (Martelli et al. 1974). Familial emphysema is characteris-
tically worse in the lower zones of the lung. Severe, pure panacinar
emphysema is uncommon.

Localized panacinar emphysema is found fairly frequently at
autopsy (Thurlbeck 1963a). It is found more commonly in older
people and is usually not associated with clinical evidence of chronic
airflow obstruction. Under these circumstances, it is more frequent
in the lower and anterior parts of the lung. It may represent a focal
exaggeration of the aging process in the lung, which includes a well
documented set of changes (Thurlbeck 19761, including changes in
the shape of the lung with an increase in anteroposterior diameter,
loss of volume density of alveolar walls, increase in the distance
between alveolar walls, decrease of alveolar surface area, increase in
volume density of alveolar ducts, and decrease of volume density of
alveoli. The reason for referring to these changes with age as the
"aging lung" rather than "senile emphysema" is that it is a normal
change, affecting virtually all people. The deliniticn of emphysema
requires that the enlargment and destruction of respiratory tissue be
abnormal; therefore, it is probably inappropriate to categorize these
changes as emphysema.

Bronchial and bronchiolar obliteration may be associated with
panacinar emphysema. Most commonly it is associated with Swyer-
James (1953) or MacLeod's (1954) syndrome of unilateral pulmonary
hyperlucency, in which one lung or a major portion of the lung is
unduly transradiant. The involved region or regions of the lung
characteristically trap air on expiration so that the mediastinum
then moves to the unaffected side. The syndrome is usually due to
severe acute bronchitis and bronchiolitis in childhood, resulting in
obliteration of airways. A detailed study of the lung parenchyma in
cases of unilateral pulmonary transradiancy has never been
reported, but it seems likely that emphysema may not be present in
the affected lung tissue. However, when emphysema is present, it is
panacinar in type.

Panacinar emphysema may be found in the lower zones of the lung
in patients with upper zonal centrilobular emphysema. The combi-
nation of the two forms of emphysema is probably the classical
finding in patients with severe chronic airflow obstruction, and it is
also one reason for the controversy concerning similarities or
differences between centrilobular and panacinar emphysema. Tran-
sitions, real or imagined, may be apparent between the upper zonal
centrilobular emphysematous spaces and lower zonal panacinar
emphysema in this situation. Some believe the transitions are real,
and maintain that centrilobular emphysema has progressed to

236


FIGURE 4.-Distal or paraseptal acinar emphysema
NOTE: See footnote to Figure I for definmons
!WJRCE~Thurlteck (19761

panacinar emphysema and that these lungs should be classified as
examples of centrilobular emphysema. Others feel that it is panaci-
nar emphysema, and thus the same lung may be classified different-
ly.

Distal (Paraseptal) Acinar Emphysema

Distal (paraseptal) acinar emphysema is the third generally
recognized form of emphysema. In this form, the alveolar ducts and
sacs are predominantly involved, and there may be substantial
associated fibrosis (Figure 4). Since the distal acinus abuts on pleura,
vessels, airways, and lobular septa, the emphysema is worse in these
regions. The occurrence of distal acinar emphysema along the
lobular septa had led to the term "paraseptal emphysema." A
characteristic clinical association of distal acinar emphysema is
spontaneous pneumothorax of young adults (Edge et al. 1966).

rregular Emphysema

In irregular emphysema, the acinus is irregularly enlarged (Figure
il. It is nearly always associated with scarring. It may be the most
`ommon form of emphysema, because nearly all lungs on close
axamination will disclose a scar associated with emphysema. The
najority of these examples of irregular emphysema are unassociated
fith symptoms.

237


FIGURE B.--Irregular emphysema

NOTE Se footnote to Figure 1 for debutions
SOURCE Thurlbeck (1976)

Tobacco Smoking and Emphysema

The apparently neat and orderly classification described above and
the classical examples of emphysema illustrated in original articles
and monographs should not obscure the lack of agreement between
expert observers in the classification of severely emphysematous
lungs (Thurlbeck et al. 1968, Mitchell et al. 1970). Severe emphyse-
ma is usually atypical in morphology, and often more than one type
of emphysema is present. It might be more rational to speak of "end
stage emphysema" when describing an extensively damaged lung,
rather than attempting to fit all of the damage under one classifica-
tion.

These differences in classification may lead to differing assess-
ments of degrees of association between smoking and individual
forms of emphysema. For example, Anderson and Foraker (1973)
found that all of their 21 patients with centrilobular emphysema
were cigarette smokers, whereas 8 of the 17 patients with panacinar
emphysema were cigarette smokers. Contrarily, Mitchell et al. (1970)
found that 20 of their 21 patients with centrilobular emphysema
were cigarette smokers and all 6 of their patients with panacinar
emphysema were cigarette smokers.

Including all of the different abnormalities described above under
the single term "emphysema" may lead to confusion about the
relationship between smoking and emphysema. Each of the different
forms of emphysema may have different etiologies; while cigarette
smoking is clearly implicated in the etiology of centrilobular
emphysema (Mitchell et al. 1970, Anderson and Foraker 19731, it
may not play a role in irregular or distal acinar emphysema and is

238


clearly not implicated in the etiology of unilateral pulmonary
transradiancy.

Another problem is the sensitivity with which emphysema is
recognized. Thurlbeck (1976) reviewed the incidence of emphysema
found at autopsy in 28 series. An extremely wide variation has been
recorded, including three series with an incidence of 100 percent.
The variation in incidence probably represents the care with which
the lung is examined and the threshold for defining emphysema
being present as much as a true difference in incidence.

It is not relevant to the present discussion whether rare or
unusual disease processes can cause abnormal enlargement of the
air spaces or whether, after careful and exhaustive search, all lungs
demonstrate minute areas of focal enlargement. The lung has
substantial ventilatory reserve; therefore, what is significant is not
the presence or absence of any emphysema, but rather the extent or
severity of the emphysematous change in the lung. What is both
clear and relevant to the present discussion is that the relationship
between smoking and emphysema represents an association between
smoking and the severity of emphysema, and that the relationship is
between smoking and those forms of emphysema commonly found in
patients with COLD.

In 1963, clinicopathologic findings (Thurlbeck 1963b) in a group of
patients dying at the Massachusetts General Hospital showed that
18 of 38 patients without emphysema were cigarette smokers,
whereas all of the 19 patients with severe emphysema were cigarette
smokers. A formal study of the relationship between emphysema
and smoking was first made by Anderson et al. (1964), who showed
that one-third of patients without emphysema, 19 of 37 patients with
mild emphysema, 19 of 23 patients with moderate emphysema, and
all 6 patients with severe emphysema were smokers. In 1966, an
extended study (Anderson et al. 1966) found in the four groups,
respectively, that 12 of 33 patients, 58 of 84 patients, 30 of 33
patients, and 14 of 15 patients were smokers. Mitchell et al. (1964)
found 62 smokers among 85 patients with no or mild emphysema
and 39 smokers among 40 patients with moderate or severe
emphysema. These researchers also extended their series (Petty et
al. 1967) and found 6 nonsmokers among 57 patients with moderate
emphysema and 1 nonsmoker among 61 patients with severe
emphysema. A very dramatic difference was shown between smokers
and nonsmokers by Ryder et al. (1971). Figures 6 and 7 indicate very
graphically the rarity of emphysema of even moderate severity in
nonsmokers and the high incidence of emphysema in smokers over
50 years of age. Of the 21 patients in their series whose lungs had a
more than 25 percent involvement by emphysema, only 1 was a
nonsmoker.

239


Nonsmokers

   70



   60

E
%   50
z
f
`0   40
E
2
B   30
?A
_m
5
E   20
a

   IO

10    20    30    40    50    60    70    80    90

              Age (!n years)

FIGURE 6.-Percentage of lung occupied by emphysema in

       nonsmokers
SOURCE Ryder et al 11971,

Only a small effect of smoking was noted in coal miners by Naeye
et al. (1971), an increase from 24.3 percent of the lung involved in
nonsmokers to 30 percent in smokers. A much greater effect of
smoking was noted by Auerbach et al. (19721, who studied lungs from
2,613 autopsies and were able to obtain smoking histories in 1,831 of
the patients. They found that 10 percent of male patients who had
not smoked had emphysema; this percentage rose to 53.5 percent for
pipe smokers and cigar smokers, 86.9 percent for smokers of less
than a pack per day, and 99.7 percent for smokers of more than a
pack per day. Of the 130 patients with severe emphysema, 126
smoked more than a pack a day, 2 smoked less than a pack, 2 were
pipe or cigar smokers, and none were nonsmokers. Their findings
were subsequently extended and confirmed by histologic examina-
tion of these lungs (Auerbach et al. 1974). Findings in women were
similar. Spain et al. (1973) studied lungs from 134 persons who died
suddenly and unexpectedly and who had no previous known
pulmonary disease. In men, they found an incidence of emphysema
of more than grade 20 (mild emphysema) of 10 percent in nonsmok-
ers, 36 percent in smokers of less than a pack per day, and 39 percent

240


7C

Smokers

.

     `*
    o  ? ?
       ?
? o
o ?      ?
?      ? ?

0 20
$ :i                                I

                         .       .      . '
   10                       o ?
              ?? o ? ?        ?
                  ???? ? o ????  o ?
      ? ???                      ?
               ? ? ? ? ?    ?? ???? ?? ?

t        I     I     I     I     I     I     I     I
  10    20    30    40    50    60    70    80    90

                Age (m yearsI

FIGURE 7.-Percentage of lung occupied by emphysema in
        smokers
SOURCE Ryder& al. 119711.

in smokers of more than a pack. In women the incidences in the
same categories were 0, 17, and 23 percent, respectively. Bonfiglio
and Schenk (1974) found that the diagnosis of emphysema was made
in 40 percent of autopsy protocols from smokers and in 12 percent
from nonsmokers.

Using the autopsy populations of teaching hospitals in three
separate cities, Thurlbeck et al. (197413) reported the average
emphysema score per decade for male and female nonsmokers
(Figure 8) and for male and female smokers combined with ex-
smokers (Figure 9). The severity of emphysema is expressed using
the panel grading method (Thurlbeck et al. 1970). With this method,
a score of up to 25 is "mild emphysema." As Figure 8 indicates, in
nonsmokers there is an increasing average severity of emphysema
with age, starting in the fifth decade, reaching an average score in
the eighth and ninth decades of 10 to 15 in men and 4 to 6 in women.
There is a dramatic difference in male heavy smokers and ex-
smokers, for whom the average score of 25 to 30 in the seventh
decade is maintained for the next two decades. The number of heavy
smoking and ex-smoking women is very small, and the effects in

241


-- --                 .,
     -- --   ---      ..,1
                      1
                -- ---x---_
               "Q..     \
                        ,`.. `2.. '
                          \`..  I
                           \`. \
                     \`; \
                            I i
                         , : '
                 I :;'
                \ `i
                   \ .\
  \c
                          `.; \
                  \ :
                           `\ `,.
                              \
                               `\

           "1
           :' `\

.--.     : `\
     --       `.._ \\
        --        . . .  \
        --._ ..\
                  ".._ \
           `.,`.`,.
                    \ I `i.
1 (\
             / \ :..,
           ; \
                     `\  ,>
            \\ 1,.
                          `c'..
                        `\ Q..
                         `\  <`X..
                          \. \x

FIGURE S.-Average emphysema score in male and
       female nonsmokers in Montreal, Cardiff, and
       MaIma, by decade

NOTE All The average for the three cities.
SOURCE l'burlbeck et al t 1974bl

242


FIGURE b.-Average emphysema score in male and female
     heavy cigarette smokers (>pack per day) and
      ex-smokers, by decade
N(3TE: All: The average for the three aties
SOURCE Tburlteck et al 11974bl

243


women are more modest, with an average emphysema score of 8 to
12 from the sixth to the ninth decade.

Pratt et al. (1980) studied the effect of smoking on cotton textile
workers and on workers not exposed to cotton. They found that the
incidence of centrilobular emphysema was 6.7 percent in non-
smoking non-cotton-textile workers, 6.9 percent in nonsmoking
cotton-textile workers, 26.5 percent in smoking non-cotton-textile
workers, and 26.2 percent in smoking cotton-textile workers. The
variation in the incidence of centrilobular emphysema involving
more than 25 percent of the lung was even more dramatic-1.1,0.4,
11.0, and 12.6 percent for the respective categories.
Thus, despite the limitations in interpretation of the types of
emphysema and in recognition of the presence of emphysema, the
association between smoking and emphysema-particularly severe
emphysema-is overwhelming. In the various series referred to, of
the 227 patients with severe emphysema, only 3 were nonsmokers.

Summary and Conclusions

1. Smoking induces changes in multiple areas of the lung, and the
effects in the different areas may be independent of each other.
In the bronchi (the large airways), smoking results in a modest
increase in size of the tracheobronchial glands, associated with
an increase in secretion of mucus, and in an increased number
of goblet cells.

2. In the small airways (conducting airways 2 or 3 mm or less in
diameter consisting of the smallest bronchi and bronchioles) a
number of lesions are apparent. The initial response to
smoking is probably inflammation, with associated ulceration
and squamous metaplasia. Fibrosis, increased muscle mass,
narrowing of the airways, and an increase in the number of
goblet cells follow.

3. Inflammation appears to be the major determinant of small
airways dysfunction and may be reversible after cessation of
smoking.

4. The most obvious difference between smokers and nonsmokers
is respiratory bronchiolitis. This lesion may be an important
cause of abnormalities in tests of small airways function, and
may be involved in the pathogenesis of centrilobular emphyse-
ma. The severity of emphysema is clearly associated with
smoking, and severe emphysema is confined largely to smok-

ers.

244


References

ALLI, A.F. The radial intercepts method for measuring bronchial mucous gland
volume. Thorax 30(6): 687492, December 1975.
AMERICAN THORACIC SOCIETY. Chronic bronchitis, asthma and pulmonary

emphysema. A statement by the committee on diagnostic standards for nontuber-
culous respiratory diseases. American Review of Respiratory Disease 85: 762-768,
1962.

ANDERSON, A.E., Jr., FORAKER, A.G. Relative dimensions of bronchioles and
parenchymal spaces in lungs from normal subjects and emphysematius patients.
American Journal of Medicine 32(2): 218-226, February 1962.
ANDERSON, A.E., Jr., FORAKER, A.G. Populations of nonrespiratory bronchioles in
pulmonary emphysema. Archives of Pathology 833): 286-292, March 1967.
ANDERSON, A.E., Jr., FORAKER, A.G. Centrilobular emphysema and panlobular
emphysema: Two different diseases. Thorax 2W5): 547550, September 1973.
ANDERSON, A.E., Jr., HERNANDEZ, J.A., ECKERT, P.A.. FORAKER, A.G.
Emphysema in lung macrosections correlated with smoking habits. Science
144(3621): 1025-1026, May 22,1964.

ANDERSON, A.E., Jr., HERNANDEZ, J.A., HOLMES, W.L., FORAKER A.G.
Pulmonary emphysema: Prevalence, severity, and anatomical patterns in macro-
sections, with respect to smoking habits. Archives of Environmental Health 12(5):
569-577, May 1966.

AUERBACH, O., GARFINKEL, L., HAMMOND, EC Relation of smoking and age to
findings in lung parenchyma: A microscopic study. Chest 65(l): 29-35, January
  1974.

AUERBACH, O., HAMMOND, E.C., GARFINKEL, L., BENANTE, C. Relation of
smoking and age to emphysema. New England Journal of Medicine 286(16): 853-
858, April 20,1972.

BATH, J.C., YATES, P.A. Clinical and pathological correlations in chronic airways
obstructions-observations on patients with pulmonary resection. In: Current
Research in Chronic Airways Obstruction. Ninth Aspen Emphysema Conference.
Public Health Service Publication No. 1717, 1968, pp. 293-308.
BECK, G.J., DOYLE, CA., SCHACHTER, E.N. Smoking and lung function. American
Review of Respimtory Disease 123(2): 149-155, February 1981.
BEDROSSIAN, C.W.M., ANDERSON, A.E. Jr., FORAKER, A.G. Comparison of
methods for quantitating bronchial morphology. Thorax 26(4): 406-408, July 1971.
BEREND, N. Lobar distribution of bronchiolar inflammation in emphysema. Ameri-
can Review of Respimtory Disease 124(3): 218-220, September 1981.
BEREND, N., SKOOG, C., THURLBECK, W.M. The pressure-volume characteristics
of excised human lungs: Effects of sex, age and emphysema. Journal of Applied
Physiology: Respimtory, Environmental and Exercise Physiology 49i43: 558565,
October 1980.

BEREND, N., SKOOG, C., THURLBECK, W.M. Single-breath nitrogen test in excised
human lungs. Journal of Applied Physiology: Respiratory, Environmental and
Exercise Physiology 51(6): 1568-1573, December 1981a.
BEREND, N., THURLBECK, W.M. Correlations of maximum expiratory flow with
small airway dimensions and pathology. Journal of Applied Physiology: Respim-
tory, Environmental and Exercise Physiology 52(2): 34tX351, February 1982.
BEREND, N., WOOLCOCK, A.J., MARLIN, G.E. Correlation between the function
and structure of the lung in smokers. American Review of Respiratory Disease
119(5): 695-705, May 1979.

BEREND, N., WRIGHT, J.L., THURLBECK, W.M., MARLIN, G.E., WOOLCOCK, A.J.
Small airways disease: Reproducibility of measurements and correlation with lung
function. Chest 79(3): 263-268, March 1981b.

245


BIGNON, J., ANDREBOUGARAN, J., BROUET, G. Parenchymal, bronchiolar, and
bronchial measurements in centrilobular emphysema. Relation to weight of right
ventricle. Thonur 25c.5): 556567, September 1970.
BIGNON, J., KHOURY, F., EVEN, P., ANDRE, J., BROUET, G. Morphometric study
in chronic obstructive bronchopulmonary disease. American Review of Respiratory
Disease 99(5): 669-695, May 1969.

BONFIGLIO, T.A., SCHENK, E.A. Lipid deposits in pulmonary connective tissue.
Archives of Pathology 97(l): 48-50, January 1974.
BOUSE, R., SPARROW, D., ROSE, C.L., WEISS, S.T. Longitudinal effect of age and
smoking cessation on pulmonary function. American Review of Respimtory Disease
123(4): 378-381, April 1981.

BOUSHY, S.F., HELGASON, A.H., BILLIG, D.M., GYORKY, F.G. Clinical, physiolog-
ic, and morphologic examination of the lung in patients with bronchogenic
carcinoma and the relation of the fmdings to post operative deaths. American
Review of Respiratory Disease lOl(5): 685695, May 1970.
BUIST, A.S., NAGY, J.M., SEXTON, G.J. The effect of smoking cessation on
pulmonary function: A 30-month follow-up of two smoking cessation clinics
American Review of Respimtory Disease 120(4): 953-957, October 1979.
BUIST, A.S., SEXTON, G.J., NAGY, J.M., ROSS, B.B. The effect of smoking cessation
and modification on lung function. American Review of Respiratory Disease 114(l):
115122, July 1976.

CIBA FOUNDATION GUEST SYMPOSIUM. Terminology, definitions, and classifica-
tion of chronic pulmonary emphysema and related conditions. Thomr 14(4): 286-
299, December 1959.

COSIO, M.G., GHEZZO, H., HOGG, J.C., CORBIN, R., LOVELAND, M., DOSMAN, J.,
MACKLEM, P.T. The relations between structural changes in small airways and
pulmonary function tests. New England Journal of Medicine 298(23): 1277-1281,
June 8.1978.

COSIO, M.G., HALE, K.A., NIEWOEHNER, D.E. Morphologic and morphometric
effects of prolonged cigarette smoking on the small airways. American Review of
Respimtory Disease 122(2): 265-271, August 1980.
DUNNILL, M.S., MASSARELLA, G.R., ANDERSON, J.A. A comparison of the
quantitative anatomy of the bronchi in normal subjects, in status asthmaticus, in
chronic bronchitis, and in emphysema. 2'hom.x 24(Z): 176-179, March 1969.
EBERT, R.V., TERRACIO, M.J. The bronchiolar epithelium in cigarette smokers.
Observations with the scanning electron microscope. American Review of Respim-
tory Disease 111(l): 4-11, January 1975.

EDGE, J., SIMON, G., REID, L. Peri-acinar (paraseptal) emphysema: Its clinical,
radiological, and physiological features. British Journal of Diseases of the Chest
60(l): 10-18, January 1966.

ERIKSSON, S. Studies in alphal-antitrypsin deficiency. Acta Medica Scandinauica
177(Supplement 432): l-125,1965.

FIELD, W.E.H., DAVEY, E.N., REID, L., ROE, F.J.C. Bronchial mucus gland
hypertrophy: Its relation to symptoms and environment. British Journal of
Diseases of the Chest 60(2): 66430, April 1966.
FLETCHER, C.M., ELMS, P.C., FAIRBAIRN, A.S., WOOD, C.H. The significance of
respiratory symptoms and the diagnosis of chronic bronchitis in a working
population. British Medical Journal Z(5147): 257-266, August 29,1959.
GELB, A.F., GOLD, W.M., WRIGHT, R.R., BRUCH, H.R., NADEL, J.A. Physiologic
diagnosis of subclinical emphysema. American Review of Respiratory Disease
107(l): 50-63, 1973.

GREAVES, I.A., COLEBATCH, H.J.H. Elastic behavior and structure of normal and
emphysematous lungs post mortem. American Review of Respimtory Disease
121(l): 127-136, January 1980.

246


HALE, F.C., OLSEN, C.R., MICKEY, M.R., Jr. The measurement of bronchial wall
components. American Review of Respimtory Disease 98(6): 97%987, December
  1968.

HALE, K.A., NIEWOEHNER, D.E., COSIO, M.G. Morphologic changes in the
muscular pulmonary arteries: Relationship to cigarette smoking, airway disease,
and emphysema. American Review of Respimtory Disease 122(Z): 273-278, August
  1980.

HAYES, J.A. Distribution of bronchial gland measurements in a Jamaican popula-
tion. Thorax 24(5): 619-622, September 1969.
HELGASON, A.H., BOUSHY, S.F., BILLIG, D.M., GYORKY, F. Changes with time in
morphologic chronic bronchitis: Comparison of surgically resected lungs and the
remaining lung obtained after death. Geriatrics 25(5): 101-106, May 1970.
HOGG, J.C., MACKLEM, P.T., THURLBECK, W.M. Site and nature of airway
obstruction in chronic obstructive lung disease. New England Journal of Medicine
278CZ): 1355-1360,1968.

HOSSAIN, S., HEARD, B.E. Hyperplasia of bronchial muscle in chronic bronchitis.
Journal of Pathology lOl(2): 171-184, June 1970.
JAMAL, K., COONEY, T.P., FLEETHAM, J.A., THURLBECK, W.M. Chronic
bronchitis: Correlation of morphological findings in sputum production and flow
i&es. American Review of Respimtory Disease, in press,
KARPICK, R.J., PRATT, P.C., ASMUNDSSGN, T., KILBURN, K.H. Pathological
findings in respiratory failure. Goblet cell metaplasia, alveolar damage, and
myocardial infarction. Annals of Internal Medicine 72(2): 189-197, February 1970.
LAENNEC, R.T.H. A Treatise on the Disease of the Chest. Fourth edition. New York,
Hafner Publishing Co.. 1962. (First edition published in 1835 by Wood.)
LEOPOLD, J.G., GOUGH, J. The centrilobular form of hypertrophic emphysema and
its relation to chronic bronchitis. 2'horo.r 12: 219235,1957.
LINHARTOVA, A., ANDERSON, A.E., Jr., FORAKER, A.G. Intraiuminal exudates of
nonrespiratory bronchioles in pulmonary emphysema. Human Pathology Z(2): 333-
336, June 1971.

LINHARTOVA, A., ANDERSON, A.E., Jr., FORAKER, A.G. Nonrespiratory bronchi-
olar deformities. Graphic assessment in normal and emphysematous lungs.
Archives of Pathology and ikbomtory Medicine 95(l): 45-47, January 1973.
LINI-LARTOVA, A., ANDERSON, A.E., Jr., FORAKER, A.G. Topology of nonrespira-
tory bronchioles of normal and emphysematous lungs. Human Pathology X6): 729-
735, November 1974.

LINHARTOVA, A., ANDERSON, A.E., Jr., FORAKER, A.G. Further observations on
luminal deformity and stenosis of nonrespiratory bronchioles in pulmonary
emphysema. Thoraz 32(l): 53-50, February 1977.
MacKENZIE, H.I., GLICK, N., OUTHRED, K.J. Chronic bronchitis in coal miners:
Ante-mortem/post-mortem comparisons. Thomx 24(5): 627-535, September 1969.
MACKLEM, P.T. Airway obstruction and collateral ventilation. Physiological Reviews
51(2): -36, April 1971.

MacLEOD, W.M. Abnormal transradiancy of one lung. Thorax 9(2): 147-153, June
  1954.

MARTELLI, N.A., GOLDMAN, E., RONCORONI, A.J. Lower-zone emphysema in
young patients without alphai-antitrypein deficiency. Thorax 29(2): 237-244,
March 1974.

MATSUBA, K., THURLBECK, W.M. The number and dimensions of small airways in
emphysematous lungs. American Journal of Pathology 67(Z): 265-275, May 1972.
MATSUBA, K., THURLBECK, W.M. Disease of the small airways in chronic
bronchitis. American Review of Respimtory Disease 107(4): 552-558, April 1973.
MEGAHED, G.E., SENNA, G.A., EISSA, M.H., SALEH. S.Z., EISSA, H.A. Smoking
versus infection as the aetiology of bronchial mucous gland hypertrophy in chronic
bronchitis. Thorax 22(3): 271-278, May 1967.

247


MITCHELL, R.S., RYAN, S.F., PETTY, T.L., FILLEY, G.F. The significance of
morphologic chronic hyperplastic bronchitis. American Reuieu: of Respiratory
Disease 935): 720-729, May 1966.

MITCHELL, R.S., SILVERS, G.W., DART, G.A., PETTY, T.L., VINCENT, T.N.,
RYAN, SF., FILLEY, G.F. Clinical and morphologic correlations in chronic airway
obstruction. American Review of Respiratory Disease 97(l): 54-61, January 1968.
MITCHELL, R.S., SILVERS, G.W., GOODMAN, N., DART, G.A., MAISEL, J.C. Are
centrilobular emphysema and panlobular emphysema two different diseases?
Human Pathology l(3): 433-441, September 1970.
MITCHELL, R.S., STANFORD, R.E., JOHNSON, J.M., SILVERS, G. W., DART, G.A.,
GEORGE, M.S. The morphologic features of the bronchi, bronchioles, and alveoli
in chronic airway obstruction: A clinicopathologic study. American Review of
Respiratory Disease 114(l): 137-145, July 1976.
MITCHELL, R.S., VINCENT, T.N., FILLEY, G.F. Cigarette smoking, chronic bronchi-
tis, and emphysema. Journal of the American Medical Association 188(l): 12-16,
April 6, 1964.

MORGAN, W.K.C., SEATON, A. Occupational Lung Diseases. Philadelphia, W.B.
Saunders, 1975.

NAEYE, R.L., MAHON, J.K., DELLINGER, W.S. Effects of smoking on lung structure
of Appalachian coal workers. Archives of Envimnmental Health 22(2): 190-193,
February 197 1.

NIEWOEHNER, D.E., KLEINERMAN, J., LIOTTA, L. Elastic behaviour of postmor-
tem human lungs: Effects of aging and mold emphysema. Journal of Applied
Physiology 36: 943-949.1975.

NIEWOEHNER, D.E., KLEINERMAN, J., RICE, D.B. Pathologic changes in the
peripheral airways of young cigarette smokers. New England Journal of Medicine
291(15): 755-758, October 1974.

OBERHOLZER, M., DALQUEN, P., WYSS, M., ROHR, H.P. The applicability of the
gland/wall ratio (Reid-Index) to clinicopathological correlation studies. Thorax
33(6): 779-784, December 1978.

PARE, P.D., BROOKS, L.A., BATES, J., LAWSON, L.M., NELEMS, J.M.B., WRIGHT,
J.L., HOGG, J.C. Exponential analysis of the lung pressure-volume curve as a
predictor of pulmonary emphysema. American Review of Respiratory Disease
126(l): 54-61, July 1982.

PARK, S.S., JANIS, M., SHIM, C.S., WILLIAMS, M.H., Jr. Relationship of bronchitis
and emphysema to altered pulmonary function. American Review of Respiratory
Disease 102(6): 927-936, December 1970.

PETTY, T.L., RYAN, S.F., MITCHELL, R.S. Cigarette smoking and the lungs.
Relation to postmortem evidence of emphysema, chronic bronchitis and black lung
pigmentation. Archives of Environmental Health 14: 172-177, January 1967.
PETTY, T.L., SILVERS, G.W., STANFORD, R.E. Small airway dimension and size
distribution in human lungs with an increased closing capacity. American Review
of Respiratory Disease 125(5): 53S539, May 1982.
PETTY, T.L., SILVERS, G.W., STANFORD, R.E., BAIRD, M.D., MITCHELL, R.S.
Small airway pathology is related to increased closing capacity and abnormal slope
of phase III in excised human lungs. American Review of Respiratory Disease
121(3): 449-456, March 1980.

PRATT, P.C., JUTABHA, O., KLUGH, G.A. Quantitative relationship between
structural extent of centrilobular emphysema and postmortem volume and flow
characteristics of lungs. Medicina Thoracalis 22(Z): 197-269.1965.
PRA'lT, P.C., VOLLMER, R.T., MILLER, J.A. Prevalence and severity of morphologic
emphysema and bronchitis in nrn-textiie and cotton-textile workers. Chest 77:
323-325, February 2,198O.

REID, L.M. Pathology of chronic bronchitis. Luncet l(6806): 275-278, February 6,
  1954.

248


REID, L.M. Correlation of certain bronchographic abnormalities seen in chronic
bronchitis with the pathological changes. Thorax lo(5): 199-204, September 1955.
REID, L.M. Measurement of bronchial mucous gland layer: A diagnostic yardstick in
chronic bronchitis. Thorax X(2): 132-141, June 1960.
RESTREPO, G., HEARD, B.E. The size of the bronchial glands in chronic bronchitis.
Journal of Pathologv and Bacteriology 85(2): 305-310, April 1963.
RYDER, R.D., DUNNILL, MS., ANDERSON, J.A. A quantitative study of bronchial
mucous gland volume, emphysema and smoking in a necropsy population. Joclrnal
ofpathology 104(l): 5971, May 1971.

SCOTT, K.W.M. An autopsy study of bronchial mucous gland hypertrophy in
Glasgow. American Review of Respimtory Disease 107(2): 239-245, February 1973.
SCOTT, K.W.M. A pathological study of the lungs and heart in fatal and non-fatal
chronic airways obstruction. Thorax 31(l): 7&79, February 1976.
SCOTT, K.W.M., STEINER, G.M. Postmortem assessment of chronic airways obstruc-
tion by tantalum bronchography. Thomr 30(4): 40-14. August 1975.
SILVERS, G.W., PETTY, T.L., STANFORD, R.E. Elastic recoil changes in early
emphysema. Thom.r 3X7): 490-495, July 1980.
SOBONYA, R.E., KLEINERMAN, J. Morphometric studies of bronchi in young
smokers. American Review of Respiratory Disease 10X5): 768-775, May 1972.
SPAIN, D.M., KAUFMAN, G. The basic lesion in chronic pulmonary emphysema.
American Review of Tuberculosis 68: 24-30.1953.
SPAIN, D.M., SIEGEL, H., BRADESS, V.A. Emphysema in apparently healthy adults:
Smoking, age, and sex. Journal of the American Medical Association 124(3): 322-
325, April 16,1973.

SWYER, P.R., JAMES, G.C.W. A case of unilateral pulmonary emphysema. Thorax
8(2): 13%136, June 1953.

TAKIZAWA, T., `I'HURLBECK, W.M. Muscle and mucous gland size in the major
bronchi of patients with chronic bronchitis, asthma and asthmatic bronchitis.
American Review of Respimtory Disease 104(3): 331336, September 1971.
THURLBECK, W.M. The incidence of pulmonary emphysema: With observations on
the relative incidence and spatial distribution of various types of emphysema.
American Review of Respiratory Disease 87(2): 206-215, February 1963a.
THURLBECK, W.M. A clinicopathological study of emphysema in an American
hospital. Thorax 18(l): 59-67, March 1963b.
THURLBECK, W.M. Chronic Airflow Obstruction in Lrtng Disease. Major Problems in
Pathology, Volume 5. Philadelphia, W.B. Saunders Company, 1976.
THURLBECK, W.M. Overview of the pathology of pulmonary emphysema in the
human. Clinics in Chest Medicine 4(3): 337-350, September 1983.
THURLBECK, W.M., ANDERSON, A.E., JANIS, M., MITCHELL, R.S., PRATT, P.,
RESTREPO, G., RYAN, SF., VINCENT, T.N. A cooperative study of certain
measurements of emphysema. American Review of Respimtory Disease 98(2): 217-
228, August 1968.

THURLBECK, W.M., ANGUS, G.E. A distribution curve for chronic bronchitis.
Thorax 1%5): 436442, September 1964.
THURLBECK, W.M., ANGUS, G.E., PARE, J.A.P. Mucous gland hypertrophy in
chronic bronchitis, and its occurrence in smokers. British Journal of Diseases of
the Chest 57(2): 73-78, April 1963.

THURLBECK, W.M., DUNNILL, MS.. I-IARTUNG, W., HEARD, B.E., HEPPLE-
STON, A.G., RYDER, R.C. A comparison of three methods of measuring emphyse-
ma. Human Pathology l(2): 215-226, June 1970.   .a
THURLBECK, W.M., PUN, R., TCYI'H, J., FRAZER, R.G. Bronchial cartilage in
chronic obstructive lung disease. American Review of Respimtop Disease 109(l):
73-80. January 1974a.                    S--d

249


THURLBECK, W.M., RYDER, R.C., STERNBY, N. A comparative study of the
severity of emphysema in necropsy populations in three different countries.
American Review of Respimtory Disease 109f2): 239-248, February 1974b.
VARGHA, G. A new origin theory for obstructive emphysema based on hyperplasia of
the bronchial mucous glands. Actu iviedica Academiae Scientiarum Hungaricae
26(l): 7178,1969.

WORLD HEALTH ORGANIZATION. Chronic Car Pulmonak: Report of an Expert
Committee. World Health Organization Technical Report Series No. 213, 1961, p.
  15.

WRIGHT, J.L., LAWSON, L.M., PARE, P.D., HOOPER, R.O., PERETZ, D.I., NEL-
EMS, J.M.B., SCHULZER, M., HOGG, J.C. The structure and function of the
pulmonary vasculature in mild chronic obstructive pulmonary disease. The effect
of oxygen and exercise. American Review of Respiratory Disease 128(4): 702-707,
October 1983a.

WRIGHT, J.L., LAWSON, L.M., PARE, P.D., KENNEDY, S., WIGGS, B., HOGG, J.C.
Pulmonary function and peripheral airways disease. American Review of Respim-
tory Disease, in press.

WRIGHT, J.L., LAWSON, L.M., PARE, P.D., WIGGS, B.J., KENNEDY, S., HOGG,
J.C. Morphology of peripheral airways in current smokers and ex-smokers.
American Review of Respiratory Disease 127(4): 474-477, April 1983b.

250


CHAPTER 5. MECHANISMS BY
         WHICH CIGARETTE
         SMOKE ALTERS THE
         STRUCTURE AND
         FUNCTION OF THE
         LUNG

251


CONTENTS

EFFECT OF CIGARETTE SMOKING ON
INFLAMMATORY AND IMMUNE
PROCESSES IN THE LUNG

Introduction

Effect of Smoking on Numbers and Types of
Inflammatory Cells

Effect of Smoking on the Morphology and Function of
Inflammatory Cells

Emphysema
Populations Deficient in Alpha,-antitrypsin
  Alpha,-antitrypsin
Proteolytic Enzymes Inducing Emphysematous
   Change
    Papain
     Pancreatic Elastase
    Polymorphonuclear Leukocyte Elastase
    Alveolar Macrophage Elastase
  Protease-Antiprotease Hypothesis
    Increased Elastase Owing Lo the Cellular
     Response to Smoke
       Number of Cells
       Elastase Content
       Release
     Proximity
       Milieu
    Decreased Antiprotease Owing to Oxidation
    Explanation for Upper Lobe Distribution
    Animal Models of Emphysema
     Spontaneous Emphysema
     Experimentally Induced Emphysema
      Oxides of Nitrogen
      Cadmium Salts
     Cigarette Smoke

253


The Effects of Smoking on Cellular and Immune Defense
Mechanisms

In Vitro Effects of Cigarette Smoke on Inflammatory
and Immune Effector Cells
The Effect of Cigarette Smoke on Antibody
Production

EFFECTS OF CIGARETTE SMOKE ON
AIRWAY MUCOCILIARY FUNCTION

Introduction

Normal Mucociliary Function
  Cilia
  Mucus
Mucociliary Interaction

Effects of Cigarette Smoke on Mucociliary Function
  Short-Term Exposure
     Cilia
     Mucus
    Mucociliary Interaction
Long-Term Exposure
     Cilia
     Mucus
    Mucociliary Interaction
Fractionation and Filtering of Cigarette Smoke
  Effects of Filters

Mucociliary Function in Chronic Bronchitis
  Cilia
  Mucus
Mucociliary Interaction

Summary and Conclusions

References

254


EFFECT OF CIGARETTE SMOKING ON
INFLAMMATORY AND IMMUNE PROCESSES
IN THE LUNG

Cigarette smoke is a complex mixture of several thousand
different constituents that may produce physiologic and pathologic
changes. This discussion focuses on the cellular and immune
responses of the lung to cigarette smoke, the mechanism by which
smoking can cause emphysema, and the impact of smoking on
mucociliary clearance. The last 20 years have witnessed dramatical-
ly increased understanding of cigarette-induced lung injury, particu-
larly emphysema, thus enhancing our understanding of the process
by which cigarette smoking can lead to emphysema.

Introduction

Inhalation of cigarette smoke markedly alters the inflammatory
and immune processes in the lung, leading to increases in the total
number of inflammatory cells and to changes in cell type and
function. These effects of cigarette smoke on lung inflammatory cells
may play a role in decreased pulmonary host defenses against
various microorganisms and the development of lung cancer, chronic
bronchitis, and pulmonary emphysema (USPHS 1971, 1972, 1973,
1974,1975; USDHHS 1981).

Effect of Smoking on Numbers and Types of Inflammatory
Cells

One of the most consistently observed effects of cigarette smoking
on the lung is a marked increase in the numbers of inflammatory
cells, especially at sites of disease. Increased numbers of inflammato-
ry cells have been seen in pathological studies of the lungs of
cigarette smokers, as well as in lungs of animals exposed to cigarette
smoke. In addition, increased numbers of inflammatory cells occur in
bronchoalveolar lavage fluid of cigarette smokers and in lavage fluid
of animals exposed to cigarette smoke.

Spain and Kaufman (1953) noted inflammatory changes in the
lung bronchi of cigarette smokers. Later, Anderson and Foraker
(1961) described the presence of an alveolitis, and McLean (1959)
described the presence of a bronchiolitis in these patients. In an
autopsy study of patients with early emphysema (McLaughlin and
Tueller 19711, numerous abnormal, brownish-pigmented alveolar
macrophages were found in adjacent, otherwise intact parenchyma,
but none were found in normal lungs. Identical pigmented macro-
phages were found in the sputum of patients obtained from
apparently healthy cigarette smokers. The frequency of occurrence
of these macrophages in the tissue appeared to be related to the

255


number of cigarettes consumed. Niewoehner et al. (1974) evaluated
the lungs of young smokers and controls of comparable age from a
population that had experienced sudden nonhospital deaths. In
smokers, a characteristic lesion occurred in the form of respiratory
bronchiolitis associated with clusters of pigmented alveolar macro-
phages. This lesion was present in the lungs of all smokers studied,
but was rarely seen in nonsmokers. Lungs of smokers also showed
small, but significant, increases in mural inflammatory cells and
denuded epithelium in the membranous bronchioles as compared
with controls. The researchers suggested that this respiratory
bronchiolitis may be a precursor of emphysema and may be
responsible for the subtle functional abnormalities that are observed
in young smokers. Mitchell et al. (1976) also noted the presence of
significant amounts of inflammation in the small airways of
cigarette smoker lungs, and Cosio et al. (1978) suggested that the
primary lesion in the small airways was a progressive inflammatory
reaction, leading to fibrosis with connective tissue deposition in the
airway walls. These lesions were closely correlated with abnormali-
ties in pulmonary function.

As noted above, most early investigators concentrated on the role
of the increased numbers of pigmented alveolar macrophages
present at disease sites in cigarette smokers. These pigmented
macrophages, because of their numbers and prominent coloration on
histologic sections, were initially the sole focus of research on the
inflammatory response in these patients. More recently, however,
Ludwig et al. (1983) evaluated the relationship between cigarette
smoking and the accumulation of neutrophils in the lungs of
smoking and nonsmoking humans. Human lungs were obtained from
autopsies of 10 cigarette smokers and 5 nonsmokers who experienced
nonhospital death. These studies indicated a marked increase in
neutrophil infiltration in the lungs of cigarette smokers compared
with nonsmokers, and identified the site of the accumulation as the
alveolar septa. Neutrophils were found in the alveolar walls of
smokers both with and without emphysema. The researchers con-
cluded that a marked neutrophil accumulation occurs in the lungs of
cigarette smokers, that it precedes the development of emphysema,
and that it continues once emphysema is established. They further
suggested that the neutrophils may play a role in the destruction of
the alveolar septa of the lungs in cigarette smokers. The presence of
increased numbers of neutrophils in cigarette smokers' lungs has
also been documented by extracting inflammatory cells from open
lung biopsies of smokers and nonsmokers (Hunninghake and Crystal
1983). A higher percentage of these inflammatory cells were
neutrophils in smokers compared with nonsmokers. Finally, the
association between cigarette smoking and increased numbers of
inflammatory cells, including neutrophils. at disease sites has also

256


been confirmed in numerous animal studies (Frasca et al. 1971;
Dahlgren et al. 1972; Rylander 1974; Park et al. 1977).
Increased numbers of inflammatory cells in the lungs of smokers,
as compared with nonsmokers, have also been observed by all
investigators performing bronchoalveolar lavage studies (Davis et al.
1976; Demarest et al. 1979; Harris et al. 1970, 1975; Hunninghake et
al. 1979a, 1980a; Hunninghake and Crystal 1983; Hunninghake and
Gadek 1981-1982; Hunninghake and Moseley, in press; Reynolds et
al. 1977; Reynolds and Newball 1974, 1976; Rodriquez et al. 1977;
Warr et al. 1976,1977; Warr and Martin 1974,1978). Such increases
have been detected additionally in lavage fluid of animals chronical-
ly exposed to cigarette smoke (Davies et al. 1977; Flint et al. 1971;
Holt et al. 1973). The majority of these studies have demonstrated
increases in both the number of macrophages and the number of
neutrophils, although Hoidal and Niewoehner (1982) found increases
only in the former.

The presence of neutrophils in the lungs of cigarette smokers is of
interest because these cells contain elastase, an enzyme believed to
be important in the pathogenesis of emphysema (Lieberman 1976;
Karlinsky and Snider 1978; Kuhn and Senior 1978; Carp and Janoff
1978; Snider and Korthy 1978; Schuyler et al 1978; Janoff et al. 197'1;
Hunninghake et al. 1979a; Hunninghake and Crystal 1983; Hun-
ninghake and Gadek 1981-1982; Hunninghake and Mosley 1984;
Laurel1 and Eriksson 1963). Alveolar macrophages have also been
implicated as a source of an elastase-like metalloprotease (Harris et
al. 1975; Rodriguez et al. 1977). This enzyme is not inhibited by
alpha,-antitrypsin (a,AT) (Banda and Werb 19811, the major anti-
elastase in the lower respiratory tract (Gadek et al. 1981). Although
macrophages are clearly present in large numbers in the alveolar
structures of smokers (Niewoehner et al. 1974; Harris et al. 19751,
several lines of evidence suggest that neutrophils may play a
significant and perhaps more important role in increasing the
elastase burden of the lungs.

First, neutrophils store and release significantly more elastase
than do alveolar macrophages (Barrett 1977; Rodriguez et al. 1977;
Levine et al. 1976). Comparative estimates of elastase production by
human neutrophils and alveolar macrophages suggest that neutro-
phils are at least 1,000 times more potent elastase producers (Janoff
et al. 1979).

Second, although alveolar macrophages of cigarette smokers have
been shown to release elastase in vitro (Rodriguez et al. 19771, it is
not clear whether the elastase was produced by these cells or was
secreted by other types of cells, such as neutrophils, and subsequent-
ly ingested by the macrophages (Janoff et al. 1977). In this regard,
recent studies by Campbell et al. (1979) and McGowan et al. (1983)
have shown that alveolar macrophages are capable of phagocytosing

257


neutrophil elastase via a receptor-mediated mechanism; some of the
elastase remains enzymatically active for up to 48 hours. These
findings suggest that alveolar macrophages may, in fact, be capable
of both decreasing and increasing the protease burden of the lung.

Third, once a neutrophil has left its vascular space, its lifespan is
only a few hours; when the neutrophil dies, it may release at least a
portion of its preformed enzymes, including elastase. Thus, when a
neutrophil is present within a tissue, it is possible that the tissue will
be exposed not only to the elastase secreted by the neutrophil while
it is functional, but also to the elastase stored by the neutrophil and
released when the neutrophil disintegrates. In this context, the
finding that neutrophils represent only a small percentage of all
inflammatory and immune effector cells in the smoker's lungs would
not preclude the smoker's exposure to a large chronic burden of
neutrophil elastase. In contrast, the alveolar macrophage has a half-
life of months to years (Thomas et al. 19761, and it stores little, if any,
elastase (Rodriguez et al. 1977; Levine et al. 1976).

Macrophages may also play an important role in this process by
secreting a potent chemotactic factor for neutrophils (Hunninghake
and Crystal 1983). This hypothesis is supported by the following
observation: alveolar macrophages of cigarette smokers spontaneous-
ly release a chemotactic factor for neutrophils, whereas alveolar
macrophages of nonsmokers do not. In addition, in vitro exposure to
cigarette smoke particulates results in the release of a chemotactic
factor from the alveolar macrophages of nonsmokers. The migration
of neutrophils to the lung in response to the chemotactic factor may
be augmented by factors in cigarette smoke. In this regard, McCusk-
er et al. (1983) have shown that nicotine is a potent chemokinetic
factor for neutrophils, enhancing the migration of these cells to
other chemotactic factors. Once neutrophils are present in the lung,
they may release elastase, because both cigarette smoke (Blue and
Janoff 1978) and the macrophage-derived chemotactic factor stimu-
late these cells to release the enzyme (Gadek et al. 1979a, b).

The postulated release of elastase by neutrophils could also partly
explain how the number of macrophages are increased in this
disorder. Fragment,s of elastin (which are probably generated by the
release of neutrophil elastase at sites of disease activity) are potent
chemoattractants for blood monocytes, the precursors of alveolar
macrophages (Senior et al. 1980; Hunninghake et al. 1981). These
fragments of elastin possess no chemotactic activity for neutrophils.

Effect of Smoking on the Morphology and Function of
inflammatory Cells

No size differences have been observed between alveolar macro-
phages from smokers and those from nonsmokers when the cells are

258


fixed in suspension immediately after bronchoalveolar lavage (Table
1). Harris and coworkers (1970) observed a mean size of 23.3 pm
(range, 10 to 47 pm) for nonsmokers and 26.4 pm (range, 12 to 53 pm)
for smokers. Reynolds and Newball (1974), using similar methods,
did not find any size differences between smoker and nonsmoker
alveolar macrophages.
The morphology of smoker macrophages clearly differs, however,
from that of nonsmokers (Table 1). Macrophages of smokers show
increased numbers of large lysosomes, phagolysosomes, endoplasmic
reticulum, ribosomes, and Golgi vesicles (Golde 1977; McLemore et
al. 1977; Martin 1973; Warr and Martin 1978; Rasp et al. 1978; Pratt
et al. 1971; Brody and Craighead 1975). These findings are generally
associated with activated mononuclear phagocytes, and these macro-
phages have probably become activated by the ingestion of the
particulates present in cigarette smoke. Smoker macrophages have
pigmented inclusions that appear to have platelike or needlelike
configurations when seen by electronmicroscopy (Golde 1977; Warr
and Martin 1978; Pratt et al. 1971; Brody and Craighead 1975).
Studies of the nature of these inclusions by X-ray analysis suggest
they may be, at least in part, particulates of aluminum silicate
(Brody and Craighead 1975). Together with in vitro studies showing
that alveolar macrophages are activated following phagocytosis of
particulates (Hunninghake et al. 1980a), these findings are compat-
ible with the notion that macrophages of smokers are activated in
vivo.
Alveolar macrophages from cigarette smokers have an increased
ability to generate superoxide anion (Hoidal et al. 1979a, 1980,1981),
the functional effects of which include an increased capacity to kill
lung fibroblasts. These observations suggest that alveolar macro-
phages from cigarette smokers are increasingly able to injure lung
parenchymal cells, and that they may contribute to the observed loss
of lung cells in the alveoli of patients with pulmonary emphysema.
A variety of other effector functions of smokers' alveolar macro-
phages have also been evaluated (Table 1). Alveolar macrophages
from cigarette smokers appear to have a normal or increased ability
to migrate in response to chemotactic factors (Demarest et al. 1979;
Warr and Martin 1974). They differ, however, from normal alveolar
macrophages in several other respects: for example, increased
glucose utilization has been reported in some studies (Harris et al.
1970), but was normal in others (Hoidal et al. 1979a). Oxygen
consumption has been reported to be normal (Hoidal et al. 1979a),
but the protein content of these cells has been increased (Harris et
al. 1975; Warr and Martin 1978). Alveolar macrophages from
smokers release less PGE, and thromboxane B, than normal
macrophages (Laviolette et al. 1981), suggesting that cigarette
smoking induces a lesion in phospholipid hydrolysis or the mecha-


TABLE l.-Cigarette-smoking-induced abnormalities in the
      inflammatory and immune effector systems >
       within human alveolar structures

Parameter                    Findings in smokers

cell types present
Total number of cells
Percent polymorphonuclear leukocytes
Percent T lymphocytes
Percent B lymphocytes
Lymphocyte function
Response to mitogens
Macrophage structure
Diameter
Ruffling of cell surface
Number and size of cytoplasmx structures
Abnormal cytoplasmlc inclusions

Macrophage propertws and function
Surface receptors
  1gGFc
  C3b
Phagwy&ls and killing of microorganisms
  Bacteria
  Fungi
Effector and accessory cell function
responsiveness to chemotactic factors
  Casein
  Activated serum
Function as act-ry cell to lymphocytes
Responsiveness to MIF
Production of neutrophll chemotactlc factor
SecretIon of superoxIde anion
Secretlon of elastase
Release of prostaglandm E, and
  thromboxane B,
Miscellaneous properties and function
Glucose utdlvltion
Oxygen consumption
Protem content
Content of various enzymes
  Eklstase
  Acid protease
  Neutral protease
  Esterrise
  Acid phosphatase
  &glucuromdase
  Lysozyme
  Aryl hydrocarbon hydroxylase
  An@otensmsonvertmg enzyme
Spreading and adherence properties

Plllocytosls
Content of a,-antlproteinase

IIlCEased
Increased
Increased or normal
Normal

Decreased

Normal
Decreased
Increass
Pigmented inclusions,
particulates with plate or
needle-like confwratlon.
presence of aluminum silicate

NOM"1
Decreased

Kormal or decreased
Normal

Increased
Normal
Decreased
Decreased
Increased
Increased
Increased

Decreased

Increased or normal
Normal
Increased

Increased
IllCreased
Normal
Increased
Increased
Increased
Normal or increased
Increased
Increased
Increased in presence of serum.
decreased nylon adherence
Decreased
Increased

SOURCE Adapted from Hunnmghake et al 119791

260


nism regulating hydrolysis. Smoker macrophages also appear to
have increased amounts of various enzymes, including acid protease
(Harris et al. 1975), neutral protease (Harris et al. 1975), esterase
(Harris et al. 1975), acid phosphatase (Martin 1973!, angiotensin-
converting enzyme (Hinman et al. 1979), P-glucuronidase (Martin
1973), lysozyme (Martin 1973), and arylhydrocarbon hydrolase
(Cantrell et al. 1973; Harris et al. 1978; McLemore et al. 1977b, c,
1978; McLemore and Martin 1977). The functional significance of
increased amounts of these enzymes is not entirely clear.

In addition to its effects on the inflammatory and immune effector
cells in the lung, cigarette smoke may also affect the composition of
epithelial surface fluid. For example, some investigators have found
that the amount of immunoglobulin G (IgG) present in lavage fluid is
increased (Reynolds and Newball 1974); others have noted normal
levels (Warr et al. 1977). Interestingly, cigarette smoking appears to
cause a significant decrease in the secretory component of immuno-
globulin A (IgA) in the lavage fluid of some people who smoke
cigarettes (Merrill et al. 1980). This effect most likely indicates a
subtle injury to the epithelium of the lung that produces this factor.
The only additional factors that have been reported to be abnormal
in lavage fluid of cigarette smokers are an increase in the amounts of
fibronectin (Villiger et al. 1981) and a decrease in the function, but
not the amount, of a,AT (Gadek et al. 1979; Janoff et al. 1979). This
latter finding has been disputed by others (Stone et al. 1983).

Emphysema

A number of lines of evidence link the cellular changes described
above with the development of emphysema. They include observa-
tions in populations deficient in a,AT, in animal models of emphyse-
ma, and most important, in human cigarette smokers.

Populations Deficient in Alpha,-antitrypsin

Eriksson (1965) described the characteristic features of a,AT-
deficiency-associated lung disease. Approximately 60 percent of
affected individuals develop symptoms of airways obstruction by age
40, and 90 percent by age 50. Excluding the influence of cigarette
smoking, there is no sexual predominance of disease. Kueppers and
Black (1974) found that dyspnea occurred a decade earlier in
cigarette smokers (35 years in smokers versus 44 years in nonsmok-
ers), and estimated that 70 to 80 percent of all PiZZ persons (where
Pi= protease inhibitor) will develop lung disease. Larsson (1978) has
projected that nearly 60 percent of PiZZ people will ultimately die of
lung-related disease.

Ore11 and Mazodier (1972) reviewed the morphologic features of
a,ATdeficiency-associated emphysema and found primarily the

261


panacinar or panlobular form. Emphysematous lesions may be
distributed uniformly throughout the lungs (Ore11 and Mazodier
1972), but frequently show a predominant lower lobe distribution
(Greenberg et al 1973).

In people genetically deficient in alAT, the increased numbers of
inflammatory cells found in the lungs of smokers probably present
an increased elastase burden to the lung and magnify the protease-
antiprotease imbalance. This may explain the deleterious effects of
cigarette smoke in this population. Kueppers and Black (1974)
reviewed data on the impact of cigarette smoking in people severely
deficient in a,AT and concluded that, in addition to experiencing
earlier onset of respiratory symptoms and pulmonary function
abnormalities, cigarette smokers die at an earlier age from respira-
tory failure than similiarly afflicted nonsmokers. The increased
prevalence of emphysema in populations deficient in alAT, plus the
exacerbation of this lung disease by smoking, suggests that protease-
antiprotease imbalance may also play a role in the development of
emphysema by smokers who are not deficient in a,AT. This
suggestion has resulted in a substantial body of research that has
characterized a,AT, defined the nature of elastase-induced emphyse-
ma, and clarified and supported the protease-antiprotease hypothe-
sis of cigarette-induced emphysematous lung injury.

Alpha,-antitrypsin

The deficient constituent of a,-globulin was initially described by
Schultze et al. (1955) as a,-3,5-glycoprotein but later renamed a,-
antitrypsin (a,AT) when it was found to inhibit trypsin activity
(Schultze et al. 1962). Subsequently, a,AT has been shown to inhibit
a variety of proteolytic enzymes including neutrophil elastase
(Ohlsson 1971), neutrophil collagenase (Tokoro et al. 1972; Ohlsson
1971), cathepsin-G (Travis et al. 1978), chymotrypsin (Travis et al.
1978; Rimon et al. 1966), plasmin (Rimon et al. 1966), thrombin
(Rimon et al. 1966), Hageman factor cofactor (Crawford and Ogston
1974), coagulation factor XI (Heck and Kaplan 1974), acrosin and
kallikrein (Fritz et al. 1972a, b), urokinase (Crawford and Ogston
1974; Clemmensen and Christensen 1976), and renin (Scharpe et al.
1976). Although the range of proteases inhibited by a,AT appears
broad, the association rate constants of these enzymes for a,AT
differ (leukocyte elastase > chymotrypsin > cathepsin-G > trypsin
> plasmin > thrombin) (Beatty et al. 1980), and the inhibitory role
of a,AT against enzymes with low association rate constants, such as
trypsin, may be negligible. The names a,-protease inhibitor or al-
proteinase inhibitor better describe this broader range of inhibitory
functions and are preferred by some authors. In deference to
historical usage and in accord with the recommendations of the

262


Nomenclature Meeting for this substance (Cox et al. 1983), the name
a,AT has been retained in this discussion.
The inhibitor a,AT is a polymorphic plasma protein (Fagerhol and
Cox 1981; Cox and Celhoffer 1974; Cox et al. 1980; Cox 1981;
Fagerhol and Braend 1965) encoded by two codominant autosomal
alleles and inherited as a single Mendelian trait. The basal serum
concentration is genetically determined (Eriksson 1964; Kueppers et
al. 1964; Fagerhol and Gedde-Dahl 1969; Talamo et al. 1966). More
than 31 allelic variants or Pi types (where Pi, or protease inhibitor, is
the symbol assigned the genetic locus of the a,AT allele) have been
identified (Cox and Celhoffer 1974; Cox et al. 1980; Cox 1981). The
variants are designated by capital letters, B through Z, correspond-
ing to their approximate electrophoretic mobility, relative to the
anode, in acid starch gel electrophoresis or their relative positions on
polyacrylamide isoelectric focusing. New variants are named accord-
ing to the conventions established by the Fifth International
Workshop on Gene Mapping and the Nomenclature Meeting for
a,AT (Cox et al. 1980).
The M allele (PiM) has a gene frequency of about 0.9 and is the
most common Pi type in all populations tested (Kueppers 1978). The
a,AT serum concentration in PiMM homozygotes is between 1.3 and
2.2 g/liter (depending on the method of measurement and the purity
of standard) (Kueppers 1968; Jeppsson et al. 1978a) and, by conven-
tion, defines normal. Pi types with decreased circulating levels of
a,AT include (serum concentration expressed as percent normal)
null 0% (Feldman et al. 1975; Talamo et al. 1973), Mmalton and
Mduarte 12% (Cox 1976; Lieberman et al. 1976), Z 15% (Laurel1 and
Eriksson 1963; Fagerhol and Laurel1 1970), P 30% (Fagerhol and
Hauge 1969), S 60% (Fagerhol 1969), and I 68% (Arnaud et al. 1978).
PiZ was the first variant recognized (Laurel1 and Eriksson 1963)
and is the Pi type most frequently associated with a serum deficiency
of a,AT (Kueppers 1978). Its allele frequency varies markedly
between different ethnic and racial groups. In the United States, the
allele frequency is greater than 0.010 in whites but nearly zero in
blacks (Kueppers 1978). Approximately 1 in 2,000 whites is homozy-
gous for the Z gene (Laurel1 and Sveger 1975).
Although a decrease in hepatic synthesis is probably the major
mechanism for quantitatively significant reductions in serum a,AT,
the factors that modulate such synthesis are only partially under-
stood (Morse 1978). Impaired hepatic secretion, as evidenced by the
presence of intrahepatic cytoplasmic inclusions containing accumu-
lations of a,AT polypeptides (Blenkensopp and Haffenden 1977),
occurs in persons with the PiZ genotype. It is uncertain if these
intrahepatic inclusions exert a negative feedback inhibition on the
hepatocyte and thereby retard biosynthesis of a,AT. Intrahepatic
inclusions are not found with the S and null Pi types (Carrel1 et al.


19821, suggesting that decreased synthesis, independent of impaired
secretion, is primarily responsible for the reduced serum levels of
a,AT. Catabolic studies of the PiM and PiZ proteins have identified
similar half-lives in the circulation, 6 to 7 days and 5 days,
respectively (Laurel1 et al. 1977; Jeppsson et al. 1978b). It is therefore
unlikely that accelerated peripheral catabolism contributes signifi-
cantly to serum deficiencies in a,AT.

In addition to quantitative deficiencies in serum a,AT, a reduction
in serum inhibitory capacity could also result from a loss in the
functional activity of a,AT. Most genetic variants, however, are
functionally equivalent to normal a,AT (PiMM) in their capacities to
inhibit both trypsin and elastin (Billingsley and Cox 1982).

The inhibitor a,AT is a low molecular weight (51,000 daltons)
(Mega et al. 1980; Carrel1 et al. 1981; Chan et al. 1976; Pannell et al.
1974; Jeppsson et al. 19781 protein comprised of a single polypeptide
chain containing 394 amino acid residues. Three carbohydrate side
chains are attached, each containing terminal sialic acid residues
(Mega et al. 1980; Carrel1 et al. 1981). The a,AT reacts stoichiometri-
tally with free protease in a ratio of 1:l; one mole of a,AT inhibits
one mole of protease and yields a stable complex (Cohen 1973). An in
vitro study (James and Cohen 1978) found, however, that complete
inhibition of elastase requires molar ratios of a,AT to elastase
greater than 2.2:1. This phenomenon may be explained by elastase
having two major sites of attack on a,AT. Attack against one site
leads to a conformational change in a,AT and inhibition of elastase,
whereas attack against the other site results in cleavage and
inactivation of a,AT. The a,AT-protease complexes that form during
protease inhibition are not reutilized by the body (Balldin et al.
19781, and the body supplies of a,AT are replenished via de novo
synthesis by the liver.

In addition to hepatic biosynthesis, a,AT is synthesized by at least
two other endogenous sources. Both human peripheral lymphocytes
and rat alveolar macrophages have been shown to synthesize a,AT.
Ikuta et al. (1982) demonstrated that concanavalin A-stimulated
monocytes interact with human peripheral lymphocytes, causing a
threefold increase in a,AT synthesis. White et al. (1981) cultured rat
alveolar macrophages and recovered newly synthesized radio-labeled
FS)a,AT from the cell culture medium. Macrophages and lympho-
cytes, by virtue of their close physical proximity to the sites of
connective tissue injury, may play a significant role in defense
against proteolytic destruction. The physiologic significance of
extrahepatic synthesis of a,AT remains speculative, however.

While certain chemical and physiological aspects of a,AT are
clear, the exact biochemical mechanism by which it causes protease
inhibition is uncertain. It is generally agreed that the reactive center
of a,AT is located on a single serine-methionine segment peptide

264


bond on the carboxyl-terminal end (Carrel1 et al. 1982; Kurachi et al.
1981).

Proteolytic Enzymes Inducing Emphysematous Change
Proteolytic enzymes have been a major focus of investigation
following the demonstration by Gross et al. (1965) of papain's ability
to induce emphysematous changes in rats.

Papain

Papain, a proteolytic enzyme with a broad range of substrate
specificities (Bergmann and Fruton 1941; Kimmel and Smith 1953),
reproducibly causes emphysema-like lesions in a variety of experi-
mental animals following aerosolization or intracheal instillation
(Gross et al. 1965; Palecek et al. 1967; Goldring et al. 1968; Caldwell
1971; Pushpakom et al. 1970; Marco et al. 1969). A number of studies
have helped to clarify the critical importance of elastolysis in
papain-induced emphysema.

Snider et al. (1974) tested amorphous and crystalline forms of
papain and found that the emphysema-inducing properties of these
preparations were directly proportional to their abilities to degrade
and solubilize elastin. Heat inactivation of papain destroyed its
emphysema-inducing capabilities. Similarly, intratracheal pretreat-
ment of hamsters with human a,AT, an inhibitor of papain
elastolytic activity, ameliorates papain-induced emphysematous
changes (Martorana and Share 1976). Furthermore, Blackwood et al.
(1973) showed that the elastolytic activities of several microbial
enzymes, rather than their nonspecific protease activities, correlate
best with the enzyme's ability to induce emphysematous changes
following intravenous administration to rats. Snider et al. (1977)
showed that enzymes lacking elastolytic activity, such as collagenase
or trypsin, do not produce emphysema in hamsters.

Whereas these studies support the notion that the early histologic
changes induced by papain are a direct consequence of its elastolytic
activity, they do not preclude the possibility that endogenous factors
may contribute to subsequent disease progression. Snider and
Sherter (1977) noted a gradual increase in static lung volumes in
hamsters following a single intratracheal injection of pancreatic
elastase. Stone et al. (1979) followed the fate of tritium-labeled
pancreatic elastase and found that enzymatically active prepara-
tions are retained longer within the lung than inactive preparations,
and that 1qGguanidated elastase remains bound to lung matrix for at
least 96 hours. This suggests that tissue-bound elastase may continue
to digest elastin for extended periods of time. Martorana et al. (19821
found no progression in the mean linear intercept measurements or
internal surface areas in the lungs of papain-treated dogs between 3

265

480-144 0 - 85 - 13


and 6 months after treatment. However, the mean pulmonary
arterial pressure and pulmonary arteriolar resistance did increase
during this interval.

Papain-treated animals exhibit the expected physiologic changes
of emphysema: increased RV, FRC, and TLC, decreased elastic recoil,
increased static lung compliance at middle and low lung volumes,
and reduced diffusing capacity (DLcoVA and Delco) (Caldwell 1971;
Pushpakom et al. 1970; Marco et al. 1969; Giles et al. 1970; Johanson
and Pierce 1973). Studies by Kobrle et al. (1982) have shown that
following papain administration the elastic fibers are disrupted and
that the elastin content of the lung initially decreases, but later
returns to normal after a period of accelerated synthesis. The newly
synthesized fibers are disordered; however (Kuhn and Senior 1978;
Kuhn and Starcher 1980).

Pancreatic Elastase

The ability of porcine pancreatic elastase to rapidly hydrolyze
insoluble elastin (Partridge and Davis 1955) and its commercial
availability in a highly purified crystalline form have led to its
extensive use as an experimental agent for inducing emphysema in
animals (Karlinsky and Snider 1978). Lesions resembling human
panacinar emphysema can be induced in hamsters within 2 hours of
intratracheal instillation of pancreatic elastase (Kaplan et al. 1973).
The severity of the lesions, as assessed by histologic or physiologic
criteria, is dose related (Raub et al. 1982), with adult animals being
more susceptible to pancreatic elastase than young animals (Lucey
and Clark 1982). Within a few hours of intratracheal instillation in
hamsters, hemorrhagic lesions develop and an influx of polymorpho-
nuclear leukocytes is seen (Hayes et al. 1975; Kuhn and Tavassoli
1976). Digestion of elastin fibers is apparent in the pleura and in the
alveolar walls by 4 hours, but is more extensive at 24 and 48 hours
(Kuhn et al. 1976). By day 4, there is a diminution in the number of
polymorphonuclear leukocytes (PMNs), but many macrophages
remain (Morris et al. 1981). The hemorrhage and cellular infiltration
resolves within 3 weeks, and the ensuing lesions resemble panacinar
emphysema (Kuhn et al. 1976). Over 95 percent of the detectable
urinary excretion of desmosine and isodesmosine, amino acid
markers of in vivo elastolysis, appears within 2 days of elastase
instillation; only small amounts can be detected by day 3 (Goldstein
and &archer 1977). Kucich et al. (1980) developed a hemagglutina-
tion inhibition assay to measure elastinderived peptides in serum,
and found that elastinderived peptides could be detected in the
serum of dogs for a period of 12 days following administration of a 25
to 50 mg dose of porcine pancreatic elastase and for 40 days following
a 100 mg dose. Janoff et al. (1983b) found increases in urinary
desmosine excretion during the first 48 hours following endobronchi-


al instillation of pancreatic elastase to sheep; increases in mean
linear intercepts and decreases in lung ventilation and perfusion
were found after 4 weeks. All changes correlated positively with the
elastase dose. Studies have shown a decrease in the lung elastin
content within the first 24 hours of intratracheal injection of
elastase (Kuhn et al. 1976; Ip et al. 1980; Goldstein and Starcher
1977). Physiologic studies (Snider and Sherter 1977; Snider et al.
1977) of experimental animals after pancreatic elastase administra-
tion have shown increases in the lung compliances and in the volume
of air within the lungs at specified transpulmonary pressures (25 and
-20 cm H*O). These physiologic alterations appear to progress in
severity for about 26 weeks following exposure to elastase (Snider
and Sherter 1977).

In spite of substantial experimental verification of ability of
pancreatic elastase to induce emphysematous changes in animals
following intratracheal instillation, there is little evidence implicat-
ing endogenous pancreatic elastase in the pathogenesis of pulmonary
emphysema in humans. A serine endopeptidase of pancreatic origin
(elastase 2) has been shown to circulate in human blood (Geokas et
al. 1977). However, the enzyme is rapidly bound to serum inhibitors
a,AT and a,-macroglobulin (a,M) and inactivated (Gustavsson et al.
1980). Although a,Melastase complexes retain enzymatic activity
against low molecular weight synthetic elastin substrates (N-succi-
nyl-I-.-alanyl-Lalanyl-Lalanine-4-nitroanilide) (Twumasi and Liener
1977; Barrett and Starkey 1973); high molecular weight proteins
such as elastin are prevented from reaching the enzyme and are not
hydrolyzed (Barrett and Starkey 1973).

Attempts to induce emphysematous changes via the intravenous
injection of elastase have met with limited success. Hamsters
injected intravenously with nonfatal doses of pancreatic elastase fail
to show histologic changes characteristic of emphysema (Schuyler et
al. 1978) and do not manifest detectable reductions in lung elastin (Ip
et al. 1980). However, elastic recoil is lost at low lung volumes
(Schuyler et al. 1978). Fierer et al. (1976) has noted enlargements in
the airspaces of rats treated intravenously with large doses (330 U) of
pancreatic elastase. They also found increases in the mean linear
intercepts and rarefication of the amorphous components of elastin
within the lungs. It is doubtful, however, if proportionally similar
intravenous levels of pancreatic elastase occur in humans with
pulmonary emphysema.

Polymorphonuclear Leukocyte Elastase

Polymorphonuclear leukocytes (PMN) appear to be a more plausi-
ble source of endogenous elastase in the human lung than the
pancreas, and are more likely to be incriminated in the pathogenesis
of naturally occurring pulmonary emphysema. PMNs contain elasto-

267


lytic enzymes (Janoff 1973; Ohlsson and Ohlsson 1974; Rindler-
Ludwig et al. 1974) that can be released in active form within the
lung. Experimental studies have clearly demonstrated the ability of
PMN elastase to degrade lung elastin and to induce emphysematous
lesions in animals.

Marco et al. (1971) and Mass et al. (1972) induced experimental
emphysema in dogs by the administration of aerosolized crude
leukocyte homogenates. Using purified human leukocyte elastase,
Janoff et al. (1977) demonstrated the ability of the enzyme to digest
dog lung elastin in vitro and to cause significant dilation of terminal
respiratory structures when instilled into isolated perfused dog
lungs. The in vivo intratracheal instillation of human leukocyte
elastase in dogs produces foci of alveolar destruction within 90
minutes of administration (Janoff et al. 1977). Senior et al. (1977)
studied the effects of intratracheally injected human leukocyte
elastase on hamsters and found a reduction in lung elastin in treated
animals, as well as mild patchy airspace dilation. Sloan et al. (1981)
were able to show that purified dog leukocyte elastase could also
produce emphysematous lesions in dogs when instilled endobronchi-
ally.

Guenter et al. (1981) developed a dog model of experimentally
induced emphysema that avoided the necessity of intratracheal
instillation of enzymes. They repetitively injected E. coli endotoxin
intravenously, thereby inducing extensive leukocyte sequestration
within the lungs of the dogs. A previous study had shown that the
sequestered cells degranulate and disintegrate within the vascular
bed (Coalson et al. 1970). Histologic studies of these dogs revealed
mild airspace destruction and prominent intra-alveolar fenestra-
tions.

Alveolar Macrophage Elastase

In a widely cited article (Mass et al. 1972), dog alveolar macro-
phage homogenates (obtained by the method of Brain 19701, adminis-
tered to two mongrel dogs produced "some dilatation and nonuni-
formity in the size of the airspaces accompanied by some alveolar
wall destruction" in one of the dogs. The other dog showed no
evidence of emphysema.

In spite of the paucity of animal data, the pulmonary alveolar
macrophage (PAM) has been the focus of much investigation. Both
experimental and clinical evidence is available that implicates this
cell in the pathogenesis of pulmonary emphysema.
Two possible mechanisms by which macrophages may mediate
tissue injury are being actively studied. One mechanism involves the
release of elastolytic enzymes followed by unrestrained proteolysis.
The second mechanism involves either a direct or an indirect injury

268


following the release of toxic forms of partially reduced oxygen such
as superoxide anions, hydroxyl radicals, and hydrogen peroxide.
The ability of human alveolar macrophages to synthesize and
secrete an elastolytic enzyme distinct from PMN elastase is the
subject of controversy. Although human alveolar macrophages have
been shown to synthesize a metalloprotease distinct from the serine
protease (elastase) of the PMNs (DeCremoux et al. 19781, its
hydrolytic activity against insoluble elastin substrate has not been
conclusively demonstrated (Hinman et al. 1980; Levine et al. 1976).
Interpretation of the observation that human alveolar macrophages
raised in cell culture systems secrete an enzyme with true elastolytic
activity against insoluble elastin (Rodriguez et al. 1977; DeCremoux
et al. 1978) is complicated by the fact that alveolar macrophages bind
and internalize PMN elastase (Campbell and Greco 1982; White et
al. 1982; Campbell and Wald 1983). Hinman et al. (1980) detected a
calcium-dependent metalloprotease in the culture medium and in
the cell lysates of human alveolar macrophages and initially
demonstrated elastolytic activity against synthetic elastin substrate
and soluble elastin by both the culture medium fluid and the cell
lysates. However, after 3 and 5 days of culture, no detectable activity
against insoluble elastin was evident. The authors calculated that
the initial elastolytic activity observed could be quantitatively
explained by PMN contamination. The recognition that human
alveolar macrophages internalize human PMN elastase (Campbell
and Greco 1982; White et al. 1982; Campbell et al. 1979; Campbell
and Wald 1983) and that the internalized PMN elastase retains
enzymatic activity for at least 48 hours (McGowan et al. 1983)
suggests an alternative explanation.
Green et al. (1979) subcultured human alveolar macrophages for 3
months and found measurable elastase activity against solubilized
elastin during the entire period. They concluded that the elastase
activity appeared to be synthesized continuously rather than being
internalized from external sources.
In summary, human alveolar macrophages release elastolytic
enzymes capable of digesting connective tissue. Whether the elastase
released by these cells represents an enzyme synthesized de novo or
a previously internalized PMN elastase is uncertain and requires
further study.
Human alveolar macrophages, especially from cigarette smokers,
secrete highly reactive oxygen species (Hoidal et al. 1979a) that are
:apable of directly injuring endothelial cells (Sacks et al. 1978) and
`ibroblasts (Hoidal et al. 1981) and of inactivating a,AT (Carp and
Ianoff 1979, Janoff 1979a).
Whole cigarette smoke inhibits PMN chemotaxis in vitro in a dose-
ependent manner (Bridges et al. 1977). However, when alveolar
lacrophages are exposed to cigarette smoke either in vitro or in


vivo, they release a PMN chemotaxic factor (Hunninghake et al.
198Oc) (see above).

Protease-Antiprotease Hypothesis

The protease-antiprotease hypothesis proposes that enzymatic
digestion of lung parenchyma occurs as a direct consequence of a
genetic or acquired imbalance of the protease-antiprotease system
and that the subsequent repair of connective tissue is unable to
return the structures to normal. This hypothesis derives principally
from two observations: (1) people genetically deficient in a,AT
(Laurel1 and Eriksson 1963), the major antielastase of the lower
respiratory tract of humans (Gadek et al. 1981a), are at greatly
increased risk of developing pulmonary emphysema, and (2) proteo-
lytic enzymes produce physiologic and anatomic lesions resembling
emphysema when administered to experimental animals (Gross et
al. 1965). Attempts to integrate the clearly established relationship
of cigarette smoking and pulmonary emphysema with the protease
antiprotease hypothesis have led in-Testigators to search for ways in
which smoking perturbs this balance.

Increased Elastase Owing to the Cellular Response to Smoke

At least five variables, aside from the genetically determined level
of antiprotease activity, could influence the elastase burden of the
lungs. These variables include (1) an increase in the number of
elastase-containing cells within the lung, (2) an increase in the
quantity of prepackaged or newly synthesized elastase per cell, (3)
the quantity of elastase released from the cells, (4) the proximity of
the elastase to suitable substrate, and (5) the extracellular milieu
(i.e., pH, ionic strength, and factors such as platelet factor 4).

Number of Cells

As discussed earlier, the human cigarette smoker has increased
numbers of alveolar macrophages in the bronchoalveolar lavages
compared with nonsmokers (Rodriguez et al. 1977; Harris et al. 1975;
Reynolds and Newball 1974; Hoidal and Niewoehner 1982). Holt and
Keast (1973b) found sustained elevations of pulmonary macrophages
in mice exposed to cigarette smoke. Cigarette smoke has been shown
to recruit PMNs into the airways (Kilburn and McKenzie 1975;
Rylander 1974) and to induce alveolar macrophages to release a
chemotactic factor for PMNs (Hunninghake et al. 198Oc). The
circulating PMNs are reported to be increased in cigarette smokers
(Corre et al. 1971; Galdston et al. 1977). Hunninghake et al. (198Oc)
and Reynolds and Newball (1974) found increased numbers of PMNs
in the lavage fluid of smokers, but Hoidal and Niewoehner (1982)
reported similar numbers of PMNs in the lavages of cigarette

270


smokers and nonsmokers. Hunninghake and Crystal (1983) obtained
isolated cell suspensions from the bronchoalveolar lavage fluids and
from open lung biopsies of nonsmokers and cigarette smokers with
both normal lung parenchyma and sarcoidosis. They found a
significantly increased number of neutrophils and macrophages in
the lavage fluid and in the biopsy specimens from cigarette smokers
as compared with nonsmokers, both in patients with normal lung
parenchyma and in those with sarcoidosis.

Elastase Content

Harris et al. (1975) found an increase in the elastase-like esterase
and protease activity of macrophages obtained from smokers as
compared with nonsmokers. Galdston et al. (1977) found the PMN
elastase levels of circulating PMNs to be elevated in patients with
chronic obstructive lung disease and suggested that the intracellular
elastase levels may be genetically determined (Galdston et al. 1973).
Other investigators (Lam et al. 1979; Rodriquez et al. 1979) reported
similar findings, but Kramps et al. (1980) failed to find any
correlation between the PMN elastase levels and obstructive lung
disease in PiZZ patients, although they did note a difference in
PiMM patients. Lanky et al. (1980) demonstrated that dogs infected
with Type 3 pneumococcus had increased PMN elastase-like esterase
activity within their cells, suggesting an acute phase reaction.

Release

A variety of mechanisms may lead to the extracellular release of
lysosomal contents. These include cell lysis, regurgitation during
phagocytosis, reverse endocytosis, humoral mediation, and cytocha-
lasin B treatment of cells (Klebanoff and Clark 1978). Wright and
Gallin (1979) showed that migration of PMNs is associated with the
leakage of various enzymes. Sandhaus (1983) found that migrating
human neutrophils degrade elastin in vitro in the presence or
absence of human a,AT. A similar mechanism may occur during
neutrophil migration in vivo. Hutchison et al. (1980) found that the
soluble fraction of cigarette smoke suppressed the release of lysoso-
ma1 enzymes (acid phosphatase and acid ribonuclease) from PMNs
obtained from healthy persons, but not from the PMNs of emphy-
sematous patients. Blue and Janoff (1978) demonstrated that the
water-insoluble fraction of cigarette smoke has a cytotoxic effect on
PMNs in vitro and causes them to release their lysosomal contents,
including beta-glucuronidase, acid phosphatase, and elastase. Eliraz
et al. (1977) found that canine alveolar macrophages and PMNs,
when stimulated with the water-soluble fraction of cigarette smoke,
secrete elastase. Abboud et al. !1983), however, compared the release
of elastase and 8-glucoaminodase from PMNs obtained from ciga-

271


rette smokers and with that from nonsmokers and found no
differences. In vitro stimulation of these cells by ?ither phagocytosis
or chemotactic polypeptides did not alter the results. These research-
ers concluded that chronic smoking does not affect neutrophil
elastase release in vitro and that among smokers there is no
significant relationship between in vitro neutrophil elastase release
and abnormalities in lung function. They speculated that some of the
differences between studies may be related to experimental condi-
tions, such as the concentrations of cigarette smoke.

Because the mechanisms involved in the release of intracellular
contents are complex and the representativeness of in vitro condi-
tions to in vivo events is uncertain, definite conclusions await
further studies.

Proximity

Elastolytic activity is conditioned by the absorption of elastase
onto elastin substrate (Robert and Robert 1970); the adsorption, in
turn, results from the electrostatic attraction between negatively
charged carboxylate groups of elastin and positively charged groups
of elastase (Hall and Czerkowski 1961; Gertler 1971). Campbell et al.
(1982) found that a,AT has less inhibitory activity against PMN
elastase derived from cells in contact with substrate than against
PMN elastase free in solution. They reasoned that the partial
exclusion of protease inhibitors from the PMN-connective tissue
interface may account for this phenomena and may be an important
factor in elastase-mediated injury. Focusing more on the macroenvi-
ronment within the lung, Janoff et al. (1983c) found that the
bronchoalveolar lavage fluids of young asymptomatic cigarette
smokers contain significantly more elastase activity than the lavage
fluids from nonsmokers. Kucich et al. (1983) found that the serum
lung em&in-derived peptides were elevated in some smokers and
most patients with COLD, suggesting that elastolysis may be taking
place in smokers and COLD patients.

Milieu

A number of in vitro experiments have examined the chemical and
physical conditions that modify neutrophil elastase kinetics. Lesti-
enne and Bieth (1980) demonstrated that human leukocyte elastase
activity is activated in the presence of substrate excess, hydrophobic
solvents, and increasing ionic strength. The adsorption of sodium
dodecyl sulfate (SDS), a hydrophobic, anionic ligand, onto the surface
of elastin enhances the elastolytic activity of pancreatic elastase
(Kagan et al. 1972). Lonky et al. (1978) showed that platelet factor 4
(PF,) in physiologic concentrations is capable of in vitro stimulation
of human neutrophil elastase (HLE) against lung elastin. Low doses


of HLE instilled intratracheally in hamsters failed to induce
physiologic, morphologic, or biochemical changes, but following the
addition of PFI, a significant injury was evident, and the elastin
content of the lung was lowered by 20 percent (Lonky et al. 1978).
Boudier et al. (1981) demonstrated that human leukocyte cathepsin-
G, an enzyme in the azurophilic granules that possesses little
intrinsic elastolytic activity, stimulates the rate of solubilization of
human lung elastin by HLE. The elastolytic activity increased by
more than five times the HLE rate when the HLE-cathepsin-G
mixture was present in equimolar concentrations. The relevance of
these findings to the physiologic conditions that prevail in vivo
requires further study.

Laurent et al. (19831 recently discovered that the water-soluble
components of filtered cigarette smoke suppress, in a dose-dependent
manner, the lysyl oxidase-catalyzed oxidation of the epsilon-amino
groups of lysine residues in tropoelastin. This step is essential for the
formation of covalent cross-links between neighboring elastin poly-
peptide chains that, in turn, are necessary for normal elastic
strength within the lung.

Decreased An tiproteme Ou<ing to Oxidation

A comprehensive review of the role of oxidative processes in
emphysema has recently been published by Janoff et al. (1983a). In
vitro studies have revealed that oxidants such as chloramine T
(Abrams et al. 1381) or ozone (Johnson 19801 cause a loss in the
inhibitory capacity of a,AT for neutrophil elastase. The mechanism
of inactivation has been identified as the oxidation of methionine
and tyrosine residues (Johnson and Travis 1979; Cohen 1979; Carp
and Janoff 1978) within the a,AT molecule. Chloramine T, when
administered differentially to dogs, reduces EIC .`I TIC of serum and
also results in emphysema (Abrams et al. 1981). Cigarette smoke is
also known to contain oxidants (Stedman 1968; Pryor et al. 19831.
Aqueous solutions of cigarette smoke reduce the elastase inhibitory
capacity of human serum (Carp and Janoff 1978) and result in less
binding of elastase to a,AT in vitro (Carp and Janoff 19781. Some
investigators have found that the a,AT activity is reduced in the
lavage fluids (BALFI obtained from human cigarette smokers and
from rats exposed to cigarette smoke (Gadek et al. 1979; Carp et al.
1982; Janoff et al. 1979a). Stone et al. (1983) reported similar levels of
functional a,-antitrypsin in the bronchoalveolar lavage fluids of
human smokers and nonsmokers. Janoff and Chan (1984) have
suggested that this difference in results may reflect the timing of the
lavage in these studies, as rats chronically exposed to cigarette
smoke had rapid inactivation of u,-antitrypsin following smoke
exposure, but also had a more rapid recovery of a,-antitrypsin
activity than did rats acutely exposed to smoke. Stone et al. also


recognized that their study may not have detected a reduction in
alpha,-antitrypsin activity if it was accompanied by a rapid recovery
to normal levels. Methionine sulfoxide peptide reductase, an enzyme
present in human PMNs, can reactivate a,AT oxidized by chlora-
mine T or by the myeloperoxidase system, but a,AT exposed to
cigarette smoke plus peroxide (Carp et al. 1983) has been shown to be
either resistant to reactivation by the myeloperoxidase system (Carp
et al. 1983) or incompletely reactivated (James et al. 1984).

Human ceruloplasmin has been shown to prevent myeloperoxi-
dase mediated oxidation of a,AT under specified conditions of pH
and solvency (Taylor and Oey 19821, although the role played by
ceruloplasmin in limiting oxidation by phagocytes in vivo is unclear.
Taylor et al. (1983) examined plasma and leukocyte lysosomal
samples from a group of COLD patients and measured the ability of
these samples to inhibit lipid peroxidation. While they reasoned that
inhibitors of peroxidation could protect a,AT from inactivation by
neutralizing lipid free radicals, they found that inhibition required
factors from both plasma and lysosomal extracts and that the factor
was not ceruloplasmin. Two of ten emphysematous patients had
reduced plasma factor activity, and one of these patients also had
reduced lysosomal factor. Controls had normal values for both of
these factors.

Galdston et al. (1984) examined serum ceruloplasmin concentra-
tions and antioxidant activity in male and female smokers. Smokers
of both sexes had higher serum ceruloplasmin concentrations than
did nonsmokers; women in both smoking categories had higher
concentrations than their male counterparts. Serum antioxidant
activity showed a significant positive correlation with serum cerulo-
plasmin levels; however, for comparable ceruloplasmin concentra-
tions, serum antioxidant activity was significantly lower in smokers
than in nonsmokers of both sexes. The researchers suggest that
cigarette smoking may cause partial inactivation of serum antioxi-
dant activity that is accompanied by an insufficient increase in
ceruloplasmin concentration.

Endogenous phagocytes are also capable of generating oxidants
(Babior 1978; Klebanoff and Clark 1978). The phagocytic enzyme
myeloperoxidase, in the presence of hydrogen peroxide and halide
ions, oxidatively inactivates a,AT (Matheson et al. 1979, 1981).
Smoking, as described above, elevates the oxidative metabolism in
lung macrophages (Hoidal and Niewoehner 1982; Fox et al. 1979;
1980; 1981).
Thus, it is clear that the oxidants present in cigarette smoke and
the lung macrophages of smokers can inactivate a,AT. This inactiva-
tion, coupled with the increased elastase burden that may result
from the inflammatory cell response of the lung to smoke, could tip

274


the balance of the protease-antiprotease system in the direction of
elastin degradation.

Explanation for Upper Lobe Distribution

In accord with the protease-antiprotease hypothesis, emphysema-
tous lesions result from the unrestrained proteolytic digestion of
connective tissue elements. The regional distribution of lesions
within the lung is thought to be conditioned by both biochemical and
physiological variables,

The predilection of lower lobe involvement in persons with a,AT
deficiency is hypothesized to result from an increased number of
elastasecontaining cells because of the higher vascular perfusion to
this area in erect man. This excess could occur because of the
deposition of senescent leukocytes in these areas of higher blood flow
(Guenter et al. 1981). In addition, inhaled particulates preferentially
deposit in the lower lobes (Milic-Emili et al. 1966; Dollfuss et al.
1967), and the leukocytes release their enzyme extracellularly
during the ingestion of these particulates. Because of the genetic
deficiency of a,AT, the proteolytic activity is unopposed and
destruction occurs.

The predominance of upper lobe lesions in cigarette smokers with
normal systemic levels of a,AT is again thought to result from
variations of ventilation and perfusion within the lung (Cockcroft
and Horne 1982). However, in normal individuals the proteolytic
activity due to the excess particulate deposition in the bases is
inhibited by a,AT that is replenished by the increased vascular
perfusion also occurring in the bases. The upper lobes, although less
well ventilated than the lower lobes, nevertheless have higher
ventilationqrerfusion ratios because of the proportionately greater
fall in perfusion. The oxidative inactivation of a,AT by cigarette
smoke in the upper lobes therefore may not be compensated by
vascular repletion of the inactivated a,AT, and an imbalance of
protease-antiprotease may occur. The upper lobe injury may then be
magnified by mechanical stresses caused secondary to the negative
intrapleural pressures generated by gravitational forces in erect
man (West 1971).

Animal Models of Emphysema
Spontaneous Emphysema

Emphysema occurs spontaneously in animals in forms resembling
the types seen in human disease (Karlinsky and Snider 1978).
However, the low incidence and unpredictable occurrence of disease
in animals greatly limit their utility as experimental models.


Experimentally Induced Emphysema

A number of insults, including oxides of nitrogen, cadmium salts,
whole cigarette smoke, ozone exposure, and proteolytic enzymes,
have been used to induce or augment emphysematous lesions in a
variety of experimental animals. The reader interested in a compre-
hensive review of this topic is referred to the well-documented article
by Karlinsky and Snider (1978). The evidence for each of these
insults, as they pertain to cigarette smoke, is reviewed below.

Oxides of Nitrogen

Oxides of nitrogen, present in the gas phase of smoke, appear to
induce or potentiate emphysema-like lesions in some animals
(Karlinsky and Snider 1978).

Nitrogen dioxide (NO,) exposure causes airway narrowing and an
increase in the proteolytic burden within the lungs of experimental-
animals. Airway narrowing is postulated as a contributing factor in
the pathogenesis of pulmonary emphysema (Juhos et al. 1980).-
Following exposure to NO*, rats develop bronchiolar stenosis. The
nitrogen dioxide exposure also induces an influx of alveolar macro-
phages (AM) and polymorphonuclear leukocytes (PMNs) (cells
known to contain proteolytic enzymes) into the lungs (Juhos et al.
1980). Kleinerman et al. (1982) demonstrated an increased number of
alveolar macrophages and PMNs in lung lavages from hamsters
exposed to NO,. Although there is no detectable increase in the
elastolytic activity from lung lavages of NO,-exposed animals, the
cell-free culture medium from macrophage cultures of NO,-exposed
animals does show a twofold to fivefold increase in elastolytic
activity during the first 2 weeks of exposure (Kleinerman et al.
1982).

Nitrogen dioxide exposure has not been shown to cause alveolar
septal disruption, an essential feature of centrilobular emphysema,
but it does result in a significant reduction in the internal surface
area in the lungs of hamsters exposed for 12 to 14 months
(Kleinerman and Niewoehner 1973).

Cadmium Salts

Animals exposed to cadmium, a constituent found in the particu-
late phase of cigarette smoke, develop a number of histologic and-
biochemical changes that may lead to emphysematous lesions.

Exposed animals develop pulmonary edema, vascular congestion,
intraparenchymal hemorrhages, and a loss of Type I pneumocytes
(Palmer et al. 1975; Strauss et al. 19761, and PMNs and mononuclear
cells influx into the lungs (Snider et al. 19731. The animals develop
acute peribronchial damage followed by the accumulation of granu-
lation tissue near the respiratory bronchioles, thickened alveolar

276


septa, and distortion and distention of neighboring alveoli Snider et
al. 1973). These histologic changes are more suggestive of the scar or
paracicatricial form of emphysema than the centrilobular form
reported in some industrial workers exposed to CdCl, (Princi 1947).
This disparity in response to CdCl, could be related to species
differences or the interaction of CdCl, with other factors.

When hamsters are exposed to CdCl, plus beta-amino proprioni-
trile (f3-APN), an inhibitor of lysyl oxidase, they develop thin-walled
subpleural bullae and airspace enlargements resembling panlobular
emphysema (Niewoehner and Hoidal 1982). The mean linear dis-
tance between alveolar intercepts is significantly increased; pres-
sure-volume studies show overinflation and increased compliance of
the lungs (Niewoehner and Hoidal 1982). This study suggests that
CdClp, perhaps in conjunction with some other as yet undetermined
agent, may be important in the pathogenesis of pulmonary emphyse-
ma. The fact that CdCl, is a constituent of cigarette smoke (Randi et
al. 1969) lends support to this hypothesis.

Cigarette Smoke

Cigarette smoking has been clearly identified as a major causal
factor in the development of pulmonary emphysema in humans
(Auerbach et al. 1972; 1974; Petty et al. 1967; Andersen et al. 1967;
Niewoehner et al. 1974; USDHEW 1979). However, an animal model
for the development of emphysema using the inhalation of cigarette
smoke alone has not been convincingly demonstrated. Parenchymal
disruption resembling human emphysema has been reported in some
dogs following prolonged cigarette exposure, but this histologic
pattern is not uniformly present (Hernandez et al. 1966; Auerbach et
al. 1967a; Zwicker et al. 1978).

This difficulty in developing an animal model for cigarette-induced
emphysema may relate to the reluctance of animals to inhale smoke
and the relatively long duration of exposure required to produce
emphysema in humans. However, it may also result from the need
for a combination or sequence of effects to induce emphysematous
change. That is, an increased elastase burden might be necessary
isecondary to the cellular response to smoke) before the oxidant
damage of smoke to a,AT, or to repair mechanisms, results in
emphysema. Hoidal and Niewoehner (1983) examined this question
in hamsters exposed to low doses of smoke and elastase. Neither
exposure alone resulted in significant emphysematous change, but
the combined exposure did cause change. This suggests that an
increased elastase burden may be a precondition for smoking-
induced emphysematous lung injury, and may also explain the long
exposure period required in humans prior to the demonstration of an
increased prevalence of emphysema in smokers.

277


Experimental studies have shown that cigarette smoke can induce
a number of cellular, biochemical, and metabolic changes within the
lungs that may be causally related to the development of emphyse-
ma. Macrophages and leukocytes, cells known to contain proteolytic
enzymes, are recruited to the lungs of hamsters (Kilburn and
McKenzie 1975) and guinea pigs (Flint et al. 1971) following exposure
to cigarette smoke, thereby increasing the proteolytic burden of the
lungs. Conversely, the a,AT activity decreases in rats after inhala-
tion of cigarette smoke (Janoff et al. 1979a). The increased proteolyt-
ic burden within the lungs coupled with the concomitant diminu-
tion in inhibitory capacity tends to create a protease-antiprotease
imbalance and a situation whereby unrestrained connective tissue
destruction may occur.

The Effects of Smoking on Cellular and immune Defense
Mechanisms

There are important functional differences between macrophages
from smokers and those from nonsmokers (Table 1). For example,
Warr and Martin (1977) demonstrated that receptors for the third
component of complement (C3b) are decreased in number or function
on the surface of smokers' alveolar macrophages. The receptors for
the Fc portion of IgG, however, are normal on these cells (Warr and
Martin 1977). An important function of the C3b receptor is to
augment the attachment and phagocytosis of microorganisms and
particulates by the macrophages. It is not clear whether this subtle
defect in cell function results in a significant alteration in phagocyto-
sis or clearance of particulates or microorganisms by these cells. In
this regard, the phagocytosis and killing of a variety of microorga-
nisms by smokers' alveolar macrophages have been shown to be
normal by Harris et al. (1970) and Cohen and Cline (1977). One
report by Martin and Warr (19771, however, suggests that the
capacity of alveolar macrophages to kill bacteria is decreased in
smokers.

The observation that human alveolar macrophages from cigarette
smokers function normally to kill microorganisms appears to differ,
at first glance, from a number of animal studies demonstrating that
the capacity of alveolar macrophages to phagocytose and kill
bacteria is impaired following exposure to cigarette smoke (Halt and
Keast 1973; Rylander 1971,1973). In these animal studies, there was
an initial decrease in the numbers of alveolar macrophages and a
decrease in their bactericidal function following exposure to ciga-
rette smoke. With prolonged exposure, however, the number of
macrophages increased and their ability to kill microorganisms
returned to normal (Rylander 1973, 1974). These observations
suggest that cigarette smoke, initially, is toxic to alveolar macro-


phages. However, it is likely that the macrophages, with time, adapt
to the presence of cigarette smoke. In addition, a subpopulation of
macrophages that are more resistant to cigarette smoke may
increase in number in the lung. The macrophages isolated from the
lungs of smokers resemble those isolated from animals following
prolonged exposure to cigarette smoke. The acute effects of cigarette
smoking on the number and functions of alveolar macrophages in
man has not been systematically evaluated.

Alveolar macrophages of cigarette smokers appear to interact in
an abnormal fashion with lymphocytes (Table 1). In this regard, the
alveolar macrophages from cigarette smokers function poorly as
accessory cells in presenting antigen to autologous lymphocytes
(Laughter et al. 1977). This latter defect may be further magnified by
the observation that lymphocytes from cigarette smokers also
respond poorly to mitogens (Neher 1974; Daniele et al. 1977).
Additional evidence for an abnormal interaction of macrophages and
lymphocytes in lungs of cigarette smokers is a decreased response of
alveolar macrophages to the lymphokine, macrophage migration
inhibitory factor (Warr 1979). These observations suggest that
cigarette smoking may have broad effects on the ability of the lung
to generate a cellular immune response.

In Vitro Effects of Cigarette Smoke on Inflammatory and
Immune Effector Cells

The most readily demonstrable effect of cigarette smoke, in vitro;
is a decrease in cell viability (Holt et al. 1974; Holt and Keast 1973;
Nulsen et al. 1974; Weissbecker et al. 1969). At relatively low
concentrations, cigarette smoke and its constituents rapidly kill
alveolar and peritoneal macrophages in vitro. Lymphocytes and
polymorphonuclear leukocytes are also very susceptible to these
agents (Holt et al. 1974; Blue and Janoff 1978).

When sublethal amounts of cigarette smoke are employed, a
number of metabolic and functional changes occur in macrophages.
Phagocytosis is depressed, as is the function of a number of
macrophage enzymes (Vassallo et al. 1973; Green 1968a, b, c, 1969,
1970; Green and Carolin 1966, 1967; Green et al. 1977; Powell and
Green 1971; Hurst and Coffin 1971). In addition; protein synthesis is
also depressed (Yeager 1969; Low 19741, and stimulatory effects have
been noted. While cigarette smoke depresses phagocytosis and
intracellular killing, nitrogen dioxide increases the metabolic activi-
ty of macrophages (Vassallo et al. 1973). Similar effects have been
observed under some conditions with cigarette smoke (Holt and
Keast 1973; Leuchtenberger and Leuchtenberger 1971). Results from
a number of investigators suggest that the balance between stimula-
tion and inhibition of macrophage activity is determined by dosage,
with stimulation occurring at low exposure levels and inhibition at

279


higher concentrations (Halt and Keast 1973; Lentz and DiLuzio 1974;
York et al. 1973). The most potent stimulation occurs after prolonged
exposure to low levels of the agent.

These in vitro effects of cigarette smoke are also seen acutely in
vivo following exposure to smoke. The immediate effect of exposure
to cigarette smoke, and to agents present in the smoke, is a decrease
in viability of the pulmonary alveolar macrophages (Halt and Keast
1973a, b; Rylander 1971, 1973; Coffin et al. 1968; Dowel1 et al. 1970;
Holt and Nulsen 1975; Gardner et al. 1969). Although not well
studied, it is also likely that cigarette smoke is toxic to polymorpho-
nuclear leukocytes (Blue and Janoff 1978). In support of these
observations are studies demonstrating that acute exposure of
experimental animals to tobacco smoke, or to components of
cigarette smoke, also lowers their resistance to bacterial infection
(Rylander 1969, 1971; Acton and Myrick 1972; Gardner et al. 1969;
Goldstein et al. 1971; Huber and LaForce 1971; Huber et al. 1971).
Short-term exposure to components of cigarette smoke, particularly
nitrogen oxide, has also reduced resistance to viral infection,
probably by inhibiting interferon production by macrophages (Va-
land et al. 1970). As noted above, these in vitro and acute in vivo
effects of cigarette smoke are not seen following long-term in vivo
exposure in animals; very little work has been done on the effects of
cigarette smoke in vitro, using human cells. However, several studies
have shown that cigarette smoking and nicotine, at levels compara-
ble to those encountered in the circulation of smokers, produce a
slight but significant depression of PHA-stimulated DNA synthesis
in human peripheral blood lymphocytes (Neher 1974; Silverman et
al. 1975; Vos-Brat and Rumke 1969).

The Effect of Cigarette Smoke on Antibody Production

The available data on antibody production in human smokers
suggest that cigarette smoking may depress these responses. The
production of antibodies was investigated in a large study involving
influenza vaccination. Smokers in the population exhibited in-
creased susceptibility to infection during an influenza outbreak
(Finklea et al. 1969, 1971). Prior to immunization with influenza
vaccine, smokers exhibited significantly lower titers of specific
antibodies than did nonsmokers. Immediately following vaccination
of both groups, the smokers developed levels of antibodies compara-
ble to those of nonsmokers. However, the antibody titer in the
smokers fell below their nonsmoking counterparts within a few
weeks, and by a year after vaccination the smokers exhibited
markedly depressed levels of circulating antibodies.

The capacity of cigarette smoking to alter antibody production was
also studied by evaluating the capacity of a fetus to stimulate
lymphocytotoxic antibodies against HLA antigens in the mother


(Nyman 1974). Sera from a large number of pregnant women were
tested for the presence of lymphocytotoxic antibodies against a 4&
donor panel. The smokers exhibited a significantly lower incidence
of these antibodies than did nonsmokers, and the divergence
between groups increased with the number of deliveries. Infections
during pregnancy were observed significantly more often in the
smokers in this trial.

In several animal models, acute exposure to whole cigarette smoke
or components of cigarette smoke depressed the numbers of anti-
body-forming cells in the spleen and the serum levels of antibodies in
animals exposed to a variety of antigens (Miller and Zarkower 1974;
Zarkower and Marges 1972; Zarkower et al. 1970). The depression
was greatest when the antigen was administered by an aerosol
(rather than by systemic inoculation), indicating t,hat smoke appears
to exert an effect close to the point of entry. Prolonged exposure
ultimately resulted in severe depression both in local and in systemic
antibody responses (E&r et al. 1973; Holt et al. 1976; Thomas et al.
1973,1974a, 1974b, 1975).

Although it is tempting to relate these abnormalities in immune
response to the known association between cigarette smoking and
increased incidence of upper respiratory infection, it is not clear
whether the subtle defects in immune functions can entirely account
for the infections present in cigarette smokers. Clearance of bacteria
from the respiratory tract is a complex process that involves
interplay between a variety of different mechanisms, only some of
which include the function of alveolar macrophages and the capacity
of the lung to mount cellular and humoral immune responses. Other
abnormalities present in cigarette smokers that could account for
this increased incidence of infection include a markedly abnormal
tracheal bronchial clearance of particulates and an increased
adherence of bacteria to airway epithelium (reviewed in USPHS
1971, 1973, 1974).

281


EFFECTS OF CIGARETTE SMOKE ON AIRWAY
MUCOCILIARY FUNCTION

Introduction

There is extensive literature on the effects of cigarette smoke on
mucociliary clearance in the airways, with the majority of the
reports appearing between 1965 and 1975. Different experimental
approaches have been used, including in vivo measurement of
mucociliary function in animal models and in human subjects. The
results of some of these studies have been contradictory, presumably
because of differences in experimental technique or the influence on
mucociliary function of factors other than cigarette smoking. For
example, tracheal mucociliary transport appears to decline with age
in normal subjects (Goodman et al. 19781, an important phenomermn
to consider when assessing the effects of long-term cigarette smok-
ing. Another complicating factor is the clearly demonstrated impair-
ment of mucociliary function produced by chronic bronchitis even in
nonsmokers, such as in patients with cystic fibrosis (Wood et al.
1975) or immunoglobin deficiency (Mossberg et al. 1982). Therefore,
it is difficult to separate the direct effects of cigarette smoke on
mucociliary function from those of smoking-associated chronic
bronchitis. Finally, in vitro bioassays for ciliotoxicity may not
reliably reflect the effects of cigarette smoke on the mucociliary
apparatus in the intact airways. Thus, Dalhamn et al. (1967) found
that smoke produced by cigarettes containing a high concentration
of hydrogen cyanide was more ciliotoxic in vitro than that produced
by cigarettes containing a low concentration of hydrogen cyanide,
and the two types of cigarettes caused a comparable reduction of
mucus transport in vivo.

This review is divided into three parts. The first part summarizes
the normal structure and function of the mucociliary system in the
airways. The second part deals with the direct effects of short-term
and long-term cigarette smoke exposure on mucociliary function,
and the third part discusses mucociliary function in chronic bronchi-
tis.

Normal Mucociliary Function

The principal function of the airway mucociliary system is its
contribution to host defenses. This is accomplished by physical
removal of inhaled foreign material from the ciliated airways by
mucous transport and by biochemical and immunological processes
that protect against invasion of the mucosa by infectious agents.
Normal mucociliary clearance depends upon an optimal interaction
between cilia and mucus.

283


Cilia

The respiratory mucosa from the proximal trachea to the terminal
bronchioles consists of a pseudostratified epithelium with cilia
protruding from the luminal surface of columnar cells (Figure 1).
The larynx contains a mucus-secreting squamous epithelium over
most of its surface, and cilia are present only in the posterior
commissure (Wanner 1977). The major cell types in the respiratory
mucosa are basal cells, intermediate cells, nonciliated columnar
cells, ciliated columnar cells, and goblet cells. In the larger airways,
the major part of the epithelial surface is ciliated. The ratio of
ciliated columnar cells to goblet cells is approximately 5:l in the
trachea, with a relative decrease in the number of both cell types
toward the peripheral airways. The surface of each ciliated columnar
cell contains approximately 200 cilia with an average length of 6 pm
and diameter of 0.2 urn. Both ciliated and nonciliated columnar cells
are characterized by microvilli on their luminal surface. These
measure 0.3 pm in length and 0.1 pm in diameter. The ultrastruc-
ture of cilia in lower animals and mammals is remarkably similar.
Each cilium contains longitudinal microtubules that appear to
represent contractile elements. Two single microtubules form a
central core, and nine microtubules with a doublet structure are
arranged in a circular fashion in the periphery of the cilium. A basal
body in the apex of the cell corresponds to each cilium. Circular and
radial bridges have been demonstrated between the peripheral
microtubules and between the peripheral and central microtubules.
These bridges (dynein arms, nexin links, radial spokes) appear to be
crucial for ciliary bending.

Mucus

Respiratory secretions consist of mucus produced by submucosal
glands and goblet cells and tissue fluid. The total volume of all
mucus-producing structures has been estimated at approximately 4
ml in human lungs; submucosal glands make up most of this volume
(Wanner 1977). The submucosal glands are under parasympathetic
nervous control, with an estimated daily volume of respiratory
secretions between 10 and 100 ml. FIuman respiratory secretions
contain approximately 95 percent water. `I'he rest consists of
micromolecules (electrolytes and amino acids) and macromolecules
(lipids, carbohydrates, nucleic acid, mucins, immunoglobulins, en-
zymes, and albumin). In situ, the respiratory secretions take the
form of two layers, i.e., periciliary fluid (sol phase), and mucus (gel
phase), as shown in Figure 1. Mucus has been clearly identified as
the product of submucosal glands and goblet cells; the origin of the
periciliary fluid has not been definitely established, although
transepithelial water transport appears to be the most likely source.
Tn central airways, the mucus layer is 5 to 10 pm deep and may be

284


FIGURE l.-Schematic representation of normal mucosa
      (central airway) with the components of the
      mucociliary apparatus

N(YTE: From top (airway lumen) to bottom, note IIIUCUE layer. periclliary tluld layer, eplthelxum mrh a
predominance of ciliated mlumnar cells and an mterapemed goblet cell, basement membrane, and aubmucoaal
gland.
SOURCE. Wanner (1979)

discontinuous. In peripheral airways where submucosal glands are
absent and goblet cells are rare, mucus is either absent or present
only in small quantities. Regeneration of injured ciliated respiratory
epithelium takes approximately 2 weeks in animals; the exact
regeneration time of damaged human tracheobronchial ciliated
epithelium is not known (Wanner 1977). It appears that regeneration
does not begin until 2 to 3 days following mechanical injury.

Mucociliary Interaction

Mucociliary interaction depends on ciliary activity, the rheologic
properties and depth of the mucus layer, and the depth of the
periciliary fluid layer. The viscoelastic properties of mucus are
determined by its biochemical characteiistics (&sulfide cross-linking
and hydrogen bonding between glycoprotein molecules and water)
(Wanner 1977). Cilia beat in one plane, with a fast effective stroke
(power stroke) in the cephalad direction and a recovery stroke that is
two to three times slower. Adenosine triphosphate has been identi-
tied as the energy source for ciliary bending. In mammals, the
average normal ciliary beat frequency is approximately 1,000 beats
per minute, with coordinated motion in adjacent cilia on an
individual cell and in cilia of adjacent cells. This interciliated


TABLE 2.-Measurement of airway mucociliary function in
       humans

Method                 Reference

Clearance of inhaled radioactive
aerceols from the lungs

Morrow et al. (1967)

Transport of discrete markers

Friedman et al. (1977)
Sackner et al. (1973)

Central airway clearance of inhaled
boli of radioactive micrarpheree

Yeatea et al. (1975)

pattern of motion by which adjacent cilia beat one after another to
generate a wave of ciliary motion is called metachronism.

The "normal" thickness of the periciliary fluid layer is less than,
or at best equal to, the length of the ciliar shafts, which measure
approximately 6 pm in the central airways. The luminal surface of
the mucus layer appears smooth, whereas the surface in contact with
the cilia is irregular, and the mucus penetrates between the ciliary
shafts. This penetration and the claw-like projections at the cilia tips
may further facilitate the mechanical interaction between cilia and
mucus. In the trachea, the "normal" surface mucus transport
velocity is between 5 and 20 mm per minute depending upon the
method of measurement. Mucous transport velocity decreases
toward the peripheral airways.

The three principal methods for the measurement of tracheobron-
chial mucociliary function in humans are listed in Table 2. All of
these have been used in studies of the effects of cigarette smoke on
mucociliary function.

Theoretically, mucociliary dysfunction can result from alterations
in ciliary beat frequency and coordination, the quantity and visco-
elastic properties of mucus, and the thickness of the periciliary fluid
layer. In addition, focal destruction of the respiratory epithelium,
producing areas without cilia or mucus, is also associated with
impaired or absent mucociliary transport.

Effects of Cigarette Smoke on Mucociliary Function

The irritant effects of cigarette smoke on mucociliary clearance
were recognized by Mendenhall and Shreeve (1937). They observed a
decrease in the transport rate of carmine particles on the mucosa of
excised cat tracheas after bringing them in contact with cigarette
smoke, either directly or by dissolving it in the solution in which the
t.racheas were immersed (Mendenhall and Shreeve 1937, 1940).
These early findings were confirmed by Hilding (1956) and Dalhamn


(1959) approximately 25 years ago. Since then, investigations to
assess the effects of cigarette smoke on ciliary activity and mucocili-
ary transport have proliferated. Because cigarette smoke can impair
mucociliary transport by interfering with ciliary activity or mucus
secretion, the studies relating to these two component functions are
discussed separately and are complemented by a review of experi-
ments involving mucociliary transport, the ultimate expression of
mucociliary function.

The effects of cigarette smoke on mucociliary function have been
extensively studied in vitro, in intact animal models, and in human
subjects. Comparison among the results of these experimental
approaches is difficult, as there are major differences in inhalation
patterns even between animal models and human subjects. Cigarette
smoke is modified during its passage through the upper airways, and
this may vary depending upon the mode of inhalation. By using
smoke produced by radio-tracer spiked cigarettes, it has been shown
that mice, who are obligatory nose breathers, retain 50 percent of
the inhaled radioactivity in the nasal passages, 20 percent in the
lungs, and the rest in the esophagus, stomach, and other organs
(Page et al. 1973). Using artificial airways to bypass the nasopharynx
in experimental animals eliminates the problem of nasal cigarette
smoke absorption, but also prevents the oral modification of ciga-
rette smoke that is a typical feature of human smoking. In subjects
inhaling cigarette smoke from a smoke dosage apparatus that
delivers standard puffs, 86 to 99 percent of most components of gas
and particulate phases of cigarette smoke are retained, with the
exception of carbon monoxide (CO), of which only 54 percent is
retained (Dalhamn et al. 1968). Much of the smoke appears to be
retained in the mouth. In human subjects who hold cigarette smoke
in their mouth for 2 seconds, 60 percent of the water-soluble
components of the gas phase, 20 percent of the water-insoluble
components of the gas phase, and 16 percent of particulate matter
are absorbed or retained in the upper airways (Frances et al. 1970;
Stupfel et al. 1974). This marked modification of cigarette smoke
might decrease its ciliotoxic effect in the lower airways. Passing
unfiltered cigarette smoke through a chamber with wet surfaces
before bringing it in contact with ciliated epithelium decreased the
cilioinhibitory capacity of the cigarette smoke (Kaminski et al. 1968).
When filtered cigarette smoke was used, the wet surfaces had no
additional effect on ciliotoxicity, indicating that the mucosa of the
upper airway may serve as a filter (Kaminski et al. 1969). Similar
observations have been made when cigarette smoke was passed
through a water trap (Albert et al. 1969).

Because of the differences in inhalation pattern between humans
and animals, it might be argued that nasal mucociliary function
should be measured to assess the effects of inhaled cigarette smoke

287


TABLE S.-Effects of cigarette smoke on airway
      mucociliary system

EXposW?

                     Impaired mucociliary
Clliary dysfunction Mucus hypereecretion     clearance

Short term        Yes             ?             ?
Lang term        Yes            Ye8            YeS

in animal models. However, it has been clearly shown that nasal
mucociliary transport is not a good marker of tracheobronchial
mucociliary transport because of differential responses at the two
sites. For example, exposure to the whole cigarette smoke of up to 30
cigarettes does not impair nasal mucociliary transport in donkeys
(Frances et al. 19701, whereas the same number of cigarettes clearly
alters tracheobronchial deposition and clearance of radioactive
aerosols (Albert et al, 1969). Likewise, Hilding (1965) has concluded
from his studies that the nose is not an acceptable organ for the
study of the effects of cigarette smoke on mucociliary transport.

Realizing the problems with experimental models of ciliary
function in response to cigarette smoke inhalation, Dalhamn (1969)
postulated that a proper experimental design should fulfill the
following requirements: (1) the exposure pattern and level of
cigarette smoke inhalation should simulate that of natural smoking
in human subjects, (2) cigarette smoke should be delivered in air and
not as an aqueous solution, (3) the components of inhaled cigarette
smoke should be analyzed, and (4) exposure should be of long
duration. Although these criteria are obviously not met by many of
the studies quoted in this review, understanding these principles
allows a more critical assessment of the reported results as shown in
Table 3.

Short-Term Exposur&

The effects of short-term cigarette smoke exposure on the mor-
phology of the respiratory mucosa have not been investigated in
man. Cigarette smoke residue has been shown to cause ciliary
damage in cultured rabbit tracheal epithelium with a contact-time-
dependent effect (Kennedy and Allen 1979). The most consistent
abnormalities were cellular desquamation and alterations in mito-
chrondria, cilia, and microvilli, some of which occurred as early as 1
hour after exposure commenced.

Cytotoxicity has also been observed after short-term exposure of
ciliated epithelium to aqueous extracts of cigarette smoke conden-
sate in vitro (Donnelly 19691, but it is difficult to extrapolate data
from these in vitro studies to the in vivo conditions that occur during
cigarette smoking.

288


Cilia

With a few exceptions, e.g., Proetz (1939), most investigators have
demonstrated an irritant effect of smoke on ciliated epithelium,
usually characterized by ciliostasis. Residues of cigarette smoke
passed through an aqueous medium have been shown to produce
ciliostasis in protozoa (Weiss and Weiss 1964; Wang 1963) and in
fragments of human respiratory epithelium (Ballenger 1960). In
fragments of rat trachea, brief exposure to whole cigarette smoke
appears to elicit a biphasic response, with a short period of
stimulation during 1 to 2 minutes followed by a marked decrease in
ciliary beat frequency (Guillerm et al. 1961, 1972). In an excised
rabbit trachea model, 71 l-ml puffs or 35 lo-ml puffs of whole
cigarette smoke were necessary to produce ciliostasis; similar
relationships were demonstrated in the tracheas of living cats
(Dalhamn 1970; Dalhamn et al. 1968). Several investigators have
established a stimulus-response relationship between dilutions of
aqueous cigarette smoke extract and the time of exposure required
for total stoppage of ciliary beat frequency in different experimental
models (Donnelly 1969, 1972; Das et al. 1970; Donnelly et al. 1981).
The mechanism by which cigarette smoke acutely depresses ciliary
function is not clearly known, but may involve enzyme inhibition of
adenylate kinase, thereby reducing adenosine triphosphate (ATP),
the energy source for ciliary bending (Mattenheimer and Mohr 1975:
Schabort 1967). Ciliary function in response to short-term cigarette
smoke inhalation has not been studied in man.

Very little is known about the quantity and rheologic properties of
airway secretions after short-term cigarette smoke exposure. A brief
exposure of slugs to cigarette smoke has been-reported to stimulate
the production of mucus containing an increased number of acid
glycoprotein fibers (Wilde 1981). The significance of this observation
with respect to the human respiratory tract is not clear, except that
an increased number of acid glycoprotein fibers has also been
demonstrated in sputum obtained from cigarette smokers.

Mucociliary Interaction

Using a variety of different techniques in animal experiments,
ciliary dysfunction and impairment of mucociliary transport by
short-term exposure to cigarette smoke have been demonstrated in
rats (Iravani 1972; Dalhamn 1964; Ferin et al. 19661, rabbits
(Dalhamn 1964; Holma 19691, cats (Carson et al. 1966; Dalhamn
1964, 1969; Kaminski et al. 1968), dogs (Guillerm et al. 1972;
Sakakura and Proctor 1972; Isawa et al. 1980), donkeys (Albert et al.
1974, 19691, chickens,.and sheep (Stupfel et al. 19743. A few reports


have not demonstrated that short-term exposure to smoke depresses
mucociliary function in animal models (La Belle et al. 1966; Bair and
Dilley 1967). The reasons for the discrepancy between these and the
previously listed studies are not clear, but may be related to
methodology and dose of exposure. Stimulus response curves be-
tween dose of cigarette smoke and the degree of mucociliary
inhibition have been shown in airways of chickens and dogs (Battista
and Kensler 1970b; Sakakura and Proctor 1972; Isawa et al. 1980). In
one study, for example, 9 puffs of nonfiltered cigarette smoke had
variable effects on tracheal mucociliary transport in intact dogs, but
tracheal mucociliary transport was consistently inhibited by 12 puffs
(Sakakura and Proctor 1972). Likewise, the number of 4-second
exposures to cigarette smoke (separated by 1 minute) required to
reduce mucus transport in intact chicken tracheas by more than 90
percent has been shown to increase with increasing dilutions (from
50 to 3 percent) of smoke in air (Battista and Kensler 1970b).

Measurements of mucociliary clearance in man immediately after
smoking one or more cigarettes have shown conflicting results, with
either increased (Albert et al. 1973; Camner et al. 1971; Albert et al.
1975; Camner and Philipson 1971,1974), inconsistent, or unchanged
rates (Yeates et al. 1975; Pavia et al. 1971; Goodman et al. 1978) or
decreased (Nakhosteen et al. 1982) rates. Transient effects on
mucociliary clearance have been reported in both smokers and
nonsmokers (Hilding 1956; Pavia et al. 1971). Such differences
between human subjects may reflect a difference in the dose and
inhalation pattern of cigarette smoke.

Long-Term Exposure

In dogs inhaling cigarette smoke through a tracheostomy, histolog-
ic changes have been observed in the bronchi after 229 to 421 days of
exposure (Auerbach et al. 1967b). These changes consisted of
epithelial hyperplasia, decreased number of ciliated cells, and areas
of squamous metaplasia. This may be criticized as a poor model of
cigarette smoking in humans because the upper airway, which
absorbs part of the smoke and decreases its toxicity, is bypassed. The
irritant effect of cigarette smoke on the tracheobronchial mucosa
could be enhanced in this model. However, inflammatory changes in
the airways have also been observed in animals that inhaled
cigarette smoke via their upper airways (Leuchtenberger et al. 1958;
Rylander 1974; Mattenheimer and Mohr 1975; Park et al. 1977;
Basrur and Basrur 1976; Jones et al. 1973; Iravani 1973). Various
types of lesions have been observed, including tracheal and bronchial
epithelial hyperplasia (Park et al. 1977: Frasca et al 19741, goblet
cell proliferation and submucosal gland hypertrophy (Jones et al.
1973; Park et al. 19771, bronchiolar metaplasia of mucus-secreting
cells (Basrur and Basrur 19761, increased quantities of airway mucus

290


that appear to be adherent to submucosal gland openings (Iravani
19731, and a decreased number of ciliated epithelial cells (Basrur and
Harada 1979). One study suggested a dose-dependence of the mucosal
lesions when comparing hamsters exposed to either four cigarettes
per day or eight cigarettes per day for 2 weeks (Basrur and Basrur
1976). The pathologic changes produced by long-term cigarette
smoke exposure appear to be reversible if the exposure time is not
excessive. Thus, inflammatory changes in the airways of hamsters
exposed to cigarette smoke for 4 weeks showed marked reversibility
with a recovery time of several weeks (Basrur and Harada 1979).

The histologic changes in the airways of cigarette smokers are
similar to those produced by cigarette smoke in animal models, and
consist of varying degrees of denudation of the ciliated epithelium,
an increase in the number of goblet cells, submucosal gland
hypertrophy, and squamous metaplasia (Regland et al. 1976; Jones
1981). Morphometric studies have demonstrated an increased quan-
tity of mucus in the airway lumen without histologic evidence of
coexistent emphysema or a history of obstructive lung disease,
whereas this is not observed in the lungs of healthy nonsmokers
(Niewoehner et al. 1974; Matsuba and Thurlbeck 1971). Electron
microscopic examination of ciliated epithelium in surgical lung
specimens obtained from cigarette smokers has revealed ciliary
abnormalities consisting of compound cilia, single axoneme, intra-
cyctoplasmic microtubular doublets, and cilia within periciliary
sheaths (McDowell et al. 1976). If bronchial biopsy material is used to
detect ciliary abnormality in cigarette smokers, the results must be
interpreted with caution, for a single biopsy may be misleading
owing to the focal nature of the lesions (Fox et al. 1981).

The morphologic changes of the respiratory mucosa in animals
exposed to cigarette smoke for prolonged periods and in human
cigarette smokers strongly suggests the presence of mucociliary
dysfunction. This has been clearly demonstrated, particularly with
respect to the production and clearance of mucus.

Cilia

Ciliary function after long-term cigarette smoke exposure has not
been extensively studied. Iravani and Melville (1974) demonstrated a
decrease in ciliary beat frequency in the airways of hamsters
exposed to cigarette smoke for 1 year; however, in rats also exposed
for 1 year under almost identical conditions, ciliary frequency was
generally increased, although there were zones of ciliary inactivity
or discoordination. A sustained inhibition of adenylate kinase
activity in ciliated tracheal cells of hamsters exposed to cigarette
smoke for up to 9 months has also been reported (Mattenheimer and
Mohr 1975). Because inhibition of this enzyme leads to a decreased
generation of adenosine triphosphate. the energy source of ciliary

291


bending, a decreased ciliary activity might be expected (Mattenheim-
er and Mohr 1975).

Mucus

Mucus hypersecretion has been clearly demonstrated in the
airways of several animal species exposed to cigarette smoke for
prolonged periods of time (Battista and Kensler 1970a; Iravani and
Melville 1974). Rheologic measurements of airway mucus have not
been reported in such animal experiments, but biochemical analysis
has revealed the presence of serum proteins that might have
cilioinhibitory effect (Dalhamn and Pira 1979; Battista 1980). Mucus
hypersecretion may occur as early as 1 month after beginning a
smoke inhalation equivalent to as little as one cigarette per day
(Battista and Kensler 197Oa). Rheologic and biochemical examina-
tions of airway secretions in healthy smokers have not been carried
out, primarily because these subjects do not have a productive cough.
Once a smoker develops chronic productive cough, he or she is no
longer considered healthy, but by definition, has chronic bronchitis.

Mucociliaty Interaction

Long-term effects of cigarette smoke on airway mucociliary
transport have been studied in different animal species, In purebred
beagle dogs exposed to cigarette smoke (100 cigarettes per week) for
13.5 months via a mask that administered cigarette smoke through
both the mouth and the nose for 1.5 hours twice daily, tracheal
mucus transport rate was decreased to approximately 30 percent of
that observed in control animals (Wanner et al. 1973). Pulmonary
function did not differ significantly between the two groups. It has
subsequently been shown that the abnormality in mucociliary
transport in beagles may already be present after 6 months of
cigarette smoke exposure (Park et al. 1977). An impairment of
mucociliary clearance with long-term cigarette smoke exposure has
also been demonstrated in rabbits, guinea pigs, rats, and chickens
(Okajima 1971; Rylander 1971b; Iravani and Melville 1974; Battista
and Kensler 1970a). In some of those experiments, impaired mucoci-
liar-y clearance was already observed 4 weeks after the beginning of
exposure.

The long-term effects of cigarette smoking on mucociliary function
in human subjects has been investigated by aerosol clearance
techniques and discrete marker transport techniques. Some of the
investigators using radioactive aerosols demonstrated no abnormali-
ty of overall clearance in habitual cigarette smokers, particularly in
those who already may have had symptoms of chronic bronchitis
(Sanchix et al. 1972; Yeates et al. 1975; Pavia et al. 1970; Pavia and
Thomson 19701. However, the deposition of the inhaled radioactive

292


aerosol is more central in normal smokers and in patients with
chronic bronchitis than in nonsmokers (Lippman et al. 1970).
Because clearance is faster in central airways than in peripheral
airways, this centralization of aerosol deposition may compensate for
the overall decrease in mucociliary clearance. Investigations that
have related mucociliary clearance to deposition pattern have
generally found an impairment of mucociliary clearance in cigarette
smokers (Lourenco et al. 1971; Camner et al. 1973a; Camner and
Philipson 1972, 1974). Camner and Philipson (19721, in a study of 10
pairs of twins discordant for cigarette smoking, showed a significant-
ly lower average clearance rate in smokers compared with nonsmok-
ers; in 5 pairs clearance was slower in the smoker than in the
nonsmoker, whereas in the remaining 5 pairs there was no differ-
ence. Analysis of regional clearance has produced further evidence
that overall clearance of inhaled radioactive aerosols may fail to
detect an abnormality in mucociliary clearance. Thus, Bohning and
co-workers (1975) studied the deposition and clearance of 7 pm
diameter particles in the tracheobronchial tree of six pairs of
monozygotic twins, four of whom were discordant for cigarette
smoking. They found comparable overall mucociliary clearance in
the smoking and nonsmoking pairs, but more central deposition and
slower central clearance in the smokers. Others have reported an
impairment of peripheral mucociliary clearance and alveolar clear-
ance as well (Matthys et al. 1983; Cohn et al. 1979).

Discrete particle techniques involving either bronchoscopy or
radiography have been used to assess mucus transport in central
airways, notably the trachea. Most investigators have reported a
decrease of tracheal mucus velocity in healthy smokers, with values
ranging between 20 percent and 80 percent of those of nonsmoking
controls (Goodman et al. 1978; Toomes et al. 1981; Nakhosteen et al.
1982).

The bulk of the evidence indicates that long-term cigarette
smoking alters mucociliary transport mechanisms and that these
changes can occur as early as 1 year after smoking onset. Partial
recovery of mucociliary transport has been observed in cigarette
smokers after cessation for 3 months or more, but not after 1 week of
cessation (Camner et al. 1973). These observations have also been
supported by animal experiments (Albert et al. 1971).

Fractionation and Filtering of Cigarette Smoke

Whole cigarette smoke is composed of voiatile elements and
particulate matter, and it has become customary to distinguish
between the gas phase and the particulate phase. The gas phase, by
definition, consists of the components that remain after cigarette
smoke has been "effectively" filtered by passing it through appropri-
ate filters (Dalhamn 1966; Kensler and Battista 1963; Falk et al.

293


1959). The major constituents of the particulate phase are nicotine,
phenols, hydrocarbons, aldehydes and ketones, organic acids, and
alcohols. Although 95 percent of the gas phase (approximately 300
ml per cigarette)~cogaists of combustion products and admixed air
(nitrogen, oxygen, carbon dioxide, carbon monoxide) in concentra-
tions that do not affect mucociliary transport, some trace gases are
important (Rat&a Qt al. 1962). These include nitrogen dioxide,
ammonia, cyanides, aldehydes, ketones, acrolein, and acids. As is
shown below, some controversies still remain about whether the gas
phase or the particulate phase of cigarette smoke is primarily
responsible for its depressant effect on mucociliary activity. This
problem is relevant when comparing the effects on mucociliary
clearance of low tar versus high tar cigarettes, low nicotine versus
high nicotine cigarettes, and filtered versus nonfrltered cigarettes.
Dalhamn (1966) reviewed the controversy over the separate effects
of the gas and the particulate phases of cigarette smoke on
mucociliary function. In protozoa, both phases of cigarette smoke
have been shown to possess ciliotoxic properties (Kennedy and
Elliott 1970). Falk and associates (19591 reported that exposure to
whole cigarette smoke for 30 seconds resulted in a biphasic response,
with an initial stimulation, followed by depression with a minimum
value at about 15 minutes and a tendency toward recovery 45
minutes after exposure. Removal of the particulate matter in
cigarette smoke by passing it through filters decreased its depressant
effect on mucus transport, indicating that the major effect on
mucociliary clearance was related to the particulate phase. Similar
observations have been made by others (Rylander 1970; Falk et al.
1959). In contrast, Kensler and Rattista (1963) incriminated the gas
phase of cigarette smoke; they exposed strips of rabbit trachea to
smoke from different cigarettes for 12 seconds and identified various
gas phase constituents as having a depressan t effect on mucus
transport. These findings have also been confirmed by others in in
vitro and in in vivo animal experiments (Kensler and Rattista 1963;
Hee and Guillerm 1973; Dalhamn 1956; Albert et al. 1974; Carson et
al. 1966).
The most comprehensive study of individual gas and semivolatile
constituents of cigarette smoke has been conducted by Petterson et
al. (1982). Using chicken tracheal organ cultures, they showed that
at a 5 mm concentration, 36 percent of 316 different compounds
caused ciliostasis after 15 seconds of exposure, but 50 percent were
without effect after an exposure time of 60 seconds. On the basis of
this criterion of separation, either alkylated phenylethers, benzoni-
triles, benxaldehydes, benxenes, napthalenes and indoles, or a-satu-
rated, &unsaturated ketones and aldehydes, or aliphatic alcohols,
aldehydes, acids, and nitrates were found to be ciliotoxic. Inactive
compounds included benxoic acids, esters, polyaromatic hydrocar-

294


bons, amines, and N-heterocycles (except indoles). With respect to
aldehydes, the time to ciliostasis on tissues of rabbit trachea has
been reported shortest for formaldehyde, followed by acetaldehyde,
acrolein, crotonaldehyde, and methacrolein. The ciliotoxic effects of
aldehydes have been confirmed by others using different experimen-
tal approaches (Guillerm et al. 1968; Hee and Guillerm 1973;
Kensler and Battista 1963). It has also been shown that acute
acrolein inhalation causes denudation of ciliated cells, goblet cell
discharge, exfoliation of surface epithelial cells, and infiltration of
inflammatory cells in the lower airways of several different mam-
mals (Dahlgren et al. 1972). Another volatile constituent of cigarette
smoke with marked cilioinhibitory effects is hydrogen cyanide
(Wynder et al. 1965al.
Weissbecker et al. (1971) used a different approach to assess the
effects of several volatile cigarette smoke constituents on mucocili-
ary transport in the cat trachea. The addition of individual volatile
cigarette smoke components (isoprene, nitric oxide, and nitrogen
dioxide) to carbon-filtered cigarette smoke either aggravated the
impairment of tracheal mucus velocity produced by the filtered
smoke or abolished the protection afforded by the carbon filter.
When these constituents were added to whole cigarette smoke, no
further impairment of mucus transport velocity was observed,
indicating a saturation by whole cigarette smoke of receptors
responsible for mucociliary depression.
A direct relation has been reported between tar content and the
ciliotoxic effect of cigarette smoke (Dalhamn and Rylander 1967;
Falk et al. 1959). However, Falk and associates (1959) found no
difference between low tar and high tar cigarette residues with
regard to in vitro mucociliary transport. The effects of nicotine on
mucociliary transport are also controversial, although more investi-
gators have demonstrated a lack of effect (Falk et al. 1959; Guillerm
et al. 1972; Rakieten et al. 1952; Donnelly 1972) than a depression of
mucociliary transport (Carson et al. 1966). Indeed, a biphasic dose-
dependence has been suggested, with stimulation at lower concentra-
tions and depression at higher concentrations (Tsuchiya and Kensler
1959). The stimulation of mucociliary function may be related to
stimulation of nicotinic ganglionic receptors causing choline@
ciliostimulation. This is baaed on the observation that the stimulat-
ing effect of nicotinecontaining cigarettes on the metachronal wave
frequency in the maxillary sinus of anesthetized rabbits is blocked by
atropine and hexamethonium (Hybbinette 1982).
Among the different cigarette tobacco additives, menthol does not
interfere with mucociliary transport (Rakieten et al. 1952). With
respect to phenols, one investigator has reported that the ciliotoxici-
ty of cigarette smoke produced by freezedried tobacco is the same as
that produced by conventionally cured tobacco although the former


contains less phenol (Enzell et al. 1971). On the other hand, phenols
have been shown to impair mucociliary activity and mucus transport
both in vitro (Dalhamn and Lagerstedt 1966; Bernfeld et al. 1964;
Dalhamn 1968) and in vivo (Dalhamn 1968). Dalhamn and associates
[Dalhamn and Lagerstedt 1966; Dalhamn 1968) have even attempted
to relate the toxicity of various phenols to their boiling points.
Addition of the anti-inflammatory agents phenylvinyloxadiozole and
phenylmethyloxadiozole to tobacco has been shown to reduce the
ciliotoxicity of tobacco smoke (Dalhamn and Rylander 1971; Rylan-
der 1971b; Dalhamn 1969), and treatment of rats undergoing long-
term exposure to tobacco smoke with phenylmethyloxadiozole has
been shown to protect the animals against the cigarette-smoke-
induced increase in the number of goblet cells in the respiratory
mucosa (Jones et al. 1973).

It can be concluded from these studies that both the particulate
phase and the gaseous phase of cigarette smoke impair mucociliary
function, that a large number of volatile components are ciliotoxic,
that nicotine may or may not contribute to ciliotoxicity, and that the
additive phenol is ciliotoxic, but the anti-inflammatory agents
phenylmethyloxadiozole and phenylvinyloxadiozole afford partial
protection against the deleterious effects of cigarette smoke. The
mechanisms by which the various constituents of cigarette smoke
interfere with mucociliary transport are unknown. On the basis of
experiments in the fresh water mussel, it has been suggested that
ciliotoxicity depends on their pH in solution (Wynder et al. 1963). It
should be noted, however, that such in vitro experiments requiring
an aqueous medium do not necessarily reflect the type of exposure
occurring in smokers in whom contact between cigarette smoke and
the ciliated epithelium is made by impingement or bypass.

Effects of Filters

Because the toxic effect of cigarette smoke on mucociliary trans-
port mechanisms seems to reside both in the gas phase and in the
particulate phase, the filtering of cigarette smoke before inhalation
may be protective. It has been clearly shown that a longer exposure
time is needed for ciliostasis to occur with smoke from filtered
cigarettes than from unfiltered cigarettes, with respect to both
ciliary activity in vitro and mucociliary transport in vivo (Dalhamn
and Rylander 1964; Dalhamn 1964).

Four major types of filters have been evaluated: cellulose acetate
(Cambridge filter), charcoal, glass fiber, and aqua. The histologic
changes in the airways of guinea pigs exposed to unfiltered cigarette
smoke for 4 to 8 weeks were not seen when cigarette smoke was
passed through a Cambridge filter (Rylander 1974). Likewise,
Kaminski and coworkers (1968) have shown that cellulose-acetate
filters provide protection for the mucociliary activity in the cat

296


trachea. Similar results have been obtained in other experiments
involving in vitro and in vivo systems (Dalhamn and Rylander 1968;
Donnelly 1972; Wynder et al. 1965b), and cellulose-acetate filters
have been found to reduce the inhibitory effect of cigarette smoke on
tracheal epithelial adenylate kinase activity in hamsters exposed for
1 to 5 days (Mattenheimer and Mohr 1975). Charcoal filters are also
capable of reducing the ciliotoxicity of cigarette smoke (Kaminski et
al. 1968; Kensler and Battista 1963; Battista and Kensler 1970a, b).
In one study involving cat tracheas, short-term exposure to a
standardized dose of cigarette smoke decreased particle transport
rates by 50 percent when unfiltered smoke was used, by 40 percent
when the cigarette smoke was passed through a cellulose-acetate
filter, and by 20 percent when a carbon-cellulose filter was used
(Carson et al. 1966). In another comparison of different studies, a
charcoal filter was more effective than a cellulose-acetate filter in
reducing the metachronal wave frequency and mucus transport of
the eulamellibranch gill in vitro (Wynder et al. 1965b). Glass-fiber
and aqua filters were generally less effective (Isawa et al. 1980;
Wynder et al. 1965b).

As expected, better protection might be provided by combined
filters because they remove components of the particulate and the
gaseous phase of cigarette smoke more effectively. Thus, a combina-
tion of cellulose-acetate and charcoal filter has been found to be
more effective than either filter alone (Dalhamn 1966; Wynder et al.
1965bl.

Mucociliary Function in Chronic Bronchitis

Since chronic bronchitis is defined clinically as chronic productive
cough rather than by clearly defined morphologic or functional
abnormalities (American Thoracic Society 19621, some of the previ-
ously reviewed studies of mucociliary function in cigarette smokers
may have included patients with chronic bronchitis as well. Con-
versely, most patients with chronic bronchitis are cigarette smokers
or have been cigarette smokers in the past. Although it is very
difficult to separate the direct effects of cigarette smoke on mucocili-
ary transport from those related to the pathophysiologic changes of
chronic bronchitis, the discussion herein is limited to mucociliary
function in chronic bronchitis without considering the direct effects
of cigarette smoke on the mucosa.

The histologic changes of the mucociliary apparatus in chronic
bronchitis include hypertrophy and hyperplasia of the submucosal
glands, an increase in the number and distribution of goblet cells,
and goblet cell metaplasia in smaller airways (Reid 19671. In
addition, atrophy of the columnar epithelium (Wright and Stuart
1965) and spotty squamous metaplasia (Kleinerman and Boren 19741

297

480-144 0 - 85 - 11


have been reported. A decrease in both the number of ciliated cells
and the mean ciliary length has been noted in the larger airways in
patients with chronic bronchitis (Wanner 1977), and electron micro-
scopic examinations of the airway epithelium show subtle abnormal-
ities in bronchial biopsy material (Miskovitz et al. 1974). Auerbach
and associates (19621, in a large postrmortem study of cigarette
smokers, reported epithellal lesions with loss of cilia in up to 30
percent of random sections, compared with approximately 15
percent of sections from nonsmokers. These ultrastructural changes
consisted of swelling and serration of the epithelium with transfor-
mation of the goblet cell granules. The capsule surrounding the cilia
was irregular, with areas of breakage and outward projections; some
cilia showed fibrillar degeneration or were fused to form compound
cilia.

The presence of visible respiratory secretions is a frequent
endoscopic fmding in patients with chronic bronchitis, and increased
amount of bronchial secretions can be seen on pathologic sections of
the lung (Kleinerman and Boren 1974; Hogg et al. 1968). Thus, the
morphologic changes of chronic bronchitis involve both the ciliary
apparatus and the mucus-producing structures.

cilia

In vitro examination of ciliated lower airway epithelial cells
obtained from chronic bronchitis patients by brushing has failed to
reveal an abnormality in beat frequency Wager et al. 1980).
However, in vitro study of ciliary function is of limited informative
value since the ciliated cells are suspended in an artificial medium
and are not exposed to their natural milieu. This may explain the
discrepancy between this study and one reported by Iravani and Van
As (19721, in which ciliary motion was observed in vivo with an
incident light technique. In the carefully dissected tracheobronchial
tree of rata with experimental chronic bronchitis, the ciliary system
showed discoordination and xonal akinesia. In addition, reversals of
transport direction, whirlpool formations, and inactive zones without
ciliary motion as large as 2 mm by several hundred pm were seen.

Mucus

The distribution, amount, and rheologic properties of mucus
within the airways have not been studied in chronic bronchitis, but
extensive literature exists on the biochemistry @oat and Mathews
1973) and rheology of expectorated sputum from patients with
chronic bronchitis. These results must be interpreted with caution,
partly because of contamination with saliva and the rapid physical
alteration of expectorated sputum, and partly because normal
respiratory secretions for comparison are virtually impossible to
obtain. Mucoid sputum of patients with chronic bronchitis is


biochemically similar to sputum of normal subjects induced by
hypertonic saline aerosol, with the exception of a slightly higher
fucose and neuraminic acid content in the former (Lopata et al.
1974). In purulent sputum from these patients, biochemical changes
typical of inflammatory conditions (increases in the dry weight and
deoxyribonucleic acid content and increased cross-linking by hydra
gen bonding) were observed. Reid (1966) showed that the neuraminic
acid content of sputum is increased in chronic bronchitis, suggesting
augmented secretion by the mucus-producing structures. This find-
ing is supported by histochemical studies indicating distended acini
of the submucosal glands in patients with chronic bronchitis
compared with normal subjects, along with an increase in the
volume of both the acid and the neutral mucopolysaccharide-produc-
ing acini (Reid 1968).
Impaired mucus transport in chronic bronchitis may, in part, be
related to the rheologic abnormalities of respiratory secretions.
Deviation from the ideal ratio between viscosity and elasticity may
prevent an optimal interaction between cilia and mucus, thereby
decreasing mucus transport rates (Dulfano and Adler 1975; Adler
and Dulfano 1976). Higher values of sputum viscosity and lower
values of sputum elasticity have been observed during exacerbations
of chronic bronchitis than during clinical stability (Dulfano et al.
1971). In addition, purulent sputum has a higher viscosity than
mucoid sputum (Charman and Reid 1972; Mitchell-Heggs et al.
19741, suggesting a relationship between the concentration of certain
mucus constituents and mucus rheology. Indeed, examination of
sputum obtained from patients with chronic bronchitis has shown
positive correlations between protein content (particularly IgA) and
mucus glycoprotein content on the one hand and viscosity on the
other (Harbitx et al. 1980, Lopez-Vidriero and Reid 1978). That
altered rheologic properties of airway secretions play a role in
abnormal mucociliary clearance has been suggested by an observed
relationship between in vivo mucociliary clearance, in vitro trans-
portability of expectorated sputum (using the frog palate), and the
viscoelastic properties of sputum (Puchelle et al. 1980).

Mucociliary Interaction

Mucus transport has been studied either by directly or indirectly
observing the motion of discrete particles placed on the tracheal
mucosa (Santa Crux et al. 1974; Goodman et al. 1978) or by the
deposition pattern and clearance rates of ingaled radioactive aerc+
sols (Lourenco 1970; Camner et al. 1973a, b; Luchsinger et al. 1968;
Patrick and Stirling 1977; Dulfano et al. 1971). In one study, a
marked slacking of tracheal mucus velocity -.found in 15 patients
with chronic bronchitis who were between 57 and 71 years of age
(Santa Crux et al. 1974). Clinical examination and pulmonary


FIGURE t.-Comparison of mean (S.E. in bracket) tracheal
      mucociliary transport velocity among young
      nonsmokers (n = lo), elderly nonsmokers (n = 71,
      healthy young exemokers (n=9), healthy
      young smokers (n=lS), and patients with
       chronic bronchitis (n= 14)
so- - et al. (1878).

function tests diagnosed these patients as having both chronic
bronchitis and emphysema. Mucociliary clearance of inhaled aero
sols is also altered in patients with chronic bronchitis. The clearance
of inhaled particles from the lung is influenced by the deposition
pattern, which in turn depends on particle size and flow regime in
the airways. Clearance rates, therefore, can be interpreted only if
particle deposition is carefully monitored (Pircher et al. 1965; Lopez-
Vidriero 1973). Coughing, which is difficult to control in such
patients, may also contribute to the clearance of particles CToigo et
al. 1963). For these reasons, it is not surprising that mucociliary
clearance has been reported to be increased (Muller et al. 1975;
Luchsinger et al. 1968), normal (Thomson and Short 1969), or
decreased (Lourenco 1970; Camner et al. 1973a, b; Tiogo et al. 1963;
Mossberg and Camner 1980; Agnew et al. 1982) in patients with
chronic bronchitis.

Once a subject has developed chronic bronchitis, cessation of
smoking does not reverse the effect on mucociliary function, and a
similar impairment of mucociliary transport has been reported in
smokers and ex-smokers with this disorder (Agnew et al. 1982; Santa
Cruz et al. 1974; Goodman et al. 1978). Persistence of mucociliary


dysfunction in patients with chronic bronchitis after cessation of
smoking has also been reported in a small prospective study (Camner
et al. 1973b).

Thus, both patients with chronic bronchitis and healthy smokers
exhibit an impaired mucociliary function. However, the magnitude
of the impairment is not the same as suggested by Goodman et al.
(19781, who demonstrated a greater impairment of tracheal mucocili-
ary transport rates in smokers and nonsmokers with chronic
bronchitis than in healthy smokers (Figure 2).

The consequences of airway mucociliary dysfunction have not
been satisfactorily examined, but may include increased susceptibili-
ty to respiratory infections, airflow obstruction by excessive airway
secretions, and increased risk of carcinogenesis resulting from
prolonged contact between inhaled carcinogens and the respiratory
epithelium (Matthys et al. 1983; Hilding 1957; Moersch and McDon-
ald 1953).

Summary and Conclusions

1. Increased numbers of inflammatory cells are found in the
lungs of cigarette smokers. These cells include macrophages
and, probably, neutrophils, both of which can release elastase
in the lung.

2. Human neutrophil elastase produces emphysema when in-
stilled into animal lungs.

3. Alpha,-antiprotease inhibits the action of elastase, and a very
small number of people with a homozygous deficiency of al-
antiprotease are at increased risk of developing emphysema.
The a,-antiprotease activity has been shown to be reduced in
the bronchoalveolar fluids obtained from cigarette smokers
and from rats exposed to cigarette smoke.

4. The protease-antiprotea hypothesis suggests that emphyse-
ma results when there is excess elastase activity as the result
of increased concentrations of inflammatory cells in the lung
and of decreased levels of a,-antiprotease secondary to oxida-
tion by cigarette smoke.

5. Cigarette smokers have been shown to have a more rapid fall in
antibody levels following immunization for influenza than
nonsmokers. Whole cigarette smoke has been shown to depress
the number of antibody-forming cells in the spleens of experi-
mental animals.

6. Cigarette smoke produces structural and functional abnormali-
ties in the airway mucociliary system.

7. Short-term exposure to cigarette smoke causes ciliostasis in
vitro, but has inconsistent effects on mucociliary function in
man. Long-term exposure to cigarette smoke consistently

301


causes an impairment of mucociliary clearance. This impair-
ment is associated with epithelial lesions, mucus hypersecre-
tion, and ciliary dysfunction.

8. Chronic bronchitis in smokers and ex-smokers is characterized
by an impairment of mucociliary clearance.
9. Both the particulate phase and the gas phase of cigarette
smoke are ciliotoxic.

302


References
ABBOUD, R.T., JOHNSON, A.J., RICHTER, A.M., ELWOOD, R.K. Comparison of in
vitro neutrophil elastase release in nonsmokers and smokers. American Reuiew of
Respiratory Disease 128(3): 507510, September 1983.
ABRAMS, W., COHEN, A.B.. DAMINO, V., ELIRAY, A., KIMBEL, P., MERANZE, D.,
WEINBAUM, G. A model of decreased functional alpha,-proteinase inhibitor:
Pulmonary pathology of dogs exposed to cloramine T. Journal of Clinical
Investigation 68: 1132-1139, 1981.
ABRAMS, W.R., ELIRAZ, A., KIMBEL, P., WEINBAUM, G. The effect of the
oxidizing agents chloramine-T and cigarette smoke on dog serum proteinase
inhibitor(s). Experimental Lung Research l(3): 211-223, 1980.
ACTON, J.D., MYRVIK, Q.M. Nitrogen dioxide effects on alveolar macrophages.
Archives ofEnvironmental Health 24(l): 48-52, January 1972.
ADLER K., DULFANO, M.J. The rheological factor in mucociliary clearance. Journal
of Laboratory and Clinical Medicine 88(l): 22-28, July 1976.
AGNEW, J.E., LITTLE, F., PAVIA. D., CLARKE, S.W. Mucus clearance from the
airways in chronic bronchitis: Smokers and ex-smokers. Bulletin Europeen
Physioputhologie Respimtoire l&3): 473-484, MayJune 1982.
ALBERT, R.E., ALESSANDRO, D., BERGER, J., LIPPMANN, M. Long-term smoking
in the donkey: Effect on tracheobronchial particle clearance. Archives of Enuiron-
mental Health 22: X2-79.1971.
ALBERT, R.E., BERGER, J., SANBORN, K., LIPPMANN, M. Effects of cigarette
smoke components on bronchial clearance in the donkey. Archives of Enuironmen-
  tal Health 29(2): 96-101. 1974.
ALBERT, R.E., LIPPMANN, M., PETERSON, H.T.. Jr., BERGER J.. SANBORN, K.,
BOHNING, D.E. Bronchial deposition and clearance of aerosols. Archives of
Zntemul Medicine 131(l): 115-127, January 1973.
ALBERT, R.E., PETERSON, H.T., Jr., BOHNING, D.E., LIPPMANN, M. Short-term
effects of cigarette smoking on bronchial clearance in humans. Archives of
Enuimnmental Health 30(7): 36147, July 1975.
ALBERT, R.E., SPIEGELMAN, J.R., SHATSKY, S., LIPPMAN, M. The effect of acute
exposure to cigarette smoke on bronchial clearance in the miniature donkey.
Archives ofEnuimnmentaiHeaIth l&l): 30-41, January 1969.
AMERICAN THORACIC SOCIETY. Chronic bronchitis, asthma and pulmonary
emphysema. A statement by the committee on diagnostic standards for nontuber-
culous respiratory disease. American Review of Respimtory Disease 85: 762-766,
May 1962.
ANDERSON, A.E., Jr., FORAKER, A.G. Pathogenic implications of alveolitis in
pulmonary emphysema. Archives of Pathology 72(5): 520-534, November 1961.
ANDERSON, A.E., Jr.. HERNANDEZ, J.A., HOLMES, W.L., FORAKER, A.G.
Pulmonary emphysema. Prevalence, severity and anatomical patterns in macro
sections, with respect to smoking habits. Archives of Environmental Health 12(5):
569-577, May 1966.
ARNAUD, P., CHAPUIS-CELLIER, C., VI'ITOZ, P., FUDENBERG, H.H. Genetic
polymorphism of serum ai-protease inhibitor (alpha-1-antitrypsin): Pii, a deficient
allele of the Pi system. Journal of Labomtory and Clinical Medicine 92(2): 177-184,
August 1978.
AUERBACH, O., GARFINKEL, L., HAMMOND, E.C. Relation of smoking and age to
findings in the lung parenchyma: A microscopic study. Chest 65(l): 29-35, 1974.
AUERBACH, O., HAMMOND, E.C., GARFINKEL, L., BENANTE, C. Relation of
smoking and age to emphysema: Whole-lung section study. New England Journal
of Medicine 286(16): 853-857, April 20.1972.
AUERBACH, O., HAMMOND, E.C., KIRMAN, D., GARFINKEL, L. Emphysema
produced in dogs by cigarette smoking. Journal of the American Medical
Association 199(4): 89-94, January 23,1967a.


AUERBACH, 0.. HAMMOND, EC., KIRMAN, D., GARFINKEL, L., STOUT, A.P.
Histologic changes in bronchial tubes of cigarette-smoking dogs. Cancer 20(12):
20552066, December 1967b.

AUERBACH, 0.. STOUT, A.P., HAMMOND EC., GARFINKEL, L. Changes in
bronchial epithelium in relation to sex, age, residence, smoking and pneumonia.
New England Journal of Medicine 267(3): 111, July 19,1962.
BABIOR, B.M. Oxygendependent microbial killing by phagocytes. New England-
Journal of Medicine 98(12): 65%668, March 23, and 98t12): 721-723, March 30,
  1978.

BAIR, W.J., DILLEY, J.V. Pulmonary clearance of 5gFe&h and 51Cr& in rats and dog-s
exposed tn cigarette smoke. In: Davies, C.H. (Editor). Inhaled Particles and
Vapours, ZZ. New York, Pergamon Press, 1967, pp. 251-268.
BALLDIN, G., LAURELL, C.-B., OHLSSON, K. Increased catabolism of al-macroglob-
ulins after intravenous infusion of trypsinal-antitrypsin complexes in dogs. Hoppe-
Seylerk .&itichrift fir Physiologische Chemie 359(6): 699-708, June 1978.
BALLENGER, J.J. Experimental effect of cigarette smoke on human respiratory cilia.
New England Journal of Medicine 263(17): 832-835, October 27,196O.
BANDA, M.J., WERB, 2. Mouse macrophage elastase. Purification and characteriza-
tion as a metalloproteinase. BiochemicaE Journal 193(2): 589-605, February 1981.
BARRETT, A.J. Proteinases in Mammalian CeEls and T&sues: A Reoiew. Volume 2.
New York, North-Holland Publishing Company, 1977,735 pp.
BARRETT, A.J., STARKEY, P.M. The interaction of azmacroglobulin with protein-
ases. Characteristics and specificity of the reaction, and a hypothesis concerning its
molecular mechanism. Biochemical Journal 133(4): 709-724, August 1973.
BASRUR, P.K., BASRUR, V.R. Respiratory surface epithelium: SEM technique for
bioassay on inhalants. In: Johari O., Becker, R.P. (Editors). Scanning Electron
Micmscopy/l976. Part V. Proceedings of the Workshop on Advances in Biomedicat
Applications of the SEM. Chicago, IIT Research Institute, April 1976, pp. 623-629.
BASRUR, P.K., HARADA, T. Alterations in the nasaI mucosa of Syrian golden
hamsters exposed to cigarette smoke. Progress in Experimental Tumor Reseamh 24:
283-301,1979.

BAll'ISTA, S.P. Inhalation studies of toxicity of tobacco smoke. In: Gori, G.B., Bock
F.G. (Editors). Banbury Report 3-A Safe Cigarette? Cold Spring Harbor, New
York, Cold Spring Harbor Laboratory, March 12,1980, pp. 51-62.
BA'ITISTA, S.P., DI NUNZIO, J., KENSLER, C.J. Versatile apparatus to study effects
of gases, aerosols and drugs on ciliary activity in non-immersed mammalian
trachea. Fedemtion Proceedings 21: 701,1962.
BA'ITISTA, S.P., KENSLER, C.J., Mucus production and ciliary transport activity.
Archives of Environmental Health 20(3): 326-338, March 1970a.
BA'ITISTA, S.P., KENSLER, C.J. Use of the nonimmersed in vitro chicken tracheal
preparation for the study of ciliary transport activity. Cigarette smoke and related
components. Archives of Environmental Health 20(3): 318-325, March 1970b.
BEA'ITY, K., BIRTH, J., TRAVIS, J. Kinetics of association of serine proteinases with
native and oxidized al-proteinaae inhibitor and al-antichymotrypsin. Journal 01
Biologic Chemistry 25X9): 39313934, May 10,198O.
BERGMANN, M., FRUTON, J.S. The specificity of proteinases. Advances in Enzymol-
ogy 1: 63-98,194l.

BERNFELD, P., NIXON, C.W., HOMBURGER, F. Studies on the effect of irritant
vapors on ciliary mucus transport. Toxicology and Applied Pharmacology 6(l): 103-
111, January 1964.

BILLINGSLEY, G.D., COX, D.W. Functional assessment of genetic variant-s of al-
antitrypsin. Human Genetics 61(l): 118-122, August 1982.

304


BLACKWOOD, CF., HOSANNAH, Y., PERMAN, E., KELLER, S.. MANDL, I.
Experimental emphysema in rata: Elastolytic titer of inducting enzyme as
determinant of the response. Proceedings of the S&et! for Experimental Biology
and Medicrne 144: 450-454,1973.

BLENKINSOPP, W.K.. HAFFENDEN, G.P. Alpha,-antitrypsin bodies in the liver.
Journal of Clinical Pathaloe 30(Z): 132-137, February 1977.
BLUE, M.L., JANOFF, A. Possible mechanisms of emphysema in cigarette smokers:
Release of elastase from human polymorphonuclear leukocytes by cigarette smoke
condensate in vitro. American Review of Respiratop Disease 117r2): 317-325,
February 1978.

BOAT, T.F., MATHEWS, L.W. Chemical composition of human tracheobronchial
secretions. In: Dulfano, M.J. iEditor). Sputum. Springfield, Illinois, Charles C
Thomas, 1973, pp. 244-276.

BOHNING, D.E., ALBERT, R.E., LIPPMANN, M., FOSTER, W.M. Tracheobronchial
particle deposition and clearance. Archives of Environmental Health 3CN9): 457-
462, September 1975.

BOUDIER, C., HOLLE, C., BIETH, J.G. Stimulation of the elastolytic activity of
leukocyte elastase by leukocyte cathepsin G. Journal of Biological Chemistry
256(201: 1025610258, October 25,1981.

BRAIN, J.D. Free cells in the lungs. Archives of Internal Medicine 126(3): 477-487,
September 1970.

BRIDGES, R.B., KRAAL, J.H., HUANG, L.J.T., CHANCELLOR, M.B. Effects of
tobacco smoke on chemotaxis and glucose metabolism of polymorphonuclear
leukocytes. Infection and Immunity 15(l): 115-123, April 1977.
BRODY, A.R., CRAIGHEAD, J.E. Cytoplasmic inclusions in pulmonary macrophages
of cigarette smokers. Labomtory Investigation 32(2): 125-132, February 1975.
CALDWELL, E.J. Physiologic and anatomic effects of papain on the rabbit lung.
Journal ofApplied Physiology 31(31: 458-465, September 1971.
CAMNER, P., MOSSBERG, B., PHILIPSON, K. Tracheobronchial clearance and
chronic obstructive lung disease. Scandinavian Journal of Respimtory Diseases
54f5): 272-281,1973a.

CAMNER, P., PHILIPSON, K. Humanstudier av tracheobronchicell clearance med
monodispersa Teflonpat-tikar markta med 18F och 99mTc. [Tracheobronchial
clearance in man studied with monodispersed Teflon particles tagged with isF and
99mTc.l Nordisk Hygienisk TiaLskrift 52: l-9.1971.
CAMNER, P., PHILIPSON, K. Tracheobronchial clearance in smoking-discordant
twins. Archives of Envimnmental Health 25: 60, July 1972.
CAMNER, P., PHILIPSON, K. Mucociliary clearance. Scandinavian Journal of
Respimtory Diseases 9O@upplementl: 4548, March 9-10,1974.
CAMNER, P., PHILIPSON, K., ARVIDSSON, T. Cigarette smoking in man. Short-
term effect on mucociliary transport. Archives of Environmental Health 23: 421-
426, December 1971.

CAMNER, P., PHILIPSON, K.. ARVIDSSON, T. Withdrawal of cigarette smoking. A
study on tracheobronchial clearance. Archives of Environmental Health 26(2): 9&
92,1973b.

(TAMPBELL, E.J., GRECO, J.M. Human leukocyte elastase, cathepsin G, and
lactoferrin: A family of neutrophil granule glycoproteins that bind to an alveolar
macrophage receptor. Pmceedings of the ,Vational Academy of Sctences 79(22):
69416945, November 1982.

CAMPBELL, E.J., SENIOR, R.M , MCDONALD, J.A., COX, D.L. Proteolpsis by
neutrophils. Relative importance of cell-substrate contact and oxidative inactiva-
tion of proteinase inhibitors in vitro. Journal of Clinical Znc-estigotion 70(4): 845
852, October 1982.

305


CAMPBELL, E.J.. WALD, MS. Fate of human neutrophil elastase following receptor-
mediated endocytosis by human alveolar macrophages. Implications for connective
tissue injury. Journal of Laboratory and Clinical Medicine lOl(4): 527-536, April
  1983.

CAMPBELL, E.J., WHITE, R.R., SENIOR, R.M., RODRIGUEZ, R.J., KUHN, C.
Receptor-mediated binding and internalization of leukocyte elastase by alveolar
macrophages in vitro. Journal of Clinical Znvestigation 64(3): 824-833, September
  1979.

CANTRELL, E.T., WARR, G.A., BUSBEE, D.L., MARTIN, R.R. Induction of aryl
hydrocarbon hydroxylases in human pulmonary alveolar macrophages by ciga-
rette smoking. Journal of Clinical Znvestigation 52(8): 1881-1884. August 1973.
CARP, H., JANOFF, A. Possible mechanisms of emphysema in smokers. In vitro
suppression of serum elastaseinhibitory capacity by fresh cigarette smoke and its
prevention by antioxidants. American Review of Respiratory Disease 11&3): 617-
621, September 1978.

CARP, H., JANOFF, A. In vitro suppression of serum elaataseinhibitory capacity by
reactive oxygen species generated by phagocytosing polymorphonuclear leuko
cytes. Journal of Clinical Investigation 63(4): 79%797, April 1979.
CARP, H., JANOFF, A., ABRAMS, W., WEINBAUM, G., DREW, T.R., WEISSBACH,
H., BROT, N. Human methionine sulfoxide-peptide reductase, an enzyme capable
of reactivating oxidized alpha-l-proteinase inhibitor in vitro. American Review of
Respiratory Disease 127(3): 301305, March 1983.
CARP, H., MILLER, F., HOIDAL, R., JANOFF, A. Potential mechanism of emphyse-
ma: Ai-proteinase inhibitor recovered from lungs of cigarette smokers contains
oxidized methionine and has decreased elastase inhibitory capacity. Proceedings of
the National Academy of Sciences 7%6): 2041-2045, March 1982.
CARRELL, R.W., BOSWELL, D.R., BRENNAN, SO., OWEN, M.C. Active site of cxl-
antitrypsin: Homologous site in antithrombin-III. Biochemical and Biophysical
Research Communications 9X2): 399-402, March 28,198O.
CARRELL, R.W., JEPPSSON, J.-O., LAURELL, C.-B., BRENNAN, S.O., OWEN, M.C.,
VAUGHAN, L., BOSWELL, D.R. Structure and variation of human al-antitrypsin.
Nature 298(5872): 329-334, July 22-28,1982.
CARRELL, R.W., JEPPSSGN, J.-O., VAUGHAN, L., BRENNAN, S.O., OWEN, M.C.,
BOSWELL, D.R. Human al-antitrypsin: Carbohydrate attachment and sequence
homology. Federation of European Biochemical Societies Letters 135(2): 301-303,
  December 1981.

CARSON, S., GOLDHAMER, R., CARPENTER, R. Responses of ciliated epithelium to
irritants. American Review of Respiratory Disease 93: 86,1966.
CHAN, SK., REES, DC., LI, S.C., LI, Y.T. Linear structure of oligosaccharide chains
in al-protease inhibitor isolated from human plasma. Journal of Biological
Chemistry 251(21: 471-476, January 25,1976.
CHARMAN, J., REID, L. Sputum viscosity in chronic bronchitis, bronchiectasis,
asthma, and cystic fibrosis. Biorheology 9(3): l&199, September 1972.
CLEMMENSEN, I., CHRISTENSEN, F. Inhibition of urokinase by complex formation
with human ai-antitrypsin. Biochcmica et Biophysics Acta 429(2): 591-599, April 8,
  1976.

COALSON, J.J., HINSHAW, L.B., GUENTER, CA. The pulmonary ultrastructure in
septic shock. Experimental Molecular Pathology 12(l): 84-103, February 1970.
COCKCROFT, D.W., HORNE, S.L. Localization of emphysema within the lung. Chest
82(4): 483-487, October 1982.

COFFIN, D.L., GARDNER, D.E., HOLZMAN, R.S., WOLOCK, F.J. Influence of ozone
on pulmonary cells. Archives of Environmental Health 16f5): 633-636, May 1968.
COHEN, A.B. Mechanism of action of al-antitrypsin. Journal of Biological Chemistry
248(20): 7055-7059,1973.

306


COHEN, A.B. The effects in vivo and in vitro of oxidative damage to purified oi-
antitrypsin and to the enzyme-inhibiting activity of plasma. American Review of
Respimtory Disease 119(6): 953-960, June 1979.
COHEN, A.B.. CLINE, M.J. The human alveolar macrophage: Isolation, cultivation in
vitro, and studies of morphologic and functional characteristics. Journal of
Clinical Investigation W7): 139&1398, July 1971.
COHEN, D., ARAI, SF., BRAIN, J.D. Smoking impairs long-term dust clearance from
the lung. Science 204(4392): 514-517. May 4,1979.
CORRE, F., LELLOUCH. J., SCHWARZ, D. Smoking and leukocyte counts. Lancer
2(7725): 632-634, September 18, 1971.

COSIO, M., GHEZZO, H., HOGG, J.C., CORBIN. R., LOVELAND, M., DOSMAN, J.,
MACKLEM, P.T. The relations between structural changes in small airways and
pulmonary-function tests. New England Journal of Medxine 298(23t: 1277-1281,
June 8,1978.

COX, D.W. New variants of al-antitrypsin: Comparison of Pi typing techniques.
American Journal ofHuman Genetics 33!3): 354-365, May 1981.
COX, D.W., JOHNSEN, A.M., FAGERHOL. M.K. Report of nomenclature meeting for
ai-antitrypsin. Human Genetics 53(3): 429-433, 1980.
COX, D.W. A new deficiency allele of alpha-,-antitrypsin: PiM,.lto, In: Peters, H.
Editor). Protides of the Biological Fluids. 23rd Colloquium, 197.5. Proteins and
Related Subjects. Volume 23, Oxford, Pergamon Press, 1976. pp. 375378.
COX, D.W., CELHOFFER, L. Inherited variants of ai-antitrypsin: A new allele PiN.
Canadian Journal of Genetic Cytology 16(21: 297-303, June 1974.
CRAWFORD, G.P.M., OGSTON, D. The influence al-antitrypsin in plasmin, uroki-
nase and Hageman factor cofactor. Biochemica et Biophysics Acta 354(l): 107-113.
June 20,1974.

DAHLGREN, S.E., DALEN, H., DALHAMN, T. Ultrastructural observations on
chemically induced inflammation in guinea pig trachea. Virchows Archiu.
Abteilung B. Zellpathologie ll(21: 211-223, 1972.
DALHAMN, T. Mucous flow and ciliary activity in the trachea of healthy rats and
rats exposed to respiratory irritant gases. Acta Ph.vsioZogica Scandinavica
36(Supplement 123): l-161,1956.

DALHAMN, T. The effect of cigarette smoke on ciliary activity in the upper
respiratory tract. Archives of Otolaryngology 7Ot2): 166168, August 1959.
DALHAMN, T. Studies on tracheal ciliary activity. American Review of Respiratoory
Disease 89(6): 870-877, February 1964.

DALHAMN, T. Effect of cigarette smoke on ciliary activity. American Review of
Respimtory Disease 93(3, Supplement): 108114,1966.
DALHAMN, T. Ciliostatic effect of orthocresol and metacresol. Archives of Otolaryn-
gology 87(2): 162, February 1968.

DALHAMN, T. The anticiliostatic effect of cigarettes treated with oxolamine citrate.
American Review of Respimtory Disease 99f3): 447-448. March 1969.
DALHAMN, T. In vivo and in vitro ciliotoxic effects of tobacco smoke. Archives of
Environmental Health 21(5): 633-634, November 1970.
DALHAMN, T., EDFORS. M.L., RYLANDER, R. Retention of cigarette smoke
components in human lungs. Archioes of Environmental Health 17(5): 746-748,
November 1968.

DALHAMN, T., LAGERSTEDT, B. Ciliostatic effect of phenol and resorcinol. Archives
of Otolaryngology 84(3): 325, September 1966.
DALHAMN, T., PIRA, U. Isoelectric analysis of respiratory mucus from normal rats
and rats exposed to tobacco smoke. American Review of Respiratory Disease 11%51:
779-783, May 1979.

DALHAMN, T., RYLANDER, R. Ciliastatic action of smoke from filter-tipped and
non-tipped cigarettes. Nature201(4917): 401402, January 25.1964.

307


DALHAMN. T., RYLANDER. R. Tar content and ciliotoxicity of cigarette smoke. Acto
Phormocologico et Toxicologica 25(3): 369-372,1967.
DALHAMN, T., RYLANDER, R. Ciliotoxicity of cigarette smoke and its volatile
components. American Reulew of Respiratop Disease 98(3j: 509-511, September
  1968.

DALHAMN, T., RYLANDER, R. Ciliotoxicity of cigar and cigarette smoke. Arch&es
ofEnvironmental Health 20(2): 252-253. February 1970.
DALHAMN, T.. RYLANDER, R. Reduction of cigarette smoke ciliotoxicity by certain
tobacco additives. American Review of Respimtory Disease 103(6): 655-657, June
  1971.

DALHAMN, T.. RYLANDER, R., SPEARS, A.W. Differences in ciliotoxicity of
cigarette smoke. American Review of Respiratory Diseases 96(5): 1076-1079,
November 1967.

DANIELE, R.P., DAUBER, J.H.. ALTQSE, M.D., ROWLANDS, D.T., GORENBERG,
D.J. Lymphocyte studies in asymptomatic cigarette smokers. A comparison
between lung and peripheral blood. American Review of Respiratory Disease 11616):
997-1005, December 1977.

DAS, P.K., RATHOR, R.S., SINHA, P.S., SANYAL, A.K. Effect on ciliary movements
of some agents which come in contact with the respiratory tract. Indian Journal of
Physiology and Pharmacology 214: 297-303,1970.
DAVIES, P.. SORNBERGER, G.C., HUBER, G.L. The stereology of pulmonary
alveolar macrophages after prolonged experimental exposure to tobacco smoke.
Laturotoq Investigation 37(3): 297-306, September 1977.
DAVIS, G.S., BRODY, A.R., LANDIS, J.N., GRAHAM, W.G.B., CRAIGHEAD, J.E.,
GREEN, G.M. Quantitation of inflammatory activity in interstitial pneumonitis by
bronchofiberscopic pulmonary lavage. Chest 69f2, Supplement): 265-266, February
  1976.

DE CREMOUX, H., HORNEBECK, W., JAURAND, M., BIGNON, J., ROBERT, L.
Partial characterization of an elastaselike enzyme secreted by human and monkey
alveolar macrophages. Journal ofPothology 12x4): 171-177, August 1978.
DEMAREST, G.B., HUDSON, L.D., ALTMAN, L.C. Impaired alveolar macrophage
chemotaxis in patients with acute smoke inhalation. American Review of
Respiratory Disease 11%21: 279-266. February 1979.
DOLLFUSS, R.E., MILICEMILI, J., BATES, D.V. Regional ventilation of the lung,
studied with boluses of ISxenon. Respimtory Physiology 2(2): 234-240, February
  1967.

DONNELLY, G.M. Investigations of the effect of tobacco smoke constituents on
rodent tracheal rings grown in tissue culture. In: Griffith R.B. (Director).
Proceedings of the Tobacco and Health Workshop, Conference Report 1, February
5-6, 1969. Lexington, University of Kentucky, Tobacco and Health Research
Institute, pp. 7-11.

DONNELLY, G.M. A procedure for the routine determination of the ciliostatic
activity of smoke from experimental cigarettes. Proceedings of the Tobacco and
Health Workshop, January 11-13, 1972. Lexington, University of Kentucky,
Tobacco and Health Research Institute, pp. 269-275.
DONNELLY, G.M., McKEAN, H.E., HEIRD, C.S., GREEN, J. Bioassay of a cigarette
smoke fraction. I. Examination of dose-response relations and dilution bioassay
assumptions in a ciliostasis system. Journal of Toxicology and Environmental
Health 7(3/4): 405-417,1981.

DOWELL, A.R., LOHRBAUER, L.K., HURST, D., LEE, S.D. Rabbit alveolar macro-
phage damage caused by in vivo ozone inhalation. Archives of Environmental
Health 21(l): 121-127, July 1970.

DULFANO, M.J., ADLER, K.B. Physical properties of sputum. VII. Rheologic
properties and mucociliary transport. American Reuiew of Respiratory Disease
112(3): 341-348, September 1975.

308


DULFANO, M.J., ADLER, K., PHILIPPOFF, W. Sputum viscoelasticity in chronic
bronchitis. American Review of Respiratory Disease 104(l): 88-98. July 1971.
ELIRAZ, A., KIMBEL, P., WEINBAUM, G. Canine alveolar macrophage and
neutrophil exposure to cigarette smoke: Regulation of elastase secretion. Chest 72:
239,1977. (Abstract).

ENZELL, C.R., BERGSTEDT, E., DALHAMN, T., JOHNSON, W.H. Tobacco chemis-
try. 4. Chemical and ciliotoxic studies of smoke from freeze-dried tobacco. Bertrage
tur TabakfomchungG(1): 41-50,1971.

ERIKSSON, S. Pulmonary emphysema and alpha,-antitrypsin deficiency. Acta
Medicn Scandinauica 175: 197-205,1964.

ERIKSSON, S. Studies on ai-antitrypsin deficiency. Acto Medtca Scandinaozca
117(Supplement 432): 585, 1965.

ESBER, H.J., MENNINGER, F.F., BOGDEN. A.E., MASON, M.M. Immunological
deficiency associated with cigarette smoke inhalation by mice. Primary and
secondary hemagglutinin response. ArchiLles of EnI)ironmental Health 27(l): 99-
104, July 1973.

FAGERHOL, M.K. Quantitative studies in the inherited variants of serum CL]-
antitrypsin. Scandinavian Journal of Clinical and Laboratory InLlestigatron 23(l):
97-103, February 1969.

FAGERHOL, M.K., BRAEND, M. Serum prealbumin: Polymorphism in man. Science
14913687): 98&987, August 27,1965.

FAGERHOL, M.K., COX, D.W. The Pi polymorphism: Genetic, biochemical, and
clinical aspects of human ai-antitrypsin. In: Harris, H., Hirschhorn, K. Editors).
Advances in Human Genetics. Volume 11. New York, Plenum Press, 1981, pp. l-62.
FAGERHOL, M.K., GEDDEDAHL, T., Jr. Genetics of the Pi serum types. Family
studies of the inherited variants of serum alphal-antitrypsin. Human Heredity
19f4): 354-359,1969.

FAGERHOL, M.K., HAUGE, H.E. Serum Pi types in patients with pulmonary
diseases. Acta Allergologica 24(2): 107-114, 1969.
FAGERHOL, M.K. LAURELL, C.B. The Pi system-inherited variants of serum oi-
antitrypsin. In: Steinberg, A., Beam, A. (Editors). Progress in Medical Genetics.
Volume 7. New York, Grune and Stratton, 1970, pp. 96-111.
FALK, H.L., TREMER, H.M., KOTIN, P. Effect of cigarette smoke and its constituents
on ciliated mucus-secreting epithelium. Journal of the National Cancer Institute
23(5): 999-1012, November 1959.

FELDMANN, G., MARTIN, J.-P, SESBOUE, R., ROPARTZ, C., PERELMAN. R.,
NATHANSON, M., SERINGE, P., BENHAMOU, J.-P. The ultrastructure of
hepatocytes in alpha-1-antitrypsin deficiency with the genotype Pi. Gut 16(10):
796-799, October 1975.

FERIN, J.. URBANKOVA, G., VLCKOVA, A., REICHRTOVA, E. Effect of cold and
cigarette smoke on the elimination of dust from the lungs. PracoLmi Lekarstui 18:
26%264,1966.

FIERER, J.A., CERRETA, J.M., TURINO, G.M., MANDL, I. Ultrastructural studies of
lung elastin in elastaseinduced emphysema. American Journal of Pathology 82(2):
42a, February 1976 (Abstract).

FINKLEA, J.F., HASSELBLAD, V., RIGGAN, W.B., NELSON, W.C., HAMMER, D.I..
NEWILL, V.A. Cigarette smoking and hemagglutination inhibition response to
influenza after natural disease and immunization. American ReLGeu: of Respiratory
Disease 104f3): 368376, September 1971.

FINKLEA, J.F., SANDIFER. S.H., PECK, F.B., MANOS, J.P. A clinical and serologic
comparison of standard and purified bivalent inactivated influenza vaccines.
Journal of Infectious Diseases 120(6): 708-719, December 1969.
FLINT, G.L., MAXWELL, K.W., RENZE'ITI, A.D., Jr. Influence of cigarette smoke on
guinea pigs. Effect on pulmonary cells and serum antitrypsin levels. A&cc-es of
Environmental Health 22~3): 366-369, March 1971.

309


FOX, B., BULL, T.B., MAKEY, A.R., RAWBONE, R. The significance of ultrastructur-
al abnormalities of human cilia. Chest 80(61: 796-799, December 1981.
FRANCES, R., ALESSANDRO, D., LIPPMANN, M., PROCTOR, D.E., ALBERT, R.E.
Effect of cigarette smoke on particle transport on nasociliary mucosa of donkeys.
Archtves ofEnvironmental Health 21(l): 25-31, July 1970.
FRASCA, J.M., AUERBACH, O., PARKS, V.R., JAMIESON, J.D. Electron microscop-
ic observations on pulmonary fibrosis and emphysema in smoking dogs. Experi-
mental and Molecular Pathology 15(l): 108-125, August 1971.
FRASCA, J.M., AUERBACH, O., PARKS, V.R., JAMIESON, J.D. Alveolar cell
hyperplasia in the lungs of smoking dogs. Experimental and Molecular Pathology
21(3): 306-312, December 1974.

FRIEDMAN, M., STO'IT, F.D., POOLE, D.O., DOUGHERTY, R., CHAPMAN, G.A.,
WATSON, H., SACKNER, M.A. A new roentgenographic method for estimating
mucous velocity in airways. American Review of Respimtory Disease 115(l): 67-72,
January 1977.

FRITZ, H., HEINBURGER, N., MEIER, M., ARNOLD, M., ZANEWALD, L.J.D.,
SCHUMACHER, G.F.B. Human acrosin, kinetics of inhibition by inhibitors from
human sera. Hoppe-Seylers Zeitschrift ZGir Physiologische Chemie 353(12): 1953-
1956, December 1972a.

FRITZ, H., WEINDERER, G., KUMMER, K., HEINBURGER, N., WERLE, E.
Antitrypsin und Cl-Inaktivator. Progressiv-inhibitoren fur Serumkallikreine von
Mensch und Schwein. Hoppe-Seylers Zeitxhrift ZGir Physiologische Chemie 353(6):
906-910, June 1972b.

GADEK, J.E., FELLS, G.A.. CRYSTAL, R.G. Cigarette smoking induces functional
antiprotease deficiency in the lower respiratory tract of humans. Science 206(4424):
1315-1316, December 1979c.

GADEK, J.E., FELLS, G.A., HUNNINGHAKE, G.W., CRYSTAL. R.G. Interaction of
the alveolar macrophage (AM) and the circulating neutrophil: AM-induced
neutrophil activation. American Review of Respimtory Disease 119(4): 66A, April
1979b (Abstract).

GADEK. J.E., FELLS, G.A., HUNNINGHAKE. G.W., ZIMMERMAN, R.L., CRYS
TAL, R.G. Alveolar macrophage-neutrophil interaction: A role for inflammatory
cell cooperation in the disruption of lung connective tissue. Clinical Research 27(2):
397a. April 1979a (Abstract).

GADEK, J.E., FELLS, G.A., ZIMMERMAN, R.L., RENNARD, S.I., CRYSTAL, R.G.
Antielastases of the human alveolar structures: Implications for the protease-
antiprotease theory of emphysema. Journal of Clinical Investigation 68t4): 889-
898, October 1981a.

GADEK, J.E., HUNNINGHAKE, G.W., FELLS, G.A., ZIMMERMAN, R.L., CRYS
TAL, R.G. Production of connective tissue-specific proteases by human alveolar
macrophages in constitutive (nonregulatablel. American Review of Respiratory
Disease 123(41: 55a, April 1981b.

GADEK, J.E., KLEIN, H.G., HOLLAND, P.V., CRYSTAL, R.G. Replacement therapy
of alpha-l-antitrypsin deficiency. Reversal of protease-antiprotease imbalance
within the alveolar structures of PiZ subjects. Journal of Clinical Investigation
68(5): 1158, November 1981c.

GALDSTON, M.. JANOFF, A., DAVIS, A.L. Familial variation of leukocyte lysosomal
protease and serum alpha]-antitrypsin as determinants in chronic obstructive
pulmonary disease. American Review of Respiratory Disease 107(5): 718-727, May
  1973.

GALDSTON, M., LEVYTSKA, V., SCHWARTZ, M.S., MAGNUSSON, B. Ceroloplas-
min. Increased serum concentration and impaired antioxidant activity in cigarette
smokers, and ability to prevent suppression of elastase inhibitory capacity or
alpha-1-proteinase inhibitor. American Review of Respiratory Disease 12W2): 258
263, 1984.

310


GALDSTON, M., MELNICK, E.L., GGLDRING, R.M., LEVYTSKA, V., CURASI, C.A.,
DAVIS, A.L. Interactions of neutrophil elastase, serum trypsin inhibitory activity,
and smoking history as risk factors for chronic obstructive pulmonary disease in
patients with MM, MZ, and ZZ phenotypes for alphai-antitrypsin. American
Review of Respimtory Disease 116(5): 837846, November 1977.
GARDNER, D.E., HOLZMAN, R.S., COFFIN, D.L. Effects of nitrogen dioxide on
pulmonary cell population. Journal of Bacteriology 9&3): 1041-1043. June 1969.
GEOKAS, M.C., BRODRICK, J.W., JOHNSON, J.H., LARGMAN, C. Pancreatic
elastase in human serum. Determination by radioimmunoassay. Journal of
Biological Chemistry 2520): 61-67, January 10.1977.
GERTLER, A. The nonspecific electrostatic nature of the adsorption of elastase and
other basic proteins in elastin. European Journal of Biochemistry 20(4): 541-546,
June 1971.

GILES, R.E., FINKEL, M.P., LEEDS, R. The production of an emphysema-like
condition in rata by the administration of papain aersol. Proceedings of the Society
for Experimental Biology and Medicine 134(l): 157-162. May 1970.
GOLDE, D.W. Kinetics and function of the human alveolar macrophage. Journal of
the Reticuloendothelial Society 22(3): 223-230, September 1977.
GOLDRING, I.P., GREENBURG, L.. RATNER, I.M. On the production of emphysema
in Syrian hamster by aerosol inhalation of papain. Archives of Environmental
Health 16(l): 59-66, January 1968.

GOLDSTEIN, R.A., STARCHER, B.C. Urinary excretion of elastin peptides containing
desmosine after intratracheal injection of elastase in hamsters. Journal of Clinical
Investigation 61(5): 1286-1290, May 1977.
GOLDSTEIN, E., TYLER, W.S., HOEPRICH, PD., EAGLE, C. Ozone and the
antibacterial defence mechanisms of the murine lung. Archives of Internal
Medicine 127(6): 1099-1102, June 1971.

GOODMAN, R.M., YERGIN, B.M.. LANDA, J.F., GOLINVAUX, M.H., SACKNER,
M.A. Relationship of smoking history and pulmonary function tests to tracheal
mucous velocity in nonsmokers, young smokers, ex-smokers and patients with
chronic bronchitis. American Review of Respimtory Disease 117(2): 205-214,
February 1978.

GREEN, G.M. Cigarette smoke: Protection of alveolar macrophages by glutathione
and cysteine. Science 162@855): 810-811, November 15,1968a.
GREEN, G.M. Protection of alveolar macrophages from the cytotoxic activity of
cigarette smoke by glutathione and cysteine. Journal of Clinical Investigation
47(6): 42a-43a, June 1968b.

GREEN, G.M. Pulmonary clearance of infectious agents. Annual Review of Medicine
19: 315-336,1968c.

GREEN, G.M. The response of the alveolar macrophage system to host and
environmental changes. Archives of Environmental Health l&4): 548550, April
  1969.

GREEN, G.M. The J. Burns Amberson lecture: In defense of the lung. American
Review of Respirator-y Disease 102(5): 691-703, November 1970.
GREEN, G.M., CAROLIN, D. Inhibition of the bactericidal activity of alveolar
macrophages by cigarette smoke. Journal of Clinical Investigation 45(6): 1017,
  June 1966.

GREEN, G.M., CAROLIN, D. The depressant effect of cigarette smoke on the in vitro
antibacterial activity of alveolar macrophages. Neal England Journal of Medicine
276(8): 422427, February 23,1967.

GREEN, G.M.. JAKAB, G.J., LOW, R.B., DAVIS, G.S. Defense mechanisms of the
respiratory membrane. American Review of Respiratory Disease 115(3): 479514,
  March 1977.

311


GREEN, M.R., LIN, J.S., BERMAN, L.B., OSMAN, M.M.. CERRETA. J.M., MANDL,
I., TURINO, G.M. Elastolytic activity of alveolar macrophages in normal dogs and
human subjects. Journal of Laboratory and Clinical Medicine 94(4): 549-562,
October 1979.

GREENBERG, R.A., HALEY, N.J., EIZEL, R.A., LODA, F.A. Measuring the exposure-
of infants to tobacco smoke nicotine and cotinine in urine and saliva. New England
Journal of Medicine 31CM17): 10751078, April 26.1984.
GREENBERG, SD., JENKINS, D.E., STEVENS, P.M., SCHWEPPE, H.I. The lungs in
homozygous alphai-antitrypsin deficiency. American Journal of Clinical Pathology
60(5): 581592, November 1973.

GROSS, P., PFITZER, E.A., TOLKER, E., BABYAK, M.A., KASCHAK, M. Experimen-
tal emphysema: Its production with papain in normal and silicotic rats. Archiues of
Environmental Health 11(l): 50-58, July 1965.
GUENTER, C.A., COALSON. J.J., JACQUES, J. Emphysema associated with intra-
vascular leukocyte sequestration: Comparison with papain-induced emphysema.
American Review of Respimtory Disease 123(l): 79-84, January 1981.
GUILLERM, R., BADRE, R., HEE, J., MASUREL, G. Composition de la fumee de
tabac. Analyse des facteurs de nuisance. [Composition of tobacco smoke: Analysis
of noxious factors.] Revue de Tuberculose et de Pneumologie 36(Z): 187-208, March
  1972.

GUILLERM R., BADRE, R., SAINDELLE, A., HEE, J., FLAVIAN, N. Recent
experience with the toxicology of tobacco smoke. Gazette a& Haspitaux 140(30):
861-862,1968.

GUILLERM, R., BADRE, R., VIGNON, B. Effects inhibiteurs de la fumee de tabac sur
l'activite ciliaire de l'epithelium respiratoire et nature des composants responsa-
bles. Bulletin de I'Academie Nationale de Meakcine 145(20): 416424, June 13,
  1961.

GUSTAVSSON, E., OHLSSON, K., OHLSSON, A. Interaction between human
pancreatic elastase and plasma protease inhibitors. Hoppe-SeyZers Zeitschrift Fur
Physiologische Chemie 361(2): 169-176, February 1980.
HALL, D.A., CZERKAWSKI, J.W. The reaction between elastase and elastic tissue.
Biochemistry Journal 80(l): 121-128,1961.
HARBITZ, O., JENSSEN, A.O., SMIDSROD, 0. Q uantitation of proteins in sputum
from patients with chronic obstructive lung disease. I. Determination of immune
globulin A. European Journal of Respiratory Diseases 61(2): 84-94, April 1980.
HARRIS, C.C., HSU, I.C., STONER, G.D., TRUMP, B.F., SELKIRK, J.K. Human
pulmonary alveolar macrophages metabolize benzo[a]pyrene to proximate and
ultimate mutagens. Nature 272t5654): 633-634, April 13,1978.
HARRIS, J.O., OLSEN, G.N., CASTLE, J.R., MALONEY, A.S. Comparison of
proteolytic enzyme activity in pulmonary alveolar macrophages and blood
leukocytes in smokers and nonsmokers. American Review of Respiratory Disease
11 l(6): 579586, May 1975.

HARRIS, J.O., SWENSON, E.W., JOHNSON, J.E., III. Human alveolar macrophages:
Comparison of phagocytic ability, glucose utilization, and ultrastructure in
smokers and nonsmokers. Journal of Clinical Investigation 49(11): 2086-2996,
November 1970.

HAYES, J.A., KORTHY, A., SNIDER, G.L. The pathology of elastase-induced
panacinar emphysema in hamsters. Journal of Pathology Bacteriology 117(l): l-14,
September 1975.

HECK, L.W., KAPLAN, A.P. Substrates of Hageman factor. I. Isolation and
characterization of human factor Xl (PTA) and inhibition of the activated enzyme
by ai-antitrypsin. Journal of Experimental Medicine 14Ot6): 1615-1630, December
  1. 1974.

312


HEE, J., GUILLERM, R. Influence des facteurs de I'environnement sur l'activite
ciliaire et le transport du mucus. [The influence of environmental factors on ciliary
activity and mucus transport.] Buliettn Europeen de Phvsiopatholo@e Respimtoire
%21: 377-395, March-April 1973.

HERNANDEZ. J.A., ANDERSON, A.E.. Jr., HOLMES, W.L., FORAKER. A.G.
Pulmonary parenchymal defects in dogs following prolonged cigarette smoke
exposure. American Review of Resprmtory Dzsease 93(l): 78-83, January 1966.
HILDING, A.C. On cigarette smoking, bronchial carcinoma and ciliary action. II.
Experimental study on the filtering action of cow's lungs. the deposition of tar in
the bronchial tree and removal by ciliary action. Neu: England Journal of Medzcine
254(25): 115&1160, June 14,1956.

HILDING. A.C. Ciliary streaming in the bronchial tree and the time element m
carcinogenesis. Nevhub England Journal of Medlcrne 256(13): 63-O. March 28.
  1957.

HILDING, A.C. Nasal mucosa as a test area for the toxicity of cigarette smoke.
Archives of Otolaryngoloa 82(3): 425-426, September 1965.
HINMAN, L.M.. STEVENS, C.A., MA'ITHAY, R.A., GEE, J.B.L. Elastase and
lysozyme activities in human alveolar macrophages. Effects of cigarette smoking.
American Revieu? of Respiratory Disease 121(21: 263-271, February 1980.
HINMAN, L.M., STEVENS, C.A., MAlTHAY, R.A.. REYNOLDS, H.Y., GEE, J.B.L.
Lysozyme and angiotensin convertase activity in human alveolar macrophages:
The effects of cigarette smoking and pulmonary sarcoidosis. American Reuiew of
Respiratory Disease 119: 67A, 1979.

HOGG, J.C., MACKLEM, P.T., THURLBECK, W.M. Site and nature of airway
obstruction in chronic obstructive lung disease. New England Journal of Medicine
278(25): 1355-1360, June 20.1968.

HOIDAL, J.R., BEALL, G.D., REPINE, J.E. Production of hydroxl radical by human
alveolar macrophages. Infectious Zmmunologv 16: 1088-1094, 1979a.
HOIDAL, J.R., FOX., R.B., LeMARBRE, P.A., PERRI, R.. REPINE, J.E. Altered
oxidative metabolic responses in vitro of alveolar macrophages from asymptomatic
cigarette smokers. Amerrcan Review of Respiratory Disease 123(l): 85-89, January
  1981.

HOIDAL, J.R., FOX, R.B., LeMARBRE, P.A., TAKIFF, H.E.. REPINE, J.E. Oxidative
metabolism of alveolar macrophages from young asymptomatic cigarette smokers.
Increased superoxide anion release and its potential consequences. Chest 77(2):
270-271, February 1980.

HOIDAL, J.R., FOX, R.B., TAKIFF, H.E., REPINE, J.E. Alveolar macrophages (AM)
from young. asymptomatic cigarette smokers (CSJ and nonsmokers (NS) use equal
amounts of oxygen (0~) and glucose (1-l'). but smoker AM make more superoxide
anion (02). American Review of Respiratory Disease 119: 222A. 1979b.
HOIDAL, J.R., NIEWOEHNER, D.E. Lung phagocyte recruitment and metabolic
alterations induced by cigarette smoke in humans and in hamsters. American
Revieu of Respimtory Disease 126(3): 548352, September 1982.
HOIDAL, J.R., NIEWOEHNER, D.E. Cigarette smoke inhalation potentiates elastase-
induced emphysema in hamsters. American Review of Respiratory Disease 127(4):
478481, April 1983.

HOLMA, B. The acute effect of cigarette smoke on the initial course of lung clearance
in rabbits. Archives of Env[ronmental Health 18: 1971. 1969.
HOLT, P.G., BARTHOLOMAEUS, W.N., KEAST, D. Differential toxicity of tobacco
smoke to various cell types including those of the immune system. Australian
Journal of Experimental Biology and Medical Science 52(l): 211-214, February
  1974.

313


HOLT, P.G., CHALMER, J.E., ROBERTS, L.M., PAPADIMITRIOU, J.M., THOMAS,
W.R., KEAST, D. Low-tar and high-tar cigarettes: Comparison of effects in two
strains of mice. Archives of Environmental Health 31(4): 258-265, July-August,
  1976.

HOLT, P.G., KEAST, D. Acute effects of cigarette smoke on murine macrophages.
Archives of Environmental Health 26(6): 300-304, June 1973a.
HOLT, P.G., KEAST, D. Cigarette smoke inhalation: Effects on cells of the immune
series in the murine lung. Life Sciences 12tPart II, 8): 377-383, April 22, 1973b.
HOLT, P.G., KEAST, D. The effect of tobacco smoke on protein synthesis in
macrophages. Proceedings of the Society for Experimental Biology and Medicine
142(4): 1243-1247, April 1973c.

HOLT, P.G., NULSEN, D. Cigarette smoke inhalation: Effect on cells of the immune
series in the murine lung. Life Sciences 12: 377-383,1975.
HOMER, G., KATCHMAN, B.J., ZIPF, R.E. A spectrophotometric method .for
measuring serum trypsin inhibitory capacity. Clinical Chemistry 9t4): 42-37,
August 1963.

HUBER, G.L., LaFORCE, F.M. Comparative effects of ozone and oxygen on pulmo
nary antibacterial defense mechanisms. In: Hobby, G.L., (Editorl. Antimicrobial
Agents and Chemotherapy. Proceedings of the 10th Interscience Conference on
Antimicrobial Agents and Chemotherapy, Chicago, October 1970. Bethesda,
Maryland, American Society for Microbiology, 1971, pp. 129-136.
HUBER, G.L.. MASON, R.J., LaFORCE, M., SPENCER, N.J., GARDNER, D.E.,
COFFIN, D.L. Alterations in the lung following the administration of ozone.
Archives ofhternal Medicine 128(l): 81-87, July 1971.
HUNNINGHAKE, G.W., CRYSTAL, R.G. Cigarette smoking and lung destruction:
Accumulation of neutrophils in the lungs of cigarette smokers. American Review of
Respiratory Disease 128(5): 833838, November 1983.
HUNNINGHAKE, G.W., DAVIDSON, J., RENNARD, S., SZAPIEL, S., GADEK, J.E.,
CRYSTAL, R.G. Elastin fragments attract macrophage precursors to diseased sites
in pulmonary emphysema. Science 232(4497): 925-927, May 22,1981.
HUNNINGHAKE, G.W., FULMER, J.D.. YOUNG, R.C., CRYSTAL, R.G. Comparison
of lung and blood lymphocyte subpopulations in pulmonary sarcoidosis. In:
Williams. W.J., Davies, B.H. (Editors). Proceedings of the 8th International
Conference on Sarcoidasis and Other Granulomatous Disease. Cardiff, Wales,
Alpha Omega Publishing Ltd., 198Oa. pp. 426435.
HUNNINGHAKE, G.W., GADEK, J.E. Immunological aspects of chronic noninfec-
tious pulmonary diseases of the lower respiratory tract in man. Clinical Zmmunolo-
gy Review 1: 337-374.1981-1982.

HUNNINGHAKE, G.W., GADEK, J.E., FALES, H.M.. CRYSTAL, R.G. Human
alveolar macrophagederived chemotactic factor for neutrophils. Stimuli and
partial characterization. Journal of Clinical Znvestigation 66t3): 473-483, Septem-
ber 1980b.

HUNNINGHAKE, G.W., GADEK, J.E., KAWANAMI, 0.. FERRANS, V.J., CRYS-
TAL, R.G. Inflammatory and immune processes in the human lung in health and
disease: Evaluation by bronchoalveolar lavage. American Journal of Pathology
97(l): 149-206, October 1979.

HUNNINGHAKE, G.W., MOSELEY, P.L. Pathogenesis of chronic noninfectious lung
diseases. In: Brenestock, J. Editor). Immunology of Lung Diseases. New York,
McGraw-Hill, in press.

HURST, D.J., COFFIN, D.L. Ozone effects on lysosomal hydrolases of alveolar
macrophages in vitro. Archives of Internal Medicine 127(6): 1059-1063, June 1971.
HUTCHISON, D.C.S., DESAI, R., BELLAMY, D.. BAUM, H. The induction of
lysosomal enzyme release from leukocytes of normal and emphysematous subjects
and the effects of tobacco smoke upon phagocytosis. Clinical Science 58(5): 403-409,
May 1980.

314


HYBBINE'ITE, J.-C., A pharmacological evaluation of the short-term effect of
cigarette smoke on mucociliary activity. Acta Otolaryngogica 94(3/4): 351-359,
September-October 1982.

IKUTA, T., OKUBO, H., KUDO, J.. ISHIBASHI, H., INOUE. T. Alpha:-antitrypsin
synthesis by human lymphocytes. Biochemical and Biophysical Research Commu-
nications 104(4): 1509-1516, February 26.1982.
IP, M.C.P., KLEINERMAN, J., SORENSON, J. The effect of elastase on pulmonary
elastin and collagen: Comparison of intravenous and intratracheal exposure.
Experimental Lung Reseamh 1: 181-189.1980.
IRAVANI, J. Mucociliary abnormalities underlying impaired mucus elimination.
Bulletin Europeen a!e Physiopathologie Respiratoire 9: 397-401,1973.
IRAVANI, J. Effects of cigarette smoke on the ciliated respiratory epithelium of rats.
Respimtion 29(5): 480-487.1972.

IRAVANI, J., MELVILLE, G.N. Long-term effect of cigarette smoke on mucociliary
function in animals. Respiration 31(4): 358-366, 1974.
IRAVANI, J., VAN AS, A. Mucus transport in the tracheobronchial tree of normal
and bronchitic rats. Journal ofpathology 106(2): 81-93. February 1972.
ISAWA, T., HIRANO, T., TESHIMA, T., KONNO, K. Effect of non-filtered and
filtered cigarette smoke on mucociliary clearance mechanism. Tohoku Journal of
Experimental Medicine 130(2): 189-197, February 1980.
JAMES, H.L., COHEN, A.B. Mechanism of inhibition of porcine elastase by human
alphal-antitrypsin. Journal of Clinical Investigation 62(6): 1344-1353, December
  1978.

JANOFF, A. Purification of human granulocyte elastase by affinity chromatography.
Laboratory Investigation 29(4): 458464, October 1973.
JANOFF, A., CARP, H., LAURENT, P., RAJU, L. The role of oxidative processes in
emphysema. American Reuiew of Respiratory Disease 127: 531538,1983a.
JANOFF, A. CARP, H., LEE, D.K., DREW, R.T. Cigarette smoke inhalation decreases
al-antitrypsin activity in rat lung. Science 206(4424): 131%1314, December 14,
  1979a.

JANOFF, A., CHAN, S.K. Technical comment on Stone, et al. Science 221: 1187,1984.
JANOFF, A., CHANANA, A.D., JOEL, D.D., SUSSKIND, H., LAURENT, P., YU, S.-
Y., DEARING, R. Evaluation of the urinary desmosine radioimmunoassay as a
monitor of lung injury after endobronchial elastase instillation in sheep. American
Review ofRespimtory Disease 128t3): 545-551, September 1983b.
JANOFF, A., RAJU, L., DEARING, R. Levels of elastase activity in bronchoalveolar
lavage fluids of healthy smokers and nonsmokers. American Review of Respiratory
Disease 127(5): 540-544, May 1983c.

JANOFF, A., SLOAN, B., WEINBAUM, G., DAMIANO. V., SANDHAUS, R.A.,
ELIAS, J., KIMBEL, P. Experimental emphysema induced with purified human
neutrophil elastase: Tissue localization of the instilled protease. American Review
0fRespimtot-y Disease 115(3): 461478, March 19'77.
JANOFF, A., WHITE, R., CARP, H., HAREL, S., DEARING, R., LEE, D. Lung injury
induced by leukocytic proteases. American JournaZ of Pathology 97(l): 111-129,
October 1979b.

JEPPSSON, J.O., LAURELL, C.B., FAGERHOL, M. Properties of isolated human al-
antitrypsins of Pi types M, S, and 2. European Journal of Biochemistry 83: 14%153,
February 1978a.

JEPPSSON, J.O., LAURELL, C.B., NOSSLIN, B., COX, D.W. Catabolic rate of al-
antitrypsin of Pi types S, and M Yalta" and of asialylated M-protein in man. Clinical
Science and Molecular Medicine 531): 103-107, July 1978b.
JOHANSON, W.G., Jr., PIERCE, A.K. Lung structure and function with age in
normal rats and rats with papain emphysema. Journal of Clinical Investigation
52(l): 2921-2927, November 1973.

315


JOHNSON, D.A. Ozone inactivation of human ai-proteinase inhibitor. American
Reuiew o/&.@ratory Disease 121(6): 1031-1038, June 1980.
JOHNSON, D., TRAVIS, J. The oxidative inactivation of human alpha]-proteinase
inhibitor. Further evidence for methionine at the reactive center. Journal of
Biological Chemistry 254(10): 40224026, May 25, 1979.
JONES, N.L. The pathophysiological consequences of smoking on the respiratory
system. Canadian Journal? Public Health 72(6): 388-390, November-December
  1981.

JONES, R., BOLDUC, P., REID, L. Goblet cell glycoprotein and tracheal gland
hypertrophy in rat airways:?he effect of tobacco smoke with or without the anti-
inflammatory agent phenylmethyloxadiazole. British Journal of Experimental
Pathology 54(2): 229239, April 1973.

JUHOS, L.T., GREEN, D.P., FURIOSI, W.J., FREEMAN, G. A quantitative study of
stenosis in the respiratory bronchiole of the rat in NOeinduced emphysemsa.
American Review of Respimtory Disease 121(3): 541-549, March 1980.
KAGAN, H., CROMBIE, G., JORDAN, R., LEWIS, W., FRANZBLAU, C. Proteolysis of
elastin-ligand complexes. Stimulation of elastase digestion of insoluble elastin of
sodium dodecyl sulfate. Biochemistry li: 34X2-3419, i972.
KAMINSKI, E.J., FANCHER, O.E., CALANDRA, J.C. In vivo studies of the ciliastatic
effects of tobacco smoke. Archives of Environmental Health 16: 188-193, 1968.
KAPI;AN, P.D., KUHN, C., PIERCE, J.A. The induction of emphysema with elastase.
I. The evolution of the lesion and the influence of serum. Journal of Lubomtory
and Clinical Medicine 62: 349-356,1973.

KARLINSKY, J.B., SNIDER, G.L. Animal models of emphysema. American Review of
Respiratory Disease 117(6): 1109-1133, June 1978.
KENNEDY, J.R., ALLEN, P.L. Effects of cigarette smoke residue on rabbit tracheal
epithelium in organ culture. Archiues of Environmental Health 34(l): 5-11,
January-February 1979.

KENNEDY, J.R., ELLIOT, A.M. Cigarette smoke: The effect of residue on mitochon-
drial structure. Science 168: 1097, 1970.

KENSLER, C.J., BA'I"IISTP>, S.P. Components of cigarette smoke with ciliary-
depressant activity. New England Journal of Medicine 269(221: 1161-1166,
November 28.1963.

KILBURN, K.H., MCKENZIE, W. leukocyte recruitment to airways by cigarette
smoke and particle phase in contrast to cytotoxicity of vapor. Science 189(4202):
634637, August 15, 1975.

KIMMEL, J.R., SMITH, E.J. Crystalline papain. I. Preparation, specificity, and
activation. Journal of Biological Chemistry 227: 515-531,1953.
KLEBANOFF, S.J., CLARK, R.A. Degranulation: Extracellular enzyme release. In:
The Neutrophil: Function and Clinical Disorders. Amsterdam, North-Holland
Publishing Company, 1978, pp. 225262.

KLEINERMAN, J., BOREN, H.G. Morphologic basis of chronic obstructive lung
disease. In: Baum, G. L. (Editor). Textbook of Pulmonary Disease. Boston, Little,
Brown Company, 1974, up. 571.

KLEINERMAN. J., IP, M.P.C., SORENSON, J. Nitrogen dioxide exposure and
alveolar macrophage elastase in hamsters. American Review of Respiratory Disease
125(2): 203207, February 1982.

KLEINERMAN, J., NIEWOEHNER, D. Physiological, pathological and morphometric
studies of long-term nitrogen dioxide exposures and recovery in hamsters.
American Review of Respiratory Disease 107(6): 1081, June 1973.
KOBRLE, V., HURYCH, J., HOLUSA, R. Changes in pulmonary connective tissue
after a single intratracheal instillation of papain in the rat. American Review of
Respirato? Disease 12512): 239243, February 1982.

316


KRAMPS, J.A., BAKKER, W., DIJKMAN, J.H. A matched pair study of the leukocyte
elastase-like activity in normal persons and in emphysematous patients with and
without alpha*-antitrypsin deficiency. American Rec,zeu of Respiratop Disease
121(2): 25%261, February 1980.

KUCICH, U.. CHRISTNER. P.. LIPPMANN. M.. FEIN, A., GOLDSERG. A., KIMBCL.
P., WEINBAUM, G., ROSENBLOOM, J. Immunologic measurement of elastin-
derived peptides in human serum. American Retlieu, of Respirafop Disease 127(2):
S28-S30, February 1983.

KUCICH, U., CHRISTNER. P., WEINBAUM. G., ROSCNBLOOM. J. Immunologic
identification of elastinderived peptides in the serums of dogs with experimental
emphysema. American Revleu, of Respirato:? Dzsease 122131: 461465. September
  1980.

KUEPPERS, F. Inherited differences in alpha*-antitrypsin. In: Li?ivin, S.D. (Editor).
Genetic Determinants of F'ulmonav Disease. New York, Marcel Dekker, 1978, pp.
23-74.

KUEPPERS, F. Serum alpha,-antitrypsin levels. .Vew England Journal of Medicine
279: 164.1968.

KUEPPERS, F., BLACK, L.F. Al-antitrypsin and its deficiency. American Review of
Respiratop Disease llCM2): 17&194, August 1974.
KUEPPERS, F., BRISCOE, W.A., REARN, A.G. Hereditary deficiency of serum alpha-
l-antitrypsin. Science 146(3651): 1678, December 18. 1964.
KUHN, C., SENIOR, R.M. The role of elastases in the development of emphysema.
Lung 155: 185-197,1978.

KUHN, C., III, STARCHER, B.C. The effect of lathyrogens in the evolution of elastase-
induced emphysema. American Revieu! of Respiratory Disease 122(3): 45-60,
September 1980.

KUHN, C., TAVASSOLI, F. The scanning electron microscopy of elastaseinduced
emphysema. A comparison with emphysema in man. Laboratov Znuestigation
34(l): 2-9, January 1976.

KUHN, C., III, YU, S.Y., CHRAPLYVY, M., LINDER, H.E., SENIOR, R.M. The
induction of emphysema with elastase. II. Changes in connective tissue. Labomtoq
Investigation 34(4): 372-380, April 1976.
LABELLE, C.W., BEVILACQUA, D.M., BRIEGER, II. The influence of cigarette
smoke on lung clearance. Archives of Environmental Health 12(5): 588-596, May
  1966.

LAM, S., ABBOUD, R.T., CHAN-YEUNG, M., RUSHTON, J. Neutrophil elastase and
pulmonary function in subjects with intermediate alpha-1-antitrypsin deficiency
(MZ phenotype). American Review of Respimtory &ease 11%6): 941-951, June
  1979.

LARGMAN, C., BRODRICK, J.W., GOEKAS, M.C., SISCHO, W.M., JOHNSON, J.H.
Formation of a stable complex between human proelastase 2 and human alphal-
protease inhibitor. Journal of Biological Chemistry 254(17): 8516-8523, September
10, 1979.

LARSSON, C. Natural history and life expectancy in severe alpha]-antitrypsin
deficiency, PiZ. Acta Medica Scandinauica 204(5): 345-351. May 1978.
LAUGHTER, A.H.. MARTIN, R.R., TWOMEY, J.J. Lymphoproliferative responses to
antigens mediated by human pulmonary alveolar macrophages. Journal of
Zdomtory and Clinical Medicine 89(6): 13261332, June 1977.
LAURELL, C.B., ERIKSSON, S. The electrophoretic al-globulin pattern of serum in
al-antitrypsin deficiency. Scandinavian Journal of Clinical Labomtory Investiga-
tion 15(2): 132-140, 1963.

LAURELL, C.B., NOSSLIN, B., JEPPSSON, J.O. Catabolic rate of al-antitrypsin of Pi
type M and Z in man. Clinical Science and Molecular Medicine 52(5): 457-461, May
  1977.

317


LAURELL, C.B., SVEGER, T. Mass screening of newborn Swedish infants for ai-
antitrypsin deficiency. American Journal ofHuman Genetics 27(2): 213217, March
  1975.

LAURENT, P., JANOFF, A., KAGAN. H.M. Cigarette smoke blocks cross-linking of
elastin in vitro. American Review of Respiratory Disease 127(2): 189-192, February
  1983.

LAVIOLE'ITE, M., CHANG, J., NEWCOMBE, D.S. Human alveolar macrophages: A
lesion in arachidonic acid metabolism in cigarette smokers. American Review of
Respiratory Disease 124(4): 397401, October 1981.
LENTZ, P.E., DILUZIO. N.R. Transport of alpha-aminoisobutyric acid by alveolar
macrophages incubated with cigarette smoke and nicotine. Archives of Enuiron-
mental Health 28(6): 333-335, June 1974.

LESTIENNE, P., BIETH, J. Activation of human leukocyte elastase activity by excess
substrate, hydrophobic solvents, and ionic strength. Journal of Biological Chemis-
try 255(19): 9289-9294, October 10,198O.

LEUCHTENBERGER, C., LEUCHTENBERGER, R. The behavior of macrophages in
lung cultures after exposure to cigarette smoke. Evidence for selective inhibition
by particulate matter and stimulation by the gas phase of cell metabolism of
alveolar macrophages. Advances in Experimental Medicine and Biology 15: 347-
360,1971.

LEUCHTENBERGER, C., LEUCHTENBERGER, R., DOOLIN, R. A correlated
histological, cytochemical study of the tracheobronchial tree and lungs of mice
exposed to cigarette smoke. Journal of Cancer 11: 490.1958.
LEVINE, E.A., SENIOR, R.M., BUTLER, J.V. The elastase activity of alveolar
macrophages: Measurements using synthetic substrates and elastin. American
Review of Respiratop Disease 113(l): 25-30, January 1976.
LIEBERMAN, J. Heterozygous and homozygous alphal-antitrypsin deficiency in
patients with pulmonary emphysema. New England Journal of Medicine 281: 27%
279. 1969.

LIEBERMAN, J. Elastase, collagenase, emphysema, and alpha(l&antitrypsin deficien-
cy. Chest 70(l): 6267, July 1976.

LIEBERMAN, J., GAIDULIS, L., KLOTZ, SD. A new deficient variant of al-
antitrypsin (Mduarte). Inability to detect the heterozygous state by antitrypsin
phenotyping. American Review of Respiratory Disease 113(l): 31-36, January 1976.
LIPPMANN, M., ALBERT, R.E., PETERSON, H.T., Jr. The regional deposition of
inhaled aerosols in man. In: Walton, W.H. (Editor). Znhaled Particles ZZZ. Volume
II. Proceedings of an International Symposium organized by the British Occupa-
tional Hygiene Society, London, September 14-23, 1970. Old Woking, Surrey,
England, Unwin Brothers Ltd., pp. 105-122.

LONKY, S.A., MARSH, J., STEELE, R., JACOBS, K., KONOPKA, R., MOSER, K.M.
Protease and antiprotease responses in lung and peripheral blood in experimental
canine pneumococcal pneumonia. American Review of Respiratory Disease 121(41:
685-693, April 1980

LONKY, S.A., MARSH, J., WOHL, H. Stimulation of human granulocyte elastase by
platelet factor 4 and heparin. Biochemical and Biophysical Research Communica-
tions 85: 111.`%1118,1978.

LOPATA, M., BARTON, A.D., LOURENCO, R.V. Biochemical characteristics of
bronchial secretions in chronic obstructive pulmonary disease. American Review of
Respiratoy Dzsease llo(6): 73(X739, December 1974.
LOPEZ-VIDRIERO, M. Individual and group correlations of sputum viscosity and
airways obstruction. Bulletin Europeen de Physiopathologie Respiratoire 9: 339,
  1973.

318


LOPEZ-VIDRIERO, M.T., REID, L. Chemical markers of mucous and serum glycopro-
teins and their relation to viscosity in mucoid and purulent sputum from various
hypersecretory diseases. American Review of Respirator, Disease 117(3): 465-477,
March 1978.

LOURENCO, R.V. Distribution and clearance of aerosols. American Reuieu of
Respiratory Disease 101-102(3): 460-461. March 1970.
LOURENCO, R.V., KLIMER. M.F., BOROWSKI. C.J. Deposition and clearance of 2 p
particles in the tracheobronchial tree of normal subjects: Smokers and nonsmok-
ers. Journal of Clinical Investigation 50: 1411-1420.1971.
LOW, R.B. Protein biosynthesis by the pulmonary alveolar marcophage: Conditions of
assay and the effects of cigarette smoke extracts. American Review of Respiratov
Disease llO(4): 4-77, October 1974.

LUCEY, E.C., CLARK, B.D. Differing susceptibility of young and adult hamster lungs
to injury with pancreatic elastase. American Review of Respiratory Disease 126(5):
877-881, November 1982.

LUCHSINGER, P.C., LAGARDE. B.. KILFEATHER, J.E. Particle clearance from the
human tracheobronchial tree. American Review of Respiratory Disease 97: 1046.
  1968.

LUDWIG, P.W., SCHWARTZ, B.A., HOIDAL. J.R., NIEWOEHNER, D.E. Cigarette
smoking causes accumulation of polymorphonuclear leukocytes (PMN) in lung
parenchyma. Clinical Research 31t4): 146A, October 1983.
MARCO, J., MERANZE, D.R., BENTIVOGLIO, L.G., KIMBEL. P. Papain induced
experimental emphysema in the dog. Federation Proceedings 28: 526.1969.
MARCO, V., MASS, B., MERANZE, D.R., WEINBAUM, G., KIMBEL, P. Induction of
experimental emphysema in dogs using leukocyte homogenates. American Review
ofRespiratory Disease 104(41: 59%598, October 1971.
MARTIN, R.R. Altered morphology and increased acid hydrolase content of pulmo-
nary macrophages from cigaret.te smokers. American Review of Respiratory
Disease 107(4): 596-601, April 1973.

MARTIN, R.R., WARR, G.A. Cigarette smoking and human pulmonary macrophages.
Hospital Practice 12(g): 97-104, September 1977.
MARTORANA, P.A., SHARE, N.N. Effect of human alpha]-antitrypsin on papain-
induced emphysema in the hamster. American Review of Respiratory Disease
113(5): 607412, May 1976.

MART~RANA, P.A., WUSTEN, B., VAN EVEN, P., GOBEL, H., SCHAPER, J. A
six-month study of the evolution of papain-induced emphysema in the dog. A
morphometric and pulmonary hemodynamic investigation. American Review of
Respiratory Disease 126(51: 898-903, November 1982.
MASS, B., IKEDA, T., MERANZE, D.R., WEINBAUM, G., KIMBEL, P. Induction of
experimental emphysema. Cellular and species specificity. American Review of
Respiratory Disease 106(3): 384-391, September 1972.
MATHESON, N.R., WONG, P.S., SCHUYLER, M., TRAVIS, J. Interaction of human
ai-proteinase inhibitor with neutrophil myeloperoxidase. Biochemistry 20(2): 331-
336, January 20,198l.

MATHESON, N.R., WONG, P.S., TRAVIS, J. Enzymatic inactivation of human
alpha*-proteinase inhibitor neutrophil myeloperoxidase. Biochemical Biophysical
Research Communications 88: 402-409,1979.
MATSUBA, K., THURLBECK, W.M. The number and dimensions of small airways in
nonemphysematous lungs. American Reuiew of Respirator?, Disease 104(4): 516,
October 1971.

MA'ITENHEIMER, H, MOHR, U. Ciliotoxicity of cigarette smoke and adenylate
kinase. Zeitschrift fur Klinische Chemie und Klinkche Biachemie 13t7): 325-326,
July 1975.

319


MATI'HYS, H., VASTAG, E., KOEHLER, K., DAIKELER, G. FISHER, J. Mucociliary
clearance in patients with chronic bronchitis and bronchial carcinoma. Respiration
44(5): 329-337, September-October 1983.

McCUSKER, K.T., TQ'I'TI, N., III, CAMPBELL, E.J., SENIOR, R.M. Nicotine Is
Chemotactic for Neutrophils and Enhances Neutruphil Responsiveness to Chemo-
tactic Neptides. 49th Annual Scientific Assembly, American College of Chest
Physicians, October 23-37, 1983, p. 318.

MCDOWELL, E.M., BARRETT, L.A., HARRIS, CC., TRUMP, B.F. Abnormal cilia in
human bronchial epithelium. Archives of Pathologv and Lubomtory Medicine 100:
429-436,1976.

AMcGOWAN, SE., STONE, P.J.. CALORE, J.D., SNIDER, G.L., FRANZBLAU, C. The
fate of neutrophil elastase incorporated by human alveolar macrophages. Ameri-
can Revieu! of Respiratory Disease 127(41: 449455, April 1983.
MCLAUGHLIN, R.F., TUELLER, E.E. Anatomic and histologic changes of early
emphysema. Chest 59(6): 592-599, June 1971.
MCLEAN, K.H. The pathology of emphysema. American Review of Respiratory Disease
BO(Part 2): 58-66, July 1959.

McLEMORE, T.L., MARTIN, R.R. In vitro induction of aryl hydrocarbon hydrolase in
human pulmonary alveolar macrophages by benzanthracene. Cancer Letters 2(6):
327-333, May 1977.

McLEMORE, T.L., MARTIN, R.R., BUSBEE, D.L., RICHIE, R.C., SPRINGER, R.R.,
TOPPELL, K.L., CANTRELL, E.T. Aryl hydrocarbon hydroxylase activity in
pulmonary macrophages and lymphocytes from lung cancer and noncancer
patients. Cancer Research 37: 11751181,1977b.
McLEMORE. T.L., MARTIN, R.R., TOPPELL, K.L., BUSBEE, D.L., CANTRELL, E.T.
Comparison of aryl hydroxylase induction in cultured blood lymphocytes and
pulmonary macrophages. Journal of Clinical Investigation 60(5): 1017-1024,
November, 1977c.

McLEMORE, T.L., MARTIN, R.R., WRAY, N.P., CANTRELL, E.T., BUSBEE, D.L.
Dissociation between aryl hydrocarbon hydroxylase activity in cultured pulmo-
nary macrophages and blood lymphocytes from lung cancer patients. Cancer
Research 38(11): 3805-3811, November 1978.
McLEMORE, T.L., WARR, G.A., MARTIN, R.R. Induction of aryl hydrocarbon
hydroxylase in human pulmonary alveolar macrophages and peripheral lymph*
cytes by cigarette tars. Cancer Z..etters 2: 161-168,1977a.
MEGA, T., LUJAN, E., YOSHIDA, A. Studies in the oligosaccharide chains of human
al-protease inhibitor I. Isolation of glycopeptides. Journal of Biological Chemist?
2539): 40534056, May 10,198O.

MENDENHALL, W.L., SHREEVE, K. E. The effect of cigarette smoke on the tracheal
cilia. Journal of Pharmacologv and Experimenta Therapeutics 60(l): 111-112, May
  1937.

MENDENHALL, W.L., SHREEVE, K. Effect of tobacco smoke on ciliary action.
Journal of Pharmacology and Experimental Therapeutics 69(41: 295, August 1940.
MERRILL, W.W.. GQODENBERGER, D., STROBER, W., MA'ITHAY, R.A., NAE-
GEL, G.P., REYNOLDS, H.Y. Free secretory component and other proteins in
human lung lavage. American Rettieul of Respiratory Disease 122(l): 156161, July
  1980.

MILICEMILI, J., HENDERSON, J.A.M.. DOLOVICH, M.B., TROP, D., KANEKO, K.
Regional distribution of inspired gas in the lung. Journal of Applied PhUysioloc
21(3): 749-759, May 1966.

MILLER, SD., ZARKOWER, A. Effects of carbon dust inhalation on the cell-mediated
immune response in mice. Infection and Immunity g(3): 534-539, March 1974.
MISKOVITZ, G., APPEL, J., SZULE, P. Ultrastructural changes of ciliated columnar
epithelium and goblet cells in chronic bronchitis biopsy material. Acta Morphologi-
ca Academiue Sczentiarum Hungaricae 22(l): 91-103, 1974.

320


MITCHELL, R.S., STANFORD, R.E., JOHNSON, J.M., SILVERS, G.W., DART, G.,
GEORGE, MS. The morphologic features of the bronchi, bronchioles, and alveoli
in chronic airway obstruction: A clinicopathologic study. American Review of
Respiratory Disease 114(l): 137-145, July 1976.
MITCHELLHEGGS, P., PALFREY, A.J., REID, L. The elasticity of sputum at low
shear rates. Biorheology ll(6): 417426, November 1974.
MOERSCH, H.J., MCDONALD, J.R. Significance of cell type in bronchogenic
carcinoma. Diseases ofthe Chest 23: 621,1953.
MORRIS, SM., STONE, P.J., SNIDER, G.L., ALLRIGHT, J.T., FRANZBLAU, C.
Ultrastructural changes in hamster lung four hours to twenty-four days after
exposure to elastase. Anatomical Record 201(3): 523-535, 1981.
MORROW, P.E. GIBB, F.R., GAZIOGLU, K.M. A study of particulate clearance from
the human lungs. American Review of Respiratory Disease W6): 1209-1221,
  December 1967.

MORSE, J.O. Alphal-antitrypsin deficiency. New England Journal af Medicine
299f19): 10451048,1099-1105, November 9,1978.
MOSSBERG, B., BJORKANDER, J., AFZELIUS, B.A., CAMNER, P. Mucociliary
clearance in patients with immunoglobulin deficiency. European Journal of
Respiratory Diseases 63: 570-578,1982.

MOSSBERG, B., CAMNER, P. Mucociliary transport and cough as clearance
mechanisms in obstructive lung disease. European Journal of Respiratory Diseases
Gl(Supplement 1111: 18-20, 1980.

MULLER, M., KONIETZKO, N., ADAM, W.E.. MA'ITHYS, H. Die Mukoziliare
Klarfunction der Lunge: Untersucht mit Radioaktiv Markierten Schwefelkolloid.
Klinische Wochenschrift 53: 815, 1975.

NAKHOSTEEN, J.A.. LINDEMANN, L., VIEIRA, J. Mukoziliare Klarfunktion,
Ergebniase bei Rauchern, Nichtrauchern und Patienten mit Atemwegskrankheit-
en. [Mucociliary clearance. Data for smokers, nonsmokers, and patients with
respiratory disease.] Deutsche Medizinische Wochenschrift 107(45): 1713-1716,
November 12,1982.

NEHER, G.H. Nicotine-induced depression of lymphocyte growth. Toxicology and
Applied Pharmacology 27(2): 253-258, February 1974.
NIEWOEHNER, D.E., KLEINERMAN, J., RICE, B. Pathologic changes in the
peripheral airways of young cigarette smokers. New England Journal of Medicine
291(X$: 755-758, October 10,1974.

NULSEN, A., HOLT, P.G., KEAST. D. Cigarette smoking, air pollution and immunity:
A model system. Infection and Immunity l&6): 12261229, December 1974.
NYMAN, G. Maternal smoking and immunity. Lancet 2(7893): 13791380, December
7, 1974.

OHLSSON, K. Neutral leucocy-te proteases and elastase inhibited by plasma alpha-l-
antitrypsin. Scandinavian Journal of Clinical Investigation 28(2): 251-253, Otto
ber 1971.

OHLSSON, K., OHLSSON, I. The neutral proteases of human granulocytes. Isolation
and partial characterization of granulocyte elastases. European Journal of
Biochemistry 42(2): 519-527, March 1.1974.

OKAJIMA, Y. Long-term effect of cigarette smoking on ciliary activity. Journal of the
Nagoya City University Medical Association 21(4): 1022-1046, 1971.
ORELL, S.R., MAZODIER, P. Pathological findings in alphai-antitrypsin deficiency.
In: Pulmonary Emphysema and Ptvteolysis. City of Hope Symposium Series, Vol. 2.
New York, Academic Press, 1972, pp. 69-89.

PAGE, B.F.J., WOOLSGROVE, B., CHASSEAUD, L.F., BINNS, R. Use of radioactive
tracer techniques in investigations associated with cigarette smoking. Annals of
Occupational Hygiene 16(4): 409416, December 1973.

321


PALECEK, F., PALECKOVA, M., AVIADO. D.M. Emphysema in immature rats.
Condition produced by tracheal constriction and papain. Archives of Enuironmen-
tal Health 1%3): 332342, September 1967.
PALMER, K.C., SNIDER, G.L., HAYES, J.A. Cellular proliferation induced in the
lung by cadmium aerosol. American Reuiew of Respiratory Disease 112(2): 173-179,
August 1975.

PANNELL, R.D., JOHNSON, D., TRAVIS, J. Isolation and properties of human
plasma al-proteinase inhibitor. Biochemistry 1X26): 5439-5445, December 17,
  1974.

PARK, S.S., KIKKAWA, Y., GOLDRING, I.P., DALY, M.M., ZELEFSKY, M., SHIM,
C., SPIERER, M., MORITA, T. An animal model of cigarette smoking in beagle
dogs: Correlative evaluation of effects on pulmonary function, defense, and
morphology. American Review of Respiratory Disease 115(6J: 971-979, June 1977.
PARTRIDGE, SM., DAVIS, H.F. The chemistry of connective tissues: 3. Composition
of the soluble proteins derived from elastin. Biochemical Journal 61(l): 21-30,
September 1955.

PATRICK, G., STIRLING, C. Measurement of mucociliary clearance from the trachea
of conscious and anesthetized rata. Journal of Applied Physiology 42(3): 451, March
  1977.

PAVIA, D., SHORT, M.D., THOMSON, M.L. No demonstrable long term effects of
cigarette smoking on the mucociliary mechanism of the human lung. Nature 226:
1228,197O.

PAVIA, D., THOMSON, M.L. Unimpaired mucociliary clearance in the lung of a
centenarian smoker. Lancet 2(7663): 101-102, July 11,197O.
PAVIA, D., THOMSON, M.L., POCOCK, S.J. Evidence for temporary slowing of
mucociliary clearance in the lung caused by tobacco smoking. Nature 231(5301):
325-326, June 4,1971.

PETTERSSON, B., CURVALL, M., ENZELL, C.R. Effects of tobacco smoke compounds
on the ciliary activity of the embryo chicken trachea in vitro. Toxicology 23(l): 41-
55, 1982.

PETTY, T.L., RYAN, SF., MITCHELL, R.S. Cigarette smoking and the lungs.
Relation to postmortem evidence of emphysema, chronic bronchitis and black lung
pigmentation. Archives ofEnvironmental Health 14: 172-177, January 1967.
PIRCHER, F.J., TEMPLE, J.R., KIRSCH, W.J., REEVES, R.J. Distribution of
pulmonary ventilation determined by radioisotope scanning. American Journal of
Roentgenology, Radium Therapy and Nuclear Medicine 94(4): 807-814, August
  1965.

POWELL, G.M., GREEN, G.M. Investigation on the effects of cigarette smoke on
rabbit alveolar macrophages. Biochemical Journal 124(2): 26P-27P, September
  1971.

PRATT, S.A., SMITH, M.H., LADMAN, A.J., FINLEY, T.N. The ultrastructure of
alveolar macrophages from human cigarette smokers and nonsmokers. Laboratory
Investigation 24(5): 331-336, May 1971.
PRINCI, F. A study of industrial exposure to cadmium. Journal of Industrial Hygiene
and Toxicology 39: 315,1947.

PROETZ, A. Some preliminary experiments in this study of cigarette smoke and its
effects upon the respiratory tract. Annals of Otology 48: 176,1939.
PRYOR, W.A., HALES, B.J., PREMOVIC, P.I., CHURCH, D.F. The radicals in
cigarette tar: Their nature and suggested physiological implications. Science
220(4595):425-427,1983.

PUCHELLE. E., ZAHM, J.M., GIRARD, F., BERTRAND, A., POLU, J.M., AUG, F.,
SADOUL, P. Mucociliary transport in vivo and in vitro. Relation to sputum
properties in chronic bronchitis. European Journal of Respiratory Disease 61(5):
254-264, October 1980.

322


PUSHPAKOM, R., HOGG, J.C., WOOLCOCK. A.J. ANGUS, A.E. Experimental
papain-induced emphysema in dogs. American Review of Respiratory Disease
102(5): 778-789, November 1970.

PUTNAM, C.W., PORTER, K.A.. PETERS, R.L.. ASHCAVAI. M., REDEKER, A.G.,
STARZL, T.E. Liver replacement for alpha,-antitrypsin deficiency. Surge? 8113~:
258-261, March 1977.

RAKIETEN, N., RAKIETEN, M.L., FELDMAN, D., BOYIN, M.J. Mammalian ciliated
respiratory epithelium: Studies with particular reference to menthol, nicotine and
smoke of mentholated and non-mentholated cigarette smoke. Archives of Otola~n-
gologv 56: 495,1952.

RANDI, M., JICK, H., SLONE, D., SHAPIRO, S., LEWIS, G.P. Cadmium content of
cigarettes. Lancet 2: 1329.1969.

RASP, F.L., CLAWSON, C.C., HOIDAL, J.R., REPINE, J.E. Reversible impairment of
the adherence of alveolar macrophages from cigarette smokers. American Review
OfRespiratory Disease 118(6): 979-986. December 1978.
RAUB, J.A., MERCER, R.R., MILLER, F.J., GRAHAM, J.A.. O'NEIL, J.J. Dose
response of elastaseinduced emphysema in hamsters. American ReLlieu of
Respiratory Disease 1234): 432435, April 1982.
REGLAND, B., CAJANDER, S., WIMAN, L.G.. FALKMER, S. Scanning electron
microscopy of the bronchial mucosa in some lung diseases using bronchoscopy
specimens. Scandinavian Journal of Respiratory Diseases 57(41: 171-182,1976.
REID, L. The Pathology of Emphysema. Chicago, Year Book Medical Publishers, 1967,
p. 159.

REID, L. Bronchial mucus production in health and disease. In: Liebow, A.A. (Editor).
The Lung. Baltimore, Williams and Wilkins, 1968, pp. 98.
REYNOLDS, H.Y., FULMER, J.D.. KAZMIEROWSKI, J.A., ROBERTS, W.C.,
FRANK, M.M., CRYSTAL, R.G. Analysis of cellular and protein content of
bronchoalveolar lavage fluid from patients with idiopathic pulmonary fibrosis and
chronic hypersensitivity pneumonitis. Journal of Clinical Investigation 59(l): 165-
175, January 1977.

REYNOLDS, H.Y., NEWBALL, H.H. Analysis of proteins and respiratory cells
obtained from human lungs by bronchial lavage. Journal of Laboratory and
Clinical Medicine 84(4): 559-573, October 1974.
REYNOLDS, H.Y., NEWBALL, H.H. Fluid and cellular milieu of the human
respiratory tract. In: Kirkpatrick, C.H., Reynolds, H.Y. (Editors). Immunologic and
Infectious Reactions in the Lung. Volume 1. New York, Marcel Decker, 1976, pp. 3-
  27.

RIMON, A., SHAMASH, Y., SHAPIRO, B. The plasmin inhibitor of human plasma.
IV. Its action on plasmin, trypsin, chymotrypsin, and thrombin. Journal of
Biological Chemistry 241(21): 5102-5107, November 10,1966.
RINDLER-LUDWIG, R., SCHMALZL, F., BRAUNSTEINER, H. Eserases in human
neutrophil granulocytes: Evidence for their protease nature. British Journal of
Haematology 27(l): 57-64, May 1974.

ROBERT, B., ROBERT, L. Studies in the structure of e&tin and the mechanism of
action of elastolytic enzymes. In: Balazs, E.A. (Editor). Chemist9 and Molecular
Biology of the Intercellular Matrix. New York, Academic Press, 1970, pp. 665.
RODRIGUEZ, J.R., SEALS, J.E., RADIN, A., LIN, J.S., MANDL, I., TURINO, G.M.
Neutrophil lysosomal elastase activity in normal subjects and in patients with
chronic obstructive pulmonary disease. American Review of Respiratory Disease
119: 409.1979.

RODRIGUEZ, R.J., WHITE, R.R.. SENIOR, R.M.. LEVINE, E.A. Elastase release from
human alveolar macrophages: Comparison between smokers and nonsmokers.
Science 198(4314): 313-314, October 21,1977.

323


RYLANDER, R. Alterations of lung defence mechanisms against airborne bacteria.
Effects of cigarette smoke exposure. Archives of Environmental Health 18: 551-
  555, 1969.
RYLANDER, R. Rokning ock Lungsjukdom (3): Djurexperimentella studier av
effekter pa andningsorganen. [Smoking and lung disease: 3. Studies of the effect of
smoking in the respiratory organs using experimental animals.] Lakartidningen
67(4): 390-396, January 21, 1970.
RYLANDER, R. Free lung cell studies in cigarette smoke inhalation experiments.
Scandinavian Journal of Respimtory Diseases 52(21: 121-128,1971.
RYLANDER, R. Lung clearance of particles and bacteria. Archives of Environmental
Health 23(5): 321326. November 1971.
RYLANDER. R. Toxicity of cigarette smoke components: Free lung cell response in
acute exposures. American Review of Respiratory Disease 108(5): 1279-1282,
  November 1973.
RYLANDER, R. Pulmonary cell responses to inhaled cigarette smoke. Archives of
Environmental Health 29(6): 329-333, December 1974.
SACKNER, M.A., ROSEN, M.J.. WANNER, A. Estimation of tracheal mucous
velocity by bronchofiberscopy. Journal of Applied Physiology 34(4): 495-499, May
2, 1973.
SACKS, T., MOLDOW, C.F., CRADDOCK, P.R., BOWERS, T.K., JACOB, H.S. Oxygen
radicals mediate endothelial cell damage by complement-stimulated granulcqtes.
An in vitro model of immune vascular damage. Journal of Clinical Znuestigation
61c.5): 1161-1167, May 1978.
SAKAKURA, Y., PROCTOR, D.F. The effect of various conditions on tracheal
mucociliary transport in dogs. Proceedings of the Society for Experimental Biology
and Medicine 140(3): 870-879, July 1972.
SANCHIZ, J., DOLOVICH. M., CHALMERS, R., NEWHOUSE, M. Quantitation of
regional aerosol clearance in the normal human lung. Journal of Applied
Physiology 33(6): 757, December 1972.
SANDHAUS, R.A. Migration-induced elastolysis: Directed migration of human
neutrophils causes connective tissue proteolysis in the presence of alpha,-protein-
ase inhibitor. American Review of Respiratory Disease 127(4): 2815, April 1983
(Abstract).
SANTA CRUZ, R., LANDA, J.. HIRSCH, J., SACKNER, M.A. Tracheal mucous
velocity in normal man and patients with obstructive lung disease: Effects of
terbutaline. American Review of Respiratory Disease 109f4): 458463, April 1974.
SCHABORT, J.C. Lactic dehydrogenase from human lung inhibition by certain water-
soluble ciliastatic components of tobacco smoke. Journal of the South African
Chemical Institute 20: 103-113, 1967.
SCHARPE, S., EID, M.. COOREMAN, W., LAUWERS, A. Ai-anti-trypsin, an inhibitor
of renin. Biochemical Journal 153(2): 505-507, February 1,1976.
SCHULTZE, H.E., GOOLNER, I.. HEIDE, K., SCHONENBERGER, M., SCHWICK, G.
Zur Kenntris der Alpha Globuline des menschlichen Normalserums [On alpha
globulin in normal serum in men.] Zeitschrift fur Naturforschung 10: 463-472,
  1955.
SCHULTZE, H.E., HEIDE, K., HAUPT, H. Alpha,-antitrypsin aus humanse-
rum.[Alpha,-antitrypsin from human serum.] Klinische Wochenschrift 40: 427,
  1962.
SCHUYLER, M.R., RYNBRANDT, D.J., KLEINERMAN, J. Physiologic and morph*
logic observations of the effects of intravenous elastase on the lung. American
Review of Respiratory Disease 117: 97-102,1978.
SENIOR, R.M., GRIFFIN, G.L., MECHAM, R.P. Chemotactic activity of elastin-
derived peptides. Journal of Clinical Znuestigution 66(4): 859-863, October 1980.


SENIOR, R.M., TEGNER, H., KUHN, C., OHLSSON, K., STARCHER, B.C., PIERCE,
J.A. The induction of pulmonary emphysema with human leukocyte elastase.
American Reoieu of Respimtory Disease 116: 469-475,1977.
SILVERMAN, N.A., POTVIN, C.. ALEXANDER, J.C.. CHRETIEN, P.B. In vitro
lymphocyte reactivity and T-cell levels in chronic cigarette smokers. C/&teal and
Expertmental Immunology 22(2): 28&292, November 1975.
SIMON, H., DRETTNER, B., JUNG, B. Measurement of the mucociliary transport in
the human nose with +5+ 1 Cr-tagged resin particles. Acta Oto-Laryngologica
83(3/4): 37%390, March-April 1977.

SLOAN, B., ABRAMS, W.R., MERANZE, D.R.. KIMBEL. P., WEINBAUM, G.
Emphysema induced in vitro and in vivo in dogs by a purified elastase from
homologous leukocytes. American Reuieu, of Resprratoryv Disease 124(3): 29%301.
September 1981.

SNIDER, G.L., SHERTER, C.B. A one-year study of the evolution of elastase-induced
emphysema in hamsters. Journal of Applied Phvslology Respirator-y. Environmen-
tal and Exercise Physrology 43(4): 721-729, October 1977.
SNIDER, G.L., HAYES, J.A., FRANZBLAU, C., KAGAN. H.M.. STONE, P.S.,
KORTHY, A.L. Relationship between elastolytic activity and experimental em-
physema-inducing properties of papain preparation. American Rec,ieus of Respira-
too Disease llo(3): 254-262, September 1974.
SNIDER, G.L., HAYES, J.A., KORTHY, A.L., LEWIS, G.P. Centrilobular emphysema
experimentally induced by cadmium chloride aerosol. American Review of
Respiratory Disease 108(l): 40-48, July 1973.
SNIDER, G.L., KORTHY, A.L. Internal surface area and number of respiratory air
spaces in elastaseinduced emphysema in hamsters. American Ret,iew of Respira-
tory Disease 117(4): 68M93. April 1978.

SNIDER, G.L., SHERTER, C.B., KOO. K.W. Respiratory mechanics in hamsters
following treatment with endotracheal elastase or collagenase. Journal of Applied
Physiology: Respiratory Encironmental and Exercise Physiology 42(2): 2OG215,
February 1977.

SPAIN, D.M., KAUFMAN, G. The basic lesion in chronic pulmonary emphysema.
American Revieu of Tuberculosis 68: 24-30. 1953.
STEDMAN, R.L. The chemical composition of tobacco and tobacco smoke. Chemical
Reviews 68: 153-207, 1968.

STONE, P.J., CALORE, J.D., SNIDER, G.L., FRANZBLAU, C. The dose-dependent
fate of enzymatically active and inactivated tritiated methylated pancreatic
elastase administered intratracheally in the hamster. American Reuiew of
Respiratory Disease 120(3): 577-587, September 1979.
STONE, P.J., CALORE, J.D., McGOWAN, SE., BERNARDO. J., SNIDER, G.L.,
FRANZBLAU, C. Functional a,-proteinase inhibitor in the lower respiratory tract
of cigarette smokers is not decreased. Science 221(4616): 1187-1189, September 16,
  1983.

STRAUSS, R.H., PALMER, K.C., HAYES, J.A. Acute lung injury induced by
cadmium aerosol. I. Evolution of alveolar cell damage. American Journal of
Pathology 84(412): 561-568, September 1976.
STUPFEL, M., MORDELET-DAMBRINE, M. La penetration des pollutants atmosphe-
riques don les noies aeriennes. [Penetration of pollutants in the airways.] Bulletin
de Physio-Pathologie Respimtoire 10: 481509.1974.
TALAMO, R.C., BLENNERHASSE`IT, M.B., VUSTEN, K.F. Familial emphysema and
alpha]-antitrypsin deficiency. New England Journal of Medicine 275~23): 1301-
1304, December 8.1966.

TALAMO, R.C., LANGLEY, C.E., REED, C.E., MARKINO, S. al-antitrypsin deficien-
cy: A variant with no detectable al-antitrypsin. Science 181: 70-71, 1973.
TAYLOR, J.C., OEY, L. Ceruloplasmin: Plasma inhibitor of the oxidatlve inactivation
of alphai-protease inhibitor. Amerrcan Reuieu, of Respiratop Disease 12613~ 476-
482, September 1982.

325


TAYLOR, J.C., OEY, L.. MITTMAN, C. Protection of alpha,-protease inhibitor by
plasma antioxidants: Potential abnormality in chronic obstructive pulmonary
disease (COPD). Chest 83(5, Supplement): 905-925, 1983.
THOMAS, E.D.. RAMBERG, R.E., SALE, G.E., SPARKES, R.S., GOLDE, D.W. Direct
evidence for a bone marrow origin of the alveolar macrophage in man. Science
192(4243): 1016-1018, June 4,1976.

THOMAS, W., HOLT, P.G., KEAST, D. Effect of cigarette smoking on primary and
secondary humoral responses of mice. Nature 243(5404): 246-241, May 25, 1973.
THOMAS, W.R., HOLT, P.G., KEAST, D. Development of alterations in the primary
immune response of mice by exposure to fresh cigarette smoke. International
Archives of Allergy and Applied Immunology 4W4): 481-486,1974a.
THOMAS W.R., HOLT, P.G., KEAST, D. Humoral immune response of mice with
long-term exposure to cigarette smoke. Archives of Environmental Health 3Ot2):
78-80, February 1975.

THOMAS, W.R., HOLT, P.G., KEAST, D. Antibody production in mice chronically
exposed to fresh cigarette smoke. Experientia 3Of12): 1469-1470, December 15,
  1974b.

THOMSON, M.L., SHORT, M.D. Mucociliary function in health, chronic obstructive
airway disease, and asbestosis. Journal of Applied Physiology 266): 535-539, May
  1969.

TOIGO, A., IMARISIO, J.J., MURMALL, H., LEPPER, M.N. Clearance of large
carbon particles from the human tracheobronchial tree. American Review of
Respimtory Disease 87(4): 487492, April 1963.
TOKORO, Y., EISEN, A.Z., JEFFREY, J.J. Characterization of collagenase from rat
skin. Biochimica et Biophysics Acta 258(l): 289-302, January 20,1972.
TOOMES, H., VOGT-MOYKOPF, I., HELLER, W.D., OSTERTAG, H. Measurement of
mucociliary clearance in smokers and nonsmokers using a bronchoscopic video
technical method. Lung 159(l): 27-34, March 1981.
TRAVIS, J., BAUGH, R., GILES, P.J., JOHNSON, D., BOWER, J., REILLY, C.F.
Human leukocyte elastase and cathepsin G: Isolation, characterization and
interaction with plasma proteinase inhibitors. In: Haveman, H., Janoff, A.
(Editors). Neutral P&eases of Human Polymorphonuclear Leukocytes. Baltimore,
Urban Schworzenberg, 1978, pp. 118128.

TSUCHIYA, M., KENSLER, C.J. The effects of autonomic drugs and 2-amino-2-
methyl propanol, a choline antagonist, on ciliary movement. Federation Proceed-
ings 18: 53,1959.

TWUMASI, D.Y., LIENER, I.E. Proteases from purulent sputum: Purification and
properties of the elastase and chymotyrpsin-like enzymes. Journal of Biological
Chemistry 252: 1917-1926.1977.

U.S. PUBLIC HEALTH SERVICE. The Health Consequences of Smoking. A Report of
the Surgeon General: 1971. U.S. Department of Health, Education, and Welfare,
Public Health Service, Health Services and Mental Health Administration. DHEW
Publication No. (HSM)71-7513,1971,458 pp.
U.S. PUBLIC HEALTH SERVICE. The Health Consequences of Smoking. A Report of
the Surgeon General: 1972. U.S. Department of Health, Education, and Welfare,
Public Health Service, Health Services and Mental Health Administration. DHEW
Publication No. (HSM)72-7516,1972.

U.S. PUBLIC HEALTH SERVICE. `The Health Consequences of Smoking. A Report of
the Surgeon General; 1973. U.S. Department of Health, Education, and Welfare,
Public Health Service, Health Services and Mental Health Administration. DHEW
Publication No. (HSMj74-8704.249 pp.

U.S. PUBLIC HEALTH SERVICE. The Health Consequences of Smoking. A Report of
the Surgeon General: 1974. U.S. Department of Health, Education, and Welfare,
Public Health Service, Health Services and Mental Health Administration. DHEW
Publication No. (CD074-8704, 1974, 124 pp.

326


U.S. PUBLIC HEALTH SERVICE. The Health Consequences of Smoking. A Report of
the Surgeon General; 1975. U.S. Department of Health, Education, and Welfare,
Public Health Service, Health Services and Mental Health Administration. DHEW
Publication No. (CDC)76-8704.1975,235 pp.
U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES. The Health Conse-
quences of Smoking. The Changing Cigarette: A Report of the Surgeon General. U.S.
Department of Health and Human Services, Public Health Service, Office of the
Assistant Secretary for Health, Office on Smoking and Health. DHHS Publication
No. (PHS)81-50156,1981,269 pp.

U.S. DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE. Smoking and
Health: A Report of the Surgeon General. U.S. Department of Health, Education,
and Welfare, Public Health Service, Office of the Assistant Secretary for Health,
Office on Smoking and Health. DHEW Publication No. (PHS)79-50066,1979.
VALAND, S.B.. ACTON, J.D., MYRVIK, Q.N. Nitrogen dioxide inhibition of viral-
induced resistance in alveolar monocytes. Archives of Environmental Health 20:
30%309,1970.

VASSALLO, C.L., DOMM, B.M., POE, R.H., DUNCOMBE, M.L., GEE, J.B.L. NO, gas
and NO,-effects on alveolar macrophage phagocytosis and metabolism. Archives of
Environmental Health 26: 270-274,1973.

VILLIGER, B., BROEKELMANN, T., KELLEY, D., HEYMACH, G.J., III. McDON-
ALD, J.A. Bronchoalveolar fibronectin in smokers and nonsmokers. American
Review of Respiratory Disease 124(5): 652-654, November 1981.
VOSBRAT, L.C., RUMKE, P.H. Immunoglobuline concentraties, PHA reacties van
lymfocyten in vitro en enkele antistof titers van gezonde rakers. [Immunoglobulin
concentration, PHA reactions of lymphocytes in vitro, and certain antibody titers
of healthy smokers.] Jaarboek Kenkerondenoek en Kankerbestrijding 19: 49-53,
  1969.

WANG, H. Different responses of paramecium aurelia to cigarette components.
Nature 197: 946,1963.

WANNER, A., HIRSCH, J.A., GREENLETCH, D.E., FORREST, T., SWENSON, E.W.
Tracheal mucus velocity in beagles after chronic exposure to cigarette smoke.
Archives of Environmental Health 27: 370-371,1973.
WANNER, A. Clinical aspects of mucociliary transport. American Review of
Respimtory Disease 116: 73-125,1977.

WANNER, A. The role of mucociliary dysfunction in bronchial asthma. American
Journal of Medicine 67(g): 477465, September 1979.
WARR, G.A. The biology of normal human bronchoalveolar cells. Bulletin Europeen
a'~ Physiopathologie Respimtoire 15(3): 23-34,1979.
WARR, G.A., MARTIN, R.R. Chemotactic responsiveness of human alveolar macro-
phages: Effects of cigarette smoking. Infection and Immunity 9(4): 769-771, April
  1974.

WARR, G.A., MARTIN, R.R. Immune receptors of human alveolar macrophages:
Comparison between cigarette smokers and nonsmokers. Journal of the Reticu-
loendothelial Society 22(3): 181-187, September 1977.
WARR, G.A., MARTIN, R.R. Histochemical staining and in vitro spreading of human
pulmonary alveolar macrophages: Variability with cigarette smoking status.
Journal of the Reticuloendothelial Society 23(l): 5=2, January 1978.
WARR, G.A., MARTIN, R.R., HOLLEMAN, C.L., CRISWELL, B.S. Classification of
bronchial lymphocytes from smokers and nonsmokers. American Review of
Respiratory Disease 113: 96-100,1976.

WARR, G.A., MARTIN, R.R., SHARP, P.M., ROSSEN, R.D. Normal human bronchial
immunoglobulins and proteins. Effects of cigarette smoking. American Review of
Respiratory Disease 116: 2530,1977.

WEISS, W., WEISS, W.A. Effect of tobacco smoke solutions on paramecium. Archives
of Environmental Health 9: 500, 1964.

327


WEISSBECKER, L., CARPENTER, R.D., LUCHSINGER. R.C.. OSDENE, T.S. In vitro
alveolar macrophage viability. Effect of gases. Archives of Environmental Health
18: 756-759,1969.

WEISSBECKER, L., CRAMER, R.M., CARPENTER, R.D. Cigarette smoke and
tracheal mucus transport rate. American Review of Respiratory Disease 104: 182-
187.1971.

WEST, J.B. Distribution of mechanical stress in the lung, a possible factor in
localization of pulmonary disease. Lancet 1: 83%&l, 1971.
WHITE, R.R., JANOFF, A., GORDON, R., CAMPBELL, E.J. Evidence for in vivo
internalization of human leukocyte elastase by alveolar macrophages. American
Review of Respiratory Disease 125(6): 779-781, June 1982.
WHITE, R., LEE, D., HABICHT, G.S., JANOFF, A. Secretion of alphal-proteinase
inhibitor by cultured rat alveolar macrophages. American Review of Respiratory
Disease 123(4): 447449, April 1981.

WILDE, W. Mucociliary clearance of the slug mucosa exposed to dust and cigarette
smoke. (Letter). Medical Journal of Australia l(9): 494-495, May 2, 1981.
WOOD, R.E., WANNER, A., HIRSCH, J., DI SANT'AGNESE, A. Tracheal mucociliary
transport in patients with cystic fibrosis and its stimulation by terbutaline.
American Review of Respiratory Disease 111: 733-738,1975.
WRIGHT, D.. GALLIN, J. Secretory responses of human neutrophils. Journal of
Immunology 123: 285-293,1979.

WRIGHT, R.R., STUART, C.M. Chronic bronchitis with emphysema: A pathological
study of the bronchi. Medicinae Thoracalis 22: 210,1965.
WYNDER, E.L., GOODMAN, D.A., HOFFMANN. D. Ciliatoxic components in
cigarette smoke. II. Carboxylic acid and aldehydes. Cancer 18: 505-509, 1965a.
WYNDER E.L., GOODMAN, M.S., HOFFMANN, D. Ciliatoxic components in
cigarette smoke. III. In vitro comparison of different smoke components. Cancer 18:
1652-1658,1965b.

WYNDER, E., KAISER, H.E., GOODMAN, D.A., HOFFMANN, D. A method for
determining ciliostatic components in cigarette smoke. Cancer 16: 1222,1963.
YAGER, J.A. ELLMANN, H., DULFANO, M.J. Human ciliary beat frequency at
three levels of the tracheobronchial tree. American Reuiew of Respimtory Disease
121(4): 661-665, April 1980.

YEAGER, H., Jr. Alveolar cells: Depressant effect of cigarette smoke on protein
synthesis Proceedings of the Society for Experimental Biology and Medicine 131(l):
247-250, May 1969.

YEATES, D.B., ASPIN, H., LEVISON, H., JONES, M.T., BRYAN, A.C. Mucociliary
tracheal transport rates in man. Journal of Applied Physiology 39(3): 487495,
September 1975.

YORK. G.K., ARTH, C., STUMBO, J.A., CROSS, E.C., MUSTAFA, M.G. Pulmonary
macrophage respiration as affected by cigarette smoke and tobacco extract.
Archrues of Envrronmental Health 27(2): 9&98, August 1973.
ZARKOWER, A., MORGES, W. Alteration in antibody response induced by carbon
inhalation: A model system. Infection and Immunity 5(6): 915-920, June 1972.
ZARKOWER, A., RHOADES, R.A., ROTHENBACHER, H.J. Effect of inhaled carbon
on immune response in mice and rats. Proceedings of the Canadian Society of
Biological Sciences 13: 641, 1970.

ZWICKER, G.M., FILIPY, R.E., PARK, J.F., LOSCUTOFF, SM., RAGAN, H.A.,
STEVENS, D.L. Clinical and pathological effects of cigarette smoke exposure in
beagle dogs. Archives of Pathology and Laboratory Medicine 102(12j: 623-628.
December 1978.

328


CHAPTER 6. LOW YIELD
         CIGARETTES AND
         THEIR ROLE IN
         CHRONIC
         OBSTRUCTIVE LUNG
         DISEASE

329

480-144 0 - 85 - 12


CONTENTS

Introduction

Problems of Measurement by Machine

Effect of Low Tar and Nicotine Cigarettes on Cough and
Phlegm Production and Development of Chronic
Obstructive Lung Disease
Epidemiologic Studies

Mechanisms of Lung Damage

Variation in Smoking Pattern With Switching to Low
Tar and Nicotine Cigarettes
  Smoking Behavior
Carbon Monoxide Uptake
  Nicotine Uptake
  Role of Tar Content

Variations in Pattern of Cigarette Smoke Inhalation

Use of Additives in Low Tar and Nicotine Cigarettes

Research Recommendations

Summary and Conclusions

References

331


Introduction

Following the initial reports in the early 1950s linking cigarette
smoke with lung cancer, the pathogenic role of cigarette tar content
received considerable emphasis. Because the tar fraction of the
smoke contained the bulk of the carcinogenic effect of whole smoke,
and because lung cancer risk was closely related to other measures of
total smoke exposure (number of cigarettes smoked per day, depth of
inhalation, etc.), it was suggested that risk might be related to the
amount of tar generated by different cigarettes. This prompted
health authorities to advise smokers who were unable to quite
smoking to switch to low tar cigarettes (U.S. Senate 1967; Health
Department of the United Kingdom 1976). To facilitate this process,
the Federal Trade Commission published smoking-machine assays of
the tar and nicotine yield of different cigarette brands (Pillsbury et
al. 1969). This approach to low tar and nicotine cigarettes was based
on the assumption that smoking lower yielding brands, as deter-
mined by a smoking-machine, would result in a proportional
reduction in the lung's exposure to these toxic substances. This
approach to "safer" cigarette smoking has been promoted by the
tobacco industry and apparently accepted by the smoking public, as
evidenced by the escalation in sales of low tar and nicotine
cigarettes. However, there is increasing evidence that this concept of
a "less hazardous" cigarette is misleading; although definitive
studies are still awaited, it appears that switching from regular to
low tar and nicotine cigarettes may not substantially reduce the risk
of chronic airflow obstruction.

Problems of Measurement by Machine

The first step in evaluating the relative health risks of different
cigarettes is to establish some standardized measure of the toxic
substances in different cigarettes in order to facilitate comparison.
Quantifying each of the several thousand constituents of cigarette
smoke for each brand of cigarette, and assessing the changes in these
constituents as the manufacturing and agricultural processes
change, would be a truly herculean task; therefore, a more modest
goal of quantifying tar and nicotine yields was accepted. To date, the
yields determined by the Federal Trade Commission have been the
most widely adopted. These measurements are obtained with a
laboratory smoking-machine, which consists of a syringe pump that
takes a 35 ml bell-shaped puff from a cigarette, over a 2-second
period, once per minute until a predetermined butt length is
reached, either 23 mm for nontiltered cigarettes or 3 mm longer than
the filter overwrap for filter-tipped cigarettes (Pillsbury et al. 1969).
These parameters are based on observations of smoking patterns in
seven subjects in Europe in 1933 (Kozlowski 1983). Today's cigarette

333


is markedly different from that smoked in 1967 when these
parameters were established, yet the same parameters are still
employed.

Measurements obtained using these parameters indicate a marked
reduction in the tar and nicotine yield of cigarettes over the last
decade (Figure 1). In addition to the actual tar and nicotine yield of
the tobacco, the yield measured by a smoking-machine is influenced
by many factors, including cigarette length and diameter, porosity of
the cigarette paper, presence of a ventilated or an unventilated
filter, butt length, number of puffs, interpuff interval, puff volume,
puff duration, puff pressure profile, and frequency of puffing at
different stages of cigarette consumption. The number of puffs is
important in determining the tar yield of a cigarette, and the
number of puffs taken from some brands with the official smoking-
machine has significantly declined in recent years (Kozlowski 1981).
Since puffs are taken at l-minute intervals, a more rapidly burning
cigarette will have a smaller number of puffs. The burning time of
the cigarette is determined by porosity of the cigarette paper, the-
amount of tobacco in the cigarette, and the diameter of the cigarette
column. In a survey of Canadian cigarettes between 1969 and 1974,-
Kozlowski et al. (1980b) noted a significant reduction in the number-
of puffs taken in the official assays over this time period, which was
strongly correlated with a reduction in tar yield. Omission of the last-
few puffs can markedly affect tar yield, because tar delivery-
increases with each puff, and the last few puffs from a cigarette can
contain twice as much tar as the first few puffs (Wiley and Wickham
1974). Currently published yields do not indicate the number of puffs
taken, which may range from 7 to 12 and may result in a marked
variation of the tar yield.

Ventilated cigarette filters, which cause inhaled smoke to be
diluted with air, are one of the major methods of achieving low tar
yields (Gori and Lynch 1978). Cigarettes with ventilated filters
constituted about 25 percent of all cigarette sales in the United
States in 1979 (Hoffmann et al. 1980). During systematic interviews,
Kozlowski et al. (1980a) found that from 32 to 69 percent of low tar
smokers block these filter perforations with their fingers or lips, a
feature unaccounted for by smoking-machines. This hole blocking
increased the yield of toxic products by 59 to 293 percent.

If a person smokes a cigarette in a manner identical to the
smoking-machine, the delivery of tar and nicotine to the mouth will
be the same as that estimated by the machine. Human smoking
patterns are diverse, however, and show considerable variation from
the machine parameters; puff volumes range from less than 20 ml to
more than 90 ml (Tobin and Sackner 19821, compared with the fixed
35 ml volume employed by the machine. Differences in puff profile
from the bell-shaped puff used by the machine also alter cigarette

334


Tar mg

100 -'









  1950     1955     1960     1965     1970     1975     1980

FIGURE l.-U.S. sales-weighted average tar and nicotine
       yields

SOCRCE Amencan Cancer Scaety 11981 I

yield. Numerous studies indicate that smokers compensate for lower
yielding cigarettes by altering their style of smoking. For each
different cigarette brand, smokers may have a different smoking
oattern. To provide more meaningful information, smoking-ma-
:hines should be designed to reproduce variations in the manner of
smoking each cigarette brand, and their assays should provide both
m average and a range of tar and nicotine yields depending on the
ndividual pattern of smoking (USDHHS 1981).
Many investigators have examined the relationship between the
nachine-determined nicotine yield of a cigarette and the concentra-
ion of nicotine or its metabolites in blood or urine. A fair correlation
vas observed in some studies (Goldfarb et al. 1976; Herning et al.
9831, but most studies have revealed a poor correlation (Russell et
-1. 1975, 1980; Sutton 1982; Feyerabend 1982; Benowitz et al. 1983).
Jachinedetermined nicotine yield accounts for only from 4 (Russell
t al. 1980) to 25 percent (Herning et al. 1983) of the variation in
lood nicotine concentration, whereas 50 to 60 percent of the
ifferences in blood nicotine levels are attributable to individual


smoking behavior. The overriding importance of the pattern of
smoking in determining nicotine delivery from a cigarette was
underlined in a recent study demonstrating that the nicotine content
of the unburned tobacco was similar for cigarettes with high and low
nicotine yields determined by smoking-machine assays (Benowitz et
al. 1983).

The concept of providing the smoker with information on cigarette
yield need not be abandoned. Smoking-machines can be designed to
control the puff number, puff volume, puff pressure profile, puff
duration, puff interval, butt length, position of the cigarette during
and between puffs, and "restricted" or "free" smoking, i.e., whether
the butt end is closed or open Kreighton and Lewis (1978a, b). These
parameters should be determined and used to obtain an average and
a range of yields for each brand. Measurement of cigarette yield
should include assays not only of tar and nicotine but also of carbon
monoxide and other toxic substances, because compensatory smok-
ing behavior may alter the exposure to each substance beyond that
expected on the basis of tar and nicotine delivery.

Effect of Low Tar and Nicotine Cigarettes on Cough and
Phlegm Production and Development of Chronic Obstructive
Lung Disease

Cigarette smokers account for the vast majority of deaths from
chronic obstructive lung disease (COLD) (Peto et al. 1983), and the
relative risk for the effects of smoking on mortality from COLD is
even greater than that for lung cancer (see the chapter on Mortality
in this Report). Chronic obstructive lung disease in smokers may
take the following three forms: (1) cough and mucus hypersecretion,
(2) airway obstruction, and (3) emphysema. Frequently the three
components coexist, as all are related to cigarette smoking, but the
agents in cigarette smoke responsible for each type of lung injury
may be different. Over the past 25 years, considerable progress has
been made in our understanding of the role of cigarette smoking in
the pathogenesis and natural history of COLD, but most of the
available data have not related lung function to cigarette yield.

Epidemiologic Studies

The cardinal importance of cigarette smoking in the pathogenesis
of COLD has been repeatedly documented, and generally the
severity of disease increases with increasing cigarette consumption
(Ferris et al. 1976). Because of this dose-response relationship, it has
been hoped that a reduction in cigarette yield by filtration or other
means would reduce the risk of disease (Gori 1976). Available
epidemiologic studies of the effect of low yield cigarettes on the
development of COLD have shown variable results, which reflects

336


marked differences between the studies in terms of the population
studied, sample size, variation in cigarette brands, reference period
of the study, criteria of respiratory involvement, and type of
statistical analysis, and whether the study was of a cross-sectional or
a longitudinal design. Separating the studies by the three compo-
nents of smoking-induced COLD indicates that there is a growing
body of data on the effect of cigarette yield on the development of
mucus hypersecretion and airway obstruction, but currently no
information on the development of emphysema.

Several studies have examined the effect of cigarette yield on
respiratory symptoms and have observed a relationship between
reduction in cigarette yield and the prevalence of cough (Comstock et
al. 1970: Freedman and Fletcher 1976; Fletcher et al. 1976; Dean et
al. 1978; Schenker et al. 1982) and phlegm production (Comstock et
al. 1970; Rimington 1972; Hawthorne and Fry 1978; Higenbottam et
al. 1980b). Tar yield was not defined in some of these earlier studies
(Comstock et al. 1970; Rimington 1972; Dean et al. 1978; Hawthorne
and Fry 19781, but instead a comparison was made between smokers
of plain cigarettes and smokers of filter-tipped cigarettes. The tar
yield was specified in some studies: in the recent study by Schenker
et al. (1982) it ranged from 0.4 to 28 mg; in the studies by Freedman
and Fletcher (19761, from 17 to 20 mg; and in the studies by
Higenbottam et al. (1980b1, from 18 to more than 33 mg, higher than
that observed in many of today's cigarettes. In a cross-sectional
survey of over 18,000 men (Higenbottam et al. 1980b), the beneficial
effect of low tar cigarettes on phlegm production was lost when
subjects smoked 20 or more cigarettes per day, as their prevalence of
phlegm production increased to that observed in higher tar cigarette
smokers. In contrast, in another cross-sectional study of 5,686
women (Schenker et al. 19821, cigarette tar content was a significant
risk factor for chronic cough and of borderline significance for
phlegm production; this effect of cigarette tar content was indepen-
dent of the number of cigarettes smoked per day. Chronic cough or
phlegm production was approximately twice as common in smokers
of high tar (at least 20 mg) cigarettes as it was in low tar (less than 10
mg) smokers. In the latter study, however, multiple logistic regres-
sion analysis indicated that the risk of chronic cough and phlegm
production is more strongly affected by daily cigarette consumption
than by tar content: these symptoms were 4.5 times more common in
smokers of 25 or more cigarettes per day than in smokers of less than
15 cigarettes per day.

A small number of studies have examined the importance of
cigarette yield on change in pulmonary function. In a prospective
study of 680 men, Comstock et al. (1970) noted that smokers of plain
cigarettes, compared with smokers of filter-tipped cigarettes, had a
lower FEV, at entry into the study. Followup measurements showed

337


I a23   24-27   2E32    .33

Tar per cigarette Prv$

FIGURE 2.-Relationship between mean FEVI of
      asymptomatic smokers (adjusted for height and
       weight) and tar yield of cigarettes, by number
      of cigarettes smoked per day
SOURCE: Hlgenbottam et al rlS&Wbi.

a greater mean reduction of FEVl in users of filter-tips, so that the
reduction was similar in the two groups after 5 to 6 years of followup.
Unfortunately, the variance of the data was not stated, and tests of
statistical significance were not performed. In another longitudinal
survey of 1,355 men, Sparrow et al. (1983) determined the effect of
cigarette tar content, which ranged from less than 16 mg to more
than 22 mg, on pulmonary function. Multiple regression analysis
indicated that tar content did not significantly influence baseline
spirometry or repeat measurements after 5 years of followup. Cross-
sectional epidemiologic surveys also indicate no relationship be-
tween abnormal pulmonary function and the use of filter-tipped
versus plain cigarettes (Beck et al. 1981) or cigarette tar content
(Higenbottam et al. 1980b) (Figure 2).

Interpretation of these studies as evidence that cigarette tar and
nicotine yield is not an important factor in the development of COLD
is premature. First, cross-sectional studies are limited in their
capability of defining the natural history of a disease. Second, COLD
has a very slow progress, and Fletcher et al. (19761 suggest that a
span of approximately 8 years is necessary to establish rates of
change of spirometric values with sufficient confidence even to
distinguish between smokers and nonsmokers. Third, we have no
information on the baseline pulmonary function of smokers at the
time they choose between high or low tar and nicotine cigarettes.
Significant differences in pulmonary function have been observed
between young adults who decide to smoke and those who avoid
cigarette smoking (Tashkin et al. 19831, and it is possible that similar

338


function differences may exist in subjects who choose between high
or low tar and nicotine cigarettes. Fourth, the yield of tar and
nicotine used in many of these studies does not lie in the same range
as that produced by many of today's cigarettes.

However, the possibility that cigarette tar content is related to the
development of cough and phlegm, but not of dyspnea or airflow
obstruction, is consistent with current concepts of COLD. In a study
of 792 men followed over an g-year period, Fletcher et al. (1976)
observed that cigarette smokers were susceptible to two distinct
chronic lung diseases-mucus hypersecretion and chronic airflow
obstruction. This has recently been confirmed in a large prospective
study (Peto et al. 1983) of 2,728 men, followed over 20 to 25 years,
which showed that the risk of death from COLD was strongly
correlated with initial degree of airflow obstruction, but bore no
relationship to initial mucus hypersecretion.

Given the evidence that mucus hypersecretion may depend on the
tar fraction of cigarette smoke, while development of airflow
obstruction is more closely linked to the ilumber of cigarettes
smoked, Higenbottam et al. (1980b) reasoned that these differences
might be due to a reduction in the particulate phase products,
without a decrease in the gas phase products, in the low tar
cigarettes. They hypothesized that tar droplets and soluble gases,
such as sulfur dioxide and hydrogen cyanide, are more likely to be
deposited or absorbed in the large airways where mucus is produced.
The smaller airways, the earliest site of airflow obstruction, are
exposed to a lower concentration of tar, but to a full concentration of
insoluble gases such as nitrogen dioxide and ozone.

This line of reasoning is in agreement with several studies showing
a reduction in lung cancer with the use of low tar and nicotine
cigarettes (Wynder et al. 1970; Lee and Garfinkel 1981; Rimington
1981; Hammond et al. 1976). The tar fraction is the component of
cigarette smoke particularly linked with the development of both
lung cancer and mucus hypersecretion. Although clinicians have
long linked chronic bronchitis (mucus hypersecretion) with emphyse-
ma, recent evidence indicates that mucus hypersecretion is not
predictive of airflow obstruction, but is significantly greater in those
smokers who develop lung cancer (Pete et al. 1983).

Mechanisms of Lung Damage

Studies of the mechanism of cigarette-smoke-induced lung damage
have contributed significantly to the present understanding of
COLD. Cigarette smoke may initiate and aggavate lung injury by a
number of mechanisms and may also interfere with the lungs'
defense responses.

These mechanisms include the prot.ease-ir$$bit,or imbalance theo-
ry for the pathogenesis of emphysema whereby alveolar wall

339


digestion results from an excess of proteases, a deficiency of their
inhibitors, or a combination of both factors (see the chapter on
Mechanisms in this Report). The sources of endogenous proteases
include polymorphonuclear neutrophils and alveolar macrophages,
both of which are found in increased number in the lungs of cigarette
smokers. Protease release from both macrophages and neutrophils is
increased in the presence of cigarette smoke (Rodriquez et al. 1977;
Blue and Janoff 1978). In health, proteases are continually inhibited
by al-antitrypsin, whereas proteases cause unimpeded digestion of
lung tissue in patients with al-antitrypsin deficiency, with a
markedly increased risk of emphysema. In addition to increasing the
protease burden, cigarette smoke causes a functional inhibition of al-
antitrypsin through the action of oxidants in cigarette smoke (Janoff
et al. 19791.

The relative potency of smoke from cigarettes of varying tar and
nicotine yields in stimulating protease production and release and in
inhibiting al-antitrypsin has received scant scientific investigation.
Travis et al. (1980) tested the effect of both filtered and unfiltered
cigarette smoke on the elastase inhibitory activity of al-antitrypsin.
Filtered smoke reduced elastase inhibitory activity by 3 percent, and
a 19 percent reduction was observed with unfiltered smoke; the tar
content of the respective smokes was not stated. The researchers
reasoned that this small in vitro effect would be greatly magnified by
in vivo conditions in the lung, particularly through its huge surface
area. In addition to examining the effect of filters, Cohen and James
(1982) recently examined the effect of tar and nicotine content on the
elastase inhibitory capacity of al-antitrypsin. The oxidant capacity of
cigarette smoke was also examined using a chromogenic electron
donor. Aqueous condensates of cigarette smoke were obtained from a
variety of brands ranging in tar content from about 1 mg to more
than 20 mg. Reported tar and nicotine content correlated well with
the amount of measured oxidants and the ability of a brand to reduce
the elastase inhibitory capacity of al-antitrypsin. Filters were found
to remove 73 percent of the oxidants from the aqueous smoke
solutions. While these findings suggest that low tar and nicotine or
filter-tipped cigarettes could reduce a smoker's predisposition to
enzymatic lung damage and consequent COLD, it should be noted
that neither study examined the effect of lower yield cigarettes on
protease production. Morosco and Gueringer (1979) demonstrated a
greater increase in elastase in dogs exposed to high nicotine cigarette
smoke compared with low nicotine cigarette smoke. More important,
these studies have not taken into account the compensatory changes
in smoking pattern likely to result with lower yield cigarettes.

The airway response to acute exposure to cigarette smoke has been
examined by several investigators employing spirometry (Da Silva
and Hamosh 19811, body plethysmograph (Nadel and Comroe 1961j.I

340


and breathing pattern analysis (Tobin et al. 1982a). Airway narrow-
ing has been consistently observed by some investigators (Nadel and
Comroe 1961; Sterling 1967; Tobin et al. 1982a), but others report a
variable response (Higenbottam et al. 1980a; Rees et al. 1982). In
some studies, the acute airway response was unrelated to cigarette
yield (Higenbottam et al. 1980a), but in most investigations (Robert-
son et al. 1969; Tobin et al. 1982a; Rees et al. 1982), smoking a low tar
or filter-tipped cigarette induced less acute bronchoconstriction. The
acute airway response is probably localized to the larger airways, as
acute cigarette exposure resulted in no change in the nitrogen
washout test of small airway function (Da Silva and Hamosh 1973;
Tobin et al. 1982al. These observations on the relative bronchocon-
strictor response of various types of cigarettes may be important in
our understanding of why some smoking novitiates persist with the
habit despite the initial unpleasant reactions (Tashkin et al. 1983),
but it is unlikely that repeated episodes of smoking-induced acute
airway narrowing finally result in COLD.

Future studies examining the mechanism of smoking-induced lung
injury must not only take into account the range of cigarette yields,
as determined by a smoking-machine, but also consider variations in
smoking behavior. Puff volumes may vary considerably with nomin-
al cigarette tar and nicotine content, thus altering the relative
amount of various toxic substances yielded by different cigarettes.
Similarly, inhalation profiles are of a diverse nature (Tobin et al.
1982b) and are likely to significantly alter the distribution, penetra-
tion, and retention of cigarette smoke constituents in the lungs.

Variation in Smoking Pattern With Switching to Low Tar and
Nicotine Cigarettes

Low tar and nicotine cigarettes have gained considerable populari-
ty among the smoking public, partly on the premise that a reduction
in the nominal tar and nicotine yield results in a proportional
reduction in the health hazards of cigarette smoking. The validity of
this approach to cigarette smoking is contingent on the accuracy of
smoking-machines in reflecting the actual manner of puffing and
also on the smoker not altering smoking behavior to compensate for
variations in nominal tar and nicotine content. Should smokers
develop compensatory alterations in their smoking behavior, this
would not only reduce the relevance of the smoking-machine assays
but might also alter the proportionate delivery of the different toxic
substances in cigarette smoke and expose the smoker to concentra-
tions beyond those predicted by the smoking-machine.

341


Smoking Behavior

Nearly 40 years ago, Finnegan et al. (1945) studied the effect of
alterations in cigarette nicotine content on smoking behavior and
noted no change in cigarette consumption. It is only in the last
decade, with the increasing popularity of low tar and nicotine
cigarettes, however, that this question has attracted signEcant
interest. The results of 38 studies examining alterations in smoking
behavior with a reduction in cigarette yield are shown in Table 1.
Considerable differences can be observed between the studies, partly
reflecting variations in the level of cigarette yield reduction,
alterations in other cigarette constituents, type and duration of
switching procedure, parameters evaluated, and techniques used in
their measurement.

Most studies agree that smokers rarely increase their daily
cigarette consumption upon switching from higher to lower yield
brands. Reports are almost equally divided as to whether a smoker
increases the number of puffs per cigarette or shows no change on
switching to a lower yielding brand. There is an almost unanimous
consensus that smokers take a larger puff volume from a lower
yielding brand. Studies of puff volume also indicate huge variation
between individual subjects (Guillerm and Radziszewski 1978; Hern-
ing et al. 1981; Tobin and Sackner 1982; Herning et al. 1983) and
that considerable increases in puff volume may occur on switching
from a higher to a lower yielding brand, with certain subjects
increasing their puff volume by up to 75 percent (Tobin and Sackner
19821. This compensatory increase in puff volume may be observed
within a single experimental session (Tobin and Sackner 1982) and
maintained over several weeks Rawbone et al. 1978; Stepney 1981).
Full compensation for a lower yielding cigarette is generally not
achieved by smokers taking a large puff volume (Rawbone et al.
1978; Herning et al. 1981; Tobin and Sackner 1982).

Instrumentation is required to quantitatively assess the pattern of
smoking, but it is important to realize that such instrumentation
may, in itself, alter usual smoking behavior. Puff volume has been
almost universally measured by using a specialized cigarette holder
incorporating different flowmeter designs (Frith 1971; Adams 1977;
Rawbone et al. 1978). These devices consist of two tubes connected to
a pressure transducer that measures the pressure drop across a
small resistance (a filter insert) in the holder; the flow measured is
integrated to obtain volume. Use of a cigarette holder has been
shown to increase the rate of puffing and puff volume, compared
with measurements made with the cheek inductive plethysmogra-
phy coil (Tobin and Sackner 1982).

Unlike the compensatory increases in puff volume, measurements
of the subsequent inhalation volume-which includes the volume of
smoke mixed with air inhaled into the lung-have shown no change

342


TABLE l.-Effect of smoking low yield cigarettes on smoking pattern

                                                (`0 paramrters           Nlcotme parameters ~____
                        Number Number        Volume   Durat Km           Relationship    Nlcotinr'rotlninr  Mouth Relationship
      Reference Expenmental of cigs of     Puff     of       of        Expwd     to          level      CCpOS"W    LO
First author    year     de@   smoked puffs/cig volume mhalatmn  mhalatlon  C'OHb   (`0  nominal yield   tblood!ur~ne/salw;i)  Index normal yield

F1llIIegaIl      I945
Ashton       1970
Fnth        1971
(bhen        1971
Rwssell       1973
Turner       1974
Russell       1975
Coldfarb      1976
FO&8       I976
Adams       1977
Wald        1977
Sutton        I978
R&s&one      1976
Schulz        197X
(`wghtnn     1978a.b
Adams       1978
(;udlerm      1978
clamk        1978
Ashton       1979
tiarfinkrl      1979
HI11         19fUl
RobInson      I980
Russell       1980
Hrnnmgtield    1980
Wald        19&I

cl3      NC
VCF
CS
CS
cs      t
CS
cs       I
CS      f
CS
cs      NC
svs
VCF      NC
C'S
CS      NC
s
CS
cs
CS
CS      NC
svs      NC
cs
svs
svs
VCF      NC
svs

NC
1 /1N(

NC     NC

                         I
NC     i      N(

t     t
1     NC     NC

t                         t     NC

PcKJr
(hod
PO0 I

1      POW


E   TABLE I.-Continued
Dr-                                                      CO paramrten           Nicotme parameters

                             NUdW  NUdW        Volume   rhmitml           Belatlonshlp   Nwtmeicotinme  Mouth Belatlonship
           Reference Experimental of CITY    of     Puff     of       of        EXPlWd     to          level      exposure    t4,
    Fwst author    year     design   smoked puffs/cig volume lnhaletwn lnhalatlon  COHb (`0  nominal yleld   ibloodod/urme/saliva~ Index  normal yield


   Hernmg       1981       cs            NC'     I                         t

    Wtlld        19R1       svs      NC                            I           Poor
   Stepney       1981      cs      NC     t      f                       I      Fair         I        I
    Jaffe        1981      svs    NC/ 1                                   NC     PCXJr
    Tobin        1982      cs            NC     I      NC      NC
   Battig        1982      svs      NC           t                        NC
    Sutton        1982      svs                t                              coed                        Poor
    Griffith8      1981       CS             NC     t
    Jaffe        1982      cs     NC/ 1                                   NC     Poor
   Feyrrabend     1982      svs                                                                           Poor
   HtTWlg       1983      cs                                                                           FHIT
    Benowitz      19n3      svs

     NOTE Cs controlled swtchmg. VCF - var,able c,garette filters. SVS a~wntaneo~rs voluntary wltchw. NC = no change. T - mcreaee. ;  = dexeaee. CO - ctlrbon monvx,dr


on switching to a low yield cigarette. Likewise, in one short-term
study (Tobin and Sackner 1982), duration of inhalation showed no
relationship to nominal cigarette yield. Perhaps compensatory
changes in inhalation parameters require a longer period of time
than puff volume does.

Measurement of carboxyhemoglobin (COHb) concentration has
been proposed as an index of the pattern of inhalation (Wald et al.
1975, 1978). While COHb provides valuable information on the
amount of carbon monoxide absorbed from the lung during compen-
satory alterations in smoking behavior, it is an indirect index and
provides complementary information on cigarette smoke inhalation
rather than replacing direct measurements of the volume of
inhalation.

Carbon Monoxide Uptake

Unlike tar and nicotine, which are present in the particulate
phase, carbon monoxide (CO) is a constituent of the vapor phase of
cigarette smoke. For this reason, cigarettes purported to produce a
low tar and nicotine yield may not necessarily provide a lower yield
of carbon monoxide. Compared with tar and nicotine yield, carbon
monoxide yield is more dependent on cigarette design, including
such features as paper porosity and perforations in the filter tips.
These factors regulate the dilution of smoke with air and the
burning profile of the cigarette, and thus can significantly reduce
carbon monoxide yield. Wald (1976) showed that the carbon monox-
ide yield of filter-tipped cigarettes was 28 percent higher than that of
plain cigarettes, although the average nicotine yield was lower in the
filter-tipped cigarettes. He reasoned that smoke passing through a
cigarette is diluted by air entering through the porous cigarette
paper. However, the filter of filter-tipped cigarettes is surrounded by
relatively nonporous paper, resulting in a higher content of carbon
monoxide exiting from the proximal cigarette end. Perforations in
the filter tip circumvent this problem and significantly reduce
carbon monoxide yield (Hoffmann et al. 1980; Wald and Smith 1973).

Many investigators have measured COHb or carbon monoxide
concentration in expired gas following cigarette smoking and
compared the levels achieved in smoking brands with different
nominal yields (see Table 1). An increase, decrease, or no change in
carbon monoxide intake has been observed, depending on relative
differences in cigarette design and experimental procedure. As
expected,  unventilated filter-tipped cigarettes produced higher
COHb levels than those observed with unfiltered cigarettes (Wald et
al. 1977). This is in agreement with information provided by
smoking-machine assays (Wald et al. 19731, but the use of ventilated
filter-tipped cigarettes may produce COHb levels similar to those
observed with unfiltered cigarettes despite lower carbon monoxide

345


yields on smoking-machine assay (Wald et al. 1977). Comparison of
cigarettes with a marked difference in nominal carbon monoxide
yield usually results in a lower COHb level when the lower yielding
brand is being smoked (Russell et al. 1973; Turner et al. 1974; Sutton
et al. 1978; Ashton et al. 1979); but over the range of different carbon
monoxide yields there is a poor correlation between levels of COHb
and measured carbon monoxide yield. Similar information has been
observed using expired carbon monoxide concentrations.

Nicotine Uptake

It has been long considered that nicotine might serve as a primary
reinforcer of cigarette smoking and that smokers might adjust their
smoking behavior to regulate their level of nicotine intake. Several
investigators have measured the blood, urinary, or salivary levels of
nicotine or its major metabolite cotinine during the smoking of
cigarettes of varying nominal nicotine yields (see Table 1). A
reduction in blood (Russell et al. 1975; Sutton et al. 1978; Ashton et
al. 1979; Hill and Marquardt 1980) and urinary (Goldfarb et al. 1976;
Ashton et al. 1979; Stepney 1981) nicotine levels or in plasma (Hill
and Marquardt 1980; Stepney et al. 1981) and urinary (Ashton et al.
1979; Hill and Marquardt 1980) cotinine levels has generally been
observed on switching to a cigarette with a lower nominal nicotine
yield. However, smokers show variable degrees of compensation for
the lower yield, as there is generally a poor relationship between
nominal nicotine yield and measured blood nicotine levels (Russell et
al. 1980; Sutton et al. 1982; Feyerabend et al. 1982; Benowitz et al.
1983).

Relating nominal nicotine yield and blood nicotine levels, Ashton
et al. (1979) estimated that smokers compensated for about two-
thirds of the difference in nominal yields when they switched from
medium nicotine cigarettes to high or low nicotine brands. Using a
stepwise multiple regression analysis of nicotine yield and blood
nicotine concentration, Russell et al. (1980) observed a significant,
but very weak, correlation (r = 0.21) between the two measurements,
but the nominal nicotine yield of the cigarettes accounted for only
4.4 percent of the variability in blood nicotine concentrations. The
use of absolute rather than logarithmic analysis in this study has
been criticized (Kozlowski et al. 1982; Herning et al. 19831, and the
criticism involved the problems of trying to predict doses to
individuals rather than the dose to groups. In another study using
log-linear regression analysis (Herning et al. 19831, a better correla-
tion was observed between nominal nicotine yield and the increasing
blood nicotine after smoking (r=0.5), but this study used Kentucky
reference cigarettes rather than commercial brands, and these low
yield cigarettes have less nicotine in the unburned tobacco than
commercial low yield brands. Such a relationship still accounted for

346


only 25 percent of the individual differences in blood nicotine levels,
whereas 50 to 60 percent was accounted for by individual differences
in smoking behavior (Herning et al. 1983).

Additional information on compensatory alterations in nicotine
intake has been provided by studying the mouth exposure index,
which is calculated from analysis of cigarette butts for nicotine
content and a knowledge of the retention efficiency of the filter tip
(Ashton and Watson 1970). Because the amount of nicotine retained
by a filter is proportional to the amount that passes through, it is
possible to estimate the amount of nicotine presented to the smoker
from the nicotine content of the filter. Results using this index have
revealed a greater variation between individual studies (see Table 1)
than obsewed with blood nicotine measurements. This may be
related to the fact that filter efficiency is usually determined by a
machine, but retention of nicotine is also dependent on the way the
cigarette is smoked; therefore, the retention efficiency of the filter
may vary between smokers.

Role of Tar Content

The observations that smokers adapt their smoking behavior
according to the nicotine delivery of a cigarette and that many of the
toxic effects of smoking appear to be related to tar rather than
nicotine content has led to the suggestion that altering the tar to
nicotine ratio might produce a cigarette less hazardous to health
(Russell 1976; Stepney 1981). A cigarette with a medium nicotine,
low tar, and low carbon monoxide yield might be advantageous.
While nicotine has been the component most extensively studied, it
may not be the only substance responsible for the addictive power of
tobacco. It is not possible to separate the effects of tar and nicotine in
most studies, as their respective yields usually show a very close
correlation.

Using research cigarettes providing three different yields of
nicotine and two different yields of tar, Goldfarb et al. (1976) found
evidence of compensation for nicotine but not for tar content. The
authors urged cautious interpretation of the results because of the
limited range of tar yields examined. Examining a large number of
subjects smoking cigarettes of varying tar and nicotine yield, Wald et
al. (1981) found that both tar and nicotine were significantly related
to blood COHb, taken as an index of cigarette smoke inhalation. Two-
way analysis of variance of the data indicated that after allowing for
the effect of either tar or nicotine yield, the COHb index was no
longer significantly influenced by the other. A cross-over study of
medium tar smokers who were switched to low nicotine, low tar
cigarettes and medium nicotine, low tar cigarettes has been reported
by Stepney (1981). While the intake of carbon monoxide was least
with the medium nicotine, low tar cigarette, the mouth exposure

347


index to tar was similar among the brands. Indeed, the pattern of
smoking adopted by the subjects was more effective in reducing the
difference in tar delivery between the cigarettes than in compensat-
ing for nicotine delivery. Further evidence indicating the importance
of cigarette tar delivery in-determining smoking behavior was
reported by Sutton et al. (1982). Using multiple regression analysis,
they observed that when nicotine yield was controlled, smokers of
lower tar cigarettes had higher blood nicotine levels than smokers of
higher tar cigarettes, indicating that they inhaled a greater volume
of smoke. In contrast, when tar yield was controlled, smokers of
lower nicotine cigarettes had lower blood nicotine concentrations
than smokers of higher nicotine cigarettes, indicating that they
inhaled less smoke. These results suggest some compensation for tar
over and above any compensation for nicotine. It may be that
ncnpharmacologic, sensory stimulation by factors such as the flavor
of cigarette smoke may be more important than nicotine in
determining smoking behavior.

These new observations, especially on the role of tar delivery,
require further investigation. Most published research consists of
controlled switching experiments in which the subject smokes
cigarettes of varying yields (see Table 1). Further studies of smoking
behavior in sutjects who have voluntarily chosen cigarettes of
different yields are needed. The absence of an acceptable, palatable
"standard" research cigarette continues to be an impediment to
research in this area.

Variations in Pattern of Cigarette Smoke Inhalation

While cigarette smoking is the single most important factor in the
development of COLD, the majority of smokers never develop
clinically significant airflow obstruction (Fletcher et al. 1976).
Despite the clear dose-response relationship between number of
cigarettes smoked and death from COLD, attempts at identifying the
indi-Jidual susceptible smoker on the basis of number of cigarettes
smoked have had very limited success.

Another approach to identifying the susceptible smoker is to study
the manner of smoking, as this is probably a major determinant of
the lung's exposure to cigarette smoke. Cigarette smoking consists of
two phases: initially, the smoker takes a puff into the mouth, and
after a variable 1 to 4 second pause, the smoke mixed with air is
inhaled into the lungs (Rawbone et al. 1978; Higenbottam et al.
1980a; Tobin and Sackner 1982). Individual differences in the
pattern of cigarette smoking such as the size of the puff volume, the
duration of holding the smoke in the oral cavity before inhalation,
and the depth and duration of inhalation are among the important
factors determining the relative concentration of smoke constituents

348


that reach the lung. Despite its significance in determining the
distribution and deposition of cigarette smoke, the mode of inhala-
tion following the puff has received scant scientific investigation.

A number of epidemiologic studies have examined the relationship
between cigarette smoke inhalation, based on the smoker's subjec-
tive estimation, and the severity of pulmonary disease. Results of
these studies are conflicting; some investigators repcrted an associa-
tion between smoke inhalation and the presence of mucus hyperse-
cretion (Rimington 1974; Schenker et al. 1982; Dean et al. 1978) and
decline in pulmonary function (Ferris et al. 1976; Bosse et al. 19?5),
and others observed no relationship between inhalation and pulmo-
nary dysfunction (Beck et al. 1981; Schenker et al. 1982). The
inconsistencies in these epidemiologic studies may be due to the
smokers' inability to accurately describe their inhalation pattern.

There are three reports of the relationship between subjective
estimations of cigarette smoke inhalation and direct objective
measurement. Rawbone et al. (1978) found that the rating on a
visual analog scale was a good predictor of inhalation volume
(r=0.65). Conversely, Tobin et al. (1982a) noted no relationship
between inhalation volume and the smoker's perception of depth of
inhalation, indicated on a visual analog scale (i-=0.04); a similar
finding was reported by Adams et al. (1983) (i-=0.04). Standardizing
the inhaled volume for vital capacity did not improve the relation-
ship. Other investigators using measurements of COHb observed a
weak relationship between self-estimated inhalation and COHb
concentration (Stepney 1982; Wald et al. 1978). Measurements of
COHb reflect the amount of cigarette smoke absorbed by the long. In
addition to being affected by the depth of inhalation, COHb
concentration is influenced by the varying carbon monoxide yields of
different cigarettes, the number of puffs per cigarette, puff volume,
pulmonary function-particularly diffusing capacity and alveolar
ventilation-and hemoglobin concentration (Wald et al. 1978; Ric-
kert et al. 1980). Therefore, it yields valuable complementary
information, but it does not provide a direct measure of the pattern
of inhalation (Tobin et al. 1982a; Guyatt et al. 1983).

Direct measurements of the pattern of cigarette smo!ce inhalation
have been reported for a small number of smokers. Initially, the puff
from the cigarette is taken into the molrth, and after a variable
pause of 1 to 4 seconds, it is inhaled into the lungs (Rawbone et. al.
1978; Higenbottam et al. 1980a; Tobin and Sackner 1982; Tobin et al.
1982a; Adams et al. 1983). Higenbot,tam et a1,(1980a) reasoned that
this pause, while holding the smoke in the mouth, minimized the
irritant qualities of cigarette smoke. In a group of five subjects who
were requested to inhale smoke directly into%eii lungs, withoslt an
intervening pause in the mouth, consistent acute airway narrowing
was observed. In contrast, smokers adopting the usual two-phase

349


smoking pattern showed a variable airway response. The authors
suggested that buccal absorption of water-soluble compounds, such
as sulfur dioxide and acrolein, together with precipitation of tar,
minimized the irritating qualities of cigarette smoke. They observed
no relationship between the acute airway response and amount of
smoke inhaled in the regular two-phase smokers, although there
appeared to be a relationship in those directly inhaling smoke into
their lungs. However, there is a marked discrepancy in the inhala-
tion volumes reported in this study compared with the values
reported in other studies of cigarette smoke inhalation, probably due
to the inaccuracy of the magnetometers employed for the measure-
ments; therefore, a statement regarding the relationship between
depth of smoke inhalation and the acute airway response may be
misleading.

The report that acute airway narrowing is uncommon after
cigarette smoking is in disagreement with the findings of several
investigators who have observed bronchoconstriction to be a common
phenomenon after acute smoke exposure (Nadel and Comroe 1961;
Sterling 1967; Da Silva and Hamosh 1981; Tobin et al. 1982a);
however, it is certainly plausible that the response is greater in
smokers who inhale smoke directly into the lungs than in two-phase
smokers. The frequency of direct inhalation of cigarette smoke into
the lungs is unknown. In a small study of 10 smokers, Tobin and
Sackner (1982) observed 1 subject who showed an approximately 50
ml expansion of the abdominal compartment simultaneously with
taking the puff from the cigarette.

Adams et al. (1983) studied the relationship between puffing,
cigarette smoke inhalation, and partitioning of airflow between the
nose and mouth in 10 smokers. After taking the puff into the mouth,
two subjects actively exhaled 80 ml and 200 ml volumes, respective-
ly, before the subsequent inhalation. In this situation, the volumes of
smoke might be expelled from the mouth, and little, if any, would be
available for subsequent inhalation into the lungs. The frequency of
this smoking pattern was not given, but another report from the
same laboratory (Rawbone et al.  1978) indicated that it was
uncommon. There was marked intersubject variation in the parti-
tioning of airflow between the nose and mouth during smoking, with
four subjects inhaling almost exclusively through the mouth, four
inhaling predominantly through the nose, and the other two
demonstrating both patterns of inhalation. The importance of factors
in determining whether cigarette smoke is inhaled as a bolus
followed by a subsequent "chaser" of air or is evenly distributed
throughout the inhaled volume of air remains to be determined.

Considerable discrepancies exist between published reports of the
volume of air mixed with smoke that is inhaled into the lungs, with
reported mean inhalation volumes of 34 to 152 ml (Higenbottam et

350


3c 1  Sum

1,   I1   1   I   III1   1   I

  10     20     30     40 5c     60

FIGURE 3.-Pattern of inhalation of cigarette smoke mixed
       with air, in two smokers

SOURCE Modified from Tobm et al c 1982b!

al. 1980a), 450 to 485 ml (Guillerm and Radziszewski 1978), 389 to
1,136 ml (Adams et al. 1983), 750 to 2,000 ml (Rawbone et al. 1978),
and 170 to 1,970 ml (Tobin et al. 1982b). A major factor in the
discrepancies between these studies is probably the inaccuracies
inherent in some of the methods employed in the measurements, as
discussed by Tobin and Sackner (1982). When inhalation volumes are
standardized for body size by relating them to vital capacity, marked
interindividual variation is still observed (Figure 3), with inhalation-
al volumes ranging from 9 to 47 percent of the vital capacity and a
group mean value of 20 percent (Tobin et al. 1982b). Smokers show
considerable variation in inhaled volumes while smoking a single
cigarette. The volume of inhalation bears no relationship to cigarette
consumption in terms of pack-years (Tobin et al. 1982b). Similarly,
duration of inhalation shows considerable variation between sub-
jects, with mean individual values ranging from 1.7 to 7.3 seconds
(Adams et al. 1983; Tobin et al. 1982b). Repeat measurements at
intervals of up to 10 months apart indicate that individual subjects
tend to maintain a fairly constant inhalation volume, duration of
inhalation, and associated breathhold time (Tobin et al. 1982b;
Adams et al. 1983).


The pattern of cigarette smoking shows a wide degree of intersub-
ject variability, including differences in the number of puffs, puff
volume, holding pause in the mouth, exhalation of smoke from the
mouth before inhalation, partitioning of airflow between the nose
and mouth, and volume and duration of inhalation. Given this
degree of variation, it is not surprising that smokers might show
wide differences in their individual susceptibilities to lung injury. In
a study relating inhalation volume-standardized for vital capaci-
ty-to the time-volume and flow-volume components of a forced vital
capacity maneuver, no significant correlation was observed (Tobin et
al. 1982b). Although this lack of a relationship might be interpreted
as indicating that the pattern of smoking is unimportant in the
development of lung disease, it may also reflect the fact that
pulmonary function was normal or near normal in the majority of
subjects and that the study was of a cross-sectional design.

Use of Additives in Low Tar and Nicotine Cigarettes

The nominal tar and nicotine yield of cigarettes has continually
decreased since the time of the initial reports linking smoking with
lung cancer (USDHHS 1981). In 1954, the average tar yield per
cigarette was 38 mg, and in 1980 it was less than 14 mg. Initially, tar
reduction was achieved by decreasing the cigarette tobacco content
or removing tar by smoke filtration, both of which probably resulted
in a lower smoke exposure. Since 1971, the reduction in tar yield has
exceeded the relative reduction in the weight of tobacco per
cigarette; this difference has increased since 1975 (USDHHS 1981).
Manufacturing technology has progressed beyond simple reduction
in tobacco content: the yield and composition of smoke can be
modified by genetic modification of the tobacco leaf (Tso 1972a),
changes in its cultivation and processing (Tso 1972133, changes in the
porosity of cigarette paper, and alterations in filter design (Kozlow-
ski et al. 1980b).

When initially introduced, lower yield cigarettes lacked palatabili-
ty and acceptability. Advertisements for the current low tar and
nicotine cigarettes emphasize their flavor, presumably achieved by
the use of additives in the processing of the tobacco. Additives
employed may include artificial tobacco substitutes (Freedman and
Fletcher 1976), flavor extracts of tobacco and other plants, exogenous
enzymes, powdered cocoa (Gori 19771, and other synthetic flavoring
substances. Perhaps more additives are being used in the new lower
tar and nicotine cigarettes than in the older brands, and new agents
may also be in use. Some of the substances, such as powdered cocoa,
have been shown to further increase the carcinogenicity of tar (Gori
19771, and others may result in increased or new and different
health risks. The pyrolytic products of these additive agents may


produce novel toxic constituents. A characterization of the chemical
composition and adverse biologic potential of these additives is
urgently required, but is currently impossible because cigarette
companies are not required to reveal what additives they employ in
the manufacture of tobacco (USDHHS 1981). No government agency
is empowered with supervisory authority in the manufacture of
tobacco products. With this lack of basic information and the usually
prolonged latent period before manifestation of the adverse effects of
smoking, it is likely that a long time period will elapse before we
know the hazards of the new cigarettes in current use.

Research Recommendations

1. Longitudinal epidemiologic studies are needed to determine
the risk for pulmonary symptoms and dysfunction in smokers
of cigarettes with the low tar and nicotine yields found in
currently popular brands.

2. Further research is needed to determine the relative potency of
high and low tar and nicotine cigarettes in inducing elastase
release and producing functional inhibition of al-antitrypsin
activity.

3. Development of an animal model of cigarette-smoke-induced
emphysema would be advantageous in determining the relative
risk of lung injury of cigarettes of different composition.
4. More information is required on the smoking behavior of
smokers who have voluntarily switched from high to low tar
and nicotine cigarettes.

5. The role of cigarette tar, as opposed to nicotine content, in
determining smoking behavior needs to be defined.
6. Standard research cigarettes of varying tar and nicotine
contents that are palatable and acceptable to smokers need to
be developed.

7. The role of variation in smoking behavior in determining
susceptibility to lung injury needs to be defined. Studies are
required to determine the effect of smoking patterns on the
distribution and penetration of the smoke aerosol into the lung.
8. More information is needed on the composition and adverse
biologic effects of flavor additives in cigarettes and their
pyrolytic products.

Summary and Conclusions

1. The recommendation for those who cannot quit to switch to
smoking cigarette brands with low tar and nicotine yields, as
determined by a smoking-machine, is based on the assumption
that this switch will result in a reduction in the exposure of the

353


lung to these toxic substances. The design of the cigarette has
markedly changed in recent years, and this may have resulted
in machine-measured tar and nicotine yields that do not reflect
the real dose to the smoker.

2. Smoking-machines that take into account compensatory
changes in smoking behavior are needed. The assays could
provide both an average and a range of tar and nicotine yields
produced by different individual patterns of smoking.

3. Although a reduction in cigarette tar content appears to reduce
the risk of cough and mucus hypersecretion, the risk of
shortness of breath and airflow obstruction may not be
reduced. Evidence is unavailable on the relative risks of
developing COLD consequent to smoking cigarettes with the
very low tar and nicotine yields of current and recently
marketed brands.

4. Smokers who switch from higher to lower yield cigarettes show
compensatory changes in smoking behavior: the number of
puffs per cigarette is variably increased and puff volume is
almost universally increased, although the number of ciga-
rettes smoked per day and inhalation volume are generally
unchanged. Full compensation of dose for cigarettes with lower
yields is generally not achieved.

5. Nicotine has long been regarded as the primary reinforcer of
cigarette smoking, but tar content may also be important in
determining smoking behavior.

6. Depth and duration of inhalation are among the most impor-
tant factors in determining the relative concentration of smoke
constituents that reach the lung. Considerable interindividual
variation exists between smokers with respect to the volume
and duration of inhalation. This variation is likely to be an
important factor in determining the varying susceptibility of
smokers to the development of lung disease.

7. Production of low tar and nicotine cigarettes has progressed
beyond simple reduction in tobacco content. Additives such as
artificial tobacco substitutes and flavoring extracts have been
used. The identity, chemical composition, and adverse biologi-
cal potential of these additives are unknown at present.

354


References

ADAMS, L., LEE, C., RAWBONE, R.. GUZ. A. Patterns of smoking: Measurement and
variability in asymptomatic smokers. Clinical Science 65141: 3Kt392, October 1983.
ADAMS, P.I. Changes in personal smoking habits brought about by changes in
cigarette smoke yield. In: Proceedmgs of the Smth International Tobacco Sctentific
Congress, Tokyo, November 14-20.1976. Tokyo. The Japan Tobacco and Salt Public
Corporation, 1977, pp. 102-108.

ADAMS, P.I. The influence of cigarette smoke yields on smoking habits In. Thornton,
R.E. Editor). Smoking Behaciour. Phvsiologrcal and Psychological Influences.
Edinburgh, Churchill Livingstone, 1978. pp. 349-360.
AMERICAN CANCER SOCIETY. U.S. tar/nicotine levels dropping. World Smoking
and Health 6(21: 47, Summer 1981.

ASHTON. H., STEPNEY, R., THOMPSON, J.W. Self-titration by cigarette smokers.
British Medical Journal 2(6186): 357-360, August 11.1979.
ASHTON, H., WATSON, D.W. Puffing frequency and nicotine intake in cigarette
smokers. British Medical Journal 3(5724): 679&81, September 19,197O.
BA'ITIG. K., BUZZI. R.. NIL, R. Smoke yield of cigarettes and puffing behavior in men
and women. Psychopharmacology 76t2): 139-148, February 1982.
BECK, G.J.. DOYLE, C.A., SCHACHTER, E.N. Smoking and lung function. American
Review ofRespiratory Disease 123t2): 149155, February 1981.
BENOWITZ, N.L., HALL, SM., HERNING, RI.. JACOB, P.. III. JONES, R.T.,
OSMAN, A.-L. Smokers of low-yield cigarettes do not consume less nicotine. Neu
England Journal of Medicine 309(3): 139-142, July 21, 1983.
BLUE, M.-L., JANOFF, A. Possible mechanisms of emphysema in cigarette smokers.
Release of elastase from human polymorpho-nuclear leukocytes by cigarette smoke
condensate in vitro. American Review of Respirato? Dtsease 117(Z): 317-325.
February 1978.

BOSSE, R., COSTA, P.. COHEN, M., PODOLSKY. S. Age, smoking inhalation and
pulmonary function. Archives of Environmental Health 3CM101: 49-98, October
  1975.

COHEN, A.B., JAMES, H.L. Reduction of the elastase inhibitory capacity of alpha,-
antitrypsin by peroxides in cigarette smoke. An analysis of brands and filters.
American Reoiew of RespiratoN Disease 126(l): 25-30. July 1982.
COHEN, S.I., PERKINS, N.M., URY, H.K., GOLDSMITH, J.R. Carbon monoxide
uptake in cigarette smoking. Archirles of EntGronmental Health 22(l): 55-60.
January 1971.

COMSTOCK, G.W., BROWNLOW. W.J., STONE, R.W.. SARTWELL, P.E. Cigarette
smoking and changes in respiratory findings. Archives of EnLGronmental Health
21(l): 50-57, July 1970.

CREIGHTON, D.E., LEWIS, P.H. The effect of different cigarettes on human smoking
patterns. In: Thornton, R.E. (Editor). Smoking Behacioar. Ph.vsiolagical and
Psychological ZnfZuences. Edinburgh, Churchill Livingstone, 1978a. pp. 289-300.
CREIGHTON, D.E., LEWIS, P.H. The effect of smoking pattern on smoke deliveries.
In: Thornton, R.E. (Editor). Smoking Behauiour, Phvsiological and Psychological
Influences. Edinburgh, Churchill Livingstone, 1978b, pp. 301-314
DA SILVA, A.M.T., HAMOSH, P. Effect of smoking a single cigarette on the "small
airways." Journal ofApplied Physiology 34(3): 361-365, March 1973.
DA SILVA, A.M.T., HAMOSH. P. Airways response to inhaled tobacco smoke: Time
course, dose dependence and effect of volume history. Respiration 4112): 96-105.
1981.

DEAN. G.. LEE, P.N., TODD, G.F., WICKEN. A.J., SPARKS, D.N. Factors related to
respiratory and cardiovascular symptoms in the United Kingdom. Journal of
Epidemiology and Community Health 32~21: 86-96. June 1978.

355


FERRIS, B.G.. Jr., CHEN, H., PULEO, S., MURPHY, R.L.H., Jr. Chronic nonspecific
respiratory disease in Berlin, New Hampshire, 1967 to 1973. A further follow-up
  study. American Review of Respimtory Disease 113(4): 47w85, April 1976.
FEYERABEND, C., HIGENBOTTAM, T., RUSSELL, M.A.H. Nicotine concentrations
  in urine and saliva of smokers and non-smokers. British Medical Journal
  284(6321): 1002-1004, April 3, 1982.
FINNEGAN, J.K., LARSON, P.S., HAAG, H.B. The role of nicotine in the cigarette
habit. Science 102(2639): 94-96, July 27, 1945.
FLETCHER, C., PETO, R., TINKER, C., SPEIZER, F.E. The Natural History of
Chronic Bronchitis and Emphysema: An Eight-Year Study of Early Chronic
Obstructive Lung Disease in Working Men in London. New York, Oxford
University Press, 1976,272 pp.
FORBES, W.F., ROBINSON, J.C., HANLEY, J.A., COLBURN, H.N. Studies on the
nicotine exposure of individual smokers. I. Changes in mouth-level exposure to
nicotine on switching to lower nicotine cigarettes. International Journal of the
Addictions ll(6): 933-950. 1976.
FREEDMAN, S., FLETCHER, CM. Changes of smoking habits and cough in men
smoking cigarettes with 30% NSM tobacco substitute. British Medical Journal
  16023): 1427-1430, June 12, 1976.
FRITH, CD. The effect of varying the nicotine content of cigarettes on human
smoking behaviour. Psychopharmacologia 19(2): 186-192,1971.
GARFINKEL, L. Changes in the cigarette consumption of smokers in relation to
changes in tar/nicotine content of cigarettes smoked. American Journal of Public
Health 69(12): 1274-1276, December 1979.
GOLDFARB, T., GRITZ, E.R., JARVICK, M.E., STOLERMAN, I.P. Reactions to
cigarettes as a function of nicotine and "tar."  Clinical Pharmacology and
Therapeutics 19(6): 767-772, June 1976.
GORI, G.B. Low-risk cigarettes: A prescription. Low-toxicity cigarettes hold signifi-
cant promise in the prevention of diseases related to smoking. Science 194(4271):
124s1246, December 17.1976.
GORI, G.B. (Editor). Toward Less Hazardous Cigarettes. The Third Set of Experimen-
tal Cigarettes. U.S. Department of Health, Education, and Welfare, Public Health
Service, National Institutes of Health, National Cancer Institute, Smoking and
Health Program Report No. 3, DHEW Publication No. (NIH)77-1280,1977,152 pp.
GORI, G.B., LYNCH, C.J. Toward less hazardous cigarettes. Current advances.
Journal of the American Medical Association 240(12): 1255-1259, September 15,
  1978.
GRIFFITHS, R.R., HENNINGFIELD, J.E., BIGELOW, G.E. Human cigarette smok-
ing: Manipulation of number of puffs per bout, interbout interval and nicotine
dose. Journal of Pharmacology and Experimental Therapeutics 220(2): 256-265,
  1981.
GUILLERM. R.. RADZISZEWSKI, E. Analysis of smoking pattern including intake of
carbon monoxide and influences of changes in cigarette design. In: Thornton, R.E.
(Editor). Smoking Behaviour, Physiological and Psychological Influences. Edin-
burgh, Churchill Livingstone, 1978, pp. 361-370.
GUYA'IT. A.R., MCBRIDE, M.J., KIRKHAM, A.J.T., CUMMING, G. Smoking and
ventilatory response of man to cigarettes of different nicotine content. Clinical
Science 6x3): 3, September 1983.
HAMMOND, E.C., GARFINKEL, L.. SEIDMAN, H., LEW, E.A. "Tar" and nicotine
content of cigarette smoke in relation to death rates. Environmental Research
12(3): 263-274, December 1976.
HAWTHORNE, V.M., FRY, J.S. Smoking and health: The association between
smoking behaviour, total mortality, and cardiorespiratory disease in west central
Scotland. Journal of Epidemiology and Community Health 32(4): 260-266, Decem-
  ber 1978.


HEALTH DEPARTMENT OF THE UNITED KINGDOM. Tar and Nicotine Yield of
Cigarettes. London, Department of Health and Social Security, January 1976.
HENNINGFIELD, J.E., GRIFFITH& R.R. Effects of ventilated cigarette holders on
cigarette smoking by humans. Psychopharmacology 68(2): 115-119, May 1980.
HERNING, R.I., JONES, R.T., BACHMAN, J., MINES, A.H. Puff volume increases
when low-nicotine cigarettes are smoked. British Medical Journal 283~6285): 187-
189, July 18, 1981.

HERNING, R.I., JONES, R.T., BENOWITZ, N.L., MINES, A.H. How a cigarette is
smoked determines blood nicotine levels. Clinical Pharmacology and Therapeutics
33(l): 84-90, January 1983.

HIGENBO'ITAM, T., FEYERABEND, C., CLARK, T.J.H. Cigarette smoke inhalation
and the acute airway response. Thorax 35(4): 246-254, April 1980a.
HIGENBO'ITAM, T., SHIPLEY, M.J., CLARK, T.J.H., ROSE, G. Lung function and
symptoms of cigarette smokers related to tar yield and number of cigarettes
smoked. Lancet l(8165): 409412, February 23,198Ob.
HILL, P., MARQUARDT, H. Plasma and urine changes after smoking different
brands of cigarettes. Clinical Pharmacology and Therapeutics 27(5): 652-658, May
  1980.

HOFFMANN, D., TSO, T.C., GORI. G.B. The less harmful cigarette. Preventive
Medicine %2): 287-296, March 1980.

JAFFE, J.H., KANZLER, M., FRIEDMAN, L., KAPLAN, T. Money and health
messages as incentives for smoking low/tar nicotine cigarettes: Changes in
consumption and exhaled carbon monoxide. British Journal ofAddiction 77(l): 21-
34, March 1982.

JAFFE, J.H., KANZLER, M., FRIEDMAN, L.. STUNKARD, A.J., VEREBEY, K.
Carbon monoxide and thiocyanate levels in low tar/nicotine smokers. Addictive
Behaviors 6(4): 337-343,1981.

JANOFF. A., CARP, H.. LEE, D.K.. DREW, R.T. Cigarette smoke inhalation decreases
alpha]-antitrypsin activity in rat lung. Science 206(4424): 1313-1314, December 14,
  1979.

JARVIK, M.E., POPEK, P., SCHNEIDER, N.G., BAER-WEISS, V., GRITZ, E.R. Can
cigarette size and nicotine content influence smoking and puffing rates? Psycho-
pharmacology 5&3): 303-306,1978.

KOZLOWSKI, L.T. Tar and nicotine delivery of cigarettes. Journal of the American
Medical Association 245(2): X8-159, January 9,198l.
KOZLOWSKI, L.T. Physical indicators of actual tar and nicotine yields of cigarettes.
In: Grabowski, J.. Bell, C. (Editors). Measurement in the Analysis and Treatment of
Smoking Behauior. National Institute on Drug Abuse Research Monograph 48.
Department of Health and Human Services, Public Health Service, Alcohol, Drug
Abuse, and Mental Health Administration, 1983.
KOZLOWSKI, L.T., FRECKER, R.C., KHOUW, V., POPE, M.A. The misuse of "less-
harzardous" cigarettes and its detection: Hole-blocking of ventilated filters.
American Journal of Public Health 70(11): 1202-1203, November 1980a.
KOZLOWSKI, L.T., FRECKER, R.C., LEI, H. Nicotine yields of cigarettes, plasma
nicotine in smokers, and public health. Preventive Medicine ll(2): 24&244, March
  1982.

KOZLOWSKI, L.T.. RICKERT, W.S., ROBINSON, J.C., GRUNBERG, N.E. Have tar
and nicotine yields of cigarettes changed? Science 209(4464): 15561551, September
26,198Ob.

LEE, P.N., GARFINKEL, L. Mortality and type of cigarette smoked. Journal of
Epidemiology and Community Health 35(l): 1622, March 1981.
MOROSCO, G.J., GOERINGER. G.C. Pancreatic elastase and serum alphal-antitryp
sin levels in beagle dogs smoking high- and low-nicotine cigarettes: Possible
mechanism of pancreatic cancer in cigarette smokers. Journal of Toxicolop and
Environmental Health 5(5): 879-890, September 1979.

357


NADEL. J.A.. COMROE, J.H., Jr. Acute effects of inhalation of cigarette smoke on
airway conductance. Journal ofApplied Physiology 16(4): 713-716, July 1961.
PETO. R., SPEIZER, F.E., COCHRANE, A.L., MOORE, F., FLETCHER, C.M.,
TINKER, CM., HIGGINS, I.T.T., GRAY, R.G., RICHARDS, S.M., GILLILAND, J.,
NORMAN-SMITH, B. The relevance in adults of air-flow obstruction, but not of
mucus hypersecretion, to mortality from chronic lung disease. American Review of
Respiratory Disease 128(3): 491-500, September 1983.
PILLSBURY, H.C., BRIGHT, CC., O'CONNOR, K.J., IRISH, F.W. Tar and nicotine in
cigarette smoke. Journal of the Association of Official Analytical Chemists 52(3):
458-462, May 1969.

RAWBONE, R.G., MURPHY, K., TATE, M.E., KANE, S.J. The analysis of smoking
parameters: Inhalation and absorption of tobacco smoke in studies of human
smoking behaviour. In: Thornton, R.E. (Editor). Smoking Behauiour, Physiological
and Psychological Influences. Edinburgh, Churchill Livingstone, 1978, pp. 171-194.
REES, P.J., AYRES, J.G., CHOWIENCZYK, P.J., CLARK, T.J.H. Irritant effects of
cigarette and cigar smoke. Lancet 2(8306): 1015-1017, November 6,1982.
RICKERT, W.S., ROBINSON, J.C., YOUNG, J.C. Estimating the hazards of "less
  hazardous" cigarettes. I. Tar, nicotine, carbon monoxide, acrolein, hydrogen
cyanide, and total aldehyde deliveries of Canadian cigarettes. Journal of Toricolo-
gy and Enuimnmental Health 6(2): 351-365, March 1980.
RIMINGTON, J. Phlegm and filters. British Medical Journal 2(5808): 262-264, April
29.1972.

RIMINGTON, J. Cigarette smokers' chronic bronchitis: Inhalers and non-inhalers
compared. British Journal of Diseases of the Chest 68: 161-166, July 1974.
RIMINGTON. J. The effect of filters on the incidence of lung cancer in cigarette
smokers. Enuimnmental Research 24(l): 162-166, February 1981.
ROBERTSON, D.G., WARRELL. D.A., NEWTON-HOWE& J.S., FLETCHER, C.M.
Bronchial reactivity to cigarette and cigar smoke. British Medicat Journal 3G665):
269-271, August 2,1969.

ROBINSON, J.C., FORBES, W.F. Studies on the nicotine exposure of individual
smokers. II. An analysis of smoking habits during a one-week period. International
Journal of the Addictions 15(6): 889-905, 1980.
RODRIGUEZ, R.J., WHITE, R.R.. SENIOR, R.M., LEVINE, E.A. Elastase release from
human alveolar macrophages: Comparison between smokers and nonsmokers.
Science 198(4314): 313-314, October 21,1977.
RUSSELL, M.A.H. Low tar-medium nicotine cigarettes: A new approach to safer
smoking. Brittsh Medical Journal 2: 1430-1433,1976.
RUSSELL, M.A.H., JARVIS, M., IYER, R., FEYERABEND, C. Relation of nicotine
yield of cigarettes to blood nicotine concentrations in smokers. British Medical
Journal 280(6219): 972-976, April 5,198O.

RUSSELL, M.A.H., WILSON, C., PATEL, U.A., COLE, P.V., FEYERABEND, C.
Comparison of effect on tobacco consumption and carbon monoxide absorption of
changing to high and low nicotine cigarettes. British Medical Journal 4(5891): 512-
516, December 1,1973.

RUSSELL, M.A.H., WILSON, C., PATEL, U.A., FEYERABEND, C., COLE, P.V.
Plasma nicotine levels after smoking cigarettes with high, medium, and low
nicotine yields. British Medical Journal 2(5968): 414-416, May 24, 1975.
SCHENKER, M.B., SAMET, J.M., SPEIZER, F.E. Effect of cigarette tar content and
smoking habits on respiratory symptoms in women. American Review of Respira-
tory Disease 125(6): 684-690, June 1982.

SCHULZ, W., SEEHOFER. F. Smoking behaviour in Germany-The analysis of
cigarette butts (KIPA). In: Thornton, R.E. (Editor). SmokingBehauiour, Physiologi-
cal and PsUychological Influences. Edinburgh, Churchill Livingstone, 1978, pp. 259-
  276.

358


SPARROW, D.. STEFOS, T., BOSSE, R., WEISS, S.T. The relationship of tar content
to decline in pulmonary function in cigarette smokers. American Reuiew of
Respiratory Disease 127(l): 56-58, January 1983.
STEPNEY, R. Would a medium-nicotine, low-tar cigarette be less hazardous to
health? British Medical Journal 283(6302): 1292-1296. November 14,198l.
STEPNEY, R. Are smokers' self-reports of inhalation a useful measure of smoke
exposure? Journal of Epidemiology and Community Health 36(2): 109-112. June
  1982.

STERLING, G.M. Mechanism of bronchoconstriction caused by cigarette smoking.
British Medical Journal 3(5560): 275-277. July 29.1967.
SUITON, S.R., FEYERABEND, C.. COLE, P.V., RUSSELL, M.A.H. Adjustment of
smokers to dilution of tobacco smoke by ventilated cigarette holders. Clinccal
Pharmacology and Therapeutics 24~4): 395-405. October 1978.
SUITON, S.R., RUSSELL, M.A.H., IYER. R., FEYERABEND, C., SALOOJEE, Y.
Relationship between cigarette yields, puffing patterns, and smoke intake:
Evidence for tar compensation? British Medical Journal 285(6342): -03,
August 28,1982.

TASHKIN, D.P., CLARK, V.A., COULSON, A.H., BOURQUE, L.B., SIMMONS, M..
REEMS. C., DETELS, R.. ROKAW, S. Comparison of lung function in young
nonsmokers and smokers before and after initiation of the smoking habit: A
prospective study. American Revieu, of Respiratory Dtsease 128(l): 12-16, July
  1983.

TOBIN, M.J., JENOURI, G.A.. SACKNER, M.A. Subjective and objective measure-
ment of cigarette smoke inhalation. Chest 82(6): 695700, December 1982a.
TOBIN, M.J., SACKNER, M.A. Monitoring smoking patterns of low and high tar
cigarettes with inductive plethysmography. American Recieus of Resptratop
Disease 126(2): 258-264, August 1982.

TOBIN, M.J., SCHNEIDER, A.W., SACKNER. M.A. Breathing pattern during and
after smoking cigarettes. Clinical Sczence 63(5~: 473-483. November 1982b.
TRAVIS, J., BEA'ITY, K., WONG, P.S., MATHESON, N.R. Oxidation of alphai-
proteinase inhibitor as a major. contributing factor in the development of
pulmonary emphysema. Bulletin Eumpeen de Physiopathologie Respiratoire
16fSupplement): 341-351,198O.

TSO, T.C. Manipulation of leaf characteristics through production-Role of agricul-
ture in health-related tobacco research. Journal of the National Cancer Institute
48(6): 1811-1119, June 1972a.

TSO, T.C. The potential for producing safer cigarette tobacco. Agricultural Science
Review lo(3): I-10, Third Quarter, 1972b.

TURNER, J.A.M., SILLElT, R.W., BALL, K.P. Some effects of changing to low-tar
and low-nicotine cigarettes. Lancet 2(7883): 737-739, September 28, 1974.
U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES. The Health Conse-
quences of Smoking: The Changing Cigarette: A Report of the Surgeon General. U.S.
Department of Health and Human Services, Public Health Service, Office of the
Assistant Secretary for Health, Office on Smoking and Health, DHHS Publication
No. (PHS)81-50156,1981,269 pp.

U.S. SENATE. Reviewing Pmgress Made Toward the Development and Marketing of a
Less Hazardous Cigarette. Hearings Before the Consumer Subcommittee of the
Committee on Commerce. Serial No. 90-52, August 2325, 1967,329 pp.
WALD, N. Mortality from lung cancer and coronary heart-disease in relation to
changes in smoking habits. Lancet l(79511: 136138. January 17.1976.
WALD. N., HOWARD, S., SMITH, P.G., BAILEY, A. Use of carboxyhaemoglobin
levels to predict the development of diseases associated with cigarette smoking.
Thorax 30(2): 133-139, April 1975.

359


WALD. N.. HOWARD. S., SMITH, P.G., KJELDSEN, K. Association between
atherosclerotic diseases and carboxyhaemoglobin levels in tobacco smokers.
Brutish Medical Journal U5856): 761-765, March 31,1973.
WALD, N., IDLE, M., BAILEY, A. Carboxyhaemoglobin levels and inhaling habits in
cigarette smokers. 7'horo.x 33(Z): 201-206, April 1978.
WALD, N., IDLE, M.. BOREHAM, J., BAILEY, A. Inhaling habits among smokers of
different types of cigarettes. Thorax 35(12): 925-928, December 1980.
WALD, N.. IDLE, M., BOREHAM, J., BAILEY, A. The importance of tar and nicotine
in determining cigarette smoking habits. Journal of Epidemiology and Community
Health 35(l): 23-24, March 1981.

WALD, N., IDLE, M., SMITH, PG., BAILEY, A. Carboxyhaemoglobin levels in
smokers of filter and plain cigarettes. Luncet l(8003): 11&112, January 15, 1977.
WALD, N., SMITH, P.G. Smoking tables for carbon monoxide. Lancet 2: 907-908,
October 20.1973.

WILEY, R.M., WICKHAM, J.E. The fabrication and application of a puff-by-puff
smoking machine. Tobacco Science 18: 69-72,1974.
WYNDER, E.L., KIYOHIKO, M., BEATTIE, E.J., Jr. The epidemiology of lung cancer.
Recent trends. Journal of the American Medical Association 213(13): 2221-2228,
September 28,197O.

360


CHAPTER 7. PASSIVE SMOKING

361

480-244 0 - 85 - 13


CONTENTS

Introduction

Differences in Composition of Sidestream Smoke and
Mainstream Smoke

Measurement of Exposure

Acute Physiologic Response of the Airway to Smoke in
the Environment

Symptomatic Responses to Chronic Passive Cigarette
Smoke Exposure in Healthy Subjects

Respiratory Infections in Children of Smoking Parents

Pulmonary Function in Children of Smoking Parents

Pulmonary Function in Adults Exposed to Involuntary
Cigarette Smoke

The Effect of Passive Smoke Exposure on People With
Allergies, Asthma, and COLD

Summary and Conclusions

References

363


Introduction

This chapter explores recent data that relate involuntary cigarette
smoke exposure to the occurrence of physiologic changes, symptoms,
and diseases in nonsmoking adults and children. Health effects
related to fetal exposure in utero, a subject that has been extensively
studied, are not discussed, although instances where such exposure
may relate to potential development are pointed out. The interested
reader is referred to several excellent recent reviews for a more
complete treatment of this issue KJSDHEW 1979; USDHHS 1980;
Abel 1980; Weinberger and Weiss 1981).

Differences in Composition of Sidestream Smoke and
Mainstream Smoke

Involuntary (passive) smoking is defined as the exposure of
nonsmokers to tobacco combustion products from the smoking of
others. Analysis of the health effects of passive smoking requires not
only some knowledge of the constituents of tobacco smoke, but also
some quantitation of tobacco smoke exposure. Tobacco smoke in the
environment is derived from two sources: mainstream smoke and
sidestream smoke. Mainstream smoke emerges into the environment
after having first been drawn through the cigarette, which filters
some of the active constituents. The smoke is then filtered by the
smoker's own lungs, and exhaled. Sidestream smoke arises from the
burning end of the cigarette and enters directly into the environ-
ment. Differences in the temperature of combustion, the degree of
filtration, and the amount of tobacco consumed all lead to marked
differences in the concentration of the constituents of mainstream
smoke and sidestream smoke (USDHEW 1979; Sterling et al. 1982;
Brunneman et al. 1978; National Academy of Sciences 1981;
Rylander et al. 1984). Many potentially toxic gas phase constituents
are present in higher concentration in sidestream smoke than in
mainstream smoke (Brunneman et al. 1978) (Table 11, and nearly 85
percent of the smoke in a room results from sidestream smoke.
Smaller amounts of smoke are contributed to the environment from
the nonburning end of the cigarette by diffusion through the paper
wrapping and by the smoke exhaled by the smoker. Therefore, both
active and passive smokers may be similarly exposed to sidestream
smoke. Mainstream smoke is inhaled directly into the lungs and is
diluted only by the volume of air breathed in by the smoker when he
or she inhales. Sidestream smoke is generally diluted in a considera-
bly larger volume of air. Thus, passive smokers are subjected to a
quantitatively smaller and qualitatively different smoke exposure
than active smokers. The quantification of the exposure of a passive
smoker to these sidestream smoke constituents is often difficult.
Factors such as the type and number of cigarettes burned, the size of


the room, the ventilation rate, and the smoke residence time are all
important variables in determining levels of exposure. Thus, no
single variable accurately characterizes exposure to smoke constitu-
ents.

Repace and Lowrey (1980, 1982, 1983) have shown that, to a
reasonable approximation, exposure to the particulate phase is
predicted by the ratio of the smoker density to the effective
ventilation rate of the area in which the smokers are located.

Measurement of Exposure

Levels of indoor byproducts of tobacco smoke, with measurements
made under realistic exposure conditions, are presented in Table 2.
Among the constituents that have been measured, nitrogen oxide,
carbon monoxide, nicotine and respirable particulates, nitrosamines,
and aldehydes have been shown to be significantly elevated indoors
as a result of cigarette smoking. Nitrogen oxide is rapidly oxidized to
nitrogen dioxide (NOZ) in air, and reaches equilibrium with outdoor
levels of NOa, provided there are suitable air exchange rates and no
other indoor sources, such as a gas stove. The particulate concentra-
tion indoors clearly increases with increasing numbers of smokers,
although the background level is determined by the outdoor level.
The conclusions from the few studies that actually measure ventila-
tion rates during exposure suggest that under "normal" air circula-
tion conditions, carbon monoxide (CO) levels will be relatively low,
but still may exceed the ambient air quality standard of 9 ppm
(NIOSH 1971). However, even modest reductions in ventilation rates
can lead to CO accumulation.

A variety of measures have been utilized to quantify the nonsmok-
er's exposure to tobacco smoke. No single measure has been
uniformly accepted as characterizing the level of smoke. Nicotine is
the most tobacco-specific of these measures, but it is relatively
complicated and expensive to measure and settles out of the air with
the particulate phase, making it a poor measure of gas phase
constituents. In addition, nicotine may rapidly deposit on surfaces
and subsequently evaporate into the environment (Rylander et al.
1984), making it a poor measure of acute smoke exposure levels.
Measurements of total particulate matter are a broader measure of
smoke exposure, particularly if the measurements are limited to
particles in the respirable range and to environments without other
major sources of respirable particles. The smoke particles also settle
out of the air and therefore may not reflect the levels of gas phase
constituents, and a wide variety of other dusts may contribute
particulates to the air, particularly in the occupational setting. A
number of authors have measured levels of CO. This measurement is
relatively simple and a measure of absorption (carboxyhemoglobin)

366


TABLE l.-Ratio of selected constituents in sidestream smoke (SS) to mainstream smoke (MS)

a.9 phase aJn#tituenta

MS

s/MS ratio

Particulate phase constituents

MS         ss/Ms ratio

Carbon dioxide
Carbon monoxide
Methane
Acetylene
Ammonia
Hydmgen cyanide
Methylfuran
Acetnnitrile
Pyridine
Dimethylnitwamine

8.1              TM
2.5               Water
3.1              Toluene
0.8              Phenol
73.0            Methylnaphthalene
0.25            Pyrene
3.4            Benuo(a$wne
3.9               Aniline
10.0              Nicotine
52.0            SNaphthylamine

1.3
2.4
5.6
2.6
28
3.6
3.4
30
2.7
39

Adapted from U.S. Department of Health. Education. sod Welfare (1979).


TABLE 2a.-Acrolein measured under realistic conditions

Study

Type of
premisea

Ventilation

Monitoring
conditions

MMtl

Badre et al.
(1978)

cafea
Room
Hospital lobby
2 train compartmenta
cm

Fischer et al.
(1978) and
Weber et al.
(1979)

Rentaurant
Restaurant
Bar
cafeteria

Varied         Not given
18 smokera       Not given
12 to 30 smokenr    Not given
2 to 3 smokers     Not given
3 emokem       Natural, open
2 smokers       Natural, closed

50-M/470 m'
60-lCW440 m'
3&40/50 m'
&I-150/574 m'

Mechanical
Natural
Natural. open
11 ehanges/hr

loo mL sample.8
loo mL Bamples
100 mL samples
loo mL .samples
100 mL Eamplea
loo mL samples

27 x 30 min samples
29 x xl mill samples
28 X 30 min samples
24 x 30 mill samplea

            0.03-0.10 mg/m'
0.185 mg/m'
0.02 mglm
           O.Ou).lZ mg/m*
0.03 mg/m'
0.30 mg/ms

7 wb
8 wb
10 Ppb
6 wb (5 ppb
nonsmoking section)


TABLE 2b.-Aromatic hydrocarbons measured under realistic conditions

Study

Ventilation

Monitoring
conditions

   Levels      Nommokmg controls

Mean     Range    Mean Range

Badre et al.
(1978)

cafes
Room
Train compartmenta
car

cafea          Varied             Not given       100 mL samples             004-1.04
Room           18 smokers          Not gwen      100 mL samples      0 215
Train compartmenta  2 to 3 smokers         Not given       100 mL samples      1.87
car           2 smokers           Natural, clceed    100 mL samples      0.50

Elliott and Rowe
(1975-l

ArHla

Galuskinova
(1964-l

Restaurant

Varied             Not given       100 mL samples             005-0.15
18 smokenr          Not given      100 mL samples      0109
2 to 3 smokers        Not given      100 mL eamplea             0.024 10
3 smokers           Natural, open     100 mL samples      0.04
2 smokers           Natural, closed    100 mL samples      0 15

8,647-10,786 people       Mechanical
12,000-12.8-44 people       Mechanical
13,W14J77 people       Mechanical

Not given           Not given

Not given
Not given
Not given
Separate non-
activity days

20 days m .3ummel
18 days in the fall

Benzene (n&m')

Toulene (mglm')

Etenxjajpyrene (,ng/m')

71
99
21.7

0 69

6.2
  282-144


Y   TABLE 2b.-Continued

a                                                                           Level0      Nonsmoking controls
               lLpe of                                  Monitoring
   Study          premises         ~UpancY          Ventilation        conditiona       MSII    Ranse    Mean bnge

Just et al.
(1972)

Coffee houses     Not given

Not given

6 hr continuous

0.25-10.1      4.M.3 (outdcom)

  Berw$ehymne (nglm')

3.3-23.4      3.0-5.1 (outdoord
Benz&&erylene (w/m')

5.9-10.5      6.9-13.8 (outdoors)

   Perylene (rig/m')


0.7-1.3       0.1-1.7 (OUtd~Ia)

Perry (1973

14 public placee

Not given

Not given

4.1-9.4       2.C7.0 (outdoors)

  Anthanthmne (ng/m")

O.Sl.9       0.61.8 (outdoors)
   Coronene (ng/m')

OS-l.2        1.0-2.8

   Phenols C&m')

samples, 5 outdoor
locations

7.4-11.5

Benzo(aipyrene (r&m')

< 20-760            <2O-QJ


TABLE 2c.-Carbon monoxide measured under realistic conditions

Study

Type of
pmllliSW

Ventilation

MOd.OliDg
conditions

  Levels @pm)        Nonsmoking controls @pm)

MWll       Ranse        Mean

Badre et al.
(1978)

Gcafea
Room
Hospital lobby
2 train
compartments
car

Can0 et al.     Submarines
(19703         66 m'

ChappeU and
Parker
(1977)

10 OfflQs


15 rwtaurant.9

14 night&be
and taverna
Tavern

Varied
18 smokers
12 to 30 smokers
2 to 3 smokers

3 smokers
2 smokers

157 cigfuettes
per &Y
94-103 cigarettes
per bY
Not given

Not given

Not given

Not given

Not given
Not given
Not given
Not given

Natural, open
Natural, cloeed

Yea

Yea

values not
given
valuee not
given
valuw not
given
Artificial

offia?

1440 ft'

Natural, open

20 min samples
20 min @amplea
20 min samples
20 min Bamplea


20 min enmplee
20 min aamplee

17 x 2-3 min
WIllpleS
17 x 2-3 min
samples
19xMmin
WlUPlW
16 x W min
BampleS
2x2-3min
SampIeS
2-3 mill eamples
3ominafter
smoking

50
5

1.4
20

(40 PPm

(40 wm

2.5 + 1.0


4.0 k 2.5


13.0 Ik 7.0


8.5

1.5-4.5


l.cL9.5


3.0X9.0

2.5 + 1.0       1.5-45
    (outdoom)
2.5 f 1.5       1.a5.0
    (outdoom)
3.0 + 2.0       1.0-5.0

35 @?ak)

10.0 (peak)

1.0


:   TABLE 2c.-Continued

                                                        Levels @pm)         Nonsmoking controls (ppm)
             lLpe of                         Monitoring
   Study        premieee      ~F-7      Ventilation      conditions        Mean       Ranse        MWIl      Range

C&urn et al.
(19653

Cuddeback
et al.
(1976-I

U.S. Dept. of
Transportation
U971P

Elliott and
Rowe
(1975F

Fisher et al.
(1978) and
Weber et al.
(2979)

Codin et al.    Ferryboat      Not given       Not given    11 grab eamplee     18.4 + 8.7                3.0 f 2.4 (nonsmoking room)
(197.8       Theater foyer   Not given       Not given    Glnh samplea      3.4 + 0.8                   1.4 _t 0.8 (auditorium)

Rooms       Not given       Not given

Tavern 1      10-294 people     6 changeslhr

Tavern 2

Not given

l-2 che.ngea/hr

I8 military
Plan=
8 domestic
ph.W

165-219 people

27-113 people

Mechanical

Arena 1      11.806 people      Mechanical
Arena2      2,ooO people      Natural

Ewtaurant      50-W/470 m'      Mechanical


R&aurant     60-lW440 m'      Natural


Bar         3J-i0/50 m'      Natural, open


Cafeteria       W-150/574 m'     11 changea/hr

Not given
Nonsmokers' rooma

8 hr continuous
2 hr after smoking
8 hr continuous
2 hr after smoking

6-7 hr continuous

1 `I,-2'1, hr
continuoue

Not given
Not given
Nonsmoking
srens

27 x 30 min
Lwnplee
2SX3OlUiIl
SampIeS
28X3Oti
SampIeS
24X3Oti
Nonsmoking
rwm

11.5
-1
17
-12

4.3-9.0



lo-12


-3-22


<2-5

9.0
25.0

5.1          2.1-9.9


2.6          1.43.4


4.8          2.4-9.6


1.2          0.7-1.7

2.2 + 0.98      0.445

   2 (outdoorL3)

  Values not given
  Values not given

3.0 (nonactivity day)
3.0 (nonactivity day)
  9.0

  4.8 (outdcmrs)


  1.5 (outdoolB8)


  1.7 (outdwrs)


  0.4 (outdoors)
0.5         0.3-0.8


TABLE Lc.-Continued

Study

m of
premises

Ventilation

Monitoring
conditions

  Levels @pm)         Nonsmoking controls (ppm)


MWUl       Ranse        MWll      Range

Harke
(1974a)

Harke and
Peters
(19747

Harnwen and
Effenherger
f lY57v

Perry
t IY 7s

Portheine
I I.V71lS

Sebhen et al
(IH771

officed
oflie

car

-72 m'
-78 ma

2 smokers
(4 cigs)

236 m'/hr
Natural

Natural

Mechanical

14 public
Pla=

Rams

Not given       Not given    One grab sample    <: 10

Not given       Not given    Not given                     625

9 night&be    Not given

14 restauranta
45 rwtaurante
33 stmw
3 hospital
lobbies

1-18 smokers      Natural     Not given                     O-40

Not given       Not given
Not given       Not given
Not given       Not given
Not given       Not given

30 min samples
30 min samples
Samples

77 x 1 min
BarnpIeS
outdmrs
Spot checks
Spot checks
Spot checks
Spot checks

< 2.5-4.6
< 2.sJ.o

42 (peak)      (Nonsmoking rums)
            13.5 @eak)
32 @eak)      (Nonsmoking runs)
           15.0 @?ak)

13.4          6541.9

                      9.2 3.0-35.0
9.9 + 5.5               Values not given
8.2 f 2.2                7.1 + 1.7 (outdoom)
10.0 + 4.2               11.5 f 6.9 (outdoora)
           48         Values not given


Y   TABLE 2c.-Continued
IP                                                      Levels @pm)        Nonsmoking controls @pm)
             Type of                        Monitoring
   Study        pmilliSW      &UpaneY      Ventilation      condition8        MWll       Raose        Mean

seiff
(1973)

Intercity bus    Not given

15 changeE/hr,
23 cigarettes
burning
wntiuuolWly
3 cigarettea
burning
continuously

33 wm




18 wm

Slavin and
Hertz
(1975)

2 conference
moms

Not given

8 changealhr   Continuous.
         morning
6 changeelhr   Continuous,
         morning

8 (pdd

10 @&

l-2 kleparate
nonsmoking day)
l-2 heparate
nonsmoking day)

&dkOWSki
et al.
(1976)

25 officea

Not given

Not given

continuous        2.78 + 1.42                   2.59 f 2.23
                              bqarate nonsmoking
                                    offi9s)

`Thrseciganttesandooecigarsmokedin20minutee.
whe Drager tube used is accurate only within f 25 percent.
= The M6A Monitaire Sampler ubed in acnuate only within f 7.5 percent
dAbout 40 t&srettw/day were smoked.
o Ahout 70 cigar&Am/day were smoked.
`Four filter cigar&m were smoked.
rNoerperimentaldeacriptiongiven.


TABLE U-Nicotine measured under realistic conditions

Study

nw of
premises

Ventilation

Monitoring
conditions

            Nonsmoking
Levels Q/m')        wntmls


Mt?.tUl    Range Man Range

Badre et al.
u978l

Gcafea
Boom
Haspitnl lobby
2 train compartmenta
car

Can0 et al.
(2970)

Harmsen and
Effenberger
(f96Tl

HindaandFirst
(197.P

Submarines
66m'

Train

Train          Not given
BIU           Not given
Bus waiting room     Not given
Airline waiting room   Not given
Ftastaurant        Not given
Cocktail lounge      Not given
Student lounge      Not given

Weher and Fischer
m8w

44 oftk!s

Varied

Varied
18 smokers
12 to 30 smoker9
2 to 3 smokera
3 smokers

167 cigarett4w
per day
94-103 cigarettea
Per day

Not given

Not given
Not given
Not given
Not given
Natural, open
Natural, clawed

YeS

YeS

Natural. cloeed

Not given
Not given
Not given
Not given
Not given
Not given
Not given

Varied

50 min BarnpIe              25-52
50 min sample      500
50 min aample       37
50 min sample              3640
50 min anmple       65
50 min sample      1010

            32 palm'

1535 palm'

30-45min
samplea

2'/, hr aamplen       4.9
2'1, hr aamplea      6.3
2'1, hr aample       1.0
2'1, hr samples      3.1
2'1, hr samples       5.2
2% hr samples      10.3
2'1, hr samples       2.6

07.9.1

Values not given
Values not given
Values not given
Values not given
Values not given
Values not given
Valuea not given

140 x 3 hr
samples

0.9 + 1.9  13.8 &AK)  Values not given


TABLE 2e.-Nitrogen oxides measured under realistic conditions

Study

Tvpe of
premises

Ventilation

Monitoring
conditiona

               Nonsmoking
   Levels     -     controls (ppb)

Mf?iUl      Ranse      MMl    Range

Fischer et al
(1978) and
Weber et al.
11979)

Restaurant


Restaurant


Bar



cafeteria

f&60/470 ma


6&100/440 m'


3@-40/50 m'



@J-150/574 m"

Mechanical     27xZOmin
          SampleS
Natural       29X3Omin
         @amplea
N8tld.      28x3Omin
open       SampIeS

11 changee/hr   24 X 30 min
         Eamplen

Otber-non-
smokers rcom

NO,: 76       59-106
NO 120       %218
NO,: 63       2499
NO: 80        14-21
NO,: 21        l-61

NO: 195
NO,: 58

66-414
35-103

NO: 9

2-38

63 (outdwra)
115 (outdoors)
50 (outdoore)
11 @&atdoors)
48 (outdml8) 3

4-l (outdoora)
34 (outdoolB)

4 (outdooIB)
NO,: 27      1.544


NO: 5        2-9

Weber and
Fischer
(198OP

44 OffIces       Varied             VlU%d               NO,: 2.4 + 22    115 (peak)     Values not given
                               samples
                                               NO:  32 + 60    280 @eak)     Values not given

tintml values (unoccupied rooms) have been subtract&


TABLE 2f.-Nitrosamines measured under realistic conditions

Study

Ventilation

Monitoring
conditions

  Levels (ng/L)

MWII         Range

Brunneman and
Hoffmann
11978)

Train bar car
Train bar car

Brunneman et al
(1977)

Bar
sporta hall
Betting parlor
Discotheque
Bank
House
House

Not given       Mechanical        90 min continuous         0.13
Not given       Natural         90 min continuous         0.11

Not given
Not given
Not given
Not given
Not given
Not given
Not given

Not given
Not given
Not given
Not given
Not given
Not gwen
Not given

3 hr continuous
3 hr continuous
90 min continuous
2'1, hr continuous
5 hr continuous
4 hr continuous
4 hr continuous

N-Nitroedimethylamine

0.24
0.09
0.05
0.09
0.01
`: 0.005
~-0003


Y  TABLE 2g.-Particulate8 measured under realistic conditions

Study

~UpancY
(active smokers
per 100 mrl

Ventilation

Monitoring
condition8
bid

Levels (pg/m')

Mean Std. dev.

Nonemoking
controls C&m')

Mean Std. dev.

Bepace and     Cocktail party             0.75         Natural                   15          351 + 38         24
b-Y       Lodge hall               1.26         Mechanical                50         697 f 26         60'
w3~        Barandgrill              1.78         Mechanical                 18         589 k28         63'
         Firehow bingo            2.11         M&hIliCd                16         417 3I 63         51'
           Pizzeria                 2.94         Mechanical                32         414 + 58         40'
         Bar/cocktail lounge          3.24         Mechanical                 26          334 f120         50'
         Church biio game          0.47         MeLhUlhl                42          279 * 18         30
           Inn                   0.74         MdWliCd                 12          239+9         22'
         Bowling alley             1.53         Me&IlOiCal                20          al2 + 19         49'
         Hmpital waiting room         2.15         M8ZtiCd                 12          187 f 52         58'
         Shopping plaza restaurant
          Sample 1               0.18         M&MliCd                18          153 + 8         59'
          Sample 2              0.18         MeChanical                18          163 f 4         36'
         Barbeque restaurant          0.89         Mechanical                10          136 f 17         40'
           Snndwich restaurant A
          Smoking section           0.29         Md8lhXl                20          110 f 36         40'
          Nonsmoking section          0         MedUUlid                20          55t 5         30
           F&food restaurant          0.42         Me`hIliCd                40          109 * 38         24'
         sporta arena             0.09 I        MWtid                 12          94 f 13         55'
        Neighborhood restaurant/bar     0.40         Mechanical                12          93 + 17         5.5'
           Hotel bar               0.59         MdaIlk.d                 12          93 * 2         30
          Sandwich restaurant B
          Smoking &ion          0.13         M@hItiCd                 8          86f7         55
          Nonsmoking section          0         M@hllical                21            51
           Roadside restaurant         1.12         Mechanical (9.5 ach')           18           107'           30
           Cmference room            3.54         Mechanical (4.3 ach')           6          1947'           55


TABLE 2g.-Continued

Study

-vaw
btive smokera
per loo n-l31

Ventilation

Monitoring
conditions
bin)

Levels @g/m')

Mean Std. dw.

Nonsmoking
controls Q&m')

Mean Std. dev.

F&pace and      Dinner theater
h-Y       Reception halJ
(1982l       Bingo ball

0.14
1.19
0.93 '
0.93 a

Mechanical
MeCbEUhl
Netural
Mechanical W39 ach')

44         145 t- 43         47   c 10
20         301 + 30         33'
2           1140            40'
6           443'           40'

`Sequential outdoor measurement (6 minute average).
`Esltiited.
' Air dmngea per hour.

o Equilibrium level BI determioed from ooncantration VI. time CUM.


E  TABLE 2g.-Continued                                      .-.-*                                .-

                                                     Levels @g/m')       Nonsmoking controls (pg/mJ)
             Type of                         Monitoring
   Study        pmmises      ~UpaneY      Ventilation      conditions        MHUI       Range        Mean      iiancJe

Cuddleback et al. Tavern

(29767


U.S. DetBt. of

Not given

Tavern      Not given
18 military planes 16219 people

8 domestic plaaes 27-113 people

6 changeelhr   4xahr

1-2 changedbr 8 hr continuous

Mechanical    12 x 6-l hr
         SampIeS
Mechanical    24 x I'/,-2'1, hr
         SallIpleS

Dcckery and
Spengler
(1981)

Elliott and
Rowe
(1975)

Hamrwn and
Effenberger
(1957)

Just et al.
(1972)

Neal et al.
(1976)

Residences

Not given

AlWUIl      11,806 people
Arena2       Zoo0 people
Arena 3 (smoking 11,COO people
prohibited)

Train0

15-120 people

4 coffee houeee

Not given

Hospital unit
Hospital unit

Not given
Not given

310


986

Not given

Varied

2-4 hr samples       32

MeChanical
Natural
Ml?&Mlical

During activities     323                42 (nonactivity day)
hrring activities     620               92 (nonactivity day)
During activities     148                11 (nonactivity day)

Natural

Not given

Nonsmokere' cam

Not given

6 hr averages

48 hr samples
48 br Barnplea

1150



21 f 14
40 It 21

< lo-120

particleelcm'                 20-15
                particles/cm"

500-1900      510 (outdootn)    10&1900

MB        13 f 25
13-19       12 + 25


TABLE Zg.-Continued

                                                Levels (pg/m')       Nonsmoking controls f&m')
          Type of                         Monitoring
Study        premises      @CUpaneY      Ventilation      conditions        Mean       Ranse        Mean      Range


Spender et al.   Residences     2+ smokers       Natural     24 hr samples       70 t 43
UW)                                                                  21 + 12 (outdoors)
                      1 smoker        Natural     24 hr samples       37 f 15               21 f 12 butdooln)

W&r and     44 officea      Varied          Natural and   429 x 2 min
Fischer (1981)                                                 133 f 130'    962' @?ak)
                                  mechanical    fk3tUpleS
Quad et al.    OfTice No. 1     0.62 a           Mechanical   Five 10 hr workday    45         3954
(2932l                                                                           5-15
          O&e No. 2     0.66'           Mechanical     averages; wntiiruoua 45         3740                    l&m
         OfTice No. 3     1.46'           Mechanical     monitoring        68         42439                    15-20

Brunekreef and   26 houaes      1-3 smokers       Natural     2 mo averages       153"        60-340        55
Boleij (198zl                                                                           20-90



I Values above baclground.
`Habitual amokem per 100 III*,
' Wciahti mean


%  TABLE ah.-Residuals measured under realistic conditions

Study

k of
premieee

Ventilation

Monitoring
conditions

             Nonsmoking
     Levels          contmle


MeaIl    Ranse    Mean Bange

Badre et al.
(1978r

Gcafea
Room
Hospital lobby
2 train
wmpartmenta
car
car

Dockery and
Spengler
m91)

Residences       Not given            Varied        24 hr samples         4.81

Fischer et al.
(1978)

Beataurant        5O-SOl470 ma          Mechanical
Restaurant        60-lW440 m'         Natural
Bar            30-40/50 mr         Natural, open
Cafeteria         80-W/574 ma          11 ch/hr

Juet et al.
(1972)

4 coffee houses     Not given          Not given       6 hr continuous      12.0-15.3

Varied
18 smokers
12 to 30 smokers
2 or 3 smokers

3 smokere
2 smokers

Not given      100 mL samples
Not given      100 mL eamplea
Not given      100 mL samples
Not given      loo mL samples

Natural, open    100 mL samples
Natural, cloeed    100 mL samples

27 X 30 min samples
29 X 30 min samples
26 x 30 mill samples
24 X 30 min samples
Other nonsmokers'
rwm

Acetone bng/m")

     0.91-5.88
0.51
1.16
     Ox-O.75

0.32
1.20

Sulfur dioxide (ppb)

xl     9-32        12 Ppb
13     5-18        6
30     13-75       8
15     l-27        12
                7

3-13


is also readily available. CO reflects the gas phase components of
smoke and thus may not reflect the levels of particulate phase
constituents. There are also a number of other CO sources in
addition to cigarettes, both in the external environment (e.g.,
automobiles) and in the indoor environment (e.g., gas stoves). As a
result, even the subtraction of external atmospheric levels may not
entirely eliminate the contribution of other sources of CO to the
indoor environment.
Given these problems, use of several of these measures, or the
tailoring of the measurement to the phenomenon being measured,
seems appropriate. The measurement of total particulate matter
may be a reasonable indicator of exposure to the particulate phase of
smoke, once the measurement is limited to respirable particulates
and once background levels with the same level of activity, but
without smoke, are subtracted. Relatively precise methods have been
developed to predict the levels of exposure to carbon monoxide
(Jones and Fagan 1975; Coburn et al. 1965) and total particulate
matter (Repace and Lowrey 1980) that would be expected in rooms of
different size and ventilation with different rates of smoking.
Stewart et al. (19741, using blood donors, found the median blood
carboxyhemoglobin level for smokers and nonsmokers in selected
populations to be 5.0 and 1.2 percent, respectively. This corresponds
to a steady state ambient CO level of 7 ppm, which represents a
combination of atmospheric pollution from cigarette smoke and the
background level of urban pollution and is consistent with the levels
described in Table 2. Exposure levels to carbon monoxide are highly
dependent on ventilation, occupancy, smoking rates, and background
levels in the ambient air. The half life of carboxyhemoglobin is
approximately 4 hours, making blood carboxyhemoglobin a useful
biologic monitor of acute exposure to passive smoking, but one that
does not provide useful data for chronic exposure.
Assessment of chronic exposure with a biologic marker requires
the ability to measure some accumulating product of smoke. To date,
substances such as cotinine (Matsukura et al. 1979; Langone et al.
1973; Williams et al. 1979; Feyerabend and Russell 1980; Russell et
al. 19821, thiocyanate (Bottoms et al. 1982; Cohen and Bartsch 19801,
and polonium-210 (Radford and Hunt 1964; Little and McGendy
1966) have been measured in active smokers. Plasma and urinary
nicotine, plasma and urinary cotinine, and salivary nicotine and
cotinine have been reported in nonsmokers exposed to tobacco smoke
(Jarvis and Russell 1984; Russell and Feyerabend 1975; Feyerbend et
al. 1982). Of these measures, it would appear that urinary cotinine
offers the most promise as an index of exposure. However, there are
no published data using these measures as biologic markers of
chronic involuntary smoke exposure.


In contrast to physiologic investigations, epidemiologic studies
have used the number of smokers in the home or in the working
environment as the principal exposure variable. These relatively
crude indices, in general, ignore time spent with the smoker and the
environmental factors known to influence ambient smoke concentra-
tion noted above.

In summary, involuntary smoking research deals with an expo-
sure that is qualitatively and quantitatively different from that of
active smoking. Adequate characterization of passive exposure in
both epidemiologic and physiologic studies is substantially more
difficult for involuntary exposure than for active smoking exposure.
While the active smoker's total current cigarette consumption is
relatively easily quantitated, the lower dose and greater influence of
ventilation and ambient environment for involuntary smoke expo-
sure makes assessment of exposure one of the most important
methodologic issues of this research. Clearly, a biologic marker of
chronic exposure that reflects the amount of tobacco smoke to which
nonsmoking persons are exposed would be a useful tool. In addition,
carefully formulated questionnaires quantifying passive smoking are
also necessary, and may prove equally valid for assessing exposure.
No single index has yet been accepted by all investigators, and
comparison between studies remains difficult. However, Repace and
Lowrey (1983) have estimated that the nonsmoking population may
be exposed to from 0 to 14 mg of tar per day, with an average expo-
sure of 1.43 mg per day.

Acute Physiologic Response of the Airway to Smoke in the
Environment

Relatively little acute exposure data exist concerning the effects of
passive inhalation of cigarette smoke on pulmonary function (Table
3). The data that are available have been obtained in exposure
chambers under carefully monitored and controlled circumstances
(Pimm et al. 1978; Shephard et al. 1979; Dahms et al. 1981).

Pimm and colleagues (1978) exposed nonsmoking adults to smoke
in an exposure chamber. Relatively constant levels of carbon
monoxide (approximately 24 parts per million) were achieved in the
chamber during involuntary smoking. Peak blood carboxyhemoglo-
bin levels were always less than 1 percent in subjects before smoke
exposure, but were significantly greater during the study exposure.
Lung volumes, flow volume curves, and heart rate were measured
for all subjects. Measurements were made at rest and following
exercise under control conditions and smoke-exposure conditions.
Flow at 25 percent of the vital capacity decreased significantly with
smoke exposure at rest in men and with exercise in women. The
magnitude of the change was small: a 7 percent decrease in flow in

384


TABLE 3.-Acute effects on pulmonary function of pas&e exposure to cigarette smoke

Study            Type of exposure

Magnitude of exposure

Effect0                Comments

Pimm et al.
u9m

Chamber 14.6 m' with
sparse furniture; smoking
machine in room

Peak [co] - 24 ppm;
particulate8 >4 mg/m'

Men: 5% increase FRC,
11% increase RV, 4%
decrease v-as during
exerciee

Nonsmokers; average age of
men = 22.7, women = 21.9;
sham expoeure aa control

Women: 7% decrease ON
post exercise; no effect4 on
vc. TLC. Fvc. lmv,.

Shepard et al.
(1979)

As above

Low erpoeurz peak (Co] -
20 ppm, particulate8 -
mg/m'; high erpoeure: [Co]
- 31 ppm

Jhhma et al.
(19Rl)

Chamber 30 m I; climate
controlled

Room leveb not measured;
estimated at penk [Co] -
20 PFm

Low exposure: 3% decrease
FEV,, 4% decrease VU
5% decrease 0-z~ with
ererciee; no increaned effect
with high exposure

0.9% increnee in FVC.
5.2% increase in FEY,,
2.2% increase in FJIFs,a at
1 hour

Nonsmokers; average age of
men = 23, women = 25,
sham exposure as control;
subjects estimated to have
inhaled - l/2 cigarette/2
hours

10 nonsmokers; age range
2453 years; not blinded; no
sham exposure


men and 14 percent in women. No other consistent changes in lung
function were observed. Shepard and coworkers (1979) utilized a
similar crossover design in a chamber of exactly the same size as
Pimm's. Their results were almost identical, with a small (3 to 4
percent) decrease in FVC, FEVl, VmaJr50, and Vrnax~. They concluded
that these changes were of the magnitude anticipated from an
exposure of less than I/2 cigarette in 2 hours (the exposure
anticipated for a passive smoker).

Dahms et al. (1981) used a slightly larger chamber with an
estimated peak CO level of approximately 20 parts per million. They
found no change in FVC, FEVI, or FEFw75 after 1 hour of exposure in
normal subjects. This experiment was not blinded and had no sham
exposure.

The data from these studies suggest that involuntary smoke
exposure can probably produce measurable, albeit small, changes in
the airways of normal individuals. This response is consistent with
the acute response to the inhalation of cigarette smoke by the active
smoker, and it is not surprising that high dose involuntary exposure
to tobacco smoke might produce similar results. The magnitude of
these changes is small, even at moderate to high exposure levels, and
it is unlikely that this change in airflow per se results in symptoms;
however, it may be only one manifestation of a broader irritant
response to smoke in nonsmokers.

Symptomatic Responses to Chronic Passive Cigarette Smoke
Exposure in Healthy Subjects

Eye irritation is the most common complaint experienced by
normal people acutely exposed to cigarette smoke. In one study, 69
percent of subjects reported ever experiencing this symptom @peer
1968). Headache, nasal irritation, and cough were reported by
approximately one-third of the subjects in this and other investiga-
tions (Weber and Hertz 1976; Slavin and Hertz 1975). Several factors
may alter the prevalence of irritant symptoms, including the amount
of smoking, the size of the area involved, the humidity and
temperature of ambient air, and the extent of ventilation (Johansson
1976). No longitudinal studies of these irritant effects (e.g., develop-
ment of increased sensitivity or tolerance) have been reported.

Weber (1984) has examined the effect of dose and duration of
exposure to environmental tobacco smoke on subjective reporting of
eye irritation and objective measurement of eye blink rate. Figure 1
reveals that both eye irritation and blink rate increase with
increasing dose of smoke exposure, and that substantial subjective
irritation and objective increase in blink rate occur at levels of
smoke exposure (CO levels of 20 to 24 ppm) equivalent to those used
to evaluate pulmonary function changes in response to environmen-

386


   eye lrritatlon
vary strong 5 l-

strong

medium

weak

none

co


NO

HCHO


ecroloin

~  . . . . . . . .



4






3

      /' .--.... --- . . . . . _......
     *.*'
    ..a'
    *:.
   *:.
  ,:.
.f
..:
.:*
.:'
,:*

- 60

- 40

j/y
    I I I     I     1    1 1:
   0 10        2c      mln
    1 1 I     I     I    1
   1 11 22   32   42   43 pm
    I     I     I     I     I    1
  0.08 0.42 0.77  1.11  1.45  1.50 ppm
    f     I     I     I     I    1
  0.03 0.16 0.32  0.47  0.62  0.64 ppm
    I     I     I     I     I    1

eye blink rstdmin

c 60

     number of cig. 0         10        20
FIGURE l.-Mean subjective eye irritation, mean eye blink
      rate, and concentrations of some pollutants
     during continuous smoke production in an
       unventilated climatic chamber
NOTE- Thirty-three subjects. ventdatmn rate 0 01 h 1, eye ~rritatmn Index calculated from the answers ?A four
questions concerning eye ~mtatmn: 0 mm = measurement before smoke production
SOURCE. Weber (1984)

tal tobacco smoke exposure. Both irritation and blink rate increase
with duration of exposure to environmental tobacco smoke (Figures
2 and 3). After 60 minutes of exposure, distinct changes are evident
in level of irritation with a smoke exposure of 1.3 ppm CO, and the
blink rate increased with smoke exposures as low as 2.5 ppm CO.
These levels of smoke exposure (1.3 to 2.5 ppm CO) are well within
those measured under realistic conditions (see Table 1). Therefore, it
is possible to demonstrate an objective irritant response in normal
subjects at levels of smoke exposure substantially lower than the
levels where an airway response (also presumably an irritant
response) has been demonstrated. Whether this difference represents
a difference in threshold for irritation in the eye and airway or a
limitation in the ability to measure subtle changes in the airway is
uncertain.


eye irritation index

-r-- - 10ppm
       5 pm

2.5 ppm

1.3 ppm

control

0

20

40      60
exposure min

FIGURE S.-Subjective eye irritation due to environmenta
       tobacco smoke, related to smoke concentratio
      and duration of exposure

NOTE: 0 values M levels dwing smoke pmduction minus backgnund level before smoke prcduction; 32 t
subjects; 0 min = measurements before tunoke production.
SOURCE: Weber W841.

Chronic respiratory symptoms have been reported most common
in children. Studies from several different countries (Table 4) ha
shown a positive relationship between parental cigarette smoke;
and the reporting of the symptoms of chronic cough, chronic phlegm
and persistent wheeze (Colley et al. 1974; Bland et al. 1978; L&ow-
and Burrows 1976; Weiss et al. 1980; Ware et al. 1984; Schilling et.
1977; Kasuga et al. 1979; Schenker et al. 1983). Some of these studi
may be confounded by an increased reporting of symptoms in t
child by parents who smoke and have symptoms (Colley et al. 19'.
Bland et al. 1978; Kasuga et al. 1979) or by the child's own smoki
habits (Colley et al. 1974; Bland et al. 1978; Kasuga et al. 1979). 5
all studies show statistical significance for all symptoms @bow
and Burrows 1976; Schilling et al. 1977; Schenker et al. 198
However, a consistent finding in all reported data is an increase
symptoms with an increased number of smoking parents in t

388


eye blink ratelmin

40-

35-

25-

20-




15-

OJ

5 ppm
5 rwm

_--   1.3 ppm

    control

2.5 ppm
2.5 ppm
1.3 ppm

control

I     I     I     I     I     I    1
0      20     40     60

exposure min

FIGURE 3.-Effects of environmental tobacco smoke on eye
        blink rate

home. This effect persists after controlling for parental cough and is
most marked in the first year of life.

British researchers, studying a birth cohort, demonstrated an
increased incidence of wheezing over a 5-year period among nonasth-
matic children who had two parents who smoked. However, when
examined by logistic regression, parental smoking was not a
significant predictor of occurrence of wheeze or the future occur-
rence of asthma (Bland et al. 1978). In a subgroup of the cohort-861
children of asymptomatic parents, Leeder and colleagues (1976al
found no significant trend in asthma-wheeze symptoms with in-
creasing levels of parental smoking over a 5-year period. In a study
of 650 children aged 5 to 10 years (Weiss et al. 19801, a significant
trend in the reported prevalence of chronic wheezing with current
parental smoking was found; the rates were 1.85 percent, 6.85
percent, and 11.8 percent for zero, one smoking parent, and two
smoking parents, respectively. Although the data given are for all

389


TABLE 4.--Respiratory symptoms in children in relation to invohntary smoke exposure

Study

Subjecta

Respiratory
symptoms or illness

  Rates pm 100 by
number of smoking parents
   0    1 2

Comment

Colley et al.      2,426 children, aged 6-14,
(1974        England

Chronic cough assessed by
questionnaire completed by
P==t

15.6   17.7   22.2      Trend significant; possible that
             8ymptoms in parent8 could result
             in reporting biae; active amok&
             in children could aleo bias resulta;
             bias unlikely to explain full effect
                of trend

Bland et al.
(1978)









Weiss et al.
(19Bo)

Ware et al.
u984

3,105 children, aged 12-13. who
did not admit to ever smoking
cigarettea, England








650 children, aged 5-9, united
States


6,628 children, aged 5-9. with
two parents of known smoking
atatua, air U.S. cities

Cough during day or at night        16.4   19.0 23.5

Morning cough                  1.5   2.6   2.9








Chronic cough and phlegm          1.7 2.7   3.4

Self-reported symptoms and
smokiug history collected
aimultaneoualy from children;
difference between morniug and
daytime cough suggested ae
different dkaees, but could be
difference in exposure, in that
exposure more likely in daytime
than when asleep
Trend not aiguiticant

Persistent wheeze

Chronic cough

Per&tent wheeze

1.6   6.6   11.8      Trend &u&ant

7.7   6.4   10.6      Adjusted for age, sex, and city
            cohort effects, significant trends
9.9   11.0 13.1


TABLE 4.-Continued

Study             Subjecta

Respiratory
nymptomn or iunem

  Bates per 196 hy
number of amokin parents
   0 1 2

Comment

Dodge
W8fT)

626 children, graden 3-4, in
tweparent householde;
questionnaire renponee of
parenta, United Statee

Schenker et al.
U983)

4.971 chikhan, aged 614. in
weatern Pennsylvania

cough
Chronic cough

Chronic phlegm

Pereistent wheem

21.6   27.9   40.0      All trends significant; some of
             effect might relate to parental
6.4   10.9   12.0      symptoms, but not likely to
                influence trends
14.6   23.0   27.8

6.3   7.0   6.3      None of these rates significant;
              data not adjusted for parental
4.1   4.6   4.0       Bymptom


7.2   7.7   5.4

Lebowitz and
Burrows
(1976)



SchiUing et al.
(1977)

1,252 children, (16 years
old. United States




816 children, age 7 t. United
smea

Persiatent cough

Persistent phlegm

whew?

Cough, phlegm, wheeze

Never        Parent
smoking      smoking

  3.7         7.2      Higher rates in symptomatic
               households with trends persisting,
10          12.6      but not significant for
                asymptomatic households
23.4         24.1

No significant         Specific data not provided
effect

Knsuga et al.
(1979)

1.937 children, aged 6-11.
Japan

wheeze, asthma

Increased prevalence in families
with a heavy smoker (2 21
ciglday); km clear effwt in
family with a light smoker ((21
ciglday)

Data adjusted for distance of
home fmm main traftic, highway


households, when the analysis was restricted to those households
where neither parent reported symptoms, the results were identical,
suggesting that in this population, significant reporting bias was not
responsible for the observed results. Lebowitz and Burrows (1976), in
a group of 463 current-smoking and never-smoking households with
children below age 15, found trends-but no statistically significant
differences-for a variety of symptoms, including wheeze most days,
in households with smokers. In the same study, among 849 house-
holds with older children and adults, there were no significant
differences for any symptom prevalence between current-smoking
and never-smoking household members. In a general population
study, Schilling et al. (1977) reported no association between wheeze
and involuntary smoking.

A preliminary report from one of the largest studies currently
under way (Speizer et al. 1980) indicated no association of persistent
wheeze with the presence of smoking in the household for approxi-
mately 8,000 children aged 6 to 11 in six communities. However,
subsequent analyses of these same cohorts with the addition of
approximately 2,000 more children and a more detailed assessment
of the smoking behavior of each parent revealed a positive relation-
ship that increased with the amount of maternal smoking and was
only modestly affected by taking into account the parents' own
symptoms (Ware et al. 1984). Dodge (1982), studying third and fourth
grade children, found that symptoms, including wheeze, were related
to both the presence of symptoms in the parents and the number of
smokers in the household. The gradient of the wheeze effect
persisted even after excluding the potential effect of reporting bias
by symptomatic parents. Few data are available on the level of
exposure necessary to produce symptoms or on the implication of
these symptoms for future lung growth and development. No data
are currently available on the relationship of passive smoking to
other putative risk factors for wheezing such as atopy, respiratory
infection, and increased levels of airways responsiveness, nor are
sufficient data available to estimate whether these early exposures
affect the occurrence of respiratory disease later in life. The
characteristics of the child who may be susceptible to this type of
exposure are unknown. However, the data are sufficiently consistent
to suggest that pediatricians should routinely inquire about smoking
habits of parents when caring for children with chronic or recurrent
respiratory symptoms and illnesses. It would also be prudent to
advise parents of children who are suffering from recurrent respira-
tory illnesses or persistent wheeze or asthma not to smoke.

392


Respiratory Infections in Children of Smoking Parents

Bronchitis and pneumonia and other lower respiratory illnesses
are significantly more common in the first year of life in children
who have one or two smoking parents (Table 5). Bonham and Wilson
(1981) showed that in 1970 the majority of homes with children
under 17 years of age had at least one smoker. Thus, passive smoking
by children, even in early childhood, is widespread. Harlap and
Davies (1974) studied 10,672 births in Israel between 1965 and 1968
and observed that infants whose mothers said they smoked (as
determined at a prenatal visit) experienced a 27.5 percent greater
hospital admission rate for pneumonia and bronchitis than children
of nonsmoking mothers. In addition, they demonstrated a dose-
response relationship between the amount of maternal smoking and
the number of hospital admissions for these conditions. It should be
noted that the mothers were reporting prenatal smoking and not
postnatal smoking for the first year of life.

British investigators studying live births between 1963 and 1965 in
London also observed an increased frequency of bronchitis and
pneumonia in the first year of life associated with involuntary
smoking that did not carry over to years 2 to 5 (Colley et al. 1974).
This effect was independent of parents' own symptoms and increased
with the amount of smoking by parents. Bronchitis and pneumonia
also increased with an increased number of siblings, and this was not
controlled in the analysis.

Fergusson et al. (19811, studied 1,265 New Zealand children from
birth to age 3. They demonstrated an increase in both bronchitis and
pneumonia and lower respiratory illness during the first 2 years of
life in children whose mothers smoked. Corrections for maternal age,
family size, and socioeconomic status did not affect the linear
relationship between the degree of maternal smoking and the rate of
respiratory illness. This effect declined with the increasing age of the
child.

Leeder and colleagues (1976b) studied a British cohort of children
born between 1963 and 1965 and demonstrated that parental
cigarette smoking was associated significantly with bronchitis and
pneumonia during the first year of life. A dose-response association
persisted after correction for parental respiratory symptoms, sex of
the child, number of siblings, and a history of respiratory illness in
the siblings.

Pullan and Hey (1982) studied children who were hospitalized with
documented respiratory syncytial virus (RSV) infection in infancy.
They found a significant difference in the smoking habits of mothers
at the time of the infection, compared with children hospitalized for
other illnesses-including respiratory diseases for which RSV infec-
tion was not documented. These children reported an excess
occurrence of wheeze and asthma and had lower levels of pulmonary

393

ART)-144 0 - Rk14


%  TABLE Z-Early childhood respiratory illness and involuntary cigarette smoking

Study              Subjecta

Findings

lllneea rates per 100

Commenta

Harlap and
Davies
(1974

10,672 births, 1965-1966.
Weat Jeruealem, Israel

Hospitalized for
bronchitis/pneumonia in first
year of life
RB'=1.38

By cigarettee per day

0    l-10   11-20 20+

9.5    10.8    16.2    31.7    Smoking history obtained
                antenatally; maternal smoking
                OdY

Collev s
(1974)

2,205 births. 1963-1965.       Questionnaire on               7.6    10.4    11.1    15.2    = Asymptomatic parents

London, England

bmnchitislpneumonia in first
year of lie
RlL1.73 for one parent smoker
RR=260 for two parent smokers

10.3

15.1

14.6

23.2

= SyLptomatic p&W8
Neither mntmlled for number
of siblings or sex of smokers

Fergwwn et al.
(1981)

1@5 births, 4 months,
1977, Christchurch. New
Zealand

Queationnairea on doctor or
hospital visita for
bmnchitis/pneumonia; check
by hospital records
Aaemement at 4 months, 1, 2.
and3yearm
RR=2.04 if mother smoked

7.0    12.8


7.0    4.6

13.4   Maternal  Combined effect Significant for
   OdY    maternal smoking in first year
6.6 Paternal  of life only
   OdY

By number of smoking parents

0     1     2

Ware et al.
wJ4l

8,528 children, aged 5-9,
with two pnrenta of known
smoking ntatun. six U.S.
cities

lIeapiratory illness in last year

12.9

13.7

14.8

Adjusted for age, eex:, and city
cohort effect; significant trends


TABLE 5.-Continued

Study              Subjecta

Findinga

nlnees rates per 1M)            commente

Said et al.
(1978)

3.920 cbildm. agfd lcF20,
France

Toneillectomy and/or
adenoid&my. generally
before age 5, 88 indicator of
frequent rcapiratory tract
infection

28.2

41.4

50.9

Self-reporting by children; not
clear that smoking habite of
pm-de at time of reporting
directly related to erpoeure
appmximately lO+ years
earlier

Schenker et al.     4,071 children, aged 614,       &St illrem before age 2             6.1    7.9    11.5       Trends for both &nificant
UW         wfmtern Pennsylvania        chmtinn~ >3dayainpaet          8.8    11.8    13.6
                                    Year

Cameron et al.
W%.!3

158 chikiren, aged 6%
parents completed telephone
questionnaim, United Statm

Respiratory illness with
restricted activity and/or
medical consultation in last
Y-

1.33

1.4

nh38 reporting 00t verified;
not clear how reporting adult
was related to child

Leeder et al.
(1976a, b)

2,149 infants. horn 1963-
1965, Harmw, England

RR - 2.0 for infants with two
smoking parente

Not provided

Parents answered for children,
but response bii eeeme
unlikely hesaw effect.3 were
obeerved for infants of
aaymptomatic parents; effects of
maternal w. paternal smoking
not inveetigated

Sim et al.
(1978)

35 children hoepitnlized
with RSV bmnchiolitie,
35 controla, England

Borderline significant inc-
in maternal smoking during
fti year of life
RR=2.65

Not provided

No significant effect for
paternal smoking. average
amount smoked greater for
parents of caeea than for
controls


TABLE %-Continued

Illness rate3 per loo

commenta

Rantakallio
(1978)

1,821 children of smoking
mothers.
1,823 children of
nonsmoking mothers

significant increase in
hospitalization for respiratory
illness during first 5 yeare of
life
RR=1.74

Not provided

F'mepective followup of doctor
visits. hospitalizations, deaths
up to age 5; only maternal
smoking evaluated

Pullan and Hey
(19LVl

130 children admitted to
hospital during finrt year of
life with RSV infection.
111 nonhoepitalized controls

Signiticant effect of maternal
(RR=l.W and paternal
CRR=1.53) smoking at time of
study; significant maternal
effect of smoking during fust
year of life CRR=1.55)

Not provided

' Relative risk for children of smoking mothers vernu~ children of nonsmoking mothers calculated from published data provided by J M. &met. M.D
`These data are considered in B more expanded analyaia provided by Leder et al (1976).


function that persisted to age 10. The authors could not distinguish
between the possibilities that infection caused damage that persisted
and affected the maturation of the lung or that these children were
already more susceptible to severe RSV infection. Greenberg et al.
(1984) examined the tobacco smoke exposure of infants in the first
year of life by measuring urinary cotinine-to-creatinine ratios. They
found that infants of mothers who smoked had a ratio of 351 ng per
mg, as contrasted with a ratio of 4 ng per mg in infants of mothers
who did not smoke. Breast-fed infants were excluded because of the
presence of nicotine in the breast milk of mothers who smoke. A
dose-response relationship was present between the cotinine-to-
creatinine ratio and the reported level of maternal smoking in the
previous 24 hours. This study suggests that infants of mothers who
smoke absorb measurable amounts of the smoke from this environ-
mental exposure.

Rantakallio (1978) studied over 3,600 children for 5 years, half of
whom had mothers who smoked and half of whom did not. Children
of mothers who smoked had a 70 percent greater chance of being
hospitalized for a respiratory illness than children of nonsmoking
mothers.

Some of these studies may be confounded by the increased
reporting of symptoms in the child by parents who smoke and have
symptoms (Cameron et al. 1969; Said et al. 1978; Leeder et al. 1976b),
but in those studies in which parental symptoms were controlled, the
effects persisted. Other studies may be influenced by the child's own
smoking habits (Said et al. 1978), although the majority of research
examined children in an age range in which smoking would be
unlikely.

In summary, several studies suggest important increases in severe
respiratory illnesses, particularly in the very young (less than 2
years old) children of smoking parents. Young children may repre-
sent a more susceptible population for adverse effects of involuntary
smoking than older children and adults. The amount of time spent
with active smokers, particularly by children under 2 years of age
with smoking mothers, may be an important factor. How in utero
exposure influences this risk is unknown.

Pulmonary Function in Children of Smoking Parents

In recent years, a number of studies have examined the relation-
ship of parental cigarette smoking to pulmonary function in children
(Table 6). The majority of these studies have been cross sectional
(Tager et al. 1979; Weiss et al. 1980; Vedal et al., in press; Burchfiel
et al., 1983; Tashkin et al. 1983; Hasselblad et al. 1981; Ware et al.
1984) and have demonstrated decreases in level of pulmonary
function (FEVo75, FEV1, FEFz75, and flows at low lung volumes) in

397


children of smoking mothers compared with children of nonsmoking
mothers.
In some studies, there seems to be a dose-response relationship
(Tager et al. 1979; Weiss et al. 1960); i.e., the greater the number of
smokers in the home, the lower the level of function. When analyzed
by multiple regression techniques, maternal smoking has the
greatest impact (as would be expected from the greater contact time
with the child), and a d-response relationship with the amount
smoked seems to exist (Weiss et al. 1980; Tager et al. 1979; Ware et
al. 1964; Vedal et al., in press). Younger children seem to be more
adversely affected than older children (Tager et al. 1979, Weiss et al.
19601, and clearly there is an added effect in older children if they
themselves smoke (Tager et al. 19791.
Tager and colleagues (1963) followed 1,156 children for 7 years to
determine the effect of maternal smoking on growth of pulmonary
function in children. After correcting for previous level of FEVi, age,
height, personal cigarette smoking, and correlation between moth-
er's and child's pulmonary function, maternal smoking was associ-
ated with a reduced rate of annual increase in F'EVl and FEF267s. The
magnitude of the effect was consistent with a 3 to 5 percent decrease
in expected lung growth due to the maternal smoking effect,
constant over the time period of the study. Because so few mothers
changed their smoking habits, the study did not attempt to differen-
tiate between postnatal and in utero effects of involuntary smoke
exposure.
Ware et al. (1964) followed 10,106 white children for two successive
annual examinations. The FEV, was 0.6 percent lower in the
children of smoking mothers at the first examination and 0.9 percent
lower at the second examination. These differences were statistically
significant, but represent very small absolute differences. In this
study, and in the other studies that show small changes in
pulmonary function, it is not clear whether these changes represent
small changes occurring uniformly among the children of smoking
mothers or somewhat larger changes occurring in a small subpopula-
tion of susceptible children.
The available data demonstrate that maternal smoking affects
lung function in young children. However, the absolute magnitude of
the difference in lung function is small; it is unlikely that this small
difference, per se, is of functional significance. The concern generat-
ed by the demonstration of even small differences is directed at the
future lung function of those children, particularly if they become
active cigarette smokers as adults. The possibility that this differ-
ence in lung function may result from pathophysiologic mechanisms
similar to those present in active smokers raises the concern that
these children may be "sensitized" to smoke at an early age, and that
this "sensitization" may result in a more rapid decline in lung


TABLE 6.-Pulmonary function in children exposed to involuntary smoking

Study              Subjecta

Pulmonary function measure

Outcome

Comment24

Schilling et al.
(1977)

816 children, aged 7-17,
Connecticut and South
Carolina

FFW, a8 percent predicted

No effect of parental smoking

No control for sib&p size or
correlation of siblings
pulmonary function; when
analysis restricted to children
who never amoked, 0~
.9igniflcant1y less in children
with smok& mothers

Teger et al.
UmQ

444 children. eg4 6-19.
East Boston, Massachusetts

MMEF in standard deviation
units

Significant effect of parental
smoking

Analysis wntrolld for sit&p
size end mrreletion of siblinga
pulmonary function

Weim et al.
(15180)

650 children, aged 6-9, EM
Boston, Maxachueetta

MMJZF in etandard deviation
unite

Significant effect of parental
smoking

Analyeie controlled for aibehip
size and correlation of siblings'
dmonaw function

Vedal et al.
(in prem)

Lebowitz end
BumW8
(1976)

4.000 children, eged Cl3


271 households with
complete hietoriea of
parents' smoking and of
pulmonary function of
children 2 age 6. Tucson,
Arimna

FEV7a Fvc, vcMlm vkwa
v-
FEV,, Fvc. vmum vmds
derived from MEF, 0 CUTV~LI,
expreaed aa etandard deviation
units

FVC positively associated, flow8
negatively aeaocieted
No effect of parental smoking

Flows doee-response with
amount smoked by mother
Suggestion that real differences
in indoor levels of erpmure
compared with more northerly
cliitfs may be occurring


TABLE 6.--Continued

Study              Subjectn

Pulmonary function measure

Outcome

Comments

558 children, aged 8-10,
ArizolUI

FEV, by age change
FEV,/H' per year

No effect of parental smoking

Potential bias in participation
rates; crwseectional data not
controlled for children's height;
annual change in FEV,/H' at
ages 8, 9, and 11 consistently
greater in nonsmoking
households than in tweparent
smoking households; statistical
test not significant, however

Tager et al.
(1981)

1,156 children, aged 5-19 at
initial survey, Eaet Boston,
Massachusetts

Significant decreased rate of
growth in FJW, and FEFzws
for children of smoking
mothers

`I-year followup; no effect of
paternal smoling; maximum
effect of maternal smoking on
fully developed lung not more
than 4 or 5 percent

Burchfiel et al.
(198.3

4,378 children. aged O-19,
Tecumeeh. Michigan

Fvc, FEV,, v-

Decreased FEV, and FVC for
boys and 0-m for girls with
increased number of smoking
paren@

Abetract, no distinction between
effects of maternal and
patemal smoking; effects most
prominent for boys and
youngest age groups

T&kin et al.
U983l


Hasselblad et al.
m!?Z)

1.070 nonsmoking,
nonasthmatic children, Lea
Angeles
16,669 children, aged 5-17,
seven geographic regions,
united states

v,, vm& Vmuzh FEFabrs



FEY78 88 percent predicted

Decreased v,, vmu26 for boyE
and FEFzM~ V-X for girls
with at leaat a smoking mother
Siiificant effect of maternal
smoking. but not paternal
smoking

No effect of paternal smoking



Large number of children
excluded became of invalid
pulmonary function data or
missing parental smoking data


TABLE 6.-Continued

Study

Subjecta

Pulmonary function measure

Outcome

Comments

Speizer et al.
W?UJ

8,120 children, aged 6-10,
in six U.S. cities

FVC and FEV, as percent
predicted

No eNect for F'EV, or FVC

Recent analysis of this cohort
demonstrated an effect for FVC
and FEV,

Ware et al.       10,COO children, aged 611,
(ZW           in six US. cities

FEX,andFVC

FVC positively associated with
smoking, FEV, negatively
associated

FEW, dose-response with
amount smoked by mother


function as adults, particularly if they become smoking adUS. no
data are currently available to establish the role, if any, of the small
physiologic changes in children on the development of adult obstruc-
tive lung disease.

Pulmonary Function in Adults Exposed to Involuntary
Cigarette Smoke

White and Froeb (1980) reported on 2,100 asymptomatic adults
drawn from a population about to enter a physical fitness program.
They demonstrated statistically significant decreases in FEVI and
MMEF as a percent of predicted in nonsmokers exposed to tobacco
smoke in the work environment compared with nonexposed workers.
The decrement was comparable to that seen in smokers inhaling 1 to
10 cigarettes per day. However, the absolute magnitude of the
difference in mean levels of function in the smoke-exposed and
unexposed groups was quite small: 160 ml (5.5 percent) for FEVl and
465 ml/set (13.5 percent) for MMEF. Carbon monoxide levels were
measured in the workplace and ranged from 3.1 to 25.8 ppm. The
population was self-selected, response was related to current work-
place exposure and did not account for people who changed jobs, and
it is unclear how the ex-smokers in the population were handled in
the analysis.

Comstock et al. (1981) examined 1,724 subjects drawn from two
separate studies in Washington County, Maryland. They found no
statistically significant greater risk of having an FEVl less than 80
percent of predicted in male nonsmokers exposed to wives' cigarette
smoke at home. &hilling et al. (1977) did not find an effect of passive
smoking exposure in adults. Both of these studies included adults in
their samples who were relatively young and generally would not
have had a long-term passive exposure in adult life. This point was
brought out by a recently reported large study from France.
Kauffmann et al. (1983) reported on a seven-city investigation in
which a total of 7,818 adults were studied. In a subsample of 1,985
nonsmoking women aged 25 to 29, in which 58 percent were exposed
to smoking husbands, there was a significant difference in level of
MMEF between truly nonsmoking women and women of comparable
ages exposed to passive smoking. This effect did not become apparent
until age 40. These changes were small, and although not adjusted
for differences in body size, may suggest a possible effect of long-term
exposure in adult life.

The physiologic and clinical significance of these small changes in
pulmonary function in adults remains to be determined. In addition,
variables such as ventilation, room size, number of rooms in the
home, duration of contact with the active smoker, and number of
cigarettes smoked could significantly influence total exposure and

402


need to be explored more fully. Differences in these exposure
variables and the characterization of exposure may explain some of
the differences in these study results (Table 7).

The Effect of Passive Smoke Exposure on People With
Allergies, Asthma, and COLD

There are very limited data on the effects of passive smoke
exposure in patients with preexisting pulmonary disease, and the
available data are conflicting. Clinical studies have suggested a
relationship between respiratory symptoms in asthmatics and expo-
sure to parental cigarette smoke, but methodologic problems compli-
cate the interpretation of the limited available data.

O'Connell and Logan (1974) identified 37 asthmatic children who
were "bothered" by parental cigarette smoke. Parents of 20 of the
children stopped smoking and 18 (90 percent) of the 20 children had
an improvement in symptoms. The control group consisted of 15
children (2 were not followed up) whose parents did not stop
smoking. Only 4 (27 percent) of the children in the control group
improved. The self-selection of those parents who quit, subjective
criteria for improvement, and an unclear duration of followup limit
the interpretation of this data.  Gortmaker and coworkers (1982)
studied two populations of children aged newborn to 17 years. They
found a significant association between parental reporting of chil-
dren's asthma and maternal smoking. Maternal smoking alone was
associated with approximately 20 percent of all asthma. The effect
persisted when age and sex of the child, allergies, and family income
and education were controlled in the analysis. No control was
attempted for the children's own smoking habits or for increased
reporting of symptoms in children of symptomatic parents. Other
population-based studies (Lebowitz and Burrows 1976; Speizer et al.
1980; Schilling et al. 1977) have not shown such results,

Dahms et al. (1981) studied 10 patients with bronchial asthma and
10 normal subjects passively exposed to smoke in an environmental
chamber. Pulmonary function was measured at 15-minute intervals
for 1 hour after smoke exposure. Blood carboxyhemoglobin levels
were measured before and after the l-hour exposure. Carboxyhemo-
globin levels in subjects with asthma increased from 0.82 to 1.20
percent. In normal subjects the increase was from 0.62 to 1.05
percent. The increases in carboxyhemoglobin in the two study
groups were not significantly different. Asthmatic subjects had a
decrease in forced vital capacity (FVC), forced expiratory volume in 1
second (FEVl),and maximum mid expiratory flow rate (MMEF) to a
level significantly different from their preexposure values. The
decreases in asthmatic subjects were present at 15 minutes, but
worsened over the course of the hour to approximately 75 percent of

403


IP
p TABLE `I.-Pulmonary function in adults exposed to involuntary smoking

Study

Subject8

Pulmonary function meaeupe

Outcome

Comments

White and Froeb    2,100 adult.9, San k430,
U980)          California

PVC, FEV,, and Mh@ aa
percent predicted

Siiticant effect of office
eqxmm to involuntary
smoke

Cometock et al.
11981)

1,724 adults, waehington
County, Maryland

FEV, an percent predicted

No effect of wives' smoking
on huebands' pulmonary
function

Knuffma~~ et al.
(198.3

7.818 ad&e, eeven French
cities, eelected subgroupE

FE!`,, FVC, and MMEF

Significant effect in wives
of smoking husbands in all
measures; significant Only
for hMEF in husbands of
smoking wives

Potential bti in selection;
d only current
cimrette smoke exposure

Includes adults aged zOt

Not adjusted for height;
doee-reepoose to amount of
hu&mda' smoking for
MMEF in wivf!e; no effect
below age 40


the preexposure values. Normal subjects had no change in pulmo-
nary function with this level of exposure. In this study, subjects were
not blinded as to the exposure and were selected because of
complaints about smoke sensitivity. Shephard et al. (1979), in a very
similar experiment, subjected 14 asthmatic subjects to a 2-hour
cigarette smoke exposure in a closed room (14.6 ma). The carbon
monoxide levels (24 ppm) were similar to those predicted in the study
of Dahms and coworkers. No blood carboxyhemoglobin levels were
measured. Subjects were randomized and blinded to sham (no smoke)
and smoke exposure and tested on two separate occasions. Data were
expressed as a percentage change from the sham exposure. No
significant changes in FVC or FEVI were observed between sham
and smoke exposure periods, although 5 of 12 subjects did report
wheezing or tightness in the chest on the day of smoke exposure.

The limited existing data yield conflicting results concerning the
relationship between passive smoke exposure and symptoms in
patients with known pulmonary disease. Further study of this
important question is warranted.

Summary and Conclusions

1. Cigarette smoke can make a significant, measurable contribu-
tion to the level of indoor air pollution at levels of smoking and
ventilation that are common in the indoor environment.
2. Nonsmokers who report exposure to environmental tobacco
smoke have higher levels of urinary cotinine, a metabolite of
nicotine, than those who do not report such exposure.
3. Cigarette smoke in the air can produce an increase in both
subjective and objective measures of eye irritation. Further,
some studies suggest that high levels of involuntary smoke
exposure might produce small changes in pulmonary function
in normal subjects.

4. The children of smoking parents have an increased prevalence
of reported respiratory symptoms, and have an increased
frequency of bronchitis and pneumonia early in life.

5. The children of smoking parents appear to have measurable
but small differences in tests of pulmonary function when
compared with children of nonsmoking parents. The signifi-
cance of this finding to the future development of lung disease
is unknown.

6. TWO studies have reported differences in measures of lung
function in older populations between subjects chronically
exposed to involuntary smoking and those who were not. This
difference was not found in a younger and possibly less exposed
population.

405


7. The limited existing data yield conflicting results concernmg
the relationship between passive smoke exposure and pulmo-
nary function changes in patients with asthma.

406


References

ABEL, E.L. Smoking during pregnancy: A review of effects on growth and develop
ment of offspring. Human Biology 52: 593-625,1980.
BADRE, R., GUILLERM, R., ABRAN, N., BOURDIN, M., DUMAS, C. Pollution
Atmospherique par la Fumed de Tabac. [Atmospheric pollution by smoking.]
Annales Pharmaceutiques Fmncaises 36(9/10): 443-452,1978.
BLAND M., BEWLEY, B.R., POLLARD, V.. BANKS, M.H. Effect of children's and
parent's smoking on respiratory symptoms. Archives of Disease in Childhood 53(2):
10&105, February 1978.

BONI-IAM, G.S., WILSON, R.W. Children's health in families with cigarette smokers.
American Journal of Public Health 71(3): 290-293, March 1981.
BOTTOMS, S.F., KUHNERT, B.R., KUHNERT, P.M., REESE, A.L. Maternal passive
smoking and fetal serum thiocyanate levels. American Journal of Obstetrics and
Gynecology 144(7): 787-791, December 1.1982.

BRUNNEMANN, K.D., ADAMS, J.D., HO, D.P.S., HOFFMANN, D. The Influence of
Tobacco Smoke on Indoor Atmospheres. ZZ. Volatile and Tobacco-Specific Nitrosa-
mines in Main- and Sia%.stream Smoke and Their Contribution to Indoor Pollution.
Proceedings of the Fourth Joint Conference on Sensing of Environmental
Pollutants, New Orleans, 1977. American Chemical Society, 1978, pp. 876880.
BRUNNEMANN, K.D., HOFFMANN, D. Chemical studies on tobacco smoke. LIX.
Analysis of volatile nitrosamines in tobacco smoke and polluted indoor environ-
ments. In: Walker, E.A., Griciute. L., Castegnaro, M., Lyle, R.E., Davis, W.
(Editors). Environmental Aspects of N-Nitroso Compounds. IARC Publication No.
19. Lyon, France, International Agency for Research on Cancer, 1978, pp. 343-356.
BURCHFIEL, CM., HOWA'IT, W.F., KELLER, J.B., BUTLER, W.J., HIGGINS, I.T.T.,
HIGGINS, M.W. Passive smoking, respiratory symptoms and pulmonary function
in the pediatric population of Tecumseh. (Abstract). American Review of Respira-
tory Disease 127fSupplement 4, part 2): 156, April 1983.
CAMERON, P., KOSTIN, J.S., ZAKS, J.M., WOLFE, J.H., TIGHE, G., OSELETI', B.,
STOCKER, R., WINTON, J. The health of smokers' and nonsmokers' children.
Journal of Allergy 436): 336-341, June 1969.

CANO, J.P., CATALIN, J., BADRE, R., DUMAS, C., VIALA, A., GUILLERME, R.
Determination de la nicotine par chromatographie en phase g-use. II-Applica-
tions. [Determination of nicotine by chromatography in the gaseous phase. II-
Applications.]Ann&s Pharmaceutiques Fmncaises 28(11): 633-640,1970.
CHAPPELL, S.B., PARKER, R.J. Smoking and carbon monoxide levels in enclosed
public places in New Brunswick. Canadian Journal of Public Health 68: 159-161,
  1977.

COBURN, R.F., FGRSTER, R.E., KANE, P.B. Considerations of the physiological
variables that determine the blood carboxyhemoglobin concentration in man.
Journal of Clinical Investigation 44(11): 1899-1910, November 1965.
COHEN, J.D., BARTSCH, G.E. A comparison between carboxyhemoglobin and serum
thiocyanate determinations as indicators of cigarette smoking. American Journal
of Public Health 70(3): 284-286, March 1980.

COLLEY, J.R.T. Respiratory symptoms in children and parental cigarette smoking
and phlegm production. British Medical Journal 2: 201-204, April 27,1974.
COLLEY, J.R.T., HOLLAND, W.W., CORKHILL, R.T. Influence of passive smoking
and parental phelgm on pneumonia and bronchitis in early childhood. Lancet
2(7888): 1031-1034, November 2.1974.

COMSTOCK, G.W., MEYER, M.B., HELSING, K.J., TOCKMAN, M.S. Respiratory
effects of household exposures to tobacco smoke and gas cooking. American Review
of Respimtory Disease 124(2): 143-148, August 1981.
CUDDEBACK, J.E., DONOVAN, J.R., BURG, W.R. Occupational aspects of passive
smoking. American Industrial Hygiene Association Journal 37(5): 263-267, 1976.

407


DAHMS, T.E.. BOLIN, J.F.. SLAVIN, R.G. Passive smoking: Effects on bronchial
asthma. Chest 80(5): 530-534, November 1981.
DOCKERY, D.W.. SPENGLER, J.D. Indoor*utdoor relationships of respirable
sulfates and particles. Atmospheric Erwironment 1331: 335-343, 1981.
DODGE, R. The effects of indoor pollution on Arizona children. Archiues of
Encironmentaf Health 37(3): 151-155, May/June 1982.
ELLIOTT, L.P., ROWE, D.R., Air quality during public gatherings. Journal of the Air
Pollution Control Association 2561: 635-636. June 1975.
FERGLJSSON. D.M., HORWOOD, L.J., SHANNON, F.T., TAYLOR, B. Parental
smoking and lower respiratory illness during the first three years of life. Journal
of Eptdemtologv and Community Health 3X31: 180-184, September 1981.
FEYERABEND, C., HIGGINBO'ITAM, T., RUSSELL, M.A.H. Nicotine concentra-
tions in urine and saliva of smokers and non-smokers. British Medical Journal 284:
  1002-1004.1982.
FEYERABEND, C., RUSSELL, M.A.H. Rapid gas-liquid chromatographic determina-
tion of cotinine in biological fluids. Analyst 10X1255): 9981001, October 1980.
FISCHER, T., WEBER, A., GRANDJEAN, E. Luftveruneinigung durch Tabakrauch in
Gaststatten.[Air pollution due to tobacco smoke in restaurants.] International
Archives of Occupational and Environmental Health 41(40): 267-280, 1978.
GALUSKINOVA, V. 3,4-Benzpyrene determination in the smoky atmosphere of social
meeting rooms and restaurants, A contribution to the problem of the noxiousness
of so-called passive smoking. Neoplasma ll(5): 465-468, 1964.
GODIN, G., WRIGHT, G., SHEPHARD, R.J. Urban exposure to carbon monoxide.
Archives of Environmental Health 2X5): 305313, November 1972.
GORTMAKER, S.L., WALKER, D.K., JACOBS, F.H., RUCH-ROSS, H. Parental
smoking and the risk of childhood asthma. American Journal of Public Health
72(6): 574-579, June 1982.
GRIMMER, G.. BOHNKE, H., HARKE, H.-P. Zum Problem des Passivrauchens:
Aufnahme von polycyclischen aromatischen Kohlenwasserstoffen durch Einatmen
von zigarettenrauchhaltiger Luft. [Problem of passive smoking intake of polycyclic
aromatic hydroacrons by breathing air containing cigarette smoke.] International
Archives of Occupational and Environmental Health 4CK2): 93-99,1977.
HARKE, H.-P. Zum Problem des Passivrauchens. I. Ueber den Influss des Rauchens
auf die CO-konzentration in Bueroraeumen. [The problem of passive smoking. 1.
The influence of smoking on the CO concentration in office rooms.] Znternationales
Archiv firilrbeitsmedizin 3X3): 199206,1974.
HARKE, H.-P., PETERS, H. Zum Problem des Passivrauchens. III. Ueber den Influss
des Rauchens auf die CO-konzentration im Kraftfahrxeug bei Fahrten im
Stadtgebiet. [The problem of passive smoking. III. The influence of smoking on the
CO concentration in driving automobiles.] Znternationales Arch& fur Arbeitsmed-
izin 33(3): 221-229,1974.
HARLAP, S., DAVIES, A.M. Infant admissions to hospital and maternal smoking.
Loncet l(7857): 529532, March 30, 1974.
HARMSEN, H., EFFENBERGER, E. Tabakrauch in Verkehrsmitteln, Wohn- und
Arbeitsraumen. [Tobacco smoke in transportation vehicles, living and working
rooms.] Archiv ftir Hygiene und Bakteriologie 141(5): 383400, 1957.
HASSELBLAD, V., HUMBLE, C.G., GRAHAM, M.G., ANDERSON, H.S. Indoor
environmental determinants of lung function in children. American Reuieus of
Respiratory Disease 123(51: 479-485, May 1981.
HINDS, W.C., FIRST, M.W. Concentrations of nicotine and tobacco smoke in public
places. Hew England Journal of Medicine 292(16): 844-845, April 17, 1975.
JARVIS, M.J., RUSSELL, M.A.H. Measurement and estimation of smoke dosage to
nonsmokers from environmental tobacco smoke. European Journal ofRespirator?,
Disease 65Supplement 133): 68-75,1984.


JOHANSSON, C.R. Tobacco smoke in room air: An experimental investigation of
odour perception and irritating effects. Building Sewices Engineer 43: 254-262,
  March 1976.
JONES, R.M., FAGAN. R. Carboxyhemoglobin in nonsmokers. A mathematical
model. Archives ofEnvironmental Health 30(4): 184-189, April 1975.
JUST, J., BORKOWSKA, M., MAZIARKA, S. Zanieczyszczenie dymen tytoniowym
powietrza kawiarn Warszawskich. [Air pollution due to tobacco smoke in Warsaw
coffee house.] Roczniki Pantstwowego Zakladu Hygieny 23(2): 129-135.1972.
KASUGA, H., HASEBE, A., OSAKA, F., MATSUKI. H. Respiratory symptoms in
school children and the role of passive smoking. Tokyo Journal of Experimental
Clinical Medicine 4: lOl-114,1979.
KAUFFMANN, F., TESSIER, J.-F., ORIOL, P. Adult passive smoking in the home
environment: A risk factor for chronic airflow limitation. Amerwan Journal of
Epidemiology 117(3): 269-280, March 1983.
LANGONE, J.J., GJIKA. H.B., VAN VUNAKIS, H. Nicotine and its metabolites.
Radioimmunoassays for nicotine and cotinine. Biochemistp 12(24,: 502%5030,
November 20.1973.
LEBOWITZ, M.D., BURROWS, B. Respiratory symptoms related to smoking habits of
family adults. Chest 69(l): 48-50, January 1976.
LEEDER, S.R.. CORKHILL, R.T., IRWIG, L.M., HOLLAND, W.W.. COLLEY. J.R.T.
Influence of family factors on the incidence of lower respiratory illness during the
first year of life. Brat&h Journal of Preventive and Social Medicine 3CX4): 203-212,
  December 1976a.
LEEDER, S.R., CORKHILL, R.T., IRWIG, L.M., HOLLAND, W.W., COLLEY, J.R.T.
Influence of family factors on asthma and wheezing during the first five years of
life. British Journal of Preoentiue and Social Medicine 30(4): 213-218. December
  1976b.
LEFCOE, N.M., INCULET, 1.1. Particulates in domestic premises. II. Ambient levels
and indoor+utdoor relationships. Archives of Environmental Health 30(12): 565-
570, December 1975.
LITTLE. J., McGENDY, R.B. Measurement of dolonium-210 in human blood. Nature
211(5051): 842-843, August 20, 1966.
MATSUKURA. S., SAKAMOTO, N., SEINO, Y., TAMADA, T., MATSUYAMA, H.,
MURANAKA, H. Cotinine excretion and daily cigarette smoking in habituated
smokers. Clinical Pharmacology and Thempeutics 2X5): 55L561, May 1979.
NATIONAL ACADEMY OF SCIENCES, NATIONAL RESEARCH COUNCIL. Indoor
Pollutants. Washington, D.C., National Academy Press, 1981,552 pp.
NEAL, A.D., WADDEN, R.A., ROSENBERG, S.H. Evaluation of indoor particulate
concentrations for an urban hospital. American Industrial Hygiene Association
Journal 3x7): 578-582, July 1978.
O'CONNELL, E.J.. LOGAN, G.B. Parental smoking in childhood asthma. Annals of
Allergy 32: 142-145, March 1974.
PERRY, J. Fasten your seatbelts: No smoking. British Columbia Medical Journal
15(10~: 304-305, November 1973.
PIMM, P.E., SILVERMAN, F., SHEPHARD, R.J. Physiological effects of acute passive
exposure to cigarette smoke. Archives of Environmenlal Health 33(4): 201-213,
July-August 1978.
PORTHEIN. F. Zum Problem des Passivrauchens. [A contribution to the problem of
passive smoking.] M&nchener Medizinische Wochenschrift 113(18): 707-709, April
30,1971.
PULLAN, C.R., HEY, E.N. Wheezing, asthma, and pulmonary dysfunction 10 years
after infection with respiratory syncytial virus in infancy British Merlu-al Journal
284(6330): 1665-1669. June 5,1982.
RADFORD, E.P.. Jr., HUNT, V.R. Polonium-210: .4 volatile radioelement in clga-
rettes. Sc&enre 143. 247-249, January 1964.


RANTAKALLIO, P. Relationship of maternal smoking to morbidity and mortality of
the child up to the age of live. Acta Paediatrica Scandinauica 67(5): 621-631,
September 1978.

REPACE, J.L., LOWREY, A.H. Tobacco smoke, ventilation, and indoor air quality.
American Society of Heating, Refrigerating, and Air-Conditioning Engineers, Znc.
Transactions El&Part 1): 895-914, 1982.

REPACE, J.L., LOWREY, A.H. Indoor air pollution, tobacco smoke and public health.
Science 208: 462-472, May 2,198o.

REPACE, J.L., LOWREY, A.H. Modeling Exposure of Nonsmokers to Ambient Tobacco
Smoke. Paper presented at the 76th Annual Meeting of the Air Pollution Control
Association, Atlanta, June 19-24,1983.

RUSSELL, M.A.H., SUTTON, S.R., IYER, R., FEYERABEND, C., VESEY, C.J. Long-
term switching to low-tar low-nicotine cigarettes. British Journal of Addiction
77(21: 145-158, June 1982.

RUSSELL, M.A.H., FEYERABEND, C. Blood and urinary nicotine in nonsmokers.
Lancet 1: 179-181,1975.

RYLANDER, R., PETERSON, V., SNELLA, M.-C. (Editors). Environmental tobacco
smoke: Report from a workshop on effects and exposure levels. Journal of
Respiratory Disease 65tSupplement 133): l-152, 1984.
SAID, G., ZALQKAR, J., LELLOUCH, J., PATOIS, E. Parental smoking related to
adenoidectomy and tonsillectomy in children. Journal of Epidemiology and
Community Health 32(2): 97-101, June 1978.
SCHENKER, M.B., SAMET, J.M., SPEIZER, F.E. Risk factors for childhood respira-
tory disease. The effect of host factors and home environmental exposures.
American Review of Respiratory Disease 12&6X 103%1043, December 1983.
SCHILLING. R.S.F., LETAI, A.D., HUI, S.L., BECK, G.J., SCHOENBERG, J.B.,
BOUHUYS, A.H. Lung function, respiratory disease, and smoking in families.
American Journal of Epidemiology 106f4): 274-283,1977.
SEBBEN, J., PIMM, P., SHEPHARD, R.J. Cigarette smoke in enclosed public
facilities. Archioes of Environmental Health 32(2X 5358, March/April 1977.
SEIFF, H.E. Carbon Monoxide as an Indicator of Cigarette-Caused Pollution Levels in
Inter-city Buses. U.S. Department of Transportation, Federal Highway Administra-
tion, Bureau of Motor Carrier Safety, April 1973,ll pp.
SHEPHARD, R.J., COLLINS, R., SILVERMAN, F. "Passive" exposure of asthmatic
subjects to cigarette smoke. Environmental Research 20(2): 392-402, December
  1979.

SIMS, D.G., DOWNHAM, M.A.P.S., GARDNER, P.S., WEBB, J.K.G., WEIGHTMAN,
D. Study of %yearold children with a history of respiratory syncytial virus
bronchiolitis in infancy. British Medical Journal 1: 11-14, January 1978.
SLAVIN, R.G.. HERTZ, M. Indoor Air Pollution. Paper presented at the 36th annual
meeting of the American Academy of Allergy, San Diego, February 1519, 1975, 4
  PP.

SPEER, F. Tobacco and the nonsmoker. A study of subjective symptoms. Archives of
Environmental Health 16(3): 443-446, March 1968.
SPEIZER, F.E., FERRIS, B., Jr., BISHOP, Y.M.M., SPENGLER, J. Respiratory disease
rates and pulmonary function in children associated with NO2 exposure. American
Review of Respiratory Disease 121(l): 3-10, January 1980.
SPENGLER, J.D., DOCKERY, D.W., TURNER, W.A., WOLFSON, J.M., FERRIS,
B.G., Jr. Long-term measurements of respirable sulphates and particles inside and
outside homes. Atmospheric Environment 15(l): 2330.1981.
STERLING, T.D., DIMICH, H., KOBAYASHI, D. Indoor byproduct levels of tobacco
smoke: A critical review of the literature. Journal of the Air Pollution Control
Association 32(3): 25G-259, March 1982.

410


STEWART, R.D., BARE'ITA, E.D., PLATTE, L.R., STEWART, E.B., KALEFLEISCH,
J.H., VAN YSERLOO, B., RIMM, A.A. Carboxyhemoglobin levels in American
blood donors. Journal ofAmerican Medical Association 22%): 1187-1195. August
26,1974.

SZADKOWSKI, D., HARLE, H.-P., ANGERER, J. Kohlenmonoxidbelastung durch
Passivrauchen in Bueroraeumen. [Body burden of carbon monoxide from passive
smoking in offices.] Innere Medizin 3(6): 310-313,1976.
TAGER, I.B., WEISS, S.T., ROSNER, B., SPEIZER, F.E. Effect of parental cigarette
smoking on the pulmonary function of children. American Journal of Epidemiolo-
gy 110(l): 15-26, July 1979.

TAGER, LB., WEISS, S.T., MUNOZ, A., ROSNER, B., SPEIZER. F.E. Longitudinal
study of the effects of maternal smoking on pulmonary function in children. New
England Journal of Medicine 309(12): 699-703, September 22.1983.
TASHKIN, D.P., CLARK, V., COULSON, A., SIMMONS, M., REEMS, C., BOURQUE,
L., SAYRE, J., DETELS, R., ROKAW, S. Effect of exposure to parental smoking on
lung function of children 7-17 years of age. American Review of Respimtory
Disease 127(4): 157, (Part 2), 1983. (Abstract.)
U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES. The Health Conse-
quences of Smoking for Women: A Report of the Surgeon General. U.S. Department
of Health and Human Services, Public Health Service, Office of the Assistant
Secretary for Health, OfIice on Smoking and Health, 1980,359 pp.
US. DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE. Smoking and
Health: A Report of the Surgeon General. U.S. Department of Health, Education,
and Welfare, Public Health Service, Office of the Assistant Secretary for Health,
Office on Smoking and Health, DHEW Publication No. (PHSj79-50066, 1979, pp.
11-6-11-24.

U.S. DEPARTMENT OF TRANSPORTATION and U.S. DEPARTMENT OF
HEALTH, EDUCATION, AND WELFARE. Health Aspects ofSmoking in T?ans-
port Aircmft. U.S. Department of Transportation, Federal Aviation Administra-
tion, and U.S. Department of Health, Education, and Welfare, National Institute
for Occupational Safety and Health, December 1971,85 pp.
U.S. ENVIRONMENTAL PROTECTION AGENCY. National primary and secondary
ambient air quality standards. Federal Register 36@4-Part II): 8186-8201, April 30,
  1971.

VEDAL, S., SCHENKER, M.B., SAMET, J.M.. SPEIZER, F.E. Risk factors for
childhood respiratory disease: Analysis of pulmonary function. American Review
of Respimtory Disease, in press.

WARE, J.H., DOCKERY. D.W., SPIRO, A., III, SPEIZER, F.E., FERRIS, B.G., Jr.
Passive smoking, gas cooking, and respiratory health of children living in six cities.
American Review of Respimtory Disease 129(3): 366-374, March 1984.
WEBER, A. Acute effects of environmental tobacco smoke. European Journal of
Respimtory D&use 65tSupplementum 133): 98-108,1984.
WEBER, A., FISCHER, T. Passive smoking at work. International Archives of
Occupational and Environmental Health 47{31: 209-221, 1980.
WEBER, A., FISCHER, T., GRANDJEAN, E. Passive smoking in experimental and
field conditions. Environmental Research 20: 205-216,197s.
WEBER, A., JERMINI, C., GRANDJEAN, E. Irritating effects on man of air pollution
due to cigarette smoke. American Journal of Public Health 66(7X 672-676, July
  1976.

WEINBERGER, SE., WEISS, S.T. Pulmonary diseases. In: Burrow, G.N., Ferris, T.F.
(Editors). Medical Co mp ica ions During Pregnancy. 2nd Edition. Philadelphia,
                 1' t
W.B. Saunders, 1981, pp. 405-434.

411


WEISS, ST.. TAGER, I.B., SPEIZER, F.E., ROSNER, B. Persistent wheeze. Its relation
to respiratory illness, cigarette smoking, and level of pulmonary function in a
population sample of children. American Review of Respiratory Disease 122(5):
697-707, November 1960.

WHITE, J.R., FROEB, H.F. Small-airways dysfunction in nonsmokers chronically
exposed to tobacco smoke. New England Journal of Medicine 302(13): 720-723,
March 27,198O.

WILLIAMS, CL., ENG, A., BOTVIN, G.J., HILL, P., WYNDER, E.L. Validation of
students' self-reported cigarette smoking status with plasma cotinine levels.
American Journal of Public Health 69(12): 1272-1274, December 1979.

412


CHAPTER 8. DEPOSITION AND
        TOXICITY OF
        TOBACCO SMOKE IN
        THE LUNG

413


CONTENTS

CIGARETTE SMOKE DEPOSITION IN THE
LUNG
  Introduction
  Characterization of an Aerosol
Characterization of Cigarette Smoke Aerosols
Factors That Affect Particulate Deposition
Deposition of Cigarette Smoke Particulates
  Particulate Retention in the Lung
  Passive Smoking
  Conclusions

CIGARETTE SMOKE TOXICOLOGY
  Introduction
  Preliminary Considerations
Effects on Airway Function and Ventilation
     Human Studies
     Animal Studies
Effects on Permeability of the Pulmonary Epithelium
     Human Studies
     Animal Studies
Effects on Mucociliary Structure and Function
  Effects on Cells
     Human Studies
     Animal Studies
  Effects on Protease Inhibitors
     Human Studies
     Animal Studies
Effects on Lung Tissue Repair Mechanisms
     Human Studies
     Animal Studies

Summary and Conclusions

References

415


CIGARETTE SMOKE DEPOSITION IN THE
LUNG

Introduction

Previous Reports of the Surgeon General on the health conse-
quences of smoking have focused on characterizing and quantifying
responses to the inhalation of cigarette smoke. Typically, dose is
given in terms of packs per day or cumulative pack years. However,
a more accurate description of dose would include how much smoke
is inspired into the respiratory tract, how much is deposited and fails
to exit with the expired air, and the fate of the deposited smoke.
A commonly held fallacy is that "living in New York is like
smoking two packs per day." Is the amount of particles produced by
smoking comparable to that encountered in urban air pollution? A
person who smokes two packs of cigarettes per day with an average
tar rating of 20 mg per cigarette would breathe in 800 mg of material
per day, or 292 g of tar per year. A reasonable value for urban air
would be 100 pg, OF 0.1 mg per cubic meter. The average person
breathes approximately 20,000 liters, OF 20 cubic meters, of air per
day. Thus, 2 mg of material per day, or 0.73 g of particulate per year,
would be inspired. At the outset, it is evident that the amount of
smoke entering the lungs is considerably greater than the amount of
particulates from air pollution.

This chapter emphasizes the size and aerodynamic properties of
smoke and relates them to the fraction of the inspired smoke that
deposits in the lungs. Also considered is where the smoke deposits,
and its possible fate is described.

The particulate phase of cigarette smoke, commonly known as tar,
is inhaled as an aerosol into a smoker's respiratory tract. An aerosol
is defined as a suspension of solid or liquid particles in a gas (Hinds
1982). In the case of cigarette smoke, the aerosol contains ambient
air as well as the gases, liquids, and solids produced during tobacco
combustion. The particulates include a wide variety of organic and
metallic compounds, many of which are toxic to lung tissues.
Hydrocarbons, aldehydes, ketones, organic acids, alcohols, nicotine,
md phenols are among them. Metallic compounds such as radioac-
ive lead and polonium are also present. The gas phase is also
:omplex; in addition to the nitrogen and oxygen in the air,
,onsiderable amounts of carbon dioxide and carbon monoxide are
jresent, and also significant amounts of cyanides, acrolein, nitrogen
xides, and ammonia. The precise quantitative composition of the
obacco smoke varies with many different factors, including the type
f tobacco plant grown, the soil used to grow the plant, the method of
tiring the leaves, the temperature of combustion during smoking,
nd the composition and physical properties of the cigarette paper

417


and other additives. As the cigarette butt length decreases, many
substances that have previously condensed on the remaining tobacco
are revaporized. Generally, as butt length shortens, the smoke from
the cigarette contains an increasing concentration of these sub-
stances. Most of these constituents in smoke are toxic to lung tissues.
Their toxicity extends from impairment of mucociliary transport,
critical for clearing particles from the lungs, to carcinogenic and
cocarcinogenic activities (Wynder and Hoffmann 1979; Battista
1976). To understand where the numerous particulates in cigarette
smoke deposit in the lungs and how they are removed is important
for determining the pathologic effects of chronic cigarette smoking.

Characterization of an Aerosol

To predict the deposition patterns of any aerosol, such as cigarette
smoke, it is necessary to know the size, shape, and density of the
individual particles or droplets. Describing the distribution of
particle diameters is essential. It is convenient to describe particle
size as an aerodynamic diameter rather than as an actual particle
size based on optical measurements, because the former is a better
predictor of aerodynamic behavior (Hinds 1982). Aerodynamic
diameter is defined as the diameter of a sphere of unit density that
has the same settling velocity as the particle being measured. This
may be expressed as a count median aerodynamic diameter (CMAD)
and a mass median aerodynamic diameter (MMAD). These are,
respectively, the diameters for which half of the number or mass of
the particles are less than that diameter and half are more.

Characterization of Cigarette Smoke Aerosols

The particulates in cigarette smoke `have been measured by
several investigators using a variety of analytical devices. Because of
different apparatus and different methods of smoke generation and
dilution, results vary but are reasonably consistent. McCusker et al.
(1983) used a device called the single particle aerodynamic relaxa-
tion time @PART) analyzer to determine the size of particulates
from several brands of cigarettes, with and without filters. The mass
median aerodynamic diameter (MMAD) for all brands averaged
approximately 0.46 urn; it was not markedly different when the
filters were removed. These measurements showed that, even with a
filter, billions of particles are present in an average 35 ml puff of
cigarette smoke generated by an automatic smoking-machine. Par-
ticulate concentrations per ml ranged from 0.3 x 109 to 3.3 x log,
depending on whether the cigarettes were rated ultra-low, low, or
medium in tar content. The reduced particulate concentration
reported for low tar cigarettes results principally from filter

418


efficiency and air dilution of the smoke. When the specially designed
filters were removed or the vent holes were covered, as could be
accomplished by the smoker's fingers, particulate concentrations per
milliliter increased to levels comparable to that for higher tar
content cigarettes.

Hinds (1978) compared the particulate size distribution in ciga-
rette smoke using an aerosol centrifuge and a cascade impactor.
Although these devices are based upon different physical principles,
Hinds found that the results were comparable. The MMAD values
ranged from 0.37 to 0.52 urn. Variations depended primarily upon
the dilution of the smoke. The MMAD and concentration values
reported by Hinds and coworkers (1983) were similar to those
reported by Keith and Derrick (19601, who used a specially modified
centrifuge, called a conifuge, to analyze cigarette smoke. Particulate
analysis by a light scattering photometer yielded an MMAD of 0.29
pm and particulate concentrations of 3 x lOlo per ml (Okada and
Matsunuma 1974). Carter and Hasegawa (1975) "fixed" cigarette
particulates with methyl cyanoacrylate, a method that may produce
artifacts, and measured a mean diameter of 0.48 urn from electron
micrographs of the particulates. Earlier methods of measurement
were based upon the collection of smoke particulates on various
surfaces. Harris (1960) reported a range of 0.16 to 0.54 urn from a
replica of cigarette smoke particulates that included a correction for
droplet-spreading during sample preparation. Langer and Fisher
(1956) found a median range of 0.6 pm, but made no correction for
droplet-spreading during sample collection.

Time and concentration are important modifiers of tobacco smoke.
Cigarette smoke aerosols contain volatile components, and evapora-
tion gradually reduces particle diameters. It is also true that with
the extremely high particle concentrations encountered in main-
stream smoke, the aerosol can agglomerate rapidly because nearby
particles collide with each other and coalesce. If smoke is cooled
(reducing the vapor pressure of the volatile components) and diluted
(reducing the probability of particle collisions) the particle size will
be more stable. Thus, it is difficult to reliably measure the size and
concentration of particles in cigarette smoke produced under realis-
tic experimental conditions.

The size and concentration of the particulates are also affected by
the decreasing length of a cigarette as it is smoked. McCusker et al.
(1983) found the particulate concentration to be 67 percent greater in
the last three puffs of a filtered cigarette than in the first three.
Ishizu et al. (1978) also reported that particulate concentrations in
unfiltered cigarettes increased and that the mean geometric diame-
ter of the particles decreased with decreasing cigarette length. They
attributed the former effect to the decreased filtration by the tobacco
column and the latter effect to the shorter length traveled by the

419


particles to reach the butt end and, hence, the decreased time for
particulate coagulation. In addition, their results illustrate that
filters may trap the larger particles and generate more uniform
aerosols; McCusker et al. (1983) noted no change in MMAD between
the first and last three puffs of filtered cigarettes. Ishizu et al. (1978)
also reported that larger puff volumes decreased the average
particulate diameters. This can affect interpretation of experimental
data in that standard cigarette smoking-machines draw 35 ml puff
volumes, whereas Hinds et al. (1983) reported that 54 ml was the
average puff volume measured in smoking subjects.
Particle size is a critical factor in determining what fraction of the
particles that enter the respiratory tract will deposit there and fail
to exit with the expired air, as well as where they will deposit.
Submicrometric particles will deposit not only in small and large
airways, but also in alveoli. Breathing pattern is also important (see
review by Brain and Valberg 1979). Large tidal volumes will favor
alveolar deposition. Higher inspiratory flows will promote deposition
at bifurcations. Breath-holding is important, because the greater the
elapsed time before the next expiration, the higher the fraction
deposited (collection efficiency).

Individual anatomic differences may influence the amount and
distribution of deposited particles. The cross-section of airways will
influence the linear velocity of the inspired air. Increasing alveolar
size decreases alveolar deposition.

Factors That Affect Particulate Deposition

A typical puff volume is approximately 30 to 70 ml. It is usually
inspired with a volume of ambient air that is one to two times the
normal tidal volume. Particle size not only can change in experimen-
tal equipment as described above, but also may change within the
human respiratory tract.

After a volume of smoke is drawn into the mouth and upper
respiratory tract of a smoker, it may be retained in that humidified
air before deep inhalation. Here too, the particulates can change in
size through coagulation or evaporation. They can also grow because
of the particulates' affinity for water, termed hygroscopicity (Davies
1974; Hiller 1982b3. Other aspects of each smoker's behavior may
also influence dose. Most manufacturers achieve low tar yields by
the use of ventilated cigarette holders; this causes the inhaled smoke
to be diluted with air. However, 32 to 69 percent of interviewed
smokers of "low" tar cigarettes reported that they blocked these
filter preparations with their fingers or lips. This causes dramatic
increases in the amount of tar and nicotine in a way not predicted by
studies using smoking-machines (Kozlowski et al. 1980).

420


Such individual differences in cigarette use as well as other
strategies designed to increase the inhalation of tar and nicotine
probably account for the poor correlation between the machine-
determined nicotine yield of a cigarette and the concentration of
nicotine or its metabolites in blood or urine (Russell et al. 1975, 1980;
Sutton et al. 1982; Feyerabend et al. 1982; Benowitz et al. 1983). For
example, Herning and coworkers (1981) demonstrated that when low
nicotine cigarettes are used, most smokers compensate by increasing
the puff volume. In addition, Tobin and Sackner (19821 reported that
some subjects increase their puff volume by up to 70 percent after
switching to low tar cigarettes. In some instances, this compensatory
increase occurred during a single experimental session. In contrast,
a few smokers may reduce smoke deposition in their lungs by
retaining the smoke in their mouth for several seconds before
inhaling it. Stupfel and Mordelet-Dambrine (1974) showed that if a
smoker holds the smoke in his mouth for 2 seconds, 16 percent of the
particulate matter is removed. Also, 60 percent of the water-soluble
components of the gas phase are absorbed by the upper airways.

Chronic smoking also causes alterations in lung structure that
affect deposition patterns. Sanchis et al. (1971) studied the deposition
of an aerosol of radioactively labeled albumin inhaled by smokers
and nonsmokers. They found less aerosol deposition in the alveolar
region of smokers than of nonsmokers and suggested that the
difference may be the result of alterations in the small airways
produced by chronic smoking. Similar results were reported for
hamsters exposed to cigarette smoke for 3 weeks prior to a single
exposure of radioactively labeled cigarette smoke (Reznik and Samek
19801. More labeled smoke concentrate was found in the lungs of
hamsters not previously exposed to cigarette smoke.

The rate and pattern of breathing can also affect the total dose of
cigarette particulates deposited in the lungs. Dennis (19711 reported
that exercise increased the percent deposition of two experimentally
generated aerosols in human subjects. Increased deposition was also
measured in exercising hamsters that inhaled a radiolabeled aerosol
(Harbison and Brain 1983). These results are most relevant to those
who smoke when ventilation is increased while working or shortly
after a period of exercise.

Deposition of Cigarette Smoke Particulates

The factors discussed in the previous section illustrate that
experimental measurements of the size and concentration of ciga-
rette aerosols are insufficient for the prediction of deposition
patterns. Cigarette smoke is a mutable aerosol, which complicates
the collection of accurate and reproducible data regarding its
particulate composition. In addition, alterations in respiratory

421


structure and respiratory rate can affect the deposition of particu-
lates. These complexities stress the importance of actual measure-
ment of the regional deposition of cigarette smoke particulates in
human lungs. However, few data have been published on this
important area, despite the prevalence of smoking and its impact on
human health. Most of the available information on the deposition of
cigarette smoke particulates is based upon theoretical or physical
models of the lungs and measurements of differences in the
concentration of aerosol between inhaled air and exhaled air.

A model to predict the percent deposition of particles based upon
MMAD was presented by the Task Group on Lung Dynamics of the
International Commission on Radiological Protection (1966). The
respiratory tract was divided into three main regions: nasopharynx,
trachea and bronchi, and alveoli. In conjunction with estimates of
particulate clearance, deposition calculations were made for these
regions at three different inhalation volumes. This model suggests
that 30 to 40 percent of the particles within the size range present in
cigarette smoke will deposit in the alveolar region and 5 to 10
percent will deposit in the tracheobronchial region. This model also
emphasizes the impact of particle solubility on the total integrated
dose over time. Brain and Valberg (19741 developed convenient
nomograms and a computer program to demonstrate how particle
solubility and particle size significantly affect the net amount of
particulates retained in the lungs.

Aerosol deposition has also been studied in airway casts. Physical
models of the upper airways of human lungs have been made by a
double casting technique in order to study particulate deposition at
several airway generations (Schlesinger and Lippmann 1972). Lungs
obtained at autopsy were filled with wax or alloy. When these
materials became solid, the tissue was removed and the casts were
coated with silicon rubber or latex. The wax or alloy was then melted
and removed, leaving a cast of the original airways. Different flow
rates and particulate sizes were used to study deposition patterns.
Schlesinger and Lippman (1978) reported a correlation between the
deposition sites of test aerosols in the lung casts and the most
common sites of origin of bronchogenic carcinoma in humans. Both
occurred preferentially at bifurcations. Martonen and Lowe (1983)
added an oropharyngeal compartment and a replica cast of the
larynx to the tracheobronchial casts in order to better simulate air
flow patterns in the upper respiratory tract. They used these models
to evaluate the amount of cigarette smoke condensate deposited in
the airways at different flow rates. More condensate was present at
branching regions, especially at carinal ridges. Aerosol was also
deposited preferentially along posterior airway walls.

Most experiments designed to determine aerosol deposition in
human subjects measure differences in aerosol concentration before

422


and after inhalation. Hinds and associates (1983) measured the
percent mass of inhaled tobacco smoke particulates that deposited in
male and female smokers. A transducer placed in the filter of a
smoked cigarette relayed information to an automatic smoking-
machine to duplicate inhaled puff volume. This method was used to
produce a more natural smoking pattern. Comparisons were then
made between particulate mass concentrations in the machine-
generated smoke and the amount of smoke actually exhaled by the
smoker. With these measurements, a 57 percent deposition of
particulate mass was seen in men. This was greater than the
significant 40 percent collection efficiency measured in women
(p < 0.01). No data regarding particulate size or deposition sites were
reported. Hiller and coworkers (198213) also measured the deposition
fraction of an aerosol containing three different sizes of polystyrene
latex spheres in nonsmoking humans. They measured a 10 percent
deposition for 0.6 pm (MMAD) spheres, which is similar to the
results of Davies et al. (1972) and Muir and Davies (1967) using 0.5
pm aerosols and of Heyder et al. (1973) using aerosols with a 0.2 to
1.0 pm range. The size ranges of these aerosols are comparable to
those experimentally measured in cigarette smoke, as previously
discussed. These percentages are lower than those observed by Hinds
et al. (1983), probably reflecting differences in breathing patterns.
The measurements of Hinds et al. (1983) were made with realistic
breathing patterns used during smoking; the other investigators had
used normal breathing patterns. Increased breath-holding following
inspiration probably accounts for the enhanced collection efficien-
cies.

Particulate Retention in the Lung

The amount of particulates retained in the lung at different times
following the inhalation of an aerosol such as cigarette smoke
depends upon the balance between the amount that deposits in the
respiratory tract and the efficiency of the lung clearance mecha-
nisms in the airways and alveoli. Particles depositing in the airways
are entrained in the mucus layer lining these passages. This layer is
swept toward the mouth by the action of ciliated cells and eventually
swallowed. Macrophages present in the airways may also phagocy-
tose deposited particulates and are also carried toward the mouth by
the mucociliary transport system. Particulates reaching the alveolar
region-those that are usually smaller than several micrometers in
size-are soon engulfed by alveolar macrophages. These cells gradu-
ally migrate toward the airways and exit the lung via the mucocili-
ary escalator. Dissolution is also an important clearance mechanism
for soluble particles. Clearance mechanisms are a dynamic compo-
nent of normal lung function and operate to keep the lung sterile.

423


Lung disease and cigarette smoking itself can affect particulate
clearance and retention in smokers' lungs. Previous studies have
shown that smokers have different aerosol deposition patterns and
slower clearance rates than nonsmokers (Albert et al. 1969; Cohen et
al. 1979; Sanchis et al. 1971). These alterations in clearance are, in
part, caused by components in cigarette smoke that are ciliotoxic
(Battista 1976) and impair phagocytosis by alveolar macrophages
(Ferin et al. 1965). Clearance mechanisms in smokers may be further
compromised by lung diseases, such as emphysema and fibrosis, and
by exposure to air pollutants, Oxidants in photochemical smog, such
as ozone and nitrogen oxides, are toxic to ciliated cells and
macrophages (Bils and Christie 1980).

Measurements of retention of cigarette particulates in the lungs
over time are difficult to estimate from data obtained with airway
casts or from differences in the aerosol concentration of inhaled and
exhaled smoke because these methods do not take clearance
mechanisms into account. Unfortunately, few data are available
regarding the actual retention and sites of deposition of cigarette
smoke particulates in either humans or animals. The most accurate
method is quantification of particulate deposits in individual pieces
of tissue dissected from the lung. Impossible in living animals, this is
a tedious procedure with animal lungs or human material obtained
at surgery or autopsy and is especially difficult with large lungs.
Little et al. (1965) examined lungs from humans at autopsy and
suggested a correlation between the sites of bronchogenic carcinoma
in the lungs of smokers with the deposition of polonium21o, a
radioactive component of cigarette smoke. Resnik and Samek (1980)
used a radioactive marker to study the retention of smoke in
hamster lungs. They exposed hamsters to the smoke from cigarettes
containing a labeled component in the tobacco and then measured
the amount of radioactivity present in different lobes. They found
that more radioactivity was present in the lung tissue of hamsters
not previously exposed to unlabeled cigarette smoke. However, the
clearance of the labeled component from the lungs was slower in the
group previously exposed to smoke. There are problems with using
animal models for smoke uptake. Most rodents are obligatory nose
breathers, and significant fractions of the smoke may be taken up as
it passes through the upper airways. Page et al. (1973) studied mice
using radiolabeled cigarettes. They found that 50 percent of the
deposited smoke was recovered from the nasal passages. About 30
percent was recovered from the esophagus, stomach, and other
organs, and only 20 percent was present in the lungs. Exposing
animals via a tracheostomy avoids this excessive and unnatural
deposition in the nose, but it bypasses the mouth and larynx, which
may remove some particles during smoking in man.

424


Passive Smoking

Recently concern has increased regarding the health effects of
cigarette smoke inhaled by nonsmokers, a phenomenon called
passive smoking. The smoke is composed of that exhaled by the
smoker and the sidestream smoke produced by the burning cigarette
between inhalations. The concentration of respirable particulates in
areas where there are smokers can range from 100 to 700 pg/m3.
This is up to 25 times higher than that found in nonsmoking areas
(Repace and Lowrey 1980). Using mean deposition values of 11 and
70 percent for the passive smoker and the active smoker, respective-
ly, from the data presented by Hiller et al. (1982), the deposition
would be approximately 0.55 mg for a nonsmoker over an 8-hour day
in a room with 500 pg/m3 of smoke. In comparison, a smoker would
deposit approximately 400 mg of tar in his or her lungs if he or she
smoked two packs of cigarettes with an average tar rating of 20 mg
per cigarette during the same time period. As has been discussed
earlier, the rate and pattern of breathing can also affect the total
dose of cigarette particulates deposited in the lungs.

Although the amount of smoke depositing in the lungs of
nonsmokers during passive smoking is small compared to that
encountered by the active smoker, large numbers of people are
involved. In the United States in 1979, 36.9 percent of men and 28.2
percent of women were current smokers (USDHEW 1980).

Conclusions

Cigarette smoke is the most important cause of chronic obstructive
lung disease. This significant response is matched by the significant
dose of toxic particulates received by the respiratory tract of
smokers. The particle size of cigarette smoke is so small that little
protection is offered by the filtering capacity of the upper airways.
Cigarette smoke penetrates deep into the lungs and reaches the
small airways and alveoli. The fraction of the smoke deposited is
high because most smokers employ some breath-holding following
inhalation of a puff. Their attempt to enhance deposition of smoke is
successful, resulting in increased lung burdens of toxic smoke
products.

425

450-144 0 - 85 - 15


CIGARETTE SMOKE TOXICOLOGY

Introduction

The inhalation toxicity of tobacco smoke has become one of the
major public health problems of the 20th century. The chemical
complexity of tobacco smoke confounds the task of identifying its
toxic constituents. Tobacco smoke is comprised of thousands of
chemical components arising primarily from volatilization and
pyrolysis of the tobacco leaf (Stedman 1968; Green 1977). The
chemical gamut runs from traces of elemental metals, such as
cadmium, to nonvolatile whole tobacco leaf components that have
escaped degradation during the burning process (USDHHS 1981).
Approximately 90 percent of the individual constitutents are organic
compounds associated with both the particulate phase and the gas
phase (Guerin 1980). It is not surprising that chronic inhalational
exposure to this diverse mixture of potentially bioactive compounds
can evoke a wide variety of toxicologic responses. Over the years,
scientific and public concern has centered primarily on the carcino-
genic and atherogenic effects of tobacco smoke. In contrast, relative-
ly little is known about the involvement of tobacco smoke constitu-
ents in the pathogenesis of chronic obstructive lung disease (COLD)
(USDHHS 1981).

For the most part, smoke constituent toxicity studies, both
epidemiologic (Dean et al. 1977; Higenbottam et al. 1980) and
toxicologic (Walker et al. 1978; Lewis et al. 1979; Coggins et al. 19801,
have been confined to a comparison of the varying amounts of
particulate matter or tar delivered by smoke. In studies of this
nature, attempts have been made to distinguish between the relative
toxicities of the vapor phase and the particulate phase of tobacco
smoke. The general conclusion reached is that gas phase components
that penetrate to the small airways and alveoli may play a
significant role in the production of peripheral airway and parenchy-
ma1 diseases such as emphysema, whereas particulate phase compo-
nents that deposit in larger airways may play a role in the
development of disorders of the more proximal airways such as
chronic bronchitis (USDHHS 1981). This generalization may not
always hold, however. For example, in a review of the effects of
smoking on mucociliary clearance, Newhouse (1977) noted consider-
able disagreement among investigators with regard to whether the
vapor phase or the particulate phase was the major factor in smoke-
induced dysfunction of the mucociliary transport system. Also,
Coggins and associates (1980) observed an increase in both peripher-
al and central airway goblet cell number in rats after exposure to
tobacco smoke from which most of the vapor phase had been
removed. Cohen and James (1982) found that the level of oxidants in
tobacco smoke (oxidants have been implicated in the pathogenesis of

426


emphysema) correlated with the amount of particulate matter in
smoke from various brands of cigarettes. At present, therefore,
attempts to associate a specific toxicologic response solely with
either the vapor phase or the particulate phase of tobacco smoke are
not recommended.

Because so little is known regal-ding the role of specific constitu-
ents or phases of tobacco smoke in the pathogenesis of COLD, this
section of the Report is organized on the basis of specific insults to
the respiratory system that may be brought on by exposure to whole
tobacco smoke and that may lead to structural and functional
changes within the lung. Included, as available information permits,
are data on the known contribution of individual smoke constituents
or phases to a specific insult. Human and animal studies are
described separately to provide a perspective on the extent to which
animal research has verified or extended clinical research and vice

versa.

Preliminary Considerations

Tobacco smoking is generally accepted as the major cause of
COLD (USDHEW 1979; USDHHS 1981). COLD is often subdivided
into three categories: (1) uncomplicated bronchitis, characterized by
mucus hypersecretion and cough, (2) chronic bronchitis with bronchi-
olar inflammation and obstruction of distal airways, and (3) pulmo-
nary emphysema, characterized by distal air space enlargement with
loss of alveolar interstitium. These three pathologic condit.ions are
often considered collectively within the context of COLD because
they can coexist in the lungs of smokers and because signs and
symptoms associated with one condition may presage the develop-
ment of another.

Effects on Airway Function and Ventilation
Human Studies

Cigarette smoke appears to have both chronic and acute effects on
airway function. In adults, smoking over a period of years leads to
narrowing of and histopathologic abnormalities in small airways
(Ingram and O'Cain 1971; C osio et al. 1980; Suzuki et al. 1983). Even
in teenagers, regular smoking for 1 to 5 years is sufficient to cause
demonstrable changes in tests of small airway function in some
smokers (Seely et al. 1971); the lungs of young cigarette smokers who
die suddenly show definite pathologic changes in the peripheral
airways (Niewoehner et al. 1974).

The acute response to cigarette smoke has been reported to involve
large airways, small airways, or both. Costello and associates (1975),
in a study of asymptomatic smokers and nonsmokers, found that

427


tests of small airway function (maximum expiratory flow volume
curves, closing volume, and frequency dependence of compliance)
were unaltered after smoking one cigarette; however, specific
airways conductance, a measure of large airway function, fell
significantly in both groups. Essentially the same results were
obtained by Gelb and associates (1979), who reported a decrease in
airways conductance but little or no change in volume of isoflow
(another test of small airway function) in healthy nonsmokers after
smoking one cigarette. Likewise, McCarthy and colleagues (1976),
using several different tests, found no evidence for an acute effect pf
intensive cigarette smoking on small airways, but did demonstrate
increased large airways resistance. The decrease in conductance
caused by cigarette smoke has been shown to occur within 7 or 8
seconds of a single inhalation (Rees et al. 1982), and filtration seems
to reduce the degree of bronchoconstriction (Da Silva and Hamosh
1980). Irritant effects of tobacco smoke are not limited to the
particulate phase, because exposure to oxides of nitrogen at levels
present in cigarette smoke also can precipitate acute bronchospasm
(Tate 1977). Nicotine does not appear to be responsible for the acute
bronchoconstriction that accompanies cigarette smoking (Nadel and
Comroe 1961).

Zuskin and coworkers (1974) showed that in healthy human
subjects, smoking one or two cigarettes decreased flow rates on
maximum and partial flow-volume curves, and concluded that
smoking causes acute narrowing of small airways. Da Silva and
Hamosh (1973) and Sobol and colleagues (1977) measured airways
conductance, as well as maximum mid-expiratory flow rates, and
concluded that both large and small airways are probably affected by
the acute inhalation of cigarette smoke.

Though the bronchoconstrictive response to cigarette smoke has
most often been attributed to a cholinergic reflex originating with
stimulation of irritant receptors in the airways, there are data
suggesting that histamine may also be involved. Walter and Walter
(1982b) found a significant increase in the number of degranulated
basophils in the blood of smokers 10 minutes after smoking
compared with just before smoking. There is also some evidence to
indicate that smokers may differ from nonsmokers in their respon-
siveness to inhaled histamine (Brown et al. 1977; Gerrard et al. 1980)
as well as methacholine (Malo et al. 1982; Kabiraj et al. 1982; Buczko
et al. 1984), but smoking immediately prior to an inhalation test does
not appear to affect bronchial responsiveness to either histamine or
methacholine (McIntyre et al. 1982).

Asthmatic subjects have a greater than normal susceptibility to
the bronchoconstrictive effects of cigarette smoke when the smoke is
actively inhaled. The question whether tobacco smoke plays a role in

428


allergic asthma has yet to be resolved completely I USDHEW 1979;
Shephard 1982; Burrows et al. 1984).

Animal Studies

Binns and Wilton (1978) studied the acute ventilatory response to
cigarette smoke in rats. They found that within the first 3 minutes
after initiation of smoke exposure, tidal volume fell to 80 percent of
the preexposure level, then rose to 160 percent after 9 minutes of
exposure; respiratory rate dropped to 40 percent of the preexposure
level within 1 minute and remained there for the duration of the
exposure period. There was no adaptation of the acute ventilatory
response after 4 weeks of daily smoke exposures. In a similar study,
Coggins and associates (1982) found that rats exposed to a relatively
low dose of cigarette smoke demonstrated a persistent depression in
tidal volume and breathing frequency, whereas animals exposed to a
relatively high dose exhibited an increase in tidal volume with no
change in frequency.

Acute airway responses to cigarette smoke have not been studied
as extensively in animals as they have been in man. Experiments in
anesthetized dogs (Aviado and Palecek 1967), rabbits (Sellick and
Widdicombe 1971), and cats (Boushey et al. 1972) indicate that acute
smoke exposure elicits reflex bronchoconstriction. There also is
evidence from experiments with isolated monkey lungs that smoke
exposures stimulate histamine release (Walter and Walter 1982a).
Histamine appears to be responsible, at least in part, for mediating
.he increase in collateral resistance in dogs following administration
If cigarette smoke (Gertner et al. 1982).
The chronic effects of cigarette smoking on pulmonary function in
logs were studied by Park and coworkers (1977). Active inhalation of
100 and 200 puffs of diluted (1:4) smoke 5 days per week for periods
jf 6 months and 1 year, respectively, did not produce any noteworthy
:hanges in pulmonary function. The effects of chronic cigarette
,moke exposure on ventilation in rats were studied by Loscutoff and
*oworkers (1982). Animals exposed for up to 24 months to cigarette
<make containing various amounts of tar and nicotine were found to
rave higher tidal volumes and lower respiratory rates than sham-
zxposed animals. The most pronounced changes were seen in
nimals exposed to smoke from low tar, high nicotine cigarettes.
Iistopathologic examination of lungs taken from these animals
evealed primarily granulomatous lesions with no evidence of
mphysematous changes (Wehner et al. 1981). Roehrs and colleagues
1981) used operant conditioning techniques to get baboons to smoke
0 cigarettes per day for 3 years. Measurements of lung volumes,
ompliance, and expiratory flow showed no differences between
moking animals and sham animals, but airway reactivity to inhaled
lethacholine was decreased in animals that had smoked. Subse-

429


quently, Wallis and associates 11982) reported that both acute and
chronic Inhalation of' nicotine mimicked this effect of cigarette
smoke :in brc;llchisI reactivity in baboons.

Effects on Permeability of the Pulmonary Epithelium

The pl-i I monwry epithelium functions to protect underlying struc-
tures from injuricus agents deposited in the airway lumen. Cigarette
smoke has been shown to diminish this protective function by
increasing enithelial permeability in all regions of the tracheobron-
chial tree (Simani et al. 1974). In the airways, irritant receptors
located just beneath epithelial tight junctions are more accessible
following exposure to tobacco smoke. Stimulation of these receptors
is thought to initiate rapid changes in ventilation and to induce
bronchoconstriction (Widdicombe 1977). Likewise, mast cells, a
source of potent bronchoconstrictive mediators, become more accessi-
ble to inhaled toxicants after smoke exposure (Guerzon et al. 1979).
In the alveolar region, an increase in epithelial permeability may
promote the transfer of noxious smoke constituents and endogenous
proteases to the interstitium, thereby facilitating disruption of
alveolar septa.

Human Studies

Subepithelial structures of the lung are important targets for
smoke-induced injury, and research has shown that tobacco smoke
alters epithelial permeability to allow offending agents to gain access
to these structures. Minty and colleagues (1981) showed that,
compared with nonsmokers, smokers had significantly shorter half-
time lung clearance as measured with inhaled radiolabeled aerosols.
After cessation of smoking, half-time clearance increased, but at 21
days it was still significantly less than that reported in nonsmokers.
Using similar techniques, Kennedy and colleagues (1984) compared
pulmonary epithelial permeability and bronchial reactivity to in-
haled histamine in smokers and nonsmokers. These researchers
found increased permeability in smokers, but could find no evidence
of increased reactivity. Although the mechanism by which cigarette
smoke induces an increase in alveolar epithelial permeability is not
fully understood, it has been suggested that carbon monoxide may
play an important role, with possible additional contributions from
nicotine and oxides of nitrogen (Jones et al. 19801.

Animal Studies

In studies of rabbit tracheal rings exposed in vitro, just a few puffs
of diluted cigarette smoke have caused ultrastructural changes in
tracheal epithelial cells and an increase in the size of intracellular
spaces, but junctional complexes between cells remain intact (Davies

430


and Kistler 1975). Boucher and associates (1980, found that, com-
pared with controls, guinea pigs exposed to 100 or more puffs of
cigarette smoke exhibited a significantly faster transfer rate for
horseradish peroxidase across tracheal epithelium. These animals
also demonstrated a progressive disruption of epithelial tight
junctions as a function of the dose of tobacco smoke. Hulbert and
associates (1981) reported that smoke-induced increases in guinea
pig airway permeability were transient, reaching maximum levels at
30 minutes after acute exposure to 100 puffs and returning to control
levels 12 hours later. Gordon and associates (19831 reported that
acute exposure (48 hours) of hamsters to NO:! caused a marked
increase in bronchiolar and alveolar epithelial permeability to
horseradish peroxidase. Restoration of the epithelial barrier was
noted 48 hours after exposure in these animals. Ranga and associates
(1980) demonstrated a similar increase in guinea pig tracheal
epithelial permeability upon exposure to NO- for 14 days.

Effects on Mucociliary Structure and Function

The mucociliary system provides the lung with one of its most
effective lines of defense against inhaled pollutants. Disruption of
this system enables pollutants to remain in contact with the
respirat,ory membranes for prolonged periods and increases the risk
of toxic damage. Tobacco smoke can adversely affect mucociliary
function by increasing the amount or viscosity of respiratory tract
secretions or by depressing ciliary activity directly (Newhouse 1977;
Wanner 1977).

Effects on Cells: Pulmonary Alveolar Macrophages and
Polymorphonuclear Leukocytes

Pulmonary emphysema is believed to result from the slow
degradation of the elastin framework of lung parenchymal tissue.
Degradation of e&tin is most likely initiated by elastolytic enzymes
released locally in the lung and not adequately inhibited by
endogenous antiproteases. Recent studies of the effects of cigarette
smoke on these cellular sources of elastolytic enzymes have provided
additional insights into the relationships between smoking and
pulmonary emphysema. (See chapter 53

Human Studies

Normally, pulmonary alveolar macrophages (PAMs) function as a
defense mechanism against particulate material deposited on the
respiratory surfaces of the lung. However, cigarette smoke can
induce a number of changes in PAMs that may promote excessive
degradation of native lung tissue. For example, PAMs from smokers


have elevated elastase levels, and these cells may secrete elastase in
vitro (Harris et al. 1975; Rodriguez et al. 1977; Hinman et al. 1980).
Further, PAMs from smokers have been shown in vitro and in vivo
to bind and internalize elastase released from polymorphonuclear
leukocytes (PMNs) (Campbell et al. 1979; White et al. 1982). It has
been suggested that during the phagocytosis of smoke particulates by
PAMs, elastolytic enzymes may be released into extracellular spaces
(Hocking and Golde 1979; Brain 1980; Kuhn and Senior 1978).
Numerous investigators have reported significantly greater yields of
PAMs from the lungs of smokers compared with nonsmokers (Green
et al. 1977; Roth et al. 1981; Hoidal and Niewoehner 1982). The
effects of smoking on PAM mobility are unclear. Some researchers
have reported a significant increase in chemotactic migration of
PAMs from smokers versus PAMs from nonsmokers (Warr and
Martin 19741, but others have been unable to observe such an effect
(Demarest et al. 1979).

Macrophages from smokers exhibit various morphologic, metabol-
ic, and functional abnormalities. Structural changes noted in the
PAMs of smokers include a slight increase in cellular diameter, the
presence of "smokers inclusions" consisting predominantly of kaolin-
ite particles (which have been shown to be cytotoxic to human PAMs
in vitro (Green et al. 1977)) and increased numbers of lysosomes and
phagolysosomes (Brody and Craighead 19751. Perturbations in sever-
al metabolic pathways have been observed in PAMs from smokers,
and acrolein in smoke has been implicated in this toxicity (Green et
al. 1977; Laviolette et al. 1981). The production of superoxide
radicals and hydrogen peroxide (H202), both of which inhibit lung
antiproteases, has been reported to be enhanced in the PAMs of
smokers (Hoidal et al. 19811. Smokers' PAMs have also been shown
to release chemotactic substances for PMNs (Gadek et al. 1978;
Hunninghake et al. 1980). Additionally, there is evidence suggesting
that PAMs from smokers secrete factors that promote the release of
elastases from PMNs (Cohen et al. 1982).

As with PAMs, PMNs have been found in elevated numbers in the
lungs of smokers (Reynolds and Newball 1975; Hunninghake et al.
1980a; Hunninghake and Crystal 1983). Exposure of PMNs to
cigarette smoke condensate in vitro has been shown to promote the
release of elastolytic enzymes (Blue and Janoff 1978). Hutchison and
coworkers (1980) found that the particulate phase of cigarette smoke
stimulated the release of lysosomal enzymes from human PMNs, but
they did not quantitate this release specifically for elastases. A
recent study by Totti and colleagues (1984) showed that nicotine was
chemotactic for human PMNs and that it enhanced PMN responsive-
ness to other chemotactic factors. These results are in contrast with
a previous study by Bridges and coworkers (1977) showing that
nicotine, when used in higher concentrations than those employed

432


by Totti and colleagues, inhibited the chemotactic response of PMNs
to casein.

In a preliminary laboratory study, Janoff and colleagues (1983)
found that smokers have elevated levels of PMN elastase in their
lung fluids compared with nonsmokers. This finding is of particular
interest in that human PMN elastase has been shown to induce
emphysema in animals (Janoff et al. 1977; Senior et al. 1977; Snider
et al. 1984). There is also evidence that cigarette smoke alters PMN
metabolism in such a way as to favor the release of toxic oxygen
metabolites. PMNs from smokers with an elevated white blood cell
count show a marked increase in the release of super-oxide anions
compared with PMNs from nonsmokers or with PMNs from smokers
with a normal white cell count (Ludwig and Hoidal 1982). These
unstable oxygen metabolites have harmful effects on various cells
and tissues in vivo and in vitro (Sachs et al. 1978; Fridovich 1978),
and are capable of injuring phagocytes and promoting the release of
proteolytic enzymes (Hoidal and Niewoehner 1982). Oxidants derived
from PMNs are also capable of inactivating lung antiproteases in
vitro; this may be yet another mechanism by which smoke-affected
PMNs contribute to the development of emphysema (Zaslow et al.
1983).

Animal Studies

Laboratory animal studies of the effects of cigarette smoke on lung
free-cell population and integrity have yielded results similar to
those obtained from human studies. Recruitment of PAMs to the
lungs following cigarette smoke exposure has been demonstrated in
a number of animal species, including mice (Matulionis and Traurig
1977; Guarneri 1977); hamsters (Hoidal and Niewoehner 1982), and
monkeys (DeLucia and Bryant 1980). In the rat, PAM recruitment in
response to smoke exposure appears variable. In two relatively
similar studies, one group of investigators (Drath et al. 1978) found a
depression in the number of PAMs in the lungs of rats exposed to
smoke for 30 days, whereas another group (Walker et al. 1978)
reported a significant increase in the number of PAMs after 6 weeks
of smoke exposure.

Several authors have described the effects of cigarette smoke
exposure on the morphology of rat PAMs. Observed changes include
increases in PAM size, lipid vacuoles, and lysosomes, as well as the
presence of "smokers inclusions" (Walker et al. 1978; Davies et al.
1978; Lewis et al. 1979). Cigarette smoke exposure of mice induces a
similar pattern of morphological changes in PAMs (Matulionis 1977).

Alterations of PAM phagocytic capacity have been demonstrated
in animals exposed to cigarette smoke. Fogelmark and colleagues
(1980) reported a dose-related increase in the rate of phagocytosis of
fungal spores in vitro by PAMs from hamsters and rats that had

433


been exposed to cigarette smoke. The ability of rats to mobilize
PAMs in response to a bacterial challenge does not appear to be
altered by cigarette smoke exposure (Guarneri 1977), nor is there a
significant effect upon PAM phagocytosis of Staphylococcus aureus
in rats after 30 days of smoke exposure (Drath et al. 1981).
Macrophages from mice exposed to cigarette smoke for 4 weeks
secrete significantly higher amounts of elastase than PAMs from
controls. However, it is not known whether this effect is due to the
stimulation of resident macrophages or to the recruitment of a
highly exudative population of macrophages to the lungs (White et
al. 1979).

A number of metabolic abnormalities have been noted in PAMs
from smoke-exposed animals (Low et al. 1977). Among these is an
increase in oxidative metabolism resulting in an increased produc-
tion of superoxide anions. Hoidal and Niewoehner (1982) showed
that enhanced oxidative metabolism in hamster PAMs was dimin-
ished if the particulates were filtered from the smoke. However,
other workers (Drath et al. 1981) studying smoke enhancement of rat
PAM oxidative metabolism have attributed this effect to the vapor
phase of smoke. In another study of PAM oxidative metabolism in
rats exposed to cigarette smoke for 180. days (Huber et al. 1980), it
was reported that metabolism was activated after 30 days, and at the
same time PAM superoxide dismutase (an enzyme that detoxifies
super-oxide radical) activity was depressed by 30 percent.

Animal PAMs, like human PAMs, can secrete PMN-directed
chemotactic factor in response to various stimuli. For example,
Gadek and colleagues (1980) demonstrated that noninfectious partic-
ulate material stimulated the release of PMN-specific chemotactic
factor from guinea pig PAMs. Perhaps tobacco smoke particulates
might evoke a similar response.

Owing to the ease with which PMNs can be harvested from
peripheral blood, most research concerning the effects of tobacco
smoke on PMNs has been conducted using human cells. In one
laboratory study, hamsters exposed to cigarette smoke for 2, 8, and
20 hours showed a progressive recruitment of PMNs to the lungs.
Control saline aerosol and filtered smoke did not stimulate recruit-
ment of PMNs, suggesting that this effect of cigarette smoke resides
in the particulate phase (Kilburn and McKenzie 1975).

Effects on Protease Inhibitors

In addition to efforts to characterize the effects of tobacco smoke
on cellular sources of elastolytic enzymes, considerable research has
gone into delineating the effects of tobacco smoke on the protease
inhibitor defense mechanism in the lungs, While several protease
inhibitors have been identified, a,-protease inhibitor (a,Pi) is consid-

434


ered to be the most important in neutralizing the effects of elastase
(Gadek et al. 1981,. Chemical oxidants are known to inactivate a,Pi
and diminish its capacity to inhibit elastase both in vitro and in viva
tAbrams et al. 1980). Cigarette smoke is an abundant source of
chemical oxidants that can exert : he same effect on n,?i and thereb?
reduce lung defenses against endogenous rlzstases.

Human Studies

The toxic effect of tobacco smoke on proteave in!libitors has beei-,
demonstrated in a variety of experimental situatioz. Janoff and
Carp 11977) reported that tobacco smoke condensiit;: suppressed thk,
inhibitory action of humcn serum, J>urcficd tr,Pi, nnJ bronchopu!:::cJ-
n:;irv lavage fluids on both pctrcir~:~ :I::d ELI.:::!:; ;lastase. The
suppression of human serum e::istxtacl I,;ilib!tc>r>, r;,pa::ity 51; s:moke
condensate solutions in vitro has aisu been den-,-.:Ltl,;ltt-d bp others
~Ohlsson et al. 1980,.

Comparison of the protease inhibitory capacity ,)t` serum sarnples
from smokers and nonsmokers has revealed a significant depression
in smokers that is correlated with smoking history (Chowdhury
1981: Chowdhury et al. 1982). The latter st.udies also reported that
the depression of serum prot,ease inhibitor; was reiated to an effect
of smoke on the inhibitors per se. and not to a decrease in serum
antiprotease concentration. Still, the effect of tobacco smoke on
serum and lung lavage fluid antiprotease concenrr:~tion and activitj-
remains controversial. Several investigators have reported that
smokers have elevated serum protease inhibitor le\pels (Rees et al.
1975; Ashley et al. 1980); others (Olsen et al. 197.5: Warr et al. 19771,
like Chowdhury and colleagues, have shown no difference in serum
or lavage fluid protease inhibitor concentrations between smokers
and nonsmokers.

Gadek and associates (1979) compared cr,Pi activity of lung lavage
fluids taken from smokers and nonsmokers and found that smokers
had a twofold depression of functional a,Pi activity. The activity of
a,Pi in this study was tested against porcine pancreatic elastase. In a
similar study (Carp et al. 19821, in which human neutrophil elastase
was used, bronchoalveolar lavage fluids obtained from smokers had
40 percent less a,Pi activity than fluids from nonsmokers. However,
Stone and colleagues 11983) found that smokers' bronchoalveolar
lavage fluids did not exhibit decreased functional cr,Pi activity when
tested against either porcine pancreatic elastase or human neutro-
phi1 elastase, and suggested that increased elastaae derived from
neutrophils may be the main factor in the genesis of emphysema in
smokers.

Smokers may have a functional deficiency in bronchial mucus
protease inhibitor (BMPi) activity. A comparison of BMPi obtained
from tracheal aspirates of smokers with BMPi from nonsmokers

435


revealed that smokers' BMPi was 20 percent less active against PMN
elastase than nonsmokers' BMPi iCarp and Janoff 1980a).

Specific cigarette smoke constituents that may be responsible for
the inactivation of lung protease inhibitors have not been identified.
Nicotine and acrolein were studied for their ability to suppress a,Pi
activity and were found to be ineffective (Janoff and Carp 1977).
Several studies have shown that oxidizing compounds such as
chloramine-T and N-chlorosuccinimide can oxidize methionine
groups on a,Pi and reduce its activity against porcine pancreatic and
human PMN elastases (Cohen 1979; Johnson and Travis 1979; Satoh
et al. 1979; Abrams et al. 1980; Beatty et al. 1980). This has led to the
current belief that oxidants in cigarette smoke may be involved in
the inactivation of protease inhibitors (Janoff et al. 1983). In addition
to free radicals (Pryor 19801, cigarette smoke contains oxides of
nitrogen possessing their own free radical properties and able to
react with olefins in the gas phase or with peroxides to generate
potent oxy-radicals (Dooley and Pryor 1982; Pryor et al. 1983).

As mentioned previously, smoke condensate solution suppresses
the elastase inhibitory capacity of serum a,Pi in vitro. This
suppression can be prevented by the incorporation of phenolic
antioxidants into the test media (Carp and Janoff 1978). Similarly,
BMPi suppression by smoke condensate can be prevented by
antioxidants (Carp and Janoff 1980a). Cohen and James (1982) used
odianisidine oxidation to quantify the levels of oxidants in tobacco
smoke condensates from various brands of cigarettes and found that
oxidant levels correlated with capacity to suppress a,Pi deactivation
of elastase. Further, this study provided evidence that peroxides and
superoxide anions were responsible for the loss of a,Pi activity,
because inclusion of catalase and superoxide dismutase in the test
system reduced smoke condensate effects on a,Pi activity. Bron-
choalveolar fluid from smokers contains some amount of oxidant-
inactivated a,Pi, as evidenced by the presence of methionine
sulfoxide residues (Carp et al. 1982).

In addition to the numerous oxidizing agents present in cigarette
smoke, byproducts of smoke-stimulated phagocyte metabolism repre-
sent another potential source of oxidants capable of inactivating
lung protease inhibitors. Carp and Janoff (1979) demonstrated that
phagocytosing human PMNs produce activated oxygen species that
diminish the elastase inhibitory capacity of human serum and pure
a,Pi in vitro. These workers presented evidence to show that
hydroxyl radicals resulting from the reaction between superoxide
anions and H,O, were responsible for this effect. The inactivation of
a,Pi by a myeloperoxidase-mediated reaction was also described in
the study, which concurs with other studies demonstrating that
purified myeloperoxidase, in conjunction with H,O, and a halide ion,
can inactivate a,Pi in vitro (Matheson et al. 1979, 1981). Further

436


work has shown that activation of human blood monocytes, PMNs,
and PAMs by use of a membrane-perturbing agent (as opposed to
phagocytosis) results in the release of superoxide anions and H,O,
and the suppression of serum elastase inhibitory capacity (Carp and
Janoff 1980b). Clark and colleagues (1981) have demonstrated that
the myeloperoxidase-H,02-halide system from chemically stimulated
PMNs oxidizes a,Pi in vitro. Similar evidence ascribing inactivation
of BMPi to the myeloperoxidase-H,O,-halide system has been
reported (Carp and Janoff 1980a). In the studies noted above,
phagocytederived oxidants were shown to be capable of inactivating
a,Pi when porcine pancreatic elastase was used as the substrate.
These findings were recently extended to include the more pathophys-
iologically relevant protease, human neutrophil elastase (Zaslow et
al. 1983). Little is known about in vivo inactivation of protease
inhibitors by phagocyte-derived oxidants, other than that inactive
a,Pi (in the oxidized state) has been found in the synovial fluid of
patients with inflamed joints (Wong and Travis 1980). The extent to
which oxidants from stimulated phagocytes play a role in the
suppression of lung a,Pi activity in smokers is at present unknown.

Animal Studies

Although most of what is known about cigarette-smoke-induced
oxidant injury to lung protease inhibitors has been derived from
human studies, some work has gone into the effects of cigarette
smoke on lung protease inhibitors in laboratory animals. It has been
demonstrated that very brief exposure of rats to cigarette smoke can
cause a significant reduction in the elastase inhibitory capacity of
a,Pi obtained from lung lavage fluid (Janoff et al. 1979). Very likely
this toxic effect of cigarette smoke is caused by oxidant damage to
protease inhibitors, because treatment of the lavage fluid with a
reducing agent partially restored normal elastase inhibitory capaci-
ty and because animals rendered oxidant tolerant by preexposure to
ozone did not exhibit a significant reduction in a,Pi activity
following exposure to cigarette smoke.

Effects on Lung Tissue Repair Mechanisms

A preponderance of the research to elucidate mechanisms by
which cigarette smoking induces emphysema has focused on the
factors that initiate lung tissue degradation. Recent studies suggest,
however, that the increased risk of emphysema associated with
cigarette smoking may be due partially to the effects of smoke on
lung repair mechanisms.

437


Human Studies

For the most part, work concerning the effects of cigarette smoke
on lung repair mechanisms has been conducted in experimental
animals. It has been shown, however, that cigarette smoke contains
an inhibitor that can prevent the cross-linking of human fibrin
polymers and thereby impede normal tissue repair (Galanakis et al.
1982). Smoke and smoke constituents have also been shown to induce
membrane damage in human lung fibroblasts (Thelestam et al.
1980). Of 464 smoke constituents tested, approximately 25 percent
caused membrane damage. The most active constituents were
amines, strong acids, and alkylated phenols; nitriles and polycyclic
aromatic hydrocarbons were inactive.

Animal Studies

Cigarette smoke has been shown to affect elastin synthesis in vitro
and elastin repair in vivo. Laurent and coworkers (1983) determined
the effect of solutions of smoke condensate on elastogenesis in vitro
by measuring the formation of desmosine (one of the major cross-
linking amino acids of elastin) during conversion of tropoelastin to
elastin. Using a cell-free system of purified tropoelastin from chick
embryo aorta or porcine aorta and lysyl oxidase purified from chick
embryo or bovine lung, these investigators found that desmosine
synthesis was inhibited from 80 to 90 percent in the presence of an
aqueous solution of the gas phase of cigarette smoke. Elastin repair
in vivo has been reported to be retarded by tobacco smoke. Osman
and colleagues (1982) showed that hamsters with elastase-induced
lung injury resynthesized elastin at a reduced rate if they were
exposed to six or seven puffs of whole cigarette smoke hourly for 8
hours per day during the repair period.

Summary and Conclusions

1. The mass median aerodynamic diameter of the particles in
cigarette smoke has been measured to average approximately
0.46 pm, and particulate concentrations have been shown to
range from 0.3 x log to 3.3 x log per milliliter.
2. The particulate concentration of the smoke increases as the
cigarette is more completely smoked.
3. Particles in the size range of cigarette smoke will deposit both
in the airways and in alveoli; models predict that 30 to 40
percent of the particles within the size range present in
cigarette smoke will deposit in alveolar regions and 5 to 10
percent will deposit in the tracheobronchial region.
4. Acute exposure to cigarette smoke results in an increase in
airway resistance in both animals and humans.

438


5. Exposure to cigarette smoke results in an increase in pulmo-
nary epithelial permeability in both humans and animals.
6. Cigarette smoke has been shown to impair elastin synthesis in
vitro and elastin repair in vivo in experimental animals
(elastin is a vital structural element of pulmonary tissuei.

439


References

ABRAMS. W.R.. ELIRAZ. A., KIMBEL, I'.. WEINBAUM, G. The effect of the
oxidizmg agents chloramine-T and cigarette smoke on dog serum proteinase
inhlbitorts). Experimental Lung Research l(3): 211-223,198O.
ALBERT, R.E., LIPPMAN, M., BRISCOE, W. The characteristics of bronchial
clearance in humans and the effect of cigarette smoking. Archcues o);Environmen-
tal Health 18\5): 738-755, May 1969.

ASHLEY, M.J.. COREY. P., CHAN-YEUNG. M. Smoking, dust exposure, and serum
alpha,-antitrypsin. American ReLGuJ of Respimtory Disease 121(5): 783-788, May
  1980.

AVIADO. D.M., PALECEK, F. Pulmonary effectz of tobacco and related substances: I
Pulmonary compliance and resistance in the anesthetized dog. Archives of
Encironmental Health 15: 187-193,1967.

BA'ITISTA, S.P. Cilia toxic components of cigarette smoke. In: Wynder, E.L..
Hoffmann. D., Gori, G.B. (Editors). Mod&ing the Risk /%`or the Smoker. Proceedings
of the Third World Conference on Smoking and Health, New York City, June 24,
1975. Volume 1. U.S. Department of Health, Education, and Welfare, Public
Health Service, National Institutes of Health, National Cancer Institute, DHEW
Publication No. (NIH1761221, 1976, pp. 517534.
BEATTY, K., BIETH, J., TRAVIS, J. Kinetics of association of serine proteinases with
native and oxidized alpha,-proteinase inhibitor and alpha,-antichymotrypsin.
Journal of Biological Chemistry 25X9): 39313934, May 10,198O.
BENOWITZ, N.L., HALL, S.M., HERNING, R.I., JACOB, P., JONES, R.T., OSMAN,
A.L. Smokers of low-yield cigarettes do not consume less nicotine. New England
Journal of Medicine 309: 139-142,1983.

BILS, R.F.. CHRISTIE, B.R. The experimental pathology of oxidant and air pollutant
inhalation. International Review of Experimental Pathology 21: 19%293,198O.
BINNS. R., WILTON, L.V. Inhalation toxicity studies on cigarette smoke. (VIII). 6-
week comparative experiments using modified fluecured cigarettes: General
toxicology. Toxicology ll(3): 207-217,1978.

BLUE, M.-L., JANOFF, A. Possible mechanisms of emphysema in cigarette smokers.
Release of elastase from human polymorphonuclear leukocytes by cigarette smoke
condensate in vitro. American Review of Respiratory Disease 117(2): 317-325,
February 1978.

BOLJCHER R.C., JOHNSON, J., INOUE, S., HULBERT, W., HOGG, J.C. The effect of
cigarette smoke on the permeability of guinea pig airways. Laboratory Znvestiga-
tion 43( 1 I: 94-100. July 1980.

BOLJSHEY. H.A., RICHARDSON, P.S., WIDDICOMBE, J.G. Reflex effects of laryn-
geal irritation on the pattern of breathing and total lung resistance. Journal of
Ph.ysiologv 224(2): 501513, July 1972.

BRAIN, J.D. Pulmonary macrophages: When do they prevent and when do they cause
COPD? Chest 77t21: 264-265, February 1980.

BRAIN. J.D.. VALBERG, P.A. Models of lung retention based in ICRP Task Group
report. Archives of Environmental Health 28fll: l-11. January 1974.
BRAIN, J.D.. VALBERG, P.A. Deposition of aerosol in the respiratory tract. American
Recieux of Respiraton Disease 120(6): 13251373, December 1979.
BRIDGES, R.B., KRAAL, J.H., HUANG, L.J.T.. CHANCELLOR, M.B. Effects of
tobacco smoke on chemotaxis and glucose metabolism of polymorphonuclear
leukocytes. Infection and Zmmuntty 15(l): 115-123, January 1977.
BRODY. A.R.. CRAIGHEAD, J.E. Cytoplasmic inclusions in pulmonary macrophages
of cigarette smokers. Laboratory Investigation 32(2): 125-132, February 1975.
BROWN, N.E.. MCFADDEN. E.R.. Jr., INGRAM, R.H., Jr. Airway responses to
inhaled histamine in asymptomatic smokers and nonsmokers. Journal of Applied
Physloloa 42(4): 50%513, 1977.

440


BUCZKO, G.B., DAY, A., VANDERDOELEN, J.L., BOUCHER, R., ZAMEL, N. Effects
of cigarette smoking and short-term smoking cessation on airway responsiveness to
inhaled methacholine. American Review of Respiratory Disease 129(l): 12-14,
January 1984.

BURROWS, B., LEBOWITZ, M.D., BARBER, R.A., KNUDSON, R.J., HALONEN, M.
Interactions of smoking and immunologic factors in relation to airways obstruc-
tion. Chest 84: 657-661,1984.

CAMPBELL, E.J., WHITE, R.R., SENIOR, R.M., RODRIGUEZ, R.J., KUHN, C.
Receptor-mediated binding and internalization of leukocyte elastase by alveolar
macrophages in vitro. Journal of Clinical Investigation 64(3,: 824-833, September
  1979.

CARP, H., JANOFF, A. Possible mechanisms of emphysema in smokers: In vitro
suppression of serum elastase-inhibitory capacity by fresh cigarette smoke and its
prevention by antioxidants. American Review of Respiratory Disease 118(3,: 617-
621, September 1978.

CARP, H., JANOFF, A. In vitro suppression of serum elastase-inhibitory capacity by
reactive oxygen species generated by phagocytosing polymorphonuclear ieuko-
cytes. Journal of Clinical Investigation 63(4): 793-797, April 1979.
CARP, H., JANOFF, A. Inactivation of bronchial mucous proteinase inhibitor by
cigarette smoke and phagcqtederived oxidants Experimental Lung Research l(3):
225237.198Oa.

CARP, H., JANOFF. A. Potential mediator of inflammation: Phagocyte derived
oxidants suppress the elastaseinhibitory capacity of alpha,-proteinase inhibitor in
vitro. Journal of Clinical Investigation 66: 987-995, 198Ob.
CARP, H., MILLER, F., HOIDAL, J.R., JANOFF, A. Potential mechanism of
emphysema: Alpha,-proteinase inhibitor recovered from lungs of cigarette smok-
ers contains oxidized methionine and has decreased elastase inhibitory capacity.
Pmceedings of the National Academy of Sciences 79(b): 2041-2045, March 1982.
CARTER, W.L., HASEGAWA, I. Fixation of tobacco smoke aerosols for size
distribution studies. Journal of Colloid and Interface Science 53(l): 134-141, 1975.
CHOWDHURY, P. Correlation of cigarette smoking with human serum antitrypsin
activity. Indian Journal of Medical Research 74: 763-766, November 1981.
CHOWDHURY, P., BONE, R.C., LOURIA, D.B., RAYFORD, P.L. Effect of cigarette
smoke on human serum trypsin inhibitory capacity and antitrypsin concentra-
tions. American Review of Respiratory Disease 126(l): 177-179, July 1982.
CLARK, R.A., STONE, P.J., EL HAG, A., CALORE, J.D., FRANZBLAU, C. Myeloper-
oxidase-catalyxed inactivation of a,-protease inhibitor by human neutrophils.
Journal of Biological Chemistry 256(7): 3348-3353.1981.
COGGINS, C.R.E., FOUILLET, X.L.M., LAM, R., MORGAN, K.T. Cigarette smoke
induced pathology of the rat respiratory tract: A comparison of the effects of the
particulate and vapor phases. Toxicology 16(2): 83-101,198O.
COGGINS, C.R.E., MUSY, C., VENTRONE, R. Changes in the minute ventilation of
rats exposed to different concentrations of cigarette smoke. Toxicology Letters 11:
181-185,1982.

COHEN, A.B. The effects in viva and in vitro of oxidative damage to purified alpha,-
antitrypsin and to the enzyme inhibiting activity of plasma. American Review of
Respiratory Disease 119f6): 953960.1979.

COHEN, A.B., CHENOWETH, D.E., HUGLI, T.E. The release of elastase, myeloperox-
idase, and lysozyme from human alveolar macrophages. American Review of
Respiratory Disease 126(Z): 241-247, August 1982.
COHEN, A.B., JAMES, H.L. Reduction of the elastase inhibitory capacity of alpha,-
antitrypsin by peroxides in cigarette smoke. An analysis of brands and filters.
American Review ofRespiratory Disease 126(l): 25-30, July 1982.
COHEN, D., ARAI, SF., BRAIN, J.D. Smoking impairs long-term dust clearance from
the lung. Science 204(4392): 514517, May 4, 1979.

441


COSIO, M.G., HALE, K.A., NIEWOEHNER, D.E. Morphologic and morphometric
effects of prolonged cigarette smoking on the small airways. American Review of
Respiratory Disease 122(2): 265-271, August 1980.
COSTELLO, J.F., DOUGLAS, N.J., SUDLOW, M.F., FLENLEY, D.C. Acute effects of
smoking tobacco and a tobacco substitute on lung function in man. Z.uncet Z(7937):
67-l. October 11,1975.

DA SILVA, A.M.T., HAMOSH, P. Effect of smoking a single cigarette on the "small
airways." Journal of Applied Physiology 34(3): 361-365, March 1973.
DA SILVA, A.M.T., HAMOSH, P. The immediate effect on lung function of smoking
filtered and nonfiltered cigarettes. American Review of Respiratory Disease 122(5):
794-797,198o.

DAVIES, C.N. Deposition of inhaled particles in man. Chemistry and Industry 11:
441444, June 1,1974.

DAVIES, C.N., HEYDER, J., SUBBA RAMU, MC. Breathing of half-micron aerosols.
I. Experimental. Journal ofApplied Physiology 32(5X 591-600, May 1972.
D `.VIES, P., KISTLER, G.S. The assessment of tobacco smoke toxicity in organ
culture. II. Ultrastructural studies on the immediate response of foetal rabbit
tracheal epithelium to short-term exposures of whole smoke. Ezperentia 31(6): 682-
684, June 15,1975.

DAVIES, P., SORNBERGER, G.C., ENGEL, E.E., HUBER, G.L. Stereology of lavaged
populations of alveolar macrophages: Effects of in vivo exposure to tobacco smoke.
Experimental and Molecular Pathology 29(2): 17&182, October 1978.
DEAN, G., LEE, P.N., TODD, G.F., WICKEN, A.J. Report on a Second Retrospective
Mortality Study in North-East England. Part I. Factors Related to Mortality Fram
Lung Cancer, Bnmchitis, Heart Disease and Stroke in Clewland County, With a
Particular Emphasis on the Relative Risks Associated With Smoking Filter and
Plain Cigarettes. Research Paper 14, London, Tobacco Research Council, 1977, 95
  PP.

DeLUCIA, A.J., BRYANT, L.R. Chronic tobacco smoke exposure in primates. In:
Sullivan, S. (Editor). Proceedings of the Fifth Workshop Conference. Presented by
the Tobacco and Health Research Institute, University of Kentucky, November l-
2,1979.1980, pp. 259-283.

DEMAREST, G.B., HUDSON, L.D., ALTMAN, L.C. Impaired alveolar macrophage
chemotaxis in patients with acute smoke inhalation. American Review of
Respimtory Disease 119(2): 279-286, February 1979.
DENNIS, W.L. The effect of breathing rate on deposition of particles in the human
respiratory system. In: Walton, W.H. Editor). Inhaled Particles. Old Woking,
Surrey, England, Unwin Brothers Ltd., 1971, pp. 91-103.
DOOLEY, M.N., PRYOR, W.A. Free radical pathology: Inactivation of human a,-
proteinase inhibitor by products from the reaction of nitrogen dioxide with
hydrogen perioxide and the etiology of emphysema. Biochemical and Biophysical
Research Communications 106t3): 981-987, June 15,1982.
DRATH, D.B., HARPER, A., GHARIBIAN, J., KARNOVSKY, M.L., HUBER, G.L.
The effect of tobacco smoke on the metabolism and function of rat alveolar
macrophages. Journal of Cellular Physiology 95(l): 105-113, April 1978.
DRATH, D.B., SHOREY, J.M., HUBER, G.L., Functional and metabolic properties of
alveolar macrophages in response to the gas phase of tobacco smoke. Znfection and
Immunity 34(l): 11-15, October 1981.

FERIN, J., URBANKOVA, G., VLCKOVA, A. Influence of tobacco smoke on the
elimination of particles from the lungs. Nature 2CMX4983): 515-516, May 1, 1965.
FEYERABEND, C., HIGENBO'ITAM, T., RUSSELL, M.A.H. Nicotine concentrations
in urine and saliva of smokers and nonsmokers. British Medical Journal 284:
1002-1004,1982.

442


FOGELMARK, B., RYLANDER. R., SJOSTRAND, M.. REININGHAUS. W. Free lung
cell phagocytosis and the effect of cigarette smoke exposure. Experimental Lung
Research l(2): 131-138, 1980.

FRIDOVICH, I. Biology of oxygen radicals: The superoxide radical is an agent of
oxygen toxicity; superoxide dismutases provide an important defense. Science
201(4359): 875-880, September 8,1978.

GADEK, J.E., FELLS, G.A., CRYSTAL, R.G. Cigarette smoking induces functional
anti-protease deficiency in the lower respiratory tract of humans. Science
206C4424): 1315-1316, December 1979.

GADEK, J.E., FELLS, G.A., ZIMMERMAN. R.L., RENNARD, S.I., CRYSTAL, R.G.
Antielastases of the human alveolar structures: Implications for the protease-
antiprotease theory of emphysema. Journal of Clinical Investigation 68(4): 889
898, October 1981.

GADEK, J.E., HUNNINGHAKE, G. W., ZIMMERMAN, R.L., CRYSTAL, R.G. Mecha-
nisms controlling release of neutrophil chemotactic factor by alveolar macro-
phages. American Revieulof Respiratory Disease 117: 65, Part II. 1978.
GADEK, J.E., HUNNINGHAKE, G.W., ZIMMERMAN, R.L., CRYSTAL, R.G. Regula-
tion of the release of alveolar macrophagederived neutrophil chemotactic factor.
American Review of Respiratory Disease 121(4): 72%733, 1980.
GALANAKIS, D.K., LAURENT, P., JANOFF, A., CHUNG, S.I. Cigarette smoke
contains anticoagulants against fibrin aggregation and factor XIIIa in plasma.
Science 217(4560): 642-645, 1982.

GELB, A.F., LUGLIANI, R., SCHIFFMAN, P., KLEIN, E., ZAMEL, N. Site of airway
obstruction after acute cigarette smoking and mild smoke inhalation. Bulletin
Europeen de Physiopathologie Respiratoire lM3): 481490, 1979.
GERRARD, J.W., COCKCROFT, D.W., MINK, J.T., COTTON, D.J., POONAWALA,
R., DOSMAN, J.A. Increased nonspecific bronchial reactivity in cigarette smokers
with normal lung function. American Review of Respirator_v Disease 122(4): 577-
581, October 1980.

GERTNER, A., BROMBERGER, B., TRAYSTMAN, R., MENKES, H. Histamine and
pulmonary responses to cigarette smoke in periphery of the lung. Journal of
Applied Physiology: Respiratory, Environmental, and Exercise Physiology 53(3):
582-588, September 1982.

GORDON, R.E., CASE, B.W., KLEINERMAN, J. Acute NO, effects on penetration
and transport' of horseradish peroxidase in hamster respiratory epithelium.
American Review of Respiratory Disease 128(31: 528-533, September 1983.
GREEN, C.R. Neutral oxygenated compounds in cigarette smoke and their possible
precursors. In: Recent Advances in Tobacco Science. Series 3, Valhalla, New York,
Naylor Dana Institute for Disease Prevention, American Health Foundation, 1977,
pp. 94-120.

GREEN, G.M., JAKAB, G.J., LOW, R.B., DAVIS, G.S. Defense mechanisms of the
respiratory membrane. American Review of Respimtory Disease 1183): 479-514,
March 1977.

GUARNERI, J.J. Influence of acute exposure to cigarette smoke on the alveolar
macrophage system. Journal of Labomtory and Clinical Medicine 89(6): 1215-1224,
  1977.

GUERIN, M.R. Chemical composition of cigarette smoke. In: Gori, G.B., Bock, F.G.
(Editors). Banbury Report 3.-A Safe Cigarette? Cold Spring Harbor, New York,
Cold Spring Harbor Laboratory, March 12, 1980, pp. 191-204.
GUERZON, G.M., PARE, P.D., MICHOUD. M.C., HOGG. J.C. The number and
distribution of mast cells in monkey lungs. American Review of Respimtoty Disease
119(l): 59-66, January 1979.

HARBISON, M.L., BRAIN, J.D. Effects of exercise on particle deposition in Syrian
golden hamsters. Amerrcan Reuieu ofRespimtor?/ Disease 128(5): 904-908, Novem-
ber 1983.

443


HARRIS. J.O., OLSEN, G.ii., CASTLE, J.R., MALONEY, AS. Comparison of
prcteolytic enzyme activity in pulmonary alveolar macrophages and blood
leukocytes in smokers and nonsmokers. American Review of Respiratory Disease
11 lt51: 579586, May 1975.

HARRIS, W.J. Size distribution of tobacco smoke droplets by a replica method. Nature
186(4724): 537<38. May 14,196O.

HERNING, RI., JONES, R.T., BACHMAN, J., MINES, A.H. Puff volume increases
when low-nicotine cigarettes are smoked. British Medical Journal 283: 187-189,
  1981.

HEYDER, J., GEBHART, J., HERGIVER, G., ROTH, C., STAHLHOFEN, W.
Experimental studies of the total deposition of aerosol particles in the human
respiratory tract. Journal tif Aerosol Science 4: 191-208,1973.
HIGENBOTTAM, T., SHIPLEY, M.J., ROSE, G., CLARK, T.J.H. Lung function and
symptoms of cigarette smokers related to tar yield and number of cigarettes
smoked. Lancet l(8165): 409412, February 23,198O.
HILLER, F.C., McCUSKER, K.T., MAZUMDER, M.K., WILSON, J.D., BONE, R.C.
Deposition of sidestream cigarette smoke in the human respiratory tract.
American Review of Respiratory D&ease 125(4): 406-408, April 1982a.
HILLER. F.C., MAZUMDER, M.K., WILSON, J.D. McLEOD, P.C., BONE, R.C.
Human respiratory tract deposition using multimodal aerosols. Journal of Aerosol
Science 13: 337-343,195Zb.

HINDS, W.C. Size characteristics of cigarette smoke. American Industrial Hygiene
Association Journal 39(l): 48-54, January 1978.
HINDS, W.C. Aerosol Technology Pmperties: Be.`lavior and Measurement of Airborne
Particles. New York, John Wiley and Sons, 1982.
HINDS, W., FIRST, M.W., HUBER, G.L., SHEA, J.W. A method for measuring
respiratory deposition of cigarette smoke during smoking. American Industrial
Hygiene Association Journal 44(2): 113-118, February 1983.
HINMAN, L.M., STEVENS, C.A., MAlTHAY, R.A., GEE, J.B.L. Elastase and
lysozyme activities in human alveolar macrophages. Effects of cigarette smoking.
American Review of Respimtory Disease 121(2): 263-271, February 1980.
HOCKING, W.G., GOLDE, D.W. The pulmonary-alveolar macrophage. (First of two
parts). New England Journal of Medicine 301fll): 580-587 and 639-645, September
13, 1979.

HOIDAL, J.R., FOX, R.B., LeMARBE, P.A., PERRI, R., REPINE, J.E. Altered
oxidative metabolic responses in vitro of alveolar macrophages from asymptomatic
cigarette smokers. American Review of Respiratory Disease 123(l): 8%39, January
  1981.

HUIDAL, J.R., NIEWOEHNER, D.E. Lung phagocyte recruitment and metabolic
alterations induced by cigarette smoke in humans and in hamsters. American
Review of Respimtory Disease 12613): 548-552, September 1982.
HUBER, G.L., DRATH, D., DAVIES, P., HAYASHI, M., SHEA, J. The alveolar
macrophage as a mediator of tobaccoinduced lung injury. Chest 77(2): 272,
February 1980.

HULBERT, W.C., WALKER, D.C., JACKSON, A., HOGG, J.C. Airway permeability to
horseradish peroxidase in guinea pigs: The repair phase after injury by cigarette
smoke. American Review of Respiratory Disease 123(3): 320-326, March 1981.
HUNNINGHAKE, G.W., CRYSTAL, R.G. Cigarette smoking and lung destruction:
Accumulation of neutrophils in the lungs of cigarette smokers. American Review of
Respimtory Disease 128(5): 83-38, November 1983.
HUNNINGHAKE, G.W., GADEK, J.E., CRYSTAL, R.G. Mechanism by which
cigarette smoke attracts polymorphonuclear leukocytes to lung. Chest 77(2): 271
276,198Oa.

444


HUNNINGHAKE, G.W., GADEK, J.E., FALES, H.M. CRYSTAL, R.G. Human
alveolar macrophagederived chemotactic factor for neutrophils: Stimuli and
partial characterization. Journal ofClinical Investigation 66(l): 473483, Septem-
ber 198Ob.

HUTCHISON, D.C.S., DESAI, R., BELLAMY, D.. BAUM, H. The induction of
lysosomal enzyme release from leucocytes of normal and emphysematous subjects
and the effects of tobacco smoke upon phagocytceis. Clini:al Sxnce 58(5): 403-409.
May 1980.

INGRAM, R.H., Jr., O'CAIN, CF. Frequency dependence of compliance in apparently
healthy smokers versus nonsmokers. Bu'retin of Physlologv. Pathology and
Respiration 7: 195-210, 1971.

INTERNATIONAL COMMISSION ON RADIOLOGICAL PROTECTION, TASK
GROUP ON LUNG DYNAMICS. Deposition and retention models for internal
dosimetry of the human respiratory tract. Health Physics 12(21: 173-207, February
  1966.

ISHIZU, Y., OiITA, K., OKADA, T. Changes in the particle size and the concentration
of cigarette smoke through the column of a cigarette. Journal of Aerosol Sczence
9(l): 25-29,1978.

JANOFF, A., CARP, H. Possible mechanisms of emphysema in smckers: Cigarette
smoke condensate suppresses protease inhibition in vitro. rlmerzcan Hetxzeu, of
Respiratory Disease 116(l): 65-72, July 1977.
JANOFF, A., CARP, H., LAURENT, P., RAJU, L. The role of oxidative processes in
emphysema. American Review of Respiratory Disease 127(2): 531538. February
1983.

JANOFF, A., CARP, H., LEE, D.K., DREW, R.T. Cigarette smoke inhalation decreases
alpha,-antitrypsin activity in rat lung. Science 206(4424): 1313-1314, December 14,
  1979.

JANOFF, A., SLOAN, B., WEINBAUM, G., DAMIANO, V., SANDHAUS. R.A.,
ELIAS, J., KIMBEL, P. Experimental emphysema induced with purified human
neutrophil elastase: Tissue localization of the instilled protease. American Review
ofRespiratory D%ease 115(3): 461-478, March 1977.
JOHNSON, D., TRAVIS, J. The oxidative inactivation of alpha,-proteinase inhibitors:
Further evidence for methionine at the reactive center. Journal of Biological
Chemistry 254: 4022-4026,1979.

JONES, J.G., LAWLER, P., CRAWLEY. J.C.W., MINTY, B.D.. EULP NDS, G.,
VEALL, N. Increased alveolar epithelial permeability in cigarette smokers. Lancet
l(8159): 6667, January 12, 1980.

KABIRAJ, M.U., SIMONSSON, B.G., GROTH, S., BJORKLUND, A., BULOW. K.,
LINDELL, S.-E. Bronchial reactivity, smoking and alpha,-antitrypsin. A popula-
tion-based study of middle-aged men. American Retlieu! of Respzmtoc Diseaqe 126:
864-869, November 1982.

KEITH, C.H., DERRICK, J.C. Measurement of the particle size distribution and
concentration of cigarette smoke by the "conifuge." Journnl of Colloid Science
15(4): 340-356,1960.

KENNEDY, SM., ELWOOD, RX., WXGS, B., J.R., PARE, P.D., HOGG, J.C.
Increased airway mucosal permeabilit:, of smokers: Relationship to airway
reactivity. American Review of Respimtory Disease 129(l): 143-148. January 1984.
(ILBURN, K.H., MCKENZIE, W. Leukocyte recruitment to airways by cigarette
smoke and particle phase in contrast to cytotoxicity of vapor. Science 189(4203):
634-637, August 2.2, 1975.

(OZLOWSKI, L.T., FRECKER. R.C., KHOUW, V., POPE, M.A. The misuse of "less
hazardous" cigarettes and its detection: Hole blocking of ventilated filters.
Amrricoq Journal of Public Health 70: 1202-1203,198O.
XJHN, C., III, SENIOR, R.M. The role of elastases in the development of emphysema
Lung 1533): 185-197,1978.

445


LANGER. G., FISHER, M.A. Concentration and particle size of cigarette smoke
particles. -American Medical Association Archives ofIndustrial Health 13: 373-378,
  1956.

LAURENT, P., JANOFF. A., KAGAN. H.M. Cigarette smoke blocks cross-linking of
elastin in vitro. American Reuiew of Respiratory Disease 127(2): 182-192, February
  1983.

LAVIOLETI'E. j&f.. CHANG. J., NEWCOMBE, D.S. Human alveolar macrophages: is.
lesion in arachidonic acid metabolism in cigarette smokers. American Reuieu of
Respiratory Disease 124(4): 397-401, October 1981.
LEWIS. D.J., BRAYBROOK, K.J., PRENTICE, D.E. The measurement of ultrastruc-
tural changes induced by tobacco smoke in rat alveolar macrophages. A compari-
son of high and low tar cigarettes, Toxic0log.v Letters 4: 175-181, September 1979,.
LITTLE, J.B., RADFORD, E.P.. Jr., McCOMBS, HI,., HUNT, V.R. Distribution of
polonium in pulmonary tissues of cigarette smokers. ZQ'euv England Journal of
Medicine 273(25): 1343-1351, December 16.1965.
LOSCUTOFF, SM., JAFFE, R.A., HILTON, D.I., PHELPS, D.W.. CARR, DR..
WEHNER, A.P. Dosimetry and cardiopulmonary function in rats chronically
exposed to cigarette smoke. Toxicology and Applied Pharmacology 64(2): 335-352,
June 30,1982.           I
LOW, ES., LOW, R.B., GREEN, G.M. Correlated effects of cigarette smoke compo-
nents on alveolar macrophage adenosine triphosphatase activity and phagocytosis.
American Retlieu: ofRespiratov Disease 115(6): 963-970, June 1977.
LUDWIG, P.W., HOIDAL, J.R. Alterations of leukocyte oxidative metabolism in
cigarette smokers. American Review of Respiratory Disease 126(61: 977-980,
December 1982.

MALO, J.L.. FILIATRAULT. S., MARTIN, R.R. Bronchial responsiveness to inhaled
methacholine in young asymptomatic smokers. Journal of Applied PhysioloE.
Respiratory, Environmental and Exercise Physiology Z'(6): 1464-1470, June 1982.
MARTONEN, T.B.. LOWE, J.E. Cigarette smoke pattern in a human respiratory tracr
model. In: Proceedings of the 36th Annual Conference on Engineering, Medicine.
and Biology. Volume 25.1963, p. 171.

MATHESON. N.R., WONG, P.S., SCHUYLER, M., TRAVIS, J. Interaction of human
alpha,-proteinase inhibitor with neutrophil myeloperoxidase. Biochemist? X(21.
331-336. January 20,198l.

MATHESON, N.R., WONG, P.S., TRAVIS, J. Enzymatic inactivation of human
alpha,-proteinase inhibitor by neutrophil myeloperoxidase. BiclchemicaI and
Bioph.wcal Research Communications E&21: 402409, May 28,1979.
MATULIONIS, D.H. Biomorphology of the macrophage. In: Clark, M.A. (Editor).
Puimonaq Disease: Defense Mechanwms and Populations at Risk. Proceedings of'
the Tobacco and Health Research Institute Symposium-2, Lexington, Kentucky.
April 12-14, 1977. Lexington, University of Kentucky Printing Services, 1977. pp
  60-81.

MATULIONIS, D.H.. TRAURIG, H.H. In situ response of lung macrophages an?
hydrolase activities to cigarette smoke. Laboratop Znuestigation 37(3): 314-326.
September 1977.

MCCARTHY, D.S., CRAIG, D.B., CHERNIACK, R.M. The effect of acute intensive
cigarette smoking on maximal expiratory flow and the single breath nitrogen
washout trace. American Reoieu ofRespiratov Disease 113: 301304, March 1976
McCUSKER, K., HILLER, F.C., WILSON, J.D., MAZUMDER, M.K., BONE, R.
Aerodynamic sizing of tobacco smoke particulate from commercial cigarettes.
Arch&es ofEnuironmental Health 38(4): 215218, July-August 1983.
MCINTYRE. E.L., RUF'FIN, R.E., ALPERS, J.H. Lack of short-term effects of cigarette
smoking on bronchial sensitivity to histamine and methacholine. Europeans
Journal of Respiratoq Diseases 63(6): 535-542, November 1982.

446


MINTY, D.B., JORDON, C.. JONES, J.G. Rapid improvement in abnormal pulmonary
epithelial permeability after stopping cigarettes. British Medical Journal
282(6271): 1183-1186, April 11, 1981.

MUIR, D.C.F., DAVIES, C.N. The deposition of 0.5 p diameter aerosols in the lungs of
man. Annals of OccupationalHygiene lo(3): 161-174, July 1967.
NADEL, J.A., COMROE, J.H., Jr. Acute effects of inhalation of cigarette smoke on
airway conductance. Journal ofApplied Physiology 16(4): 713-716, July 1961.
NEWHOUSE, M.T. Effect of cigarette smoking on mucociliary clearance. In:
Steinfeld, J., Griffiths, W., Ball, K., Taylor, T.M. (Editors). Health Consequences,
Education, Cessation Actiuities, and Government Action. Volume II. Proceedings of
the Third Conference on Smoking and Health, New York, June 2-5, 1975. U.S.
Department of Health, Education, and Welfare, Public Health Service, National
Institutes of Health, National Cancer Institute, DHEW Publication No. (NIH)77-
1413,1977, pp. 131-137.

NIEWOEHNER, D.E., KLEINERMAN, J., RICE, D.B. Pathologic changes in the
peripheral airways of young cigarette smokers. Neul England Journal of Medicine
291(15): 755-758, October 1974.

OHLSSON, K., FRYKSMARK, U., TEGNER, H. The effect of cigarette smoke
condensate on alpha,-antitrypsin, antileukoprotease and granulocyte elastase.
European Journal of Clinical Investigation lo(5): 373-379. 1980.
OKADA, T., MATSUNUMA, K. Determination of particle-size distribution and
concentration of cigarette smoke by a light-scattering method. Journal of Colloid
and Interface Science 48(3): 461-469, September 1974.
OLSEN, G.N.. HARRIS, J.O., CASTLE, J.R., WALDMAN, R.H., KARMGARD, H.J.
Alpha-l-antitrypsin content in the serum, alveolar macrophages, and alveolar
lavage fluid of smoking and nonsmoking normal subjects. Journal of Clinical
Investigation 55(2): 427-430, February 1975.
OSMAN, M., CANTOR, J., ROFFMAN, S., TURINO, G.M., MANDL, I. Tobacco smoke
exposure retards elastin repair in experimental emphysema. American Review of
Respiratory Disease 125(2): 213, 1982. (Abstract.)
PAGE, B.F.J., WOOLSGROVE, B., CHASSEAUD, L.F., BINNS, R. Use of radioactive
tracer techniques in investigations associated with cigarette smoking. Annals of
Occupational Hygiene 16: 40%416,1973.

PARK, S.S., KIKKAWA, Y., GOLDRING, I.P., DALY, M.M., ZELEFSKY, M., SHIM,
C., SPIERER, M., MORITA, T. An animal model of cigarette smoking in beagle
dogs. Correlative evaluation of effects on pulmonary function, defense, and
morphology. American Review of Respimtory Disease 11%6): 971-979, June 1977.
PRYOR, W.A. Methods of detecting free radicals and free radical-mediated pathology
in environmental toxicology. In: Bhatnager, R.S. (Editor). Molecular Basis of
Environmental Toxicology. Ann Arbor, Ann Arbor Science Publications, 1980. pp.
  3-36.

PRYOR, W.A., CHOPARD, C., TAMURA, M., CHURCH, D.F. Mechanisms for radical-
mediated damage by cigarette smoke. Fe&ration Proceedings. 41(8): 2346, June
1982. (Abstract.)

RANGA, V., KLEINERMAN, M.P.C., COLLINS, A.M. The effect of nitrogen dioxide
on tracheal uptake and transport of horseradish peroxidase in the guinea pig.
American Review of Respirator-y Disease 122(3): 483490, September 1980.
REES, E.D., HOLLINGSWORTH, J.W., HOFFMAN, J.R., BLACK, H., HEARN, T.L.
Smoking and disease: Effect of serum antitrypsin in hospitalized patients. Archioes
of Environmental Health 30(8): 402-408, August 1975.
REES, P.J., CHOWIENCZYK. P.J., CLARK, T.J.H. Immediate response to cigarette
smoke. Thorax 37(6): 417-422, June 1982.

REPACE, J.L., LOWREY, A.H. Indoor air pollution, tobacco smoke, and public health.
Science 208: 464-472, May 2.1980.

447


REYNOLDS, H.Y., NEWBALL, H.H. Fluid and cellular mileu of the human
respiratory tract. In: Kilpatrick, L.H., Reynolds, H.Y. (Editors). Immunologic and
Infecriolls Reactions in the Lung. New York, Marcel Dekker, 1975, pp. 3-27.
REZNIK, G., SAMEK, M. Deposition and clearance of 14clabelled cigarette smoke
particles in Syrian hamster respiratory and digestive tract. Journal of Enuiron-
mental Pathology and Toxicologv 4(l): 371-381,1960.
RODRIQUEZ, R.J., WHITE, R.R., SENIOR, R.M., LEVINE, E.A. Elastase release from
human alveolar macrophage: Comparison between smokers and nonsmokers.
Science 198(4314): 313-314, October 21,1977.
ROEHRS, J.D., ROGER, W.R., JOHANSON, W.G., Jr. Bronchial reactivity to inhaled
methacholine in cigarette-smoking baboons. Journal of AppEied PhysioEogy:
Respiratory, Environmental and Exercise Physiology 5Of4): 754-760, April 1981.
ROTH, C., ARNOUX, A., HUCHOK, G.J., LACRONIQUE, J., MARSAC, J.H.,
CHRETIEN, J. Effet du tabagisme sur les cellules broncho-alveolaires chez
l'homme.[Effects of tobacco smoke on bronchoalveolar cells in man.] CZinical
Respiratory Physiology 17(5): 767-773, 2981.
RUSSELL, M.A.H., JARVIS, M., IYER, R., FEYERABEND, C. Relation of nicotine
yield of cigarettes to blood nicotine concentrations in smokers. British Medical
Journal 280(62191: 972-976,196O.

RUSSELL, M.A.H., WILSON, C., PATEL, U.A., FEYERABEND, C., COLE, P.V.
Plasma nicotine levels after smoking cigarettes with high, medium, and low
nicotine yields, British Medical Journal 2(5966X 414-416,1975.
SACHS, T., MOLDOW, C.F., CRADDOCK, P.R., BOWERS, T.K., JACOB, H.S. Oxygen
radicals mediate endothelial cell damage by complement-stimulated granulocytes:
An in vitro model of immune vascular damage. Journal of Clinical Investigation
61(5): 1161-1167, May 1978.

SANCHIS, J., DOLOVICH, M., CHALMERS, R., NEWHOUSE, M.T. Regional
distribution and lung clearance mechanisms in smokers and non-smokers. In:
Walton, E. H. (Editor). Inhaled Particles ZZZ. Old Woking, Surrey, England, Unwin
Brothers, Ltd., 1971, pp. 183.

SATOH, S., KURECHI, T., KRESS, L., LASKOWSKI, M. The dual nature of the
reaction between porcine elastase and human alpha,-proteinase inhibitors. Bio-
chemical Biophysical Research Communications 66: 130-137,1979.
SCHLESINGER, R.B., LIPPMANN, M. Particle deposition in casts of the human
upper tracheobronchial tree. American Zndustrial Hygiene Association Journal
33(4): 237-251, April 1972.

SCHLESINGER, R.B., LIPPMANN. M. Selective particle deposition and bronchogenic
carcinoma. Environmental Research 133): 424-431, June 1978.
SEELY, J.E., ZUSKIN. E., BOUHUYS, A. Cigarette smoking: Objective evidence for
lung damage in teenagers. Science 172(3984): 741-743, May 14,1971.
SHEPHARD. R.J. The Risks ofPas.siue Smoking. New York, Oxford University Press,
1982, pp. 102-108.

SELLICK. H., WIDDICOMBE, J.G. Stimulation of lung irritant receptors by cigarette
smoke, carbon dust and histamine aerosol. JournaL ofApplied Physiology 31(l): 15-
19, July 1971.

SENIOR, R.M., TEGNER. H., KUHN, C., OHLSSON, K., STARCHER, B.C., PIERCE,
J.A. The induction of pulmonary emphysema with human leukocyte elastaae.
American Reuieu? of Respiratory Disease 1 l&3): 469-475, September 1977.
SIMANI. AS, INOUE, S., HOGG. J.C. Penetration of the respiratory epithelium of
guinea pigs following exposure to cigarette smoke. Labomtory Znuestigation 31(l):
75-81, July 1974.

SNIDER, G.L., LUCEY, EC., CHRISTIANSEN, T.G., STONE, P.J., CALORE, J.D.,
LATANESE, A., FRANZBLAU, C. Emphysema and bronchial secretory cell
metaplasia induced in hamsters by human neutrophil products American Reoieu,
of Respiratoy Disease 129: 155160,1984.

448


SOBOL, B.J., VAN VOORHIES, L., EMIRGIL, C. Detection of acute effects of
cigarette smoking on airway dynamics. 7'horu.z 32(31: 312-316, June 1977.
STEDMAN, R.L. The chemical composition of tobacco and tobacco smoke. Chemical
Reviews 68(2): 15%207, April 1968.

STONE, P.J., CALORE, J.D., McGOWAN, S.W., BERNARDO, J., SNIDER, G.L.,
FRANZBLAU, C. Functional a-l-protease inhibitor in the lower respiratory tract
of cigarette smokers is not decreased. Science 16: 1187-1189,1983.
STUPFEL, M., MORDELET-DAMBRINE, M. Penetration of pollutants in the
airways. Bulletin de Physio-Pathologie Respiratoire 10: 481609, 1974.
SUTTON, S.R., RUSSELL, M.A.H., IYER, R., FEYERABEND, C., SALOOJEE, Y.
Relationship between cigarette yields, puffing patterns, and smoke intake:
Evidence for tar compensation? British Medical Journal 285: 600-603,1982.
SUZUKI, S., SASAKI, H., TAKISHIMA, T. Effects of smoking on dynamic compliance
and respiratory resistance. Archives ofEnvironmental Health 38(3): 133-137, May-
June 1983.

TATE, C.F. The effects of tobacco smoke on the nonsmoking cardiopulmonary public.
In: Steinfeld, J., Griffiths, W., Ball, K., Taylor, R. M. (Editors). Health Come-
quences, Education, Cessation Activities, and Governmental Action. Volume 2,
Proceedings of the Third World Conference of Smoking and Health, New York,
June 2-51975. DHEW Publication No. (NIH)77-1413,1977, pp. 329335.
THELESTAM, M., CURVALL, M., ENZELL, C.R. Effect of tobacco smoke compounds
on the plasma membrane of cultured human lung fibroblasts. Toxicology 15(3):
203-217,198O.

TOBIN, M.J., SACKNER, M.A. Monitoring smoking patterns of low and high tar
cigarettes with inductive plethysmography. American Review of Respiratory
Disease 126: 258-264,1982.

TO'ITI, N., III, McCUSKER, K.T., CAMPBELL, E.J., GRIFFIN, G.L., SENIOR, R.M.
Nicotine is chemotactic for neutrophils and enhances neutrophil responsiveness to
chemotactic peptides. Science 223(4632): 169-171, January 1984.
U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES. The Changing
Cigarette: A Report of the Surgeon Gencml. US. Department of Health and Human
Services, Public Health Service, Office of the Assistant Secretary for Health, Office
on Smoking and Health, DHHS Publication No. (PHSl81-50156,1981,252 pp.
U.S. DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE. Smoking and
Health: A Report of the Surgeon Geneml. U.S. Department of Health, Education,
and Welfare, Public Health Service, Oftice of the Assistant Secretary for Health,
Office on Smoking and Health, DHEW Publication No. (PHS)79-50066,1979,1136
  PP.

US. DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE. The Health
Consequences of Smoking for Women: A Report of the Surgeon General. U.S.
Department of Health, Education, and Welfare, Public Health Service, Office of
the Assistant Secretary for Health, Office on Smoking and Health, 1980, 359 pp.
WALKER, D., WILTON, L.V., BINNS, R. Inhalation toxicity studies on cigarette
smoke (VI). &week comparative experiments using modified flue-cured cigarettes:
Hi&pathology of the lung. Toxicology lOf31: 229-240, July 1978.
WALLIS, T.W., ROGERS, W.R., JOHNSON, W.G., Jr. Effects of acute and chronic
exposure to nicotine aerosol on bronchial reactivity to inhaled methacholine.
Journal of Applied Physiology: Respiration, Environmental and Exercise Physiolo-
gy 52(4): 1071-1076, 1982.

WALTER, A., WALTER, S. Mast cell density in insolated monkey lungs on exposure
to cigarette smoke. 27~0~~ 37(g): 699702,1982a.
VALTER, S., WALTER, A. Basophil degranulation induced by cigarette smoking in
man. Thorax 37(10): 756-759, October 1982b.
YANNER, A. State of the art. Clinical aspects of mucociliary transport American
Review of Respiratory Disease 116(l): 73-125, July 1977.

449


WARR. G.A.. MiltTIN. R.R. Chemotactic responsiveness of human alveolar macro-
phages: Effects of cigarette smoking. ZnfeectLon and Immunity %41: 769-771. April
  1974.

WARR, G..4., MARTIN, R.R.. SHARP, P.M., ROSSEN, R.D. Normal human bronchial
immunoglobulins and proteins. Effects of cigarette smoking. American Review of
RespirafoT Dwease ?16( 1 I: 2530. July 1977.
WEHNER. A.P.. DAGLE, G.E.. MILLIMAN, E.M. PHELPS, D.W., CARR, D.B.,
DECKER, J.R.. FILIPY, R.E. Inhalation bioassay of cigarette smoke in rats.
Toxicolog? and Applied Pharmacoloa 61(l): l-17, October 1981.
WHITE, R., J;\SOFF, A., GORDON, R., CAMPBELL, E. Evidence for in viva
internalization of human leukocyte elastase by alveolar macrophages. American
Review of Respiratory Disease 125(61: 779-781, June 1982.
WHITE, R., WHITE. J., JANOFF, A. Effects of cigarette smoke on elastase secretion
by murine macrophages. Journal of Laboratory and Clinical Medicine 94(3): 48%
499, September 1979.

WIDDICOMBE, J.G. Reflex control of tracheobronchial muscle in experimental and
human asthma. In: Lichtenstein, L.M., Austen, K.F. (Editors). Asthma-Physiolo-
g?, Zmmunopharmacolog-y and Treatment. New York, Academic Press, 1977, pp.
225-231.

WONG, P., TRAVIS, J. Isolation and properties of oxidized alpha-1-proteinase
inhibitor from human rheumatoid synovial fluid. Biochemical and Biophysicaf
Research Communications 96: 1449-1454,198O.
WYNDER, E.L., HOFFMANN, D. Tobacco and health: A societal challenge. Nell:
England Journal of Medicine 300(16): 894-903,1979.
ZASLOW. MC., CLARK, R.A., STONE, P.J., CALORE, J.D., SNIDER, G.L., FRANZ-
BLAU, C. Human neutrophil elastase does not bind to alpha,-protease inhibitor
that has been exposed to activated human neutrophils. iimerican Review of
Respiratop Disease 128: 434439,1983.

ZUSKIN, E.. MITCHELL, C.A., BOUHUYS, A. Interaction between effects of beta
blockage and cigarette smoke on airways. Journal of Applied Physiology 36: 449-
452,1974.

450


CHAPTER 9. ROLE OF THE
         PHYSICIAN IN
         SMOKING CESSATION

451


CONTENTS

Introduction

Patient Groups
  General Practice Patients
  Pregnant Patients
  Patients With Pulmonary Disease
  Patients With Cardiac Disease

The Use of Nicotine Chewing Gum

Discussion and Synthesis
  Methodological Considerations
  Trends in the Literature
  Patient Variables Related to Abstinence
Physician Variables Related to Effectiveness

Conclusions
  Recommendations for Physicians
  Future Research

Summary and Conclusions

References

453


Introduction

Although a variety of health care providers have attempted to
change the smoking behavior of the groups with whom they work
(USDHEW 1979), most of the research in this area, and this review,
is confined to patient populations or patient groups who provide
opportunities for physician intervention. The nature and extent of
the relationship between patient and physician enhances the oppor-
tunity for long-term behavior change. Major international studies on
utilization of health care reveal that 70 percent or more of North
Americans see a physician at least once a year (Kahn and White
1976; National Center for Health Services Research 1983; Pacific
Mutual 1978; National Center for Health Statistics 1982). Given this
frequency of contact between smokers and their physicians, some 38
million of the 54 million adults in the United States who smoke
could be reached annually with a smoking cessation message. Even if
only 5 to 10 percent quit on a long-term basis, the potential impact of
such contact is enormous. A recent study comparing free medical
care to insurance plans requiring shared cost by participants did not
show a beneficial impact on smoking (or other health habits
associated with coronary heart disease and some types of cancer)
from the average of one to two more encounters per year for several
years (Brook et al. 1983). The authors comment that "these health
habits, especially smoking, were at levels at which substantial health
benefit from behavior change was possible" (p. 1432). Thus, physician
contact alone does not increase smoking behavior change. Rather, a
mix of physician, motivation, educational, and training efforts are
doubtless called for.

Many techniques have been described in the literature to assist
physicians in treating cigarette smoking in their patients (Allaire
1983; Best 1978; Bohm and Powell 1982; Danaher et al. 1980; Fowler
1983; Hochbaum 1975; Hymowitz 1977; Indyke and Ellis 1980;
Luban-Plozza 19'77; Pechacek and Grimm 1983; Pechacek and
McAlister 1980; Pomerleau 1976; Rose 1975/76; Rosser 1977; Russell
1971; Seeker-Walker and Flynn 1983; Sherin 1982; Shipley and
3rleans 1982; Windsor et al. 1979). These range from supplying
nformation about smoking and health with advice to quit smoking
;o implementing complex behavior modification techniques with
-outine monitoring and long-term followups.
Lichtenstein and Danaher (1978) have described a hypothetical
node1 for the various roles that the physician can perform.
iccording to their formulation, the physician can "(1) act as a model
If a healthy lifestyle by not smoking, (2) provide information
larifying the risks associated with smoking and the risk reduction if
he patient stops, (3) encourage abstinence by direct advice and
uggestions, (4) refer the patient to a smoking cessation program,
nd (5) prescribe and follow up the use of specific cessation and

455


maintenance strategies in his or her own office management" (p.
233). This scheme is a hierarchical one, with each role subsuming the
behavior of the ones that precede it. Other roles such as political
lobbyist and researcher are related only indirectly to patient care
(Rosen and Ashley 1978).

In addition to advising their patients to quit, an overwhelming
majority of physicians have quit smoking; the prevalence of smoking
among physicians has most recently been estimated at 10 percent or
less in the United States, considerably below that of the general
population (Enstrom 1983; Fletcher and Doll 1969; Garfinkel 1976;
USDHEW 1976; Sachs 1983). Physicians are, therefore, carrying out
their role as exemplars. In a major national survey, over 90 percent
agreed that it was their responsibility to set a good example for
patients by not smoking cigarettes (USDHEW 1976). With regard to
other roles, the majority of reports (both research and advisory)
indicate that physicians usually function as information providers
and advice givers. However, evaluations of treatment procedures
that can be used for referral or in-depth treatment have also been
carried out. It is expected that as results become known and more
referral agencies are availa.ble, more physicians will be expanding
their roles.

The literature on rates at which physicians advise patients to quit
smoking shows a disparity between physician estimates and patient
reports. Over time, the proportion of physicians recommending
cessation has increased dramatically. A mid-1960s survey revealed
that 38 percent of physicians claimed that they advised "all" or
"almost all" (95 to 100 percent) of their patients who did not have
smoking-related disorders ,to quit or cut down (Green and Horn
1968). Eighty-eight percent of physicians claimed they gave this
advice to patients with lung and pulmonary conditions. In 1979,85 to
92 percent of physicians participating in the evaluation of a quit
smoking kit said they had spoken to smoking patients in the past few
weeks, advising quitting t,o 6 to 7 out of the last 10 smoking patients
seen (American Cancer Society 1981). In a 1981 survey of primary
care practitioners in Massachusetts, 90 percent of all physicians who
responded said they routinely asked about smoking; however, only
58 percent felt "very prepared" to counsel patients, and a mere 3
percent felt they were currently "very successful" in helping
patients to change their smoking behavior (Wechsler et al. 1983).
Ninety-eight percent of a Canadian sample of primary care physi-
cians surveyed in late 1981-1982 reported advising patients who
smoke to stop, with 45 percent claiming some success (Battista 1983;
Battista and Spitzer 1983). There is evidence that smoking physi-
cians feel less comfortable in dispensing advice to quit smoking and,
therefore, do it less forcefully (American Cancer Society 1981).

456


The majority of persons who smoke feel that physician advice to
quit or cut down on smoking would be influential (American Cancer
Society 1977; Pacific Mutual 1978). In a 1978 survey of the public,
doctor's advice was perceived to be the most effective means of
prompting cessation or reduction among six alternatives considered,
the other five being prohibition of smoking at work and in public
places; urging by children, spouse, or relatives; higher taxes on
tobacco; antismoking informational campaigns at work; and anti-
smoking advertising on television (Pacific Mutual 1978). In this
survey, 76 percent of smokers reported that doctor's advice would be
"very" or "somewhat" effective in this regard. Given this general
level of enthusiasm and confidence in physician-delivered messages,
actual rates of reported advice are quite low. In the survey just
reported, only 8 percent of former smokers spontaneously mentioned
a doctor's recommendation as a cause of their cessation, although 51
percent cited health reasons (Pacific Mutual 1978). In the 1975 Adult
Use of Tobacco survey, a full 64.6 percent of male and 60.8 percent of
female current smokers claimed they had never received advice from
any doctor about quitting, cutting down, or continuing smoking
(USPHS 1976). About 20 percent of current smokers had been
advised to quit. Combining advice to quit or cut down, the percentage
rose to approximately 35 percent. A somewhat lower estimate of
physician advice was obtained from a nationwide study of approxi-
mately 8,000 people (Stewart et al. 1979). Advice to quit or cut down
was reported by 22.4 percent, and lack of advice by 77.6 percent.
However, patient recall for the details of a physician visit may be
flawed. In one study, almost complete recall of cessation advice was
reported 1 year later (Mausner 19701, but in a second study only 50
percent of patients recalled cessation advice 2 months after it was
given (Rose and Udechuku 1971).

It seems quite likely that physicians do offer varying degrees of
advice and guidance to their patients (Fowler and Jamrozik 1983;
Wechsler et al. 19831, and in view of the decrease in social
acceptability given to the smoker, more physicians will be spending
more of their time and energy in this way in the future. A growing
number of editorials in medical journals have been devoted to the
importance of primary prevention and to motivating physicians to
this task (Check 1979; Yankauer 1983).

This chapter reviews and summarizes studies of smoking cessation
in various groups of patients, with a special focus on physician
intervention. Four classes of patients are considered: general prac-
tice, obstetric, pulmonary disease, and cardiovascular disease. Re-
views of this literature show a positive relationship between severity
of disease and the likelihood of quitting smoking (USDHEW 1979,
1980; Lichtenstein and Danaher 1978; Pederson 1982). However,
Pederson cautions that a causal interpretation of this relationship

480-144 0 - 85 - 16


may not be warranted, as physician involvement may be greater and
the effect of physician advice more salient or intense with sicker
patients. In addition, a section on research using nicotine chewing
gum as a treatment is included. Suggestions regarding future
research and treatment are also presented.

Patient Groups
General Practice Patients

Unlike the physician whose practice involves mainly patients with
pulmonary or cardiac disease, a large proportion of the general
practitioner's time may be spent in lifestyle modification of a
preventive nature with patients who are not experiencing smoking-
related problems. It may be that compliance among these patients is
dependent upon diagnosis, but no available studies have related the
reason for the office visit to success or failure in quitting, although
most counseling is said to take place during regular checkups or
during visits for respiratory problems, much less often than during
visits for unrelated major medical problems or minor problems
(Battista 1983).

Nine studies have dealt specifically with general practice pa-
tients. Mausner et al. (1968) followed 157 smoking patients of two
physicians sharing an office. One physician advised all the smokers
in his practice who came to his office over a 2-month period to quit
(n=121). Patients were told that smoking was harmful, and were
given written information on quitting techniques as well as lobeline,
a nicotine substitute. The other physician made no special mention
of smoking (n= 36 patients). At a 6-month followup, 33 percent of
those who were told to quit had reduced the amount they smoked,
compared with 9 percent in the group without such cessation advice.
Reduction was defined as a decrease of at least 10 cigarettes per day.
There was no validation of self-report. The factors found to be related
to decrement in smoking were higher initial consumption and
number of pack-years; a marginally significant relationship with
being male was noted, and for both sexes it was the heavier smokers
who changed.

Porter and McCullough (1972) compared the smoking behavior of
101 randomly selected patients who were counseled by one general
practitioner about their smoking with 90 patients who were not
counseled. Counseling consisted of advice, discussion, and a leaflet.
There was no significant difference in quit rate after 6 months
between the two groups: 2.5 percent in the counseled group and 4.4
percent in the not counseled group quit. No validation was per-
formed.

Handel (1973) followed for 1 year a group of 100 patients whom she
had advised in l- to 7-minute messages to quit smoking. The advice

458


was followed by 38 percent of the men and 11 percent of the women.
Eighteen percent of the remaining male smokers and 22 percent of
the female smokers reported reducing consumption by more than 50
percent. No control group was included in this study.

Pincherle and Wright (1970) reported a smoking intervention in a
clinic that provided health examinations of business executives on
an annual or biannual basis. Physicians were encouraged to deliver a
strong antismoking message, and a booklet was made available.
Results varied among the 10 participating physicians; between 17
and 35 percent of the 1,493 smokers seen at a followup visit at
approximately 18 months had stopped smoking cigarettes or had
reduced their smoking more than 30 percent, There were no controls
or validation of self-report. The doctor's own past or present smoking
habits only partially accounted for the variation in success rates (cf.
American Cancer Society 1981). The quit rate of 19 percent reported
by Richmond (1977) in a similar setting is consistent with their
findings. In preliminary findings, Rosser (1979) reported that 10
percent of smokers counseled by family physicians about cardiovas-
cular risk reduction report smoking cessation 1 or 2 years later.

In a large-scale study of 2,138 patients of 28 London physicians in
five practices, Russell et al. (1979) assessed the effectiveness of
physician smoking advice in comparison with no advice. Assignment
to group was by day of attendance at practice. Four groups were
used: a nonintervention control, a questionnaire-only control, an
advice-only group, and an advice group receiving a two-page
pamphlet and a warning of subsequent followup. Advice was
delivered in the physician's own style in a l- or 2-minute message. At
l-year followup, the overall quit rate was 14.4 percent-respectively
for each group, 10.3, 14.0, 16.7, and 19.1 percent. The percentages of
patients who stopped within 1 month of the initial visit and who
were still abstinent at followup were 0.3, 1.6, 3.3, and 5.1 percent,
respectively. These results were statistically significant, indicating
that advice to quit was effective and enhanced by written material
and information about a subsequent followup. The major effect was
to increase motivation in terms of the percentage of patients in each
group attempting to quit but not the success rate of quit attempts,
and to reduce relapse at the l-year point compared with the initial l-
month assessment. One can interpret this as due to the limited scope
of advice, focused on health education, and not to quitting skills. Quit
rates differed markedly among physicians and were inversely
related to the patient's initial consumption. Validation of the verbal
report of abstinence on a very small subsample of patients, using a
measure of nicotine concentration in saliva, revealed a low deception
rate (7 percent), which may have been unreliable, owing to patient
selection methods.

459


In an attempt to replicate findings of Russell et al. (1979) in a
Canadian sample, Stewart and Rosser (1982) randomly assigned 691
patients to one of three groups: control, advice, and advice plus
pamphlet. There were no differences between the groups; only 3 to 4
percent of patients had stopped smoking at the 5-month followup
and were still abstinent at 1 year. At that later followup, the overall
success rate was 11.7 percent; no objective measure of smoking
status was included. The researchers note that the control group had
a higher rate of long-term quitting (3.1 percent) than in the Russell
group's 1979 study (0.3 and 16 percent).

A second study by Russell et al. (1983131 enrolled a sample of 1,938
cigarette smokers, aged 16 and older, who visited 34 general
practitioners in six group pra.ctices in Kent and London in November
1980. All smokers were included and were assigned in balanced
design by week of attendance to one of three groups; nonintervention
controls, 1 to 2 minutes of advice in the physician's own style plus
booklet and warning of followup, and similar advice plus booklet
plus offer of a nicotine gum prescription. A questionnaire was mailed
and a personal followup was performed after 4 months and 1 year.
Patients who did not provide adequate data at both points were
counted as smokers. Two-thirds of those who claimed to have quit at
each time point were checked by measurement of expired air carbon
monoxide. At 1 year, self-reported quit smoking rates in the three
groups were 13.4, 10.8, and 16.2 percent (p ~0.021, respectively. For
those patients not smoking at 4 months and at 1 year, the cessation
rates were 6.0, 6.4, and 11.9 percent, respectively (p ~0.02). After
correction for those who refused or failed chemical validation (22
percent) and for those who switched from cigarettes to pipes or
cigars, the cessation rates were 3.9, 4.1, and 8.8 percent (p <O.OOl).
Compared with this group's earlier study (Russell et al. 19791,
cessation rates in these nonintervention controls (also see Stewart
and Rosser 1982) are much higher (3.9 versus 0.3 percent), but the
rates are not directly comparable because the initial followups are
not identical (1 month versus, 4 months). However, cessation rates in
the advice/booklet/warning groups are quite similar (5.1 versus 4.1
percent). Cessation rates in the nicotine gum group are discussed
later in this chapter.

Wilson et al. (1982) reporteld that a simple followup procedure may
enhance the effects of physician advice. A group of 211 smokers over
16 years of age attending two middle-class, university-based prac-
tices in Hamilton, Ontario, #over a 6-month period were recruited.
Nonsmokers, pregnant women who smoked, and smokers with
communication disorders or terminal illness were excluded. All
participating patients received brief (3 to 5 minute) intensive
counseling to quit smoking and a pamphlet and, subsequently, were
randomly assigned to one of' two groups. The 106 smokers in the

460


treatment group were given followup appointments at 1, 3, and 6
months to review and discuss problems, while the control group of
105 smokers received followup appointments as needed for com-
plaints, but no further smoking cessation counseling. In the treat-
ment group, 23 percent reported cessation at 6 to 14 months,
compared with 12 percent of the control condition (p ~0.05). When
losses at followup were counted as continuing smokers, the success
rates dropped to 19.8 and 10.5 percent, respectively. No objective
validation was included. Success in quitting was significantly related
to several factors: having made previous attempts to quit, judging
that it would not be extremely difficult to quit, and smoking regular
tar cigarettes (versus low tar).

Pregnant Patients

A number of studies concern smoking cessation and pregnant
women, a group of patients who are not experiencing smoking-
related disease, but for whom continued smoking has serious
implications. It has been documented that smoking during pregnan-
cy, especially in the last trimester, can result in such consequences
as reduced birthweight and increased fetal and neonatal mortality
(Landesman-Dwyer and Emanuel 1979; USDHHS 1980; USPHS
1973). Some evidence also suggests that lactation in smoking
mothers is inhibited and that smoking during pregnancy may be
related to childhood hyperkinesis (Denson et al. 1975) and develop-
mental retardation (Landesman-Dwyer and Emanuel 19791. Accord-
ing to Fielding and Yankauer (19781, the pregnant woman has been
largely ignored as a target for smoking cessation techniques because
evidence concerning the dangers to the fetus is just beginning to
emerge. Increasing concern is being expressed for the pregnant
smoker (USDHHS 19801, and many smoking cessation strategies
have been described to assist women (Gastrin 1983; King and Eiser
1981; Kretzschmar 1980).

The prevalence of smoking during pregnancy and rates of physi-
cian advice to quit or cut down have been previously summarized
(USDHHS 19801. Almost 60 percent of physicians specializing in
obstetrics and gynecology who participated in the 1975 CDC Survey
of Physician Advice claimed that they advised most to all of their
pregnant patients to quit or to cut down (Danaher 1978). As in the
general population estimates of remembered physician advice cited
earlier, fewer women report such advice given during pregnancy.
About 24 percent of women last pregnant during the 5 years from
1970 to 1975 remembered such advice (Harris 1979).
Rates of cessation among regular smokers during pregnancy
ranged from 0.9 to 35 percent, with a median of approximately 20
percent, in the 11 studies summarized in the 1980 Report of the
Surgeon General The Health Consequences of Smoking for Women

461


(USDHHS 1980). Results of m.ore recent studies were consistent with
the median figure. Hackett (I9791 interviewed 57 women at various
stages of pregnancy, and 16 percent reported quitting at some time
in the prenatal period. Fried et al. (1980) reported a similar quit rate
in a group of 67 smokers. The 1980 National Natality Survey (NNS)
examined changes in smokin.g and drinking behavior among 4,405
mothers during pregnancy (NCHSR 1983). Questionnaires were
mailed 6 months after delivery to married mothers who delivered
live-born infants. Nonmarried mothers were not included in the
analysis because of problems with the State government require-
ment of confidentiality. Mothers were much more likely to stop
drinking than to stop smoking during pregnancy. Of those who
engaged in the behavior before pregnancy, 30 percent stopped
drinking compared with almost 18 percent who stopped smoking.
White mothers had the highest smoking rates before pregnancy (32.0
percent) when compared with blacks (24.8 percent), Hispanics (23.3
percent), and others (19.9 percent). No significant differences by age,
race, or Hispanic origin were found in the proportion who stopped
smoking, although blacks appeared to have slightly lower quit rates
(13 percent) than either whites (18 percent), Hispanic (25 percent), or
other mothers (21 percent). Educational attainment, however, was
directly related to the tendency to stop smoking. Of white mothers
who smoked, the proportion who stopped during pregnancy ranged
from 10 percent for mothers with the least education (did not
graduate from high school) to 24 percent of mothers with the most
education (16 or more years education).

Three studies have combined observations of smoking discontin-
uance in pregnancy with some interventional tactic. Baric et al.
(1976) found that their entire sample of 134 pregnant British women
thought smoking could be harmful to the fetus, but only 16 percent
received this information from a doctor; most had received it from
the media. A total of 24 patients (18 percent of the sample) quit
smoking on their own; 63 of the remaining women participated in an
intervention program involving exposure to educational material by
a "doctor," and 47 served as controls. Subsequent analysis revealed
that while the groups did not differ significantly in the number of
women who quit smoking 11 weeks following treatment (14 percent),
significantly more in the intervention group modified their consump-
tion.

Dalton et al. (1981) surveyled smoking behavior (using self-report
only) in 282 pregnant British women, of whom 49 percent smoked at
the beginning of pregnancy. Thirty-two percent of the smokers in the
sample claimed they were given no medical advice to quit smoking.
Ten percent reported quittin.g smoking during pregnancy. A local
and a national poster and leaflet campaign designed to increase
smoking cessation rates at a prenatal clinic had no effect. The advice

462


to curtail smoking was given in a minimal fashion, and rarely by
general practitioners. Knowledge of the hazards of smoking was
higher among those who acknowledged receiving advice than among
those not acknowledging advice. Also, those who quit were better
informed about fetal hazards than those who continued to smoke.

Using a breath test for carbon monoxide to validate self-report,
smoking status was assessed in 179 pregnant women of moderate to
low socioeconomic status in Pittsburgh (Hughes et al. 1982). Most
women (61 percent) were in the third trimester of pregnancy. At the
beginning of pregnancy, 55 percent of the women reported smoking;
of these, 19 percent reported that they had quit and 37 percent
reported that they had reduced their smoking rate during pregnan-
cy. The rate of false positive results among self-reported nonsmokers
was 12 percent, and the rate of false negative results among self-
reported smokers was 12.5 percent. Both continuing smokers who
reduced consumption and quitters made those changes in the first
trimester, and gave pregnancy-related reasons for changing their
smoking behavior. However, none of the pregnancy-related factors
examined were statistically associated with quitting or cutting down.
Most of the continuing smokers expressed a desire to quit or to cut
down and wished to receive treatment, but only 1 woman (of 801
attended a free cessation program nearby. The authors note that
interventions scheduled early in pregnancy during prenatal outpa-
tient visits would be optimal for such a group.

A fourth test of an intervention designed for pregnant smokers
was reported by Danaher et al. (1978). Eleven women participated in
a 6-week program delivered by behavioral scientists that included
instruction in behavior modification, deep muscle relaxation, and
educational information. Of the eight women who completed the
program, four quit smoking and another three markedly reduced
consumption. At a g-month followup, three women were completely
abstinent, and one women was smoking less than one cigarette daily.
No control group was included in this study, so it is not possible to
evaluate the relative effectiveness of the treatment package.

Finally, three randomized trials of smoking cessation interven-
tions with pregnant women have been reported. Donovan (1977) and
co-workers (Donovan et al. 19751 randomly assigned 588 pregnant
British women to a control or an intervention group receiving
intensive antismoking information. Unfortunately, the number of
patients achieving abstinence at least for the duration of their
pregnancies was not reported. There was a significantly larger
reduction in amount smoked by the intervention group than by
controls, however. Almost one-third of a group of women who
voluntarily quit resumed smoking before the end of pregnancy, a
finding not replicated in 1J.S. women by Sexton and Hebel (1984).

463


Bauman et al. (1983) reasoned that exposure to alveolar carbon
monoxide (CO) levels in pregnancy would provide a concrete
demonstration of a current and personal consequence of smoking.
All pregnant women attending a public prenatal clinic over a 6-
month period were randomized to experimental and control groups;
47 percent of the 170 women were smokers. Experimental subjects,
both smokers and nonsmokers, observed their CO levels in a group
setting. Control subjects did not have the CO intervention. All
subjects were read a script on smoking, CO, and adverse effects of
smoking during pregnancy; health educators implemented all proce-
dures. In the experimental group, there were 36 women smokers
exposed to their own CO; the control group contained 43 smokers.
Six weeks after the intervention, there was no difference in quit
rates between the two groups (7 percent of experimental subjects and
13 percent of control subjects had quit) or on five other measures of
smoking behavior. After adjusting for covariates used in assessing
attrition effects and comparison group equivalence, CO levels were
significantly lower in the treatment group. The authors concluded
that the intervention had either a small or no influence on cigarette
smoking.

The first prospective, randomized, controlled clinical trial demon-
strating that a reduction of smoking produces a favorable change in
infant birthweight contained an effective smoking intervention
(Sexton and Hebel 1984). Pregnant women who smoked at least 10
cigarettes per day at the beginning of pregnancy and who had not
passed their 18th week of gestation were eligible for entry into the
trial. A total of 935 women w'ere recruited from the practices of 52
private obstetricians and a university hospital's obstetric clinic in a
large metropolitan area; subjects were randomly assigned to experi-
mental and control groups. Subjects in both groups reported smoking
an average of a pack a day at the beginning of pregnancy, but to have
reduced their smoking to about 11 cigarettes per day by the time of
randomization. The smoking intervention was delivered by health
educators, and consisted of encouragement and assistance to stop
smoking through informational and behavioral strategies. Each
woman received a minimum of one personal visit, supplemented by
telephone and mail contacts. The control subjects received no contact
until followup. A questionnaire and saliva sample (for thiocyanate
analysis) were obtained at randomization and during the followup in
the eighth month of pregnancy'. At followup, 43 percent of women in
the treatment group and 20 percent of women in the control group
reported quitting smoking. Overall, there was a significantly greater
reduction of smoking in the treatment group; group means for
number of cigarettes smoked per day were 6.4 for experimental
subjects and 12.8 for control subjects, respectively. Mean thiocyanate
levels were significantly lower in the experimental group than in the

464


control group, verifying self-report on a group level. Cessation
results in the control group, contrary to the findings of Donovan
(19771, showed that very few women who quit smoking in the first
trimester resumed smoking during the pregnancy; also, very few
who had not quit in the first trimester quit on their own later in the
pregnancy. This study clearly demonstrated that an "antismoking
intervention is feasible to conduct, accepted by pregnant women, and
effective in producing a reduction in smoking, and most important of
all, that cessation even during pregnancy improves the birthweight
of the baby" (Sexton and Hebel 1984, p. 915). These are important
results, obtained in a relatively high risk study group, and deserve to
be followed up.

Patients With Pulmonary Disease

A large proportion of the patients seen by a pulmonary specialist
are experiencing, firsthand, the health problems resulting from
continued smoking (Pederson 1982; Windsor et al. 1979). The
literature cited below demonstrates that the presence of serious
illness adds credence to the physician's message and is related to
increased compliance (Cooper-stock and Thorn 1982; Daughton et al.
1980; Davison and Duffy 1982; Hall et al. 1983; Pederson and
Baskerville 1983; Pederson et al. 1982). The evidence continues to
accumulate that smoking cessation is followed by favorable changes
in cardiopulmonary functioning (Ball and Turner 1974; Buist et al.
1976, 1979; Peterson et al. 1968; &human 1971; World Health
Organization 1975) and in morbidity and mortality (Hammond 1965,
1966; Kuller et al. 1982; USDHHS 1981; UUSDHEW 1979; Weinblatt
et al. 1971; Wilson 1973).

A number of studies (Baker et al. 1970; Burns 1969; Burnum 1974;
Dudley et al. 1977; Guzman 1978; Mausner 1970; Peabody 1972;
Pederson et al. 1980; Raw 1976; Rose and Hamilton 1978; Rose and
Udechuku 1971; Williams 1969) have investigated smoking cessation
among patients with respiratory disease. Table 1 summarizes these
studies, including data on subject groups, sample sizes, quit rates,
and duration of followup.

Eleven studies have investigated quit rates among pulmonary
disease patients following physician advice (Baker et al. 1970; Burns
1969; Burnum 1974; Cooperstock and Thorn 1982; Daughton et al.
1980; Davison and Duffy 1982; Guzman 1978; Mausner 1970;
Peabody 1971; Trahair 1967; Williams 1969). Compliance rates vary
from 15 percent to 51 percent, but none of these studies included no-
advice control groups as a test of the effectiveness of physician
counseling. A trend toward lower quit rates has occurred in the more
recent studies.

None of the investigations attempted to identify patient character-
istics associated with compliance, although some results suggest that

465


5 TABLE I.-Studies assessing smoking cessation rates among patients with pulmonary disease

                                  Quit rate           Duration of
  Study                  CrOUps            @ercent)          fouowup                   Commenta '


   Baker et al. (2970)         Multidimensional              34           6 months           No control group
                    treatment, N = 134

   Burns (2969)           Private, N=94               41           3 months           No control group; su- related ta less
                                                       withdrawal, lower neuroticism, and beii
                                                                          male

   Burnum (1974            Private                    25         Average, 5 years        No control group
  Cooperstock and        Respiratory, N =33             36          Cnxsectional         Quit rates compared with circulatory and
   ,Tiiom @YZ~                                                    mtwculoekeletal groups
  Daughton et al.         Hoepitalized, N = 107            63           -ional         No control groups, retmepective; ex-
   W3Ol                                                               smokera and smokers differed in
                                                       psychoeocial factors, pack years
  Davison and Duffy       Lung or cancer,               25          5Ye=3            No control group
   U982)                 N=52

  Dudley et al. (1977)         Cheat clinic                 76           Cronwwtional         No control group, retrospective; ex*mokers
                  Never smokers, N=66                               and smokers differed in psychosocial
                  Smokers, N = 42                                  aaaeta. at&My. and expression of
                  Quitters, N=132                                   depression

   Guman (1978)          Cheat clinic, N=123            20           3 to 24 month        No control group

   Hall et al. (1983)        Cardiopulmonary                          6 monthe           No signiticant difference in quit rate;
                  Health motivation, N= 19         10                      mood atatea related to reduction; objective
                  Aversion condition, N = 16         30                            verification

   Mauaner (1970)           Private                    51           3 to 12 months        No control group; exsmokers and smokers
                 Eight physicians, N=136                             differed in ewe&y of diewe


`FAHLE: 1 .--Continued

Study                  GrOUps

Quit rate
(percent)

Duration of
followup

Comments'

Not given

25

Not given

Only quit rate reported

Pedemn et al.
i 1980)

Private. N= 117

27.4

Retrospective
6 months to 7 years

No control group; multivariate analysis;
ex-emokers and smokers differ on
diagnosis. age, and sex

Pederson et aI
(1.9&n

Newly diagnosed
pulmonary, N = 3013

12.9

6 months

No control group; multivariate predictive
model developed, 92 prcent nczuracy

Raw (1476)           Motivating advice-"white coat"    Overall           3 months            R~~~ulta not presented for individual groups
               Motivating advice-%0 white coat"   12.5
                  Interview-"white coat"
                 Interview-"no white coat,"
               N-10 per group
             ~____          -. -~-                         -----__-.__ ~-~            ----
&me and Hamilton        Normal caee, N=731            14          3 years             High risk for cardiompirutory dmeas
197m               Intervention, N=714            36

Hospitalized with chronic bronchitis,   25          Not pven            No control group
N=29                             ~.--__  -___
Chest clinic, N=204            23            6 months             No control group


such relationships may exist (Burns 1969; Mausner 1970). Two
retrospective studies (Dudley et al. 1977; Pederson et al. 1980) used
multivariate techniques to determine the sociodemographic, physio-
logical, and psychological variables that are related to quitting.
Dudley et al. (1977) found that "good psychosocial assets, psychologi-
cal stability, and the ability to express depression openly" (p. 367)
discriminated between quitters and nonquitters. Since their mea-
surements were made cross-sectionally, the question remains wheth-
er these variables are causes or effects of smoking cessation. In a
sample of 117 pulmonary patients, 27 percent of whom quit after
physician advice, Pederson et al. (1980) found that abstinence was
related to primary diagnosis (t.hose with COLD were more likely to
quit), age (older or younger versus middle-aged), and sex (women
were more likely to quit) in order of predictive power. These results
could have been biased, however, because a number of patients were
lost to followup and no objective verification of smoking status was
used.

Pederson et al. (1982) conducted a prospective study of 308 newly
diagnosed respiratory patients, and using multivariate statistical
models, accurately categorized 92 percent of the samples as continu-
ing smokers or quitters, following physician advice. This model was
subsequently validated in a second group of similar patients with 89
percent accuracy. In both groups, cessation rates (self-report only)
were approximately 15 percent (Pederson and Baskerville 1983). The
variables from entry questionnaires useful for discriminating smok-
ers from quitters at followup were prediction of the patient as to
smoking status at followup, age, addiction as the major reason for
smoking, desire to quit, educational level, socioeconomic status,
number of children at home, and being married. Prediction of
quitting, increasing age, desire for quitting, socioeconomic status,
and being married were positvely associated with quitting. Addic-
tion, having children at home, and middle educational level were
negatively associated.

Three investigators (Hall et al. 1983; Raw 1976; Rose and
Hamilton 1978) tried to vary the type of advice given in order to
increase compliance. Raw 11976) found that increasing the motivat-
ing information about the risks of smoking and the benefits of
cessation by a psychologist subsequent to physician advice to quit did
not have a positive effect on compliance, but donning a white coat
did. The physician advice itself reduced smoking significantly among
advised patients compared with among nonadvised patients. Addi-
tionally, the group for whom the psychologist wore the white coat
during the interview (motivating or placebo) reduced smoking
significantly more than the no-white-coat group did. The dependent
variable was the percent reduction in smoking level (number of
cigarettes smoked) at 3-month followup by self-report alone. Unfor-

468


tunately, the sample was small (n =40), and abstinence rates were
not reported. The author suggests that the white coat is an advisor
characteristic that can increase effectiveness of advice.

Hall et al. (1983) found no difference in 6-month abstinence rates
between two groups of cardiopulmonary patients (n=35) randomly
assigned to a health motivation and self-management treatment (26
percent abstinence) or to an aversive smoking treatment (6 percent
abstinence), both led by nonphysician health professionals. Results
summarizing attrition rate and outcome (post-treatment and at 6-
month followup) generally favored the health motivation group,
however.

The London Civil Servants Smoking Trial (Rose and Hamilton
1978) was a randomized controlled trial of 1,445 men at high risk for
cardiorespiratory disease. Following a screening examination, 714
men were randomized to an intervention group and 731 to a normal
care group. For the normal care group, the results of the examina-
tion were forwarded to the general practitioner, leaving further
action to him. The men were not aware they were in the trial. They
were invited to return for the l-year and 3-year examinations as part
of the research. Men in the intervention group were invited by letter
to discuss the results of their examination with a physician (all
accepted). The 15-minute appointment consisted of strong advice to
quit smoking, risk appraisal (oriented to fitness and well-being more
than to disease), benefits of cessation, and the practicalities of
stopping-choice and personalized motivation. Two booklets were
provided, prepared especially for the study. Three further int,erviews
were scheduled at l-week, lo-week, and 6month points. All men
(intervention and controlj who attended the l-year and 3-year
examinations completed a self-administered questionnaire; some
were completed by mail. No validation of self-report was made. At
the l-year examination, 51 percent of intervention subjects and 10
percent of control subjects reported cessation of cigarette smoking;
excluding those men who had switched to pipes or cigars, rates of
tobacco abstinence drop to 38 and 8 percent, respectively. Of all the
men who stopped within the first year, 80 percent did so immediately
after the first interview. At 3 years, 36 percent of intervention
subjects and 14 percent of control subjects were not smoking
cigarettes; total tobacco abstinence rates were 23 and 10 percent,
respectively. A number of personal characteristics assessed at entry
were associated with increased probability of cessation: smoking less
than 20 cigarettes per day, not inhaling, use of filter tips, prior
attempts to stop, marital status "other than married," professional
or executive employment category, and neuroticism (Eysenck Per-
sonality Inventory). The level of abstinence achieved in the treat-
ment group is comparable to several other studies with similar

469


patients (Baker et al. 1970; Burns 1969; Mausner 1970; Pederson et
al. 1980) and is closer to the remainder than control group results.

Patients With Cardiac Disease

The studies concerned with smoking cessation among cardiac
patients further support the notion that presence of disease may be
an important precursor of compliance. The occurrence of a myocardi-
al infarction (MI) is a dramatic event that, in many patients, should
add credence to the physician's admonishments. Evidence demon-
strates that reduction or cessation of smoking is positively related to
survival in MI patients (Hickey et al. 1983; Mulcahy et al. 1975,
1977; Pentecost 1980; Salonen 1980; Sparrow et al. 1978; USDHHS
1983) and is negatively rela.ted to a coronary event following
uncomplicated angina (Hubert et al. 1982). It appears that smoking
cessation decreases mortality, among post-MI patients, so that
attempts to increase compliance among this group could have life-or-
death ramifications.

Table 2 summarizes the studies on this patient group. Successful
smoking cessation is relatively high among survivors of MI (Baile et
al. 1982; Burnum 1974; Burt et al. 1974; Cooperstock and Thorn 1982;
Croog and Richards 1977; Halhuber 1978; Hay and Turbott 1970;
Kirk et al. 1980; Kornfeld et al. 1982; Lloyd and Cawley 1980;
Mallaghan and Pemberton 1977; Mayou et al. 1978; Ronan et al.
1981; Sillett et al. 1978; Weinblatt et al. 1971; Wilhelmsson et al.
1975). Cessation rates range from 22 to 94 percent, with the majority
of studies falling in the 40 to 60 percent range. The discrepancies in
rates are partially attributable to sample size variations or duration
of followup. A trend is apparent, however, with more recent studies
reporting lower rates.

In a recent review of the literature on smoking following myocar-
dial infarction, Burling et al. (I9841 discuss four major methodologi-
cal limitations in these studies. First, the definition of abstinence
varies among studies, ranging from zero to five cigarettes per day;
also, the period over which abstinence is measured, from the MI
continuously to followup, should be specified.

Second, self-report of smoking status is rarely verified; a few
studies have used biochemical validation Baile et al. 1982; Burling et
al. 1982; Kirk et al. 1980; Ronan et al. 1981; Sillett et al. 1978; Wilcox
et al. 1979). Rates of deception have varied from approximately 25
percent of patients claiming abstinence (Sillett et al. 1978; Wilcox et
al. 19791 to much lower estimates of discrepancy between self-report
and objective measure (Baile et al. 1982; Burling et al. 1982; Kirk et
al. 1980; Ronan et al. 1981).

Third, specification of the treatment-the time and amount of
antismoking advice delivered--is not always explicit. Advice can be
verbal or verbal plus written, and the intensity of the message has

470


TABLE 2.-Studies assessing smoking cessation rates among patients with cardiac disease

Study                  GrOUpE

Quit rate
bxcent)

Duration of
followup

Comments '

Bade et al. U98ZJ

PC&Ml

62

Approximately
10 day8

In-hospital relapse among patients
receiving standard advice, no control
group; probability of relapse inversely
related TV severity of MI; objective
validation (breath CO) on a parallel series
of patients (unpublished), 9.2% deception
rate

Bumum (2974

Burt et al. (1974

Private, N=52

PostMI
Strong advice, N = 125
Conventional advice,
N=l35

42

62


27.5

Average, 5 years
lto3yem

No contml group

Cooper et al. U98ZI       High risk, N=519             24          2Y=@             No control group

Cooperstock and Thorn
u9m

Patienb with
circulatory problems.
N=317

13

Cmweectional

Quit ratea compared with respiratory and
mwwloekeletal groups

croog et al. (1977)        PC&MI, N=205              51         6 or 9 yeara

No control group; no differences between
ex-smokere and smokers for health beliefs
or so&demographic characteristics

Hay and Turbott
(297ol

P&MI, N = 137
Coronary inauff~ciency.
N=44

29


11

6 months to 2 years       Control for severity of disease

Halhuber (1978)         CHD, N=935                94            4 weeks            No control group

P
-1
I


rp
2   TABLE Z-Continued

                                     Quit rate           Duration of
   Study                  Groups            (percent)           followup                   Comments '

Kirk et al. (1980


Komfeld et al. (J99Zl

Arterial diseaee,
N=39

Patients after
coronary bypana
surgery. N = 100
(39 smokers)

49 repolted
44 verified

67

9 months



9 months

Objective validation Wum SCNI; pwslble
deception rate, 10.5 percent
           ___-..--. ~-
No control group

Lloyd and Cawley
(1980

MaIlaghan and
Pemberton (1977)

P&MI, N = 105
(64 smokers)

Post-MI. N=321

36



22

4 months


1 Y-

No control group


No control group; tilerewes between ex-
smokers for perceived severity and
memory of adviw

Malotte et al. (1981)       Hiah risk. N=43              53           6 montha            No control group; reaidentlal pmnqam

Mavou et al. (1978)        P&MI, N=lOO               45          1 Y=              No control group

Meyer and
Henderson (1974

Behavior Gadification.
N=5
Individual munaeIing,
N=4
Physician counseling,
N=6

20


25

3 montha

High risk patients; no wgmficant
difference between groups

33

Ockene et al. W62b)

High rink group
Special intervention,
N=4,103
Uellal care,
N=4,OSl

40 repQrted
35 verified
21 reported
19 verified

4Y-3             MRIW objective validation WN)


TABLE 2.-Continued

Study                 Gmupe

Qmt rate
(percent)

Duration of
followup

Powell and Amold
mm

High risk, N=42

50 verified

1 year

Objective validation (XN); hard core
smokers

Rahe et al. (1979)

P&MI
Croup therapy, N=22
Control, N=22

33
42

4 years             No sgnlficant difference

Bonan et al. (1981)

P&MI, N=117           51 reported
(111 smokers)             47 verified

4 to 18 years

Objective vahdation COHb~; possible
deception rate, 6.8 percent

Bose and Hamilton
(1978)

Raw et al. WWI

Normal care. N=731            14
Intervention, N=714            36

Normal cam, N=731        Not reported
Intervention, N=714            36

3YW


BY-

High risk for cardiorespiratory diseaee

            _____-
Followup of Roee and Hamilton (1978)

Rose and Udeehuku
(1971)

Hospitalized with
atherceclemtic diwnae,
N=56

44          Not given            No control group

Bcee et al. (198OJ        High ri&, N=736              29          4Y=-               Part of WHO tnal

Sillett et al. (1978)        P&Ml, N=Sl

65 reported
51 verified

1 Y=

Objectwe vahdation; pceeible deception
rate. 21 w-cent

Sivarqian et al.
UW

PC&Ml
Eherciee. N=66
Ekerciee and
counseling, N=66,
Control. N=&d

31


34
41

6 months            No significant differences

   Sparrow et al. (1978)       PC&MI, N=XJ2               El           Variable            Followup of smokera developing MI in the
%                      emokem                          2to6yeam        Fra+r&un study; no control group


4
-1   TABLE 2.-Continued

Study

Groups

Quit rate
(percent)

Duration of
foUowup

Comments '

Weinblatt et al.
(1971)

P&-MI, N=283
Angina, N=146
Nor&I-ID, N=432

50
50
19

4.5 year0

Control for severity of disease

WHO European
Collaborative Group
(lS!E?l

High risk, N=4,770             6          4Y-               No control condition

Wilhehnsson et al.
(1975)

PC&MI, N=M4

53

3 months

Differences between er-amokers and
smokers for increasing age and severity of
disease

' Objective validation of self-report of smoking abtinence wan performed only in thcee studies 80 indicated


varied from routine to strong. Results have generally been better
when stronger advice was delivered (Burling et al. 1982).

For example, in an experimental test of the effect of intense advice
on post-MI cessation, Burt et al. (1974) routinely assigned 210 male
patients to intense or to routine advice conditions. Abstinence rates
were higher in the intense advice condition, 62 versus 27.5 percent.
The intense intervention consisted of telling the patient repeated-
ly-in the critical care unit, during convalescence, and during
followup-never to smoke again in his lifetime, plus giving him a
pamphlet. However, other attempts to increase cessation rates by
using group counseling (Rahe et al. 1979) or exercise with or without
counseling (Sivarajan et al. 1983) showed no differences in absten-
tion rates for treatment groups and control groups.

Fourth, a variety of subject and environmental factors that may
influence cessation have rarely been systematically examined or
controlled. These include age, sex, race, severity of the MI, and
personality and environmental factors. Age is not found to be related
to cessation in most studies (e.g., Baile et al. 1982; Croog and
Richards 1977; Salonen 1980; Sparrow et al. 1978; Weinblatt et al.
1971). Both of the studies presenting data on sex differences in post-
MI cessation have noted somewhat higher cessation rates among
males; however, sample sizes were small and the differences were
not statistically significant (Baile et al. 1982, Sparrow et al. 1978).
Racial data have not been available for nonwhite populations.
Greater severity of an MI has been associated with higher smoking
cessation rates (Baile et al. 1982, Wilhelmsson et al. 1975). Personali-
ty and environmental factors are complex, and only a few relation-
ships have been explored. For example, neither Baile et al. (1982) nor
Croog and Richards (1977) found associations with any of the
sociodemographic or Health Belief Model variables measured, but
Baile et al. (1982) did identify an environmental factor-being
offered cigarettes by visitors-that influenced resumption of smok-
ing among hospitalized post-MI patients.

The descriptive study by Baile et al. (1982) provided several
suggestions for intervention with post-MI patients-introducing the
intervention prior to hospital discharge and as early in the hospitali-
zation as is feasible, even in the critical care unit, and involving
family members and visitors in the effort to prevent resumption of
smoking. This study was not designed to assess the mechanism by
which relapse was negatively associated with severity of the MI, but
the authors offered several possibilities: the presence of subjective
factors such as specific illness symptoms, general malaise or level of
fear, communications from the medical staff regarding severity of
heart attack, intense and specific advice to quit smoking, or
differential medical treatment that might have affected the patients'
smoking behavior. These factors should be considered in the design

475


of future experimental evaluation of post-MI smoking cessation
interventions.

Moving on from the pa5ent with established cardiovascular
disease to people classified as "at risk," it is found that a number of
large controlled trials of risk reduction have demonstrated that
counseling on individual specific risk factors and exposure to
smoking cessation techniques can be effective. These trials have been
discussed in detail in the 1983 Report of the Surgeon General The
Health Consequences of Smoking (USDHHS 1983). Rose and Hamil-
ton and their cclleagues (Rose 1977; Rose and Hamilton 1978; Rose et
al. 1982) have found higher abstinence levels in a group given
intense advice and education as compared with a control group. The
Multiple Risk Intervention Trial (MRFIT) (Ockene et al. 1982b), with
12,866 high risk men, reported 40 percent abstinence in the special
intervention group and 21 percent in the usual care group. Similar
results were found in Britain (Rose et al. 19801 as part of the WHO
multifactorial trial (WHO European Collaborative Group 1982).
Other smaller scale studies have generally found that high risk men
are susceptible to risk-reduction interventions (Cooper et al. 1982;
Malotte et al. 1981; Powell and Arnold 1982). For the most part,
these studies have been well designed and many have included
objective validation of verbal reports.

The Use of Nicotine Chewing Gum

A pharmacological aid to smoking cessation designed to decrease
the smoker's desire for nicotine and to relieve withdrawal symptoms
has recently become available as a prescription product in the
United States after development in Europe; current information and
research has been summarized (Grabowski and Hall, in press;
Hughes and Miller, unpublished manuscript). The new aid is a
chewing gum containing 2 rng nicotine bound to an ion exchange
resin for controlled release and buffered for rapid absorption
through the buccal mucosa. Compared with the rapid elevation of
blood nicotine levels achieved after smoking a cigarette, peak blood
levels with 2 mg gum are lower and are achieved more slowly
~Russell et al. 1976a; McNabb et al. 1982). Although blood levels may
peak within minutes following smoking, peak levels occur after 20 to
30 minutes of chewing the gum, presumably not reproducing the
pleasure of smoking because of the slower, nonbolus release of
nicotine (Russell et al. 1980). Nicotine chewing gum is indicated as a
temporary aid to the cigarette smoker seeking to give up his or her
smoking habit while participating in a behavioral modification
program under medical supervision. The efficacy of nicotine chewing
gum use without concomitant participation in a behavioral modifica-
tion program has not been established. Thus, nicotine gum could aid

476


in the cessation process by allowing the smoker to break the smoking
habit with abrupt cigarette cessation, while gradually withdrawing
from nicotine. In controlled studies, evidence has been offered that
nicotine gum can relieve withdrawal symptoms (Jarvis et al. 1982;
Schneider and Jarvik 1984; Schneider et al. 1983; Hughes et al. 1984;
West et al. 1984).
According to Hughes and Miller (unpublished manuscript), con-
traindications include recent MIS or life-threatening arrythmias,
severe or worsening angina, or active temporomandibular joint
disease. Nicotine may aggravate coronary heart disease, vasospastic
diseases, hypertension, diabetes, and hyperthyroidism. Because
nicotine is swallowed during use of the gum, people with peptic ulcer
or esophagitis may be particularly at risk. These contraindications
are baaed on known or presumed relationships between nicotine and
these conditions, and not upon direct t.ests of nicotine gum use.
Women who are pregnant or nursing should also avoid gum use
because nicotine decreases fetal breathing movements and is secret-
ed in maternal milk (USDHHS 1980).
Common side effects of use include air swallowing, belching, jaw
ache, sore mouth or throat, upset stomach, hiccups, nausea, and
mouth ulceration (Fagerstrom 1982; Jarvis et al. 1982; Russell et al.
1980; Schneider et al. 1983). Most side effects can be diminished by
proper instruction on mode of chewing. The percentage of subjects
who may become dependent upon gum use is not well known. In two
studies, 3 to 7 percent of all subjects were considered dependent by
the investigators (Jarvis et al. 1982; Raw et al. 1980).
Given that nicotine gum does appear to alleviate withdrawal
symptoms, to what extent has it been efficacious in cessation? Early
studies of cessation were confounded by allowing smokers to
simultaneously smoke and chew the gum (Brantn;ark al al. 1973;
Puska et al. 1979; Russell et al. 1976b). More r?~~::tly, <-ontrolled
clinic-support studies have shown enhancement ;I!' both si:::r+- and
long-term success rates with nicotine gum `Fagerstrom 19h2: Jarvis
et al. 1982; Schneider et al. 1983). Success has be*u attributed t,o an
interaction between the active gum and the support svc+e:ns ir :~ays
not yet understood Schneider et al. (1983) compared .- jc.,:l:nr :md
placebo gum in both dispensary and clinic settings. There was no
effect of active gum in the dispensary setting; subjecte &ewed the
gum for a very short time period and resumed smoking qui.-kly. In
the clinic conditions, the nicotine gum produced significantly higher
success rates than placebo, with a peak difference achieved at 6
months (48 percent versus 20 percent). In other studies with
followups of from 3 to 12 months, cessation rates were higher for
groups receiving active gum than for placebo gum gi-;`ups or groups
receiving other treatments (Fee and Stewart 1982: Hjalmarsor, 19%;
Jarvis 1983; Malcolm et al. 1980; Raw et al. 19riOl. Fagerstrom's


(1982) work suggests t,hat highly nicotine-dependent smokers may be
the best candidates for gum use.

Studies conducted in physicians' offices have produced mixed
results. In a study using over 1,500 patients with smoking-related
diseases attending a hospital or chest clinic, there was no report.ed
superiority of nicotine gum compared with several conditions
involving usual physician advice to quit and a booklet (British
Thoracic Society 1983). Overall, 9.7 percent of patients were absti-
nent at 1 year, but approximately one-fourth of patients claiming
abstinence had carboxyhemoglobin and plasma thiocyanate concen-
trations typical of smokers. This study has been criticized for the
manner in which the gum was administered to the patients (Jarvis
and Russell 1983). On the other hand, Fagerstrom (1983) found
nicotine gum use to be statistically superior to a no-gum condition at
l-year followup in a 13-physician study involving 145 patients.
Similarly, Russell and his colleagues (Russell et al. 1983a,b), in a
well-designed study involving 1,938 general practice patients, ob-
served a difference for the same time period. Success rates in the
nicotine gum plus advice group were about double those in the
nonintervention and advice-only groups (8.8 percent versus 4 percent
not smoking at 4 months and at 1 year). These results are based on
all smokers who saw their physician regardless of desire to quit. The
higher success rate of the group offered the nicotine gum was
achieved even though only 53 percent tried the gum. The self-
selected subgroup who used more than one box of gum (105 pieces)
had an adjusted long-term success rate of 24 percent.

Reasons for the inconsistent results may relate to differences in (1)
instructions on gum use given to the patient, (2) distribution of the
gum (whether it was provided directly to the patient or offered in the
form of a prescription), (3) patient personality characteristics or
motivation for smoking, (4) support or followup in addition to
providing the gum, and (5) sample sizes and duration of followup.
The first four of these factors can all affect compliance, which is
deemed critical for effective use of the gum in physician practice.
Key questions remaining to `be systematically tested relate to what
constitutes optimal gum use, such as dose, frequency, and duration
(Schneider et al. 1983). Future research should resolve the general
usefulness of this pharmacologic treatment as well as the appropri-
ate adjunct treatment strategies.

Discussion and Synthesis
Methodological Considerations

There is marked variation in the methodology and presentation of
results from the studies included in this review, posing problems for
comparison. To begin with, interventions are not always well


specified, making it difficult to categorize or to evaluate any given
technique. This is particularly true in studies in which the interven-
tion consisted of a very brief warning to quit delivered in the
physician's own style. Any accompanying written material is often
only vaguely described. There are, of course, studies in which
interventions are well detailed, such as the MRFIT trial (Ockene et
al. 1982b). In this relatively new area of smoking cessation research,
it is particularly important to researchers to report as much detail as
possible on their intervention and control methods.

In evaluating the success of interventions, standard definitions of
outcome need to be agreed upon. These include total abstinence from
tobacco use, not just cessation of cigarette smoking or reduction in
total amount smoked. If multiple measures are preferred, abstinence
should always be reported. Objective validation of self-report is
critically important, especially when at-risk or patently ill patients
may be biased to report abstinence. Followup periods should
optimally be at least 1 year. When subjects are lost to followup, the
method of calculating success rates should be clearly specified. For
example, the most conservative criterion would dictate classifying as
smokers subjects who refuse measurement. Other problems may
include incomplete data because of nonsurvivors, especially in
medical populations. If results are based only on those successfully
followed, as much information on lost subjects as is possible should
be provided. In retrospective studies, memory bias may also influ-
ence results. Other problems common to smoking cessation research
include inadequate sample sizes, which reduce statistical power; lack
of comparison or control groups; and the failure to select an
appropriate design, such as randomization or a quasi-experimental
model. Design, methodology, and interpretation issues in smoking
research have been treated in other sources in greater detail
(Pederson 1982; USDHEW 1979; USDHHS 1982,1983).

Trends in the Literature

When considering quit rates among the various patient groups
discussed in this review, it is important to keep two considerations in
mind. First, quit rates can vary as a function of the type of
intervention, not only by patient group. For example, the highest
quit rate among controlled pregnancy interventions (Sexton and
Hebel 1984) was found in the study with the largest subject sample
and strongest design, and consisted of a multiple contact interven-
tion. Second, of the four classes of patient considered, persons with
pulmonary and cardiac disease differ qualitatively from general
practice and pregnant patients. The first two categories of patients
have diseases directly related to their smoking behavior; risks and
consequences of continued smoking can be personalized and detailed.
On the other hand, general practice patients may not be coming in

479


for a problem directly related to their smoking. Battista (1983)
reported that antismoking counseling was delivered by 99 percent of
primary care physicians in his survey sample when the reason for
the medical visit was related to smoking, but by only 52 percent
when the medical problem was unrelated and a mere 11 percent
when the visit was for a minor problem. Finally, pregnant patients
seen routinely for prenatal care are usually not ill, and may have
difficulty personalizing the risks to the fetus and to themselves,
especially if they have smoked through previous pregnancies and
borne healthy babies.

Notwithstanding these limitations, some trends are evident in the
literature: the quit rates in recent research appear lower than in
older studies, and a positive association between severity of disease
and quit rate can be noted. There are exceptions to these generaliza-
tions, but the intention in presenting them is to bring some order to
the results.

The series of studies examining quit rates among pulmonary
patients indicate a decrease in success over time, with more recent
studies reporting lower rates. The same general trend appears
among post-MI patient groups when data from groups receiving
treatment in addition to physician advice are excluded. This
apparent decline in effectiveness may be attributable to higher
spontaneous quit rates in the population of smokers. Because more
people are quitting on their own, fewer current smokers and more
ex-smokers are presenting themselves to physicians. Included in the
group of ex-smokers are those who a decade or two ago would have
stopped on the advice of their physician, but who have quit because
of media educational campaigns. Physicians specializing in pulmo-
nary or cardiac disease are then left to deal with the more
recalcitrant, hard-core group. In addition, current patients may be
more honest in reporting failure to quit, and there are measures for
objectively verifying verbal reports (e.g., expired air carbon monox-
ide, car`uoxyhemoglobin, saliva or blood thiocyanate, saliva or bIood
cotinine).

Although there are comparatively few studies with general
practice patients and pregnant women, these two groups show fairly
low abstinence rates. As mentioned above, when attending for
routine visits, these patients are generally healthier than those with
chronic pulmonary disease or cardiac disease. They are also less
likely to be visiting the physician for an illness related to smoking.
When treated with a powerful intervention, however, high cessation
rates (over 40 percent) have been reported (Sexton and Hebel 1984).
The quit rates among patients with pulmonary disease vary from
12.5 to 76 percent. The highest rates are found in studies including
patients who have ever smoked in the past, as well as those who are
smoking at the time of treatment (Daughton et al. 1980; Dudley et al.

480


1977; Mausner 1970). When these studies are excluded, the between-
study rates cluster more closely between 20 and 40 percent. In
general, it appears that patients with MI, especially those receiving
strong advice, are much more likely to quit smoking than are other
patient groups, with 40 to 50 percent abstinence levels being the rule
rather than the exception. This finding matches the most successful
behavioral interventions reported in the general smoking cessation
literature-those programs with strong maintenance as well as
cessation components (USDHHS 1982). The potential effect of
continued smoking on future health status for cardiac patients has
an immediacy that appears to motivate positive action. Six studies
investigating severity of diagnosis (Baile et al. 1982; Campbell et al.
1983; Dudley et al. 1977; Mausner et al. 1970; Sillett et al. 1978;
Wilhelmsson et al. 1975) support this relationship; one does not
(Weinblatt et al. 1971). It is possible that the health benefits of
cessation have been underestimated to date, if the most severely ill
patients are the most likely to quit.

Although this discussion implies a causal relationship between
severity of disease and compliance, other explanations are possible.
Factors such as personality characteristics that are differentially
related to diagnosis and ease of quitting may influence results. In
addition, physician involvement may be much more intense with
patients who have more severe diagnoses and may be causally
related to differential outcome.

Patient Variables Related to Abstinence

There have been a number of attempts to relate variables to
successful quitting among patient groups. The underlying rationale
of these attempts can be conceived as a search for possible causal
factors. Multivariate statistical procedures have been used to
generate predictive models, which may serve as the basis for
theorizing about mechanics involved in explaining why some pa-
tients quit smoking and others do not. The results with respiratory
patients of Dudley et al. (1977) and Pederson and her colleagues
(Pederson et al. 1980, 1982; Pederson and Baskerville 1983) were
described earlier. Examining the psychological and behavioral
variables, the retrospective study of Dudley et al. (1977) identified
good adjustment variables as predictors of success, and the prospec-
tive studies (Pederson et al. 1982; Pederson and Baskerville 1983)
found that prediction of quitting and desire for quitting were
positively associated with success, but addiction was negatively
associated. In the MRFIT program (Ockene et al. 1982a), men at high
risk for CHD who were classified as Continuing Successes (stopped
smoking and maintained abstinence) were characterized as having,
in combination (and in decreasing order of importance), a high
expectation of success, few cigarettes smoked upon entry, low stress,

481


ease of prior cessation attempts, a long period of prior abstinence,
and a high degree of personal security. Together, the combination of
high stress and low psychosocial assets acted as barriers to long-term
smoking cessation, characterizing the "problem smokers" (the
combined group of nonstoppers and recidivists). The congruency of
these findings suggests the need to "develop systematic and conve-
nient ways to collect and use data regarding a participant's
experiences of stress and psychological assets," according to Ockene
et al. (1982a, p. 26). As studies of self-attribution of change related to
positive outcome (self-efficacy) in smoking ceesation have shown
(USDHHS 19821, these and related psychosocial variables may be
critical predictors for all persons attempting smoking cessation.
Thus, this approach should be expanded and tested on other patient
populations.

Physician Variables Related to Effectiveness

Success rates in physician intervention studies have been shown to
vary as a function of the participating physicians as well as of the
interventions they employ (Ewart et al. 1983; Pincherle and Wright
1970; Rose and Hamilton 1978; Russell et al. 1979). While most
smoking cessation studies using behavior modification techniques
attempt to standardize the intervention and to eliminate differ-
ences among those delivering it, physician intervention studies often
involve advice delivered in the doctor's own style and hope to
capitalize on the personal interaction with the patient, e.g., Russell
et al. (1979). As this stage of research it is sometimes difficult to
separate out the various factors contributing to the degree of success
of a particular intervention.

Both types of intervention and physician factors were found to be
important in determining success rates in two studies reported by
Ewart et al. (1983), using two very different patient populations,
asbestos-exposed shipyard workers (n = 871) and low-income women
attending family planning clinics (n=1,179). Physicians saw all
patients only once; assignment to group was random in the shipyard
study and controlled by clinic in the family planning population
(quasi-experimental design). In both studies, the more detailed
advice effort consisted of a physician's warning to stop smoking with
up to 5 minutes of individually focused cessation counseling. The
comparison technique consisted of a simple warning by the physician
(shipyard workers) or viewing an educational film (low-income
women). Cessation rates at 1 year in the detailed advice group were
double those in the comparison group in both studies. Mean quit
rates were not reported, but variability in physician success was
examined. In the shipyard study, success rates were defined as the
proportion of patient,s counseled by the physician who quit smoking

482


within 3 months. Among the four participating physicians, success
rates ranged from 6 to 14 percent at the l-year followup.

Success rates were examined by types of patients assigned to each
physician and by differences in physician behavior. Patient charac-
teristics did not explain the variable rates of success between
different physicians. These included medical symptoms, demograph-
ics, physiological characteristics, and a number of behavioral vari-
ables that have been found to predict smoking cessation (number of
cigarettes smoked daily, motivation to quit, and length of past
nonsmoking periods). On the other hand, physician motivation and
effort in patient counseling emerged as important factors. When
physician success rates were examined as a function of time since the
continuing medical education (CME) training program over a 9-
month period, all physicians were shown to become less effective as
time passed, but two of the four had dramatic drop-offs in effective-
ness. Declining rates of success were associated with lack of
compliance with the protocol by failing to have the patient select a
target date for quitting smoking. (Both patient and physician had
been asked specifically about this in an exit interview. The propor-
tion of patients who reported agreeing on such a target date was
treated as an indirect marker of compliance.) Target date setting in
noncompliant physicians decreased from 23 percent of patients
counseled in the first 3-month period to 3 percent in the final 3-
month period, with a concomitant decrease in success from 15 to 2.0
percent. In comparison, the two more successful physicians set target
dates with 57 and 49 percent of their patients in the first and final 3-
month study periods, and achieved 15 and 9 percent success rates,
respectively. Furthermore, with the passage of time, the two less
compliant physicians altered their pattern of target date setting with
patients, providing such advice to many fewer lighter smokers
(under 20 cigarettes per day) but maintaining the rate of advice with
heavier smokers. The authors interpreted this as a selective shift of
effort, but it can be seen also as a simple diminution of effort with
the former group of patients because the proportion of heavy
smokers advised did not actually increase over time.

In the family planning clinic study, maintenance of physician
performance was influenced by a feedback intervention. Perfor-
mance was monitored by asking patients who had just seen the
physician whether they had been counseled to quit smoking; when
the percentage of patients reporting advice declined, a private
personal communication was made with the physician. For both
physicians involved in this study, the percentage of patients coun-
seled to quit smoking rose after each feedback session. Although
physicians may adequately learn antismoking interventions with
training, these two studies show that their application of such skills
may decline with time and their own modifications of the interven-

483


tions, two sources of variability that are potentially controllable with
regular feedback sessions. Ewart et al. (1983) suggest that experi-
mental designs include collecting continuous time series data that
can be analyzed for individual and group performance trends. Such
analyses will also provide a means of testing the generalizability of
these findings.

Conclusions

Recommendations for Physicians

Patients, particularly those who are not experiencing life and
death decisions in which continuation of smoking is relevant, find it
difficult to comply with their physicians' advice to quit. Griffiths has
observed, however, "Physicians frequently get discouraged with
their rate of success, about one out of five, in helping patients to stop
smoking. They forget, however, that their rate of success in curing
lung cancer is much lower" (Griffiths 1981). As we have seen, a 20
percent cure rate would indeed be high for a truly minimal
intervention. What are some of the actions that the physician who is
interested in preventive action can take to assist his or her patients
to stop smoking?

Some suggestions come from a theoretical formulation known as
the Health Belief Model (Becker 1974, 1976; Becker et al. 1979).
According to the model, the following elements are hypothesized to
determine behavior: the individual's readiness to take action,
determined by perceived susceptibility to the illness and perceived
severity of the consequences of the illness; the individual's evalu-
ation of the feasibility and efficacy of health behavior; the individu-
al's evaluation of barriers to the health behavior; and a cue to action
that triggers the behavior. On several of these elements, patients
who are experiencing respiratory and cardiac problems have much
more clearly defined reasons to be compliant with the request to quit
smoking than patients seen in general practice. Thus, they would be
seen as having stronger health beliefs. Women who are pregnant fall
somewhere in between, depending on just how harmful they perceive
their smoking to be to themselves and the fetus (Dalton et al. 1981).
The clinician may succeed in motivating the members of the latter
two groups by intensifying the message. Support for this position is
found in studies that have compared more intense with less intense
advice (Burt 1974; Ockene et al. 1982b; Raw 1976; Rose 1977).

Other models with a more social learning and social psychological
orientation pose as central concepts the belief in personal control
(Bandura 1973) and the need for relearning to change the condi-
tioned emotional schema that contribute to maintaining smoking
(Leventhal and Cleary 1980). Social support has also been raised as
an important theoretical variable (Ockene et al. 1982a; USDHHS

484


1980). Practical applications of such approaches might be assessing
and bolstering the self-confidence of a patient wishing to quit
smoking and involving a spouse in the cessation effort.
The physician's message must be tempered with other factors,
such as the strength of already existing beliefs and the mechanisms
for continued smoking. Work by Leventhal (1968, 1970) on the
communication of fear messages suggests that such messages may
interfere with adoption of a recommended health-facilitating behav-
ior. For example, he found that smokers are less likely to undergo a
chest X-ray after viewing a filmed lung cancer operation than
smokers who do not view the film, because the experience produces
an increased fear that interferes with the goal of the advice. The
extent of the interference is probably related to the purpose that
smoking serves for the person (whether it is arousal reducing or
habitual).
Physicians should also appreciate the importance of both physio-
logical and personality variables that lead to the initiation and
maintenance of smoking (USDHEW 1979; USDHHS 1982). Likewise,
they should consider both the habitual and the addictive components
of smoking behavior and the consequent difficulty in producing
extinction (APA 1980; NIDA 1979). When these factors are consid-
ered, it is not surprising that a brief warning to a "healthy" patient
is not effective. In this context, "healthy" relates to the lack of
current major symptoms that the smoker relates to smoking.
Physicians do not need to assume full responsibility for helping
patients quit smoking, however. Lichtenstein and Danaher's (1978)
model suggests that the physician can become involved with patients
at a variety of levels, although Wilson et al. (1982) indicate that
continuing contact with the patient can be useful. Chu and Day
(19811, Ewart et al. (1983), and Spencer (1983) have shown that
awareness of smoking and providing antismoking materials for
clinical use can motivate physicians toward increased effort with
smoking patients. Wechsler et al. (1983) found that 81 percent of
primary care physicians surveyed personally provided patient educa-
tion as opposed to having a nurse or other health professional deliver
it. They were more likely to want to learn about a specific area (e.g.,
smoking cessation techniques) in CME classes if they believed in the
importance of changing behavior in that area and had confidence in
their chances of success in helping patients. Thus, physician self-
efficacy is an important concept in delivering smoking cessation
advice. The most valuable types of assistance identified by the
physicians in this study were information on referral sources,
financial reimbursement for health-promotion services and staffing,
literature for distribution to patients, and training for physicians,
support staff, or both. The direct provider role, as well as other roles
for the physician (such as referral to treatment), has been described,


and practical guides that cover the physician's involvement on a
number of levels do exist (Pechacek and Grimm 1983; Shipley and
Orleans 1982). Smoking cessation materials prepared especially for
the physician are available from the National Cancer Institute-the
Helping Smokers Quit Kit--and from the American Cancer Soci-
ety-the Physician's Help Quit Kit. These kits have not yet been
formally evaluated for efficacy.

Future Research

A number of salient issues for future research in the area of
physician intervention emerge from this review. First of all, the
interventions that will work best for physician providers have yet to
be identified. For example, is a minimal intervention like simple
advice to quit the optimal use of a physician's time, or can physicians
successfully integrate a multicomponent or multistage intervention
into their practice and achieve substantially higher quit rates? What
techniques supplementary to physician advice will yield maximum
return in cessation? What are the differential effects of advice alone
and of the offer of treatment on the likelihood of cessation? How does
one improve the communication skills of physicians practicing
health education with patients?

Second, will different interventions work best for different pa-
tients classified according to disease status? Will tailoring treat-
ments according to patient group or to individual patient character-
istics be useful (Best 1975; Best and Steffy 1975; Eiser 1982)? Can the
physician employ a sequential model of smoking behavior (Prochas-
ka and DiClemente 1983) so that interventions can be staged
according to the patient's readiness to quit smoking?

Third, what kind of training in smoking cessation will be most
effective for physicians? Training formats range from noninteractive
materials such as printed matter and audio or video cassettes to
formal programs such as CME classes or other instructor-led
workshops or programs. Should role modeling and direct practice
under supervision be used to help teach skills? What educational (or
other) efforts will be needed to sustain physician counseling efforts
and success?

Fourth, what are the variables controlling differential success
rates among physicians? Are they personal variables, like smoking
status (American Cancer Society 1981; Danaher 1978), or training-
influenced performance factors such as consistency of applied effort
over time (Ewart et al. 1983)? How can physician motivation to
counsel patients be increased and maintained? How can physicians
best be delivered feedback about their counseling performance as
well as the efficacy of their efforts?

Fifth, future research needs to pay closer attention to methodologi-
cal considerations that will facilitate testing hypotheses and evaluat-

486


ing outcomes. These have been summarized earlier and involve
design considerations, assignment of patients to groups, followup of
outcome, and objective verification of self-report.

Sufficient evidence has been presented here to support an effective
role for the physician, as the leading and most credible figure in the
health care world, in smoking cessation efforts. As Cullen and Grit.2
(1983) stated, "The most effective technique to be employed, as well
as when and with what specific group, can await further research.
But given the importance of smoking as the most potent, preventable
pathogen still responsible for a substantial amount of premature
mortality, morbidity, and health care costs, there is no longer an
excuse for physicians to leave this effort solely to other health
professionals" (p. 224).

Summary and Conclusions

1. At least 70 percent of North Americans see a physician once a
year. Thus, an estimated 38 million of the 54 million adults in
the United States who smoke cigarettes could be reached
annually with a smoking cessation message by their physician.
2. Current smoking prevalence among physicians in the United
States is estimated at 10 percent.

3. While the majority of persons who smoke feel that physician
advice to quit or cut down would be influential, there is a
disparity between physicians' and patients' estimates of cessa-
tion counseling, with physician advice being reported by only
approximately 25 percent of current smokers.
4. Studies of routine (minimal) advice to quit smoking delivered
by general practitioners have shown sustained quit rates of
approximately 5 percent. Followup discussions enhance the
effects of physician advice.

5. A median of 20 percent of pregnant women who smoke quit
spontaneously during pregnancy. That proportion can be
doubled by an intervention consisting of health education,
behavioral strategies, and multiple contacts.
6. Large controlled trials of cardiovascular risk reduction have
demonstrated that counseling on individual specific risk fac-
tors, including smoking cessation techniques, can be effective.
7. Studies of pulmonary and cardiac patients indicate that
severity of illness is positively related to increased compliance
in smoking cessation. Survivors of a myocardial infarction have
smoking cessation rates averaging 50 percent.
8. Nicotine chewing gum has been developed as a pharmacologi-
cal aid to smoking cessation, primarily to alleviate withdrawal
symptoms. Cessation studies conducted in offices of physicians
who prescribe the gum have produced mixed results, however,


with outcome depending on motivation and intensity of adjunc-
tive support or followup.

9. Physician-assisted intervention quit rates vary according to the
type of intervention, provider performance, and patient group.
In general, quit rates in recent research appear to be lower
than in older studies.

488


References

ALLAIRE. J.J. How you can help your patients to stop smoking. Medmal Trme; lI1171:
42-47.1983.

AMERICAN CANCER SOCIETY. A Survq, Con~*~r~tng Cigarette Smok[rlg. Health
Check-ups. Cancer Detection Tests. A Summary of the Findings;. Kw York,
American Cancer Society, 1977.

XMERICAN CANCER SOCIETY. The impact of providing phpstcians with quit-
smoking materials for smoking patients CA-A Cancer Journal for Clin~c~nns 31.
7578.1981.

AMERICAN PSYCHIATRIC ASSOCIATION Dra~nostic arzti ,S'tntzstrcnl Jlunual cir`
Mental Disorders. [Third Edition). Washington. D.C.. American Psychiatric Assoc:-
ation, 1980.

BAILE. W.F.. BIGELOW. G.E . GOTTLIEB. S.H.. S'TITZER. M.L , SXCKTOK. J.D.
Rapid resumption of cigarette smoking following myocardial infarction: In\,erse
relationship to myocardial infarction severity Addzctirv Rtehat,i,,rs 7. 373-380.
  1982.

BAKER. T.R., OSCHERWITZ, M.. CORLIN, R., JAKBOE. T.. TEIdCH. J , NICHA-
.tiAN. M.Z. Screening and treatment program for mi;o chronic obstructive
pulmonary disease. Journal of` the Amrr;cun Medrcai .~.wn.i:~/~on 2141Pl. 1441;
1455, November 23,197O.

BALL, K.. TURNER, R. Smokmq and the heart: The basis for act:on I.cznctn: 2178841:
822-826. October 5.1974.

BANDURA, A. The self-efficacy: Toward a unifying theor? of `behavior change.
Psyhologtcal Reuiecti 84: 191-215,1973.

BARIC. L., MACARTHUR. I:, SHERWOOD. M. A study of health education aspects of
smoking in   pregnancy  International *Jourrmi of Hculth   Educa tmn
19t2'Supplement). 1-17. AprilJune, 1976.
BA'ITISTA, R.N. Adult cancer prevention In prunary care Patterns of practice in
Quebec. .4mericarl Journalof Publw Health 73(91. 1036-lf139. 1983.
BA'ITISTA, R.N, SPITZER. W.O. Adult cancer prevention in primary care: Contrasts
among primary care practice settings in Quebec. Amertcan Journal of Publtc
Health 73(g): 1046-1041, 1983.

BAUMAN, K.E., BRYAN, ES., DENT, C.W., KOCH, G G. The influence of observing
carbon monoxide level on cigarette smoking by public prenatal patients. American
.Journal OfPublicHealth 73(91.1089-1091, September 1989.
BECKER, M.H. The health belief model and sick role behavior. Health Education
Monogra@ 2(4t: 409-419, Winter 1974.

BECKER, M.H. Sociobehavioral determinants of comphance. In: Sackett, D.L..
Haynes, R.B. !Editors). Compliance With Therapeutic Regimens. Baltimore, Johns
Hopkins University Press, 1976, pp. 40-50.
BECKER, M.H., MAIMAN, L.A., KIRSCHT, J.P., HAEFXER. D.P., DRACHMAN.
R.H., TAYLOR, D.W. Patient perceptions and compliance: Recent studies of the
Health Belief Model. In: Taylor, D.W.. Sackett, D.L. (EditorsI. Compliance in
Health Care Baltimore, Johns Hopkins University Press. 1979, pp. 78109.
BEST, J.A. Tailoring smoking withdrawal procedures to personality and motivational
differences. Journal of Consulting arzd C`llnicai Pyvcho/ogT 43(11: l-8, February
  1975.

BEST, J.A. Stopping smoking by tinding alternatives. Continurng Education for the
Familv Physician 9(l): 36-37,41,44-45, July 1978.
BEST, J.A., STEFFY, R.A. Smoking modification procedures for internal and external
locus of control clients. Canadian Journal of Rehacwrcl Aience 7121, 155-165.
April 1975.

BOHM. E., POWELL, D.R. A ten point practical program to help your smokers quit
Your Patient and Cancer. November 1982. pp l-9.

489


BRANTMARK, B.. OHLIN, P., WESTLING, H. Nicotine-containing chewing gum as
an antismoking aid. Psychopharmacologia 31: 191-2061973.
BRITISH THORACIC SOCIETY. Comparison of four methods of smoking withdrawal
in patients with smoking related diseases British Medical Journal 286(6366): 595
597. February 19,1983.

BROOK, R.H., WARE, J.E., Jr., ROBERS, W.H., KEELER, E.B., DAVIES, A.R.,
DONALD, C.A., GOLDBERG, G.A.. LOHR, K.N., MASTHAY, PC., NEWHOUSE,
J.P. Does free care improve adults' health? New England Journal of Medicine
309(23): 14261434,1983.

BUIST, A.S., NAGY, J.M., SEXTON, G.J. The effect of smoking cessation on
pulmonary function: A 30-month follow-up of two smoking cessation clinics.
American Review of Respiratory Disease 120: 953957,1979.
BUIST, A.S., SEXTON, G.J., NAGY, J.M., ROSS, B.B. The effect of smoking cessation
and modification on lung function. American Review of Respiratory Disease 114(l):
115-122, July 1976.

BURLING. T.A., BIGELOW, G.E., BAILE, W.F., GO'ITLIEB, S.H. Smoking Cessation
Following Acute Myocardial Infarction. Paper presented at the meeting of the
Association for the Advancement of Behavior Therapy, Los Angeles, 1982.
BURLING, T.A., SINGLETON, E.G., BIGELOW, G.E., BAILE, W.F., GO'ITLIEB, S.H.
Smoking following myocardial infarction: A critical review of the literature.
Health Psychology 3(l): 83-96,1984

BURNS, B.H. Chronic chest disease, personality and success in stopping cigarette
smoking. British Journal of Preventive and Social Medicine 23(l): 23-27, February
  1969.

BURNUM. J.F. Outlook for treating patients with self-destructive habits. Annals of
Internal Medicine 81(3): 387-393, September 1974.
BURT, A.. THORNLEY, P., ILLINGWQRTH, D., WHITE, P., SHAW, T.R.D.,
TURNER, R. Stopping smoking after myocardial infarction. Lancet l(7852): 304-
366, February 23,1974.

CAMPBELL, I.A. Predictive Factors for Smoking Withdrawal in Patients. Paper
presented at the Fifth World Conference on Smoking and Health, Winnipeg,
Canada, July 1983.

CHECK, W.A. Doctors, let's stop dragging (our feet). Journal of the American Medical
Association 242(26): 283-282, December 1979.
CHU, F.Z., DAY, R.G. Smoking recognition by family physicians.  Journal of
Family Practice 12(4): 657660, April 1981.
COOPER, R., SOLTERO, I., STAMLER, J., MOJONNIER, L., HALL, Y., MOSS, D.,
BERKSON, D.M., TOKICH, T. Smoking cessation in the Chicago Coronary
Prevention Evaluation Program. Journal of the National Medical Association
74(4): 349355, April 1982.

COOPERSTOCK, R., THOM, B. Health, smoking and doctors' advice. Journal of the
Royal College of Geneml Practitioners 32(236): 174-178, March 1982.
CROOG, S.H., RICHARDS, N.P. Health beliefs and smoking patterns in heart patients
and their wives: A longitudinal study. American Journal of Public Health 67flO):
921-930, October 1977.

CULLEN, J.W., GRITZ, E.R. Behavior modification for cancer prevention. In: Newell,
G.R. (Editor). Cancer Prevention zn Clinical Medicine. New York, Raven Press,
1983, pp. 209-229.

DALTON, E.R., HUGHES, C.A., COGSWELL, J.J. Cigarette smoking in pregnancy: A
health education problem. Public Health (London) 95: 207-214,198l.
DANAHER, B.G. OB-GYN intervention in helping smokers quit. In: Schwartz, J.L.
(Editor). Progress in Smoking Cessation. International Conference on Smoking
Cessation, June 21-23, 1978. New York, American Cancer Society, 1978, pp. 316
  328.

490


DANAHER, B.G., ELLIS, B.H., FARQUHAR, J.W. How to help smokers who want to
quit. Patient Care 14(14): 86-121, August 15, 1980.
DANAHER, B.G., SHISSLAK, C.M., THOMPSON, C.B., FORD, J.D. A smoking
cessation program for pregnant women: An exploratory study. American Journal
of Public Health 68t9): 896-898, September 1978.
DAUGHTON, D.M., FIX, A.J., KASS, I., PATIL, K.D. Smoking cessation among
patients with chronic obstructive pulmonary disease (COPD). Addictive BehaLliors
5(2): 125-128, 1980.

DAVISON, G., DUFFY, M. Smoking habits of long-term survivors of surgery for lung
cancer. Thorax 37(5): 331-333, May 1982.

DENSON, R., NANSON, J.L., McWA'ITERS, M.D. Hyperkinesis and maternal
smoking. Canadian Psychiatric Association Journal 2Of3): 181-187. April 1975.
DONOVAN, J.W. Randomized controlled trial of anti-smoking advice in pregnancy.
British Journal of Preventive and Social Medicine 31: 6-12, 1977.
DONOVAN, J.W., BURGESS, P.L., HOSSACK, CM., YUDKIN, G.D. Routine advice
against smoking in pregnancy. Journal of the Royal College of General Practition-
ers 25: 264-268.1975.

DUDLEY, P.L., AICKIN, M., MARTIN, C.J. Cigarette smoking in a chest clinic
population: Psychophysiologic variables. Journal of Psychosomatic Research 21:
367-375,1977.

EISER, J.R. Addiction as attribution: Cognitive processes in giving up smoking. In:
Eiser, J.R. (Editor). Social Psychology and Behavioml Mediczne New York, John
Wiley and Sons, 1982, pp. 281-299.

ENSTROM, J.R. Trends in mortality among California physicians after giving up
smoking: 1950-79. British Medical Journal 286: llOl-1105.1983.
EWART, C.K., LI, V.C., COATES, T.J. Increasing physicians' antismoking influence
by applying an inexpensive feedback technique. Journal of Medical Education
5&6): 468-473, June 1983.

FAGERSTRGM, K.-O. A comparison of psychological and pharmacological treatment
in smoking cessation. Journal of Behavioml Medicine 5(3): 343-351, September
  1982.

FAGERSTRGM, K.-O. Effects of Nicotine Chewing Gum and Follow-up Appointments
in Physician-Based Smoking Cessation. Paper presented at the Fifth World
Conference on Smoking and Health, Winnipeg, Canada, July 1983.
FEE, W.M., STEWART, M.J. A controlled trial of nicotine chewing gum in a smoking
withdrawal clinic. Pmctitioncr226(1363): 148-151, January 1982.
FIELDING, J.E., YANKAUER, A. The pregnant smoker. American Journal of Publzc
Health 68f9): 835-836, September 1978.

FLETCHER, C., DOLL, R. A survey of doctors' attitudes to smoking. British Journal
of Preventive and Social Medicine 23: 145153,1969.
FOWLER, G. Smoking. In: Gray, M., Fowler, G.H. (Editors). Preventive Medicine in
General Practice. Oxford, Oxford University Press, 1983, pp. 133-148.
FOWLER, G., JAMROZIK, K. The "Beliefs" and "Activities" of G.P.`s and Health
Visitors About Anti-smoking Education. Paper presented at the Fifth World
Conference on Smoking and Health, Winnipeg, Canada, July 1983.
FRIED, P.A., WATKINSON, B., GRANT, A., KNIGHTS, R.M. Changing patterns of
soft drug use prior to and during pregnancy: A prospective study. Drug and
Alcohol Dependence 6(5): 323-343, November 1980.
GARFINKEL, L. Cigarette smoking among physicians and other health professionals,
1959-1972. CA-A Cancer Journal for Clinicians 26(6): 373375, November-Decem-
  ber 1976.

GASTRIN, G. Smoke-Free Pregnancy: Smoking Cessation as an Integral Part of
Prenatal Health Care. Paper presented at the Fifth World Conference on Smoking
and Health, Winnipeg, Canada, July 1983.

491


(;RABOWSKI, c!, HALL. s IEditors I'hum~acdogcc Adjuncb in the Treatment ,,f
T:J/x~,co fipenrlrnce NIDA Research Monograph U.S. Government Printing
Office, in press.

GREEN, D E.. HORN, D. Physician's attitude toward their involvement in smoking
problems of patient.s. Diseases of the Chest 54i3): 180-181, September 1968.
GRIFFITHS. W Can human behavior be modified" Cancer 47lSupplement, 5): 1221-
1225. March 1,1981.

GUZMAN, C. Quit smoking rate in the Ottawa out-patient rehabilitation programme
for patients with chronic lung disease. (Personal communication. 1978).
HACKETf, D.R. Smoking habits during pregnancy. Irish Medical Journal 72(11):
483486, November 30,1979.

HALHUBER, C. Stop smoking training in patients with coronary heart disease. In:
Hauss. W.H., Wissler, R.W., Iehmann. R. (Editors). International Symposium:
State of Pretlention and Therapy in Human Arteriosclerosis. Opladen, Westdeutsch-
er Verlag, 1978, pp. 493498.

HALL, SM., BACHMAN. J., HENDERSON, J.B., BARSTOW, R., JONES, R.T.
Smoking cessation in patients with cardiopulmonary disease: An initial study.
Addictive Behaviors 811 I: 3342, 198.3.

HAMMOND, E.C. Evidence on the effects of giving up cigarette smoking. American
Journal of Public Health 55(5): 682-691, May 1965.
HAMMOND, E.C. Smoking in relation to the death rates of one million men and
women. In: Haenszel. W. iEditor). Epidemiological Approaches to the Study of
Cancer and Other Chronzc Diseases. National Cancer Institute Monograph 19. U.S.
Department of Health, Education, and Welfare, Public Health Service, National
Cancer Institute, January 1966, pp. 127-204.
HANDEL, S. Change in smoking habits in a general practice. Post Graduate Medical
Journal 49: 679681, October 1973.

HARRIS, J.E. Smoking During Pregnancy: PreIiminav Results From the National
Clearinghouse on Smoking and Health: 1975 Prevalence Data. September 1979.
HAY, D.R., TURBOTI, S Changes in smoking habits in men under 65 years after
myocardial infarction and coronary insufficiency. British Heart Journal 32: 738
740,197o.

HICKEY, N., MULCAHY. R., DALY, I;., GRAHAM, I, O'DONOGHUE. S., KENNE
DY, C. Cigar and pipe smoking related to four year survival of coronary patients.
British Heart Journal 49(5): 423-426,1983.
HJALMARSON, AIM. The Effect of Nicotine Chewing Gum in Smoking Cessation: A
Randomized. Placebo-Controlled, Double-Blind Study. Paper presented at the Fifth
World Conference on Smoking and Health, Winnipeg, Canada, July 1983.
HOCHBAUM. GM. Fear is not enough. American Lung Association Bulletin 61(5):
13-16. June 1975.

HUBERT. H.B., HOLFORD. T.R., KANNEL, W.B. Clinical characteristics and
cigarette smoking in relation to prognosis of angina pectoris in Framingham.
Amerrcan Journal of Eptdemtology 115(2): 231-242, February 1982.
HUGHES, J.R.. EPSTEIN, L.F., ANDRASIK, F., NEFF, D.F., THOMPSON, D.S.
Smoking and carbon monoxide levels during pregnancy. Addtctive Behaviors
7:271-276. 1982.

HUGHES, J.R., HATSUKAMI, D.K.. PICKENS, R.W., KRAHN, D., MALIN, S.,
LUKNIC, A. Effect of nicotine gum on the tobacco withdrawal syndrome.
Psychopharmacologia 83(l): 82-87, April 1984.
HUGHES, J.R., MILLER, S.A. Nicotine Gum as an Aid to Smoking Cessation.
Unpublished manuscript.

HYMOWITZ. N. The practicing physician and smoking cessation. Journal of the
Medtcal Soczety ofhieu Jersey 74(2): 139-141, February 1977.
INDYKE, D., ELLIS, B.H. There's a leading role for physicians in helping smokers to
quit. American Lung Association Bulletin 66(2): 2-6, March 1980.

492


JARVIS, M. The Use of Nicotine Chewing Gum in a Smokers' Clinic. Paper presented
at the Fifth World Conference on Smoking and Health, Winnipeg, Canada, July
  1983.

JARVIS, M.J., RAW, M., RUSSELL, M.A.H., FEYERABEND, C. Randomised
controlled trial of nicotine chewing gum. British Medical Journal 28516341): 537-
540. August 21,1982.

JARVIS, M.J., RUSSELL, M.A.H. Smoking withdrawal in patients with smoking
related diseases. (Letter). British Medical ,Journal 286(6369): 976977. March 19,
  1983.

KING, J., EISER, J.R. A strategy for counselling pregnant smokers. Health Education
Journal 4(3): 66-68, 1981.

KIRK, C.J.C., LUND, V.J., WOOLCOCK, N.E., GREENHALGH, R.M. The effect of
advice to stop smoking on arterial disease patients, assessed by serum thiocyanate
levels. Journal of Cardiovascular Surgeq 21(5): 568-569, September-October 1980
KOHN. R., WHITE, K.L. (Editorsi. Heulth Care: An International Studv. Report of the
World Health Organization/International Collaborative Study of Medical Care
Utilization. London, Oxford University Press, 1976,557 pp.
KORNFELD, D.S., HELLER, S.S., FRANK, K.A., WILSON, S.N., MALM, J.R.
Psychological and behavioral responses after coronary artery bypass surgery.
Circulation 66(5, Part II): 111-24-11-28, November 1982
KRETZSCHMAR, R.M. Smoking and health: The role of the obstetrician and
gynecologist. Obstetrics and Gynecology %X41: 40%06. April 1980.
KULLER, L., MEILAHN, E., TOWNSEND, M.. WEINBERG, G. Control of cigarette
smoking from a medical perspective. In: Breslow, L., Fielding, J.E., Lave, L.B.
IEditors). Annual Review of Public Health, Volume 3. Palo Alto, Annual Reviews
Inc., 1982, pp. 153-178.

LANDESMAN-DWYER, S., EMANUEL, I. Smoking during pregnancy. Teratology
19(l): 119-125, February 1979.

LEVENTHAL, H. Experimental studies of anti-smoking communications. In: Borgat-
ta, E.F., Evans, R.R. (Editors). Smoking, Health and Behauior. Chicago, Aldine
Publishing Company, 1968, pp. 95-121.

LEVENTHAL, H. Findings and theory in the study of fear communications. Advances
in Experimental Social Psychology 5: 12&181,1970.
LEVENTHAL, H., CLEARY, P.D. The smoking problem: A review of the research and
theory in behavioral risk modification. Psychological Bulletin 88(2): 370-405, 1980.
LICHTENSTEIN, E., DANAHER, B.G. What can the physician do to assist the patient
to stop smoking? In: Brashear, R.E., Rhoades, M.L. (Editors). Chronic Obstructiue
Lung Disease: Clinical Treatment and Management. St. Louis, Mosby, 1978, pp.
  227-241.

LLOYD, G.G., CAWLEY, R.H. Smoking habits after myocardial infarction. Journal of
the Royal College of Physicians of London 14(41: 224-226, October, 1980.
LUBAN-PLOZZA, B. The treatment of smoking from the point of view of a general
clinic. In: Steinfeld, J., Griffiths, W., Ball, K., Taylor, R.M. (Editors). Health
Consequences, Education, Cessation Activities, and Governmental Action. Proceed-
ings of the Third World Conference on Smoking and Health, New York, June 2-5,
1975. Volume 2. U.S. Department of Health, Education, and Welfare, Public
Health Service, National Institutes of Health, National Cancer Institute, DHEW
Publication No. (NIH)77-1413,1977, pp. 683-687.
MALCOLM, R.E., SILLETI', R.W., TURNER, J.A.M., BALL, K.P. The use of nicotine
chewing gum as an aid to stopping smoking. Psychopharmacology 7W31: 295-296,
  1980.

MALLAGHAN, M., PEMBERTON, J. Some behavioral changes in 493 patients after
an acute myocardial infarction. British Journal of Preventive and Social Medicine
31(2): 86-90, June 1977.

493


MALO'ITE. C.K., FIELDING, J.E., DANAHER. BG Description and evaluation ofthe
smoking cessation component of a multiple risk factor intervention program.
Amerwan Journal of Public Health 71(a): 844-847, August 1981.
MAUSNER, J.S. Cigarette smoking among patients with respiratory disease. Amen.
can Revieu,of Respiratory Disease 102(5): 704-713, November 1970.
MAUSNER. J.S. MAUSNER, B.. RIAL, W.Y. The influence of a physician on the
smoking behavior of his patients. American Journal of Public Health 58(l): 46-53,
January 1968.

MAYOU, R., FOSTER, A., WILLIAMSON, B. Psychosocial adjustment in patients one
year after myocardial infarction. Journal of Psychosomatic Research 22(5): 447-
453,1978.

McNABB, M.E., EBERT, R.V., McCUSKER, K. Plasma nicotine levels produced by
chewing nicotine gum. Journal of the American Medical Association 248(7): 865-
868, August 20,1982.

MEYER, A.J., HENDERSON, J.B. Multiple risk factor reduction in the prevention of
cardiovascular disease. Preoentive Medicine 3(2): 225-236, June 1974.
MULCAHY, R., HICKEY, N., GRAHAM, I.M., MacAIRT, J. Factors affecting the 5
year survival rate of men following acute coronary heart disease. American Heart
Journal 93(5): 556559, May 1977.

MULCAHY, R., HICKEY, N., GRAHAM, I.M., MCKENZIE, G. Factors influencing
long-term prognosis in male patients surviving a first coronary attack. British
Heart Journal 37(2): 158-165 February, 1975.
NATIONAL CENTER FOR HEALTH SERVICES RESEARCH, 1983. National Health
Care Expenditures Study-Data Preuiew. DHHS Publication No. (PHS)8%3361.
NATIONAL CENTER FOR HEALTH STATISTICS. Current Estimates From the
National Health Zntervieu Survey: United States, 1981. Vital and Health Statistics,
Series 10, No. 141, DHHS Publication No. :PHS)82-1569, October 1982. 106 pp.
NATIONAL INSTITUTE ON DRUG ABUSE. Cigarette Smoking as a Dependence
Process. Krasnegor, N.A. (Editor). NIDA Research Monograph 23. Department of
Health, Education, and Welfare. DHEW Publication No. (ADMl79-800, January
  1979.

OCKENE, J.K., BENFARI. R.C., NU'ITALL, R.L., HURWITZ, I., OCKENE, J.S.
Relationship of psychosocial factors to smoking behavior change in an intervention
program. Prevention Medicine 11(l): 13-28, January 1982a.
OCKENE, J.K., HYMOWITZ, N., SEXTON, M., BROSTE, S.K. Comparison of
patterns of smoking behavior change among smokers in the Multiple Risk Factor
Intervention Trial (MRFIT). Preventive Medicine ll(6): 621-638, November 1982b.
PACIFIC MUTUAL LIFE INSURANCE COMPANY. News Information Pacific
Mutual Life Insurance Company, November 1978.
PEABODY, H.D., Jr. A practical approach to the office management of cessation of
cigarette smoking. In: Richardson, R.G. Editor.1 The Second World Conference on
Smoking and Health. The proceedings of a conference organized by the Health
Education Council, Imperial College, London, September 20-24, 1971. London,
Pitman Medical, 1972, pp. 185189.

PECHACEK, T.F., GRIMM, R.H.. Jr. Cigarette smoking and the prevention of
coronary heart disease. In: Podell. R., Stewart, M. (Editors). Primary Prevention of
Coronary Heart Disease: A Practical Guide for the Clinician. Menlo Park,
California: Addison-Wesley, 1983, pp. 34-77.
PECHACEK, T.F., McALISTER, A.L. Strategies for the modification of smoking
behavior: Treatment and prevention. In: Ferguson, J.M., Taylor, C.B. (Editors).
Extended Applications and Issues. The Comprehensive Handbook of Behavioral
Medicine, Volume 3, Jamaica, New York, Spectrum Publications, 1980, pp. 257-
  298.

PEDERSON, L.L. Compliance with physician advice to quit smoking: A review of the
literature. Preventive Medicine 1 l(1): 71-84, January 1982.

494


PEDERSON. L.L.. BASKERVILLE, J.C. Multivariate prediction of smoking cessation
following physician advice to quit smoking: A validation study. Prerlentiue
Medicine 12c3): 439-436, May 1983.

PEDERSON, L.L., BASKERVILLE, J.C.. WANKLIN, JM Multivariate statistical
models for predicting change in smoking behavior following physician advice to
quit smoking. Preventive Medicine lli5): 536-549, September 1982.
PEDERSON, L.L., WILLIAMS, J.I.. LEFCOE, N.M. Smoking cessation among
pulmonary patients as related to type of respiratory disease and demographic
variables. Canadian Journal of Public Health 71(3): 191-194. MayJune, 1980.
PENTECOST, B.L., Preventing the second infarct. Journal of the Royal College of
Physicians of London 14(l): 22-25, January 1980.
PETERSON, D.I., LONERGAN, L.H.. HARDINGE, M.G. Smoking and pulmonary
function. Archives of Environmental Health l&2): 215-218, February 1968.
PINCHERLE, G., WRIGHT, H.B. Smoking habits of business executives: Doctor
variation in reducing cigarette consumption. Pract<tioner 205(12261: 209-212,
August 1970.

POMERLEAU, 0. You can get patients to change their habits. Medical Times 104110):
149-158, October 1976.

PORTER, A.M.W., McCULLOUGH. D.M. Counselling against cigarette smoking. A
controlled study from a general practice. Practitioner 209(12531: 686-689, Novem-
ber 1972.

POWELL, D.R., ARNOLD, C.B. Antismoking program for coronary prone men. An
evaluation study. New York State Journal of Medicine 82~101: 14351438, Septem-
ber 1982.

PROCHASKA, J.O., DiCLEMENTE, CC. Stages and processes of self-change of
smoking: Toward an integrative model of change. Journal of Consulting and
Clinical Psychology 51(3): 390-395, June 1983.
PUSKA, P., BJORKQVIST, S., KOSKELA, K. Nicotinecontaining chewing gum in
smoking cessation: A double blind trial with half year follow-up. Addictive
Behauiors 42): 141-146,1979.

RAHE, R.H., WARD, H.W., HAYES, V. Brief group therapy in myocardial infarction
rehabilitation: Three-tofour-year follow up of a controlled trial. Psychosomatic
Medicine 41(3): 229-242, May 1979.

RAW, M. Persuading people to stop smoking. Behavior Research and Therapy 14(2):
97-101.1976.

RAW, M., JARVIS, M.J., FEYERABEND, C., RUSSELL, M.A.H. Comparison of
nicotine chewing-gum and psychological treatments for dependent smokers.
British Medical Journal 281(6238): 481-482, August, 16 1980.

RICHMOND, H.W. A fifteen-year prospective study of the incidence of coronary heart
disease related to cigarette smoking habits in Cummins Engine Company
management personnel with results of a vigorous anti-smoking education cam-
paign. In: Steinfeld, J., Griffith, W., Ball, K.. Taylor, R.M. (Editors). Health
Consequences, Education, Cessation Activities, and Governmental Action. Proceed-
ings of the Third World Conference on Smoking and Health, New York, June 2-5,
1975, Volume 2. U.S. Department of Health, Education, and Welfare, Public
Health Service, National Institutes of Health, National Cancer Institute, DHEW
Publication No. (NIH)77-1413,1977, pp. 275-281.

RONAN, G., RUANE, P., GRAHAM, I.M., HICKEY. N., MULCAHY. R. The
reliability of smoking history amongst survivors of myocardial infarction. British
Journal ofAddiction 76(4): 425428. December 1981.
ROSE, G. Smoking cessation in high-risk subjects Health Magazine 1214): 19-22,
Winter 19751976.

495


ROSE. C;. Physician counseling and personal intervention. In: Steinfeld, J.. Griffith,
W Ha!]. K . Taylor, R.M. tEditorsi. Health Consequences, Educatton. Cessation
Actrt r!it.s. and &r~er~rmenta/ ilctcon. Proceedings of the Third World Conference
on Smoking and Heaith, New York, June 2-5, 1975, Volume 2. U.S. Department of
Heaith. Education. and Welfare, Public Health Service, National Institutes of
Hraith. National Cancer Institute. DHEW Publication No. (NIH)77-1413, 1977. pp.
  515.i2.3.

ROSE, G.. HAMILTON. P J.S. A randomized controlled trial of the effect on middle-
aged men of advice to stop smoking. .Iournal of Epidemiology and Community
Health 32(4): 27,5281, December 1978.

ROSE, G., HAMILTON, P.J.S., COLWELL, L.. SHIPLEY, M.J. A randomised
controlled trial of anti-smoking advice: lo-year results. Journal of Epidemiology
and Communttv Health 36(2): 102-108, June 1982.
ROSE, G., HELLER. R.F., PEDOE, H.T., CHRISTIE, D.G.S. Heart disease prevention:
A randomised controlled trial in industry. British Medical Journal 2%X6216): 747-
751, March 15.1980.

ROSE, G.. UDECHUKU. J.C. Cigarette smoking by hospital patients. British Journal
ofl'retlentzce and Social Medzclne 25(3): 160-161, August 1971.
ROSEN, C.. ASHLEY, M.J. Smoking and the health professional: Recognition and
performance of roles. Canadran Journal of Public Health 69(5): 399406. Septem-
ber-October 1978.

ROSSER. W.W. Helping patients to stop smoking. The current situation. Canadian
Family Phvsrctan 23: 101-105, 1977.

ROSSER. W.W. Ways of helping patients to stop smoking. Canadian Family Phv.sician
25: 92%926, August 1979.

RUSSELL, M.A.H. Cigarette dependence: II. Doctor's role in management. British
Medical Journal 2(5758139%395, May 15.1971.
RUSSELL, M.A.H., FEYERABEND, C.. COLE, P.V. Plasma nicotine levels after
cigarette smoking and chewing nicotine gum. British Medical Journal 1: 1043-
1046,1976a.

RUSSELL, M.A.H.. MERRIMAN, R., EDWARDS, A.R. Minimal Anti-Smoking
Knter~~ention b.v Phvsrrians and its Enhancement by Ntcotine Cheuling Gum. Paper
presented at the Fifth World Conference on Smoking and Health, Winnipeg.
Canada, <July 1983a.

RUSSELL, M.A.H.. MERRIMAN. R., STAPLETON, J., TAYLOR, W. Effect of nicotine
chewing gum as an adjunct to general practitioners' advice against smoking
British Medical Journal 287(6407): 1782-1785, December 10,1983b.
RUSSELL, M.A.H.. RAW. M., JARVIS, M.J. Clinical use of nicotine chewing-gum.
Brutish Medtcal ~Journal280(6231): 1599-1602, June 28,198O.
RUSSELL, M.A.H., WILSON, C., FEYERABEND, C., COLE, P.V. Effect of nicotine
chewing gum on smoking behaviour and as an aid to cigarette withdrawal. British
Medical Journal 216032): 391-393, August 14, 1976b.
RUSSELL, M.A.H., WILSON, C., TAYLOR. C., BAKER, C.D. Effect of general
practitioners' advice against smoking. Britzsh Medical Journal 2(61841: 231-235,
July 28. 1979.

RUSSELL, AM.A.H., WILSON, C.. TAYLOR, C., BAKER, C.D. Smoking prevalence
among general practitioners' patients. British Journal of Addicttons 75X41: 367-
373, July 5, 1980.

SACHS, D.P L. Smoking habits of pulmonary physicians. (Letter). New England
+Journai ofhfedtctne 309113): 799,1983.

SALONEN. J.T. Stopping smoking and long-term mortality after acute myocardial
infarction. Brttlsh Heart Journal 43: 46-69, 1980.
SCHNEIDER, N G.. JARVIK, M.E `Time course of smoking withdrawal symptoms as
a function of nicotine replacement. Psychopharmacology 82: 143-144,1984.

496


SCHNEIDER, N.G., JARVIK, M.E.. FORSYTHE, A.B., READ, L.L., ELLIOTT. M.L..
SCHWEIGER, A. Nicotine gum in smoking cessation: A placebocontrolled. double-
blind trial. Addictive Behaviors 8: 253-261, 1983.
SCHUMAN, L.M. The benefits of cessation of smoking. Chest 59(41: 421427. .4pril
  1971.
SECKER-WALKER, R.H., FLYNN, B.S. Importance of smoking cessation counseling.
Continuing Education for the Family Physician 18(5i: 449-453, May 1983.
SEXTON, M., HEBEL. R. A clinical trial of change in maternal smoking and its effect
on birth weight. Journal of the American Medical Association 251t71: 911-915,
  1984.
SHERIN, K. Smoking cessation: The physician's role. Postgraduate Medzcine 72~31:
99-106 September 1982.
SHIPLEY, R.H., ORLEANS, C.S. Treatment of cigarette smoking. In: Boudewyns. P.
A., Keefe, F. J. (Editors.) Behavioral Medicine in General Medical Practice. Menlo
Park, California, Addison-Wesley, 1982, pp. 23%268.
SILLETT, R.W., WILSON, M.B., MALCOLM, R.E., BALL, K.P. Deception among
smokers. British Medical Journal 2t6146): 1185-1186, October 28,1978.
SIVARAJAN, E.S., NEWTON, K.M., ALMES, M.J., KEMPF, T.M.. MANSFIELD,
L.W., BRUCE, R.A. The patient after myocardial infarction. Limited effects of
outpatient teaching and counseling after myocardial infarction: A controlled
study. Heart and Lung 12( 1): 6573 January 1983.
SPARROW, D., DAWBER, T.R., COLTON, T. The influence of cigarette smoking on
prognosis after a first myocardial infarction: A report from the Framingham
Study. Journal of Chronic Diseases 31(6/7): 42u32.1978.
SPENCER, J. General Practitioners' Views of the "Give Up Smoking" /GUS) Kit.
London, The City and Hackney Health District, Health Education Service, 1983.
STEWART, A.L., BROOK, R.H., KANE, R.L. Smoking. Conceptualization and
Measurement of Health Habits for Adults in the Health Insurance Study, Volume
1. Rand Publication Series R-2374/l-HEW. Santa Monica, Rand Corporation, 1979.
STEWART, P.J., ROSSER, W.W. The impact of routine advice on smoking cessation
from family physicians. Canadian Medical Association Journal 126(g): 1051-1054,
May 1,1982.
TRAHAIR, R.C.S. Giving up cigarettes: 222 case studies. Medical Journal of Australia
1: 929-932, May 6,1967.
U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES. The Health Conse-
quence of Smoking for Women: A Report of the Surgeon General. U.S. Department
of Health and Human Services, Public Health Service, Office of the Assistant
Secretary for Health, Office on Smoking and Health, 1980,385 pp.
U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES. The Health Conse-
quences of Smoking: The Changing Cigarette. A Report of the Surgeon General. U.S.
Department of Health and Human Services, Public Health Service, Office of the
Assistant Secretary for Health, Office on Smoking and Health, DHHS Publication
No. (PHS)&50156,1981,269 pp.
U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES. The Health Conse-
quences of Smoking: Cancer. A Report of the Surgeon General. U.S. Department of
Health and Human Services, Public Health Service, Office on Smoking and
Health, DHHS Publication No. (PHS)82-50179, 1982, 341 pp.
U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES. The Health Conse-
quences of Smoking. Cardiovascular Disease: A Report of the Surgeon General. U.S.
Department of Health and Human Services. Public Health Service, Office on
Smoking and Health. DHHS Publication No. (PHS%4-50204.1983,378 pp.
U.S. DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE. Sur~`q\ OfHealth
Professionals. 1975. U.S. Department of Health, Education, and Welfare. Public
Health Service, Office on Smoking and Health, National Clearinghouse for
Smoking and Health, Publication No. CDC 21.74-55ZP1, June 1976.


U.S. DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE. Smoking and
Health. A Report of the Surgeon General. U.S. Department of Health, Education,
and Welfare, Public Health Service, Office of the Assistant Secretary for Health,
Oftice on Smok:ng and Health. DHEW Publication No. (PHS)79-50066, 1979, 1136
  PP.

US. PUBLIC HEALTH SERVICE. Smoking and pregnancy. The Health Consequences
of Smoking. A Report of the Surgeon Geneml. U.S. Department of Health.
Education, and Welfare, Public Health Service, Health Services and Mental
Health Administration. DHEW Publication No. (HSMl73-8704, 1973, pp. 99-149.
U.S. PUBLIC HEALTH SERVICE. Adult Use of Tobacco, 1975. U.S. Department of
Health, Education, and Welfare, Public Health Service, Center for Disease Control,
National Clearinghouse for Smoking and Health, June 1976.
WECHSLER. H., LEVINE, S., IDELSON, R.K., ROHMAN, M., TAYLOR, J.O. The
physician's role in health promotion: A survey of primary-care practitioners. Nelc
England Journal of Medicine 308(21: 97-100, January 13,1983.
WEINBLATT, E., SHAPIRO, S., FRANK, C.W. Changes in personal characteristics of
men, over five years, following first diagnosis of coronary heart disease. American
Journal of Public Health 61(41: 831-842, April 1971.
WEST, R.J., JARVIS, M.J., RUSSELL, M.A.H., CARRUTHERS, M.E., FEYERA-
BEND, C. Effect of nicotine replacement in the cigarette withdrawal syndrome.
British Journal ofAddiction 7%2): 215219, June 1984.
WILCOX, R.G., HUGHES, J., ROLAND, J. Verification of smoking history in patients
after infarction using urinary nicotine and cotinine measures. British Medical
Journal 2(61971: 1026-1028, October 23,1979.
WILHELMSSON, C., VEDIN, J.A., ELMFELDT, D., TIBBLIN, G., WILHELMSEN, L.
Smoking and myocardial infarction. Lancer l(79041: 41-20, February 22, 1975.
WILLIAMS, H.O. Routine advice against smoking. A chest clinic pilot study.
Practitioner 202(12111: 672-676, May 1969.

WILSON, D., WOOD, G.. JOHNSTON, N., SICURELLA, J. Randomized clinical trial
of supportive follow-up for cigarette smokers in a family practice. Canadian
Medical Association Journal 126t2): 127-129, January 151982.
WILSON, R.W. Cigarette smoking, disability days and respiratory condition. &urnal
ofOccupational Medicine 15(31: 23&240, March 3,1973.
WINDSOR, R.A., GREEN, L.W., ROSEMAN, J.M. Health promotion and mainte
nance for patients with chronic obstructive pulmonary disease: A review. Journal
ofChronrcDiseo.scs33!11/121: 5-12.1979.

WORLD HEALTH ORGANIZATION. Smoking and disease: The evidence reviewed.
World Health Organization Chronicle 29: 40-08, October 1975.
WORLD HEALTH ORGANIZATION EUROPEAN COLLABORATIVE GROUP.
Multifactorial trial in the prevention of coronary heart disease: 2. Risk factor
changes at two and four years. European Heart Journal 3(2): 184-190, April 1982.
YANKAUER, A. Public and private prevention. (Editorial.) American Journal of
Public Health 73: 1032-1034, 1983.

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CHAPTER 10. COMMUNITY STUDIES
          OF SMOKING
          CESSATION AND
          PREVENTION

499


CONTENTS

Introduction

Characteristics of a Controlled Community Study

Theoretical Background
  Mass Communication
  Community Organization
  Environmental Change

Cessation Studies
  Stanford Three-Community Study
  Australian North Coast Program
  Swiss National Research Program
  The North Karelia Project
  Other Large-Scale Studies
  Related Studies of Cessation

Prevention Studies
  Stanford Study
  The North Karelia Youth Project
  Other Prevention Studies

Methodological Issues

Directions for Future Studies

Summary and Conclusions

References

501


Introduction
Community studies of smoking cessation and prevention are
defined as research in which geographically defined populations or
age cohorts are selected for experimental intervention or as control
or comparison groups. In this chapter, four major studies of cessation
are described, and related research findings are briefly considered.
Three major studies of prevention are also reviewed, with less
extensive presentations of other recent research. The theoretical
background for these studies is outlined, methodological issues are
discussed, and directions for future research are suggested. It is
concluded that community studies represent a significant emerging
paradigm for public health research.
The first public health "revolution," the recently achieved control
of major infectious disease, evolved in two phases: (1) recognition
that certain aspects of the environment are associated with disease,
and (2) establishment of sanitation facilities and services, such as
refuse collection and plumbing systems, for entire communities of
people. Basic public health engineering that was revolutionary a
century ago is now taken for granted by society. Today we emphasize
the second public health "revolution," the current efforts to control
chronic disease through behavior change. This development has also
evolved in two stages: (1) recognition of behaviors, such as cigarette
smoking, as being associated with disease, and (2) development of
new services to change ihose behaviors (Wynder and Hoffman 1979).
As might be expected, this most recent history of public health is no
less turbulent than that which preceded it.
Various factors have hindered progress. After the basic causes of
smoking-related diseases were recognized, there has been a tendency
to invest scarce resources in increasingly intricate studies of disease
causation processes. In addition, once funding is secured for inter-
vention to reduce smoking, efforts often focus on individual-level,
clinically oriented interventions (Lichtenstein 1982). If these inter-
ventions do not succeed, society is inclined to "blame the victim,"
much as the poor were held responsible for the microbes in their
water by 19th century social conservatives. The socioeconomic
gradient in rates of smoking and smoking-related disease may also
slow society's response at a community level to this modern,
noncommunicable disease epidemic. The greatest factor inhibiting
progress, however, is the cost of prevention. Such costs are com-
pounded by political obstacles stemming from the tremendous
influence of the tobacco industry, which employs thousands of people
and regularly delivers a substantial portion of tax revenues (Breslow
1982; Fritschler 1975; Sapolsky 1980). On a national scale, dramatic
changes in tobacco consumption have occurred in response to
successive measures (Warner 1977; Warner and Murt 1982). but
these have been limited largely to higher income groups. Few


examples of bold community or regional efforts comparable to those
involved in the control of infectious disease have been witnessed, and
the prevalence of smoking has declined much less dramatically
among women and has even increased in some minorities.

Characteristics of a Controlled Community Study

For this discussion, a controlled community study is defined
according to the scope of intervention and quality of research design,
with the essential feature being identification of natural, location-
based aggregations of individuals as well as formal and informal
social systems. In a community study, the entire population of a
geographic area is considered, so that a church or worksite is not a
community itself, but one of many systems constituting the total
network of interactions. The term "community" originally referred
to small systems numbering no more than several thousand persons.
This discussion, however, includes research on towns, counties, or
other relatively independent zones with up to several hundred
thousand inhabitants. Because educational systems represent all age
cohorts of youth, school-based studies are also reported. Studies of
entire States or nations are only briefly considered.

Because the population size to be addressed is a limiting factor in
any social program, the large numbers of people involved in a
community study dictate selection of intervention methods. Clinical
or other people-oriented approaches that typify behavioral research
on smoking cessation and prevention (Bernstein 1969; Bernstein and
McAlister 1976; Pechacek and McAlister 1980; Lando and McGovern
1982; Lichtenstein 1982) are not feasible for programs directed
toward many thousands of people. Community studies instead
emphasize large-scale delivery systems such as the mass communica-
tion media. Because community participation is now considered
essential for success, such studies also include community organiza-
tion programs seeking to stimulate interpersonal communication in
ways that are feasible on a large-scale basis. Community studies also
may involve environmental change, such as programs to modify the
purchase price or availability of consumer products or to sanction
public behaviors.

Because the emphasis herein is on controlled community research,
attention is limited to studies in which valid inferences can be made
concerning the effects of intervention on smoking rates in an entire
population. The essential elements are use of adequate measures of
smoking behavior applied over time in order to estimate long-term
trends, and equally important, the inclusion of control or reference
areas for the purpose of comparison. There are, of course, many
questions and controversies regarding the usefulness and validity of
large-scale experimental or quasi-experimental research (Campbell

504


and Cook 1979). Social policies such as those needed to sharply
reduce smoking are not likely to be introduced without experimental
trials, however, and the studies reported herein probably represent
the best currently attainable compromise between external and
internal validity. Given the very small number of studies meeting
even the minimal methodological criteria, it would be unwise to
restrict this review t,o the standards required by laboratory or
clinica! st.udies.

Theoretical Background

Effective mass communication, community organization, and
environmental change require a theoretical basis for planning. Most
community studies of health promotion and disease prevention are
based on fundamental theories and concepts from the behavioral
sciences. The most important of these are briefly outlined below.

Mass Communication

Theories on mass media effect have changed during the recent
history of communication research, and several clear stages have
been identified (Klapper 1960; Griffiths and Knutson 1960; Atkin
1979; Flay et al. 1980; Wallack 1981). Media were initially considered
nearly omnipotent in directly altering behavior, but it was later
discovered that they are incapable of producing effects independent
of other, more powerful social forces. The most recent view is that
mass media may have effects, but that they are smail and largely
dependent on facilitation from interpersonal influences and favor-
able environmental circumstances. Notwithstanding these limita-
tions, shifts of a few percentage points in consumer preferences may
be very significant in product marketing, while similar reductions in
chronic disease-promoting behaviors may have enormous absolute
significance in a population of several millions. One mass media
effect that is agreed upon by most communication scientists is
termed the "agenda-setting function" (McCombs and Shaw 19721, in
which the media powerfully influence topics generated in formal and
informal social gatherings. Media communication can also inform
and teach simple skills (Bandura 1977). But the manner in which
people actually behave with regard to a particular topic of discus-
sion, and whether or not information or skills are actually used,
depends more upon interpersonal forces than upon the medin
messages themselves.

Community Organization

The theories and concepts that underlie communit,y organization
are less well developed than those applied to media planning.
Although there is broad agreement that the effects of the media are

505


,.;:y: <!`<`l s! '     ,,,' z.., ,I' ;;..a.:: ;-... i : here is DO clear consensus on the

, )/,_ : ,,:~ :      `~ \`:.- \:I` ho:&- they can be feasibly modified in
~`Il111`c i';Li :,;.: j:.e. : .4.~t.f`;.~i principle is derived from Bandura's
! 1977 i ciistinct `lln br:\veen factors influencing acquisition of new
behaviors and : ~11 )se influencing performance of new behaviors.
Media communications can model new behaviors so that they are
learned (acquired) on a cognitive level (the person knows how to
perform the behavior). However, cueing and feedback (direct social
reinforcement: are usually needed for behavioral learning, or actual
performance of the new behavior. Numerous studies of learning via
media commumcation show that when a complex beha?rior is being
learned, effectiveness is sharply enhanced by providing supplemen-
tary interpersonal communication for encollragement, feedback, and
reinforcement (Bandura 1977). To create feedback and reinforce-
ment in a communiLy setting, organizations must be involved to
provide roles and structure for interpersonal communication. Where
formal so&: networks are not involved, communication and influ-
ence will be diffused through families and other informal systems
(Meyer ct al. 1977). The effectiveness of interpersonal communica-
tion can be greatly enhanced, however, by organizing formal or
semiformal structures, such as learning groups using leaders trained
to lead discussions, answer questions, and provide encouragement
and followup. Various campaigns in agricultural development illus-
trate these principles (Green 1970; Rogers and Shoemaker 1971).

A related factor is the notion of generalized social support (Caplan
et al. 19751, which refers not to the differential social reinforcement
of specific behaviors, but to the general extent and quality of
interpersonal relationships. Social relations appear to be generally
helpful, probably because of their "stress-buffering" effects. Social
ties within the family probably enhance cessation and prevention of
tobacco use. For example, spousal support leads to higher successful
quit rates (West et al. 1977; Mermelstein et al. 19831, and lower rates
of teenage smoking occur in families in which neither parent smokes
(National Institute on Education 1979). The general enhancement of
interpersonal support networks is, of course, a primary objective of
religious groups and social work and most other helping professions.

Environmental Change

There are also theories and concepts from which environmental
changes can be planned (Bandura 1977; Craik 1973), the basic
principle of which is to modify the availability and cost of products or
behaviors (such as by limiting supply or prohibiting behaviors in
public settings). Not all such measures can be applied by communi-
ties as defined herein. For example, regulations on mass media
advertising can probably be controlled in most cases only at the
Federal level, although billboard advertising may be amenabie to

506


more local control. Other promising interventions such as taxation
&wit et al. 1981; Fugi 1980) can be applied within fairly small
localities, but the risk of "black market" competition is lessened
when economic controls are fairly uniform across larger geographic
units. Product availability and regulation of behavior can be
achieved by towns or countries, but restrictive regulations almost
invariably arouse opposition unless the public is yvilling to self-
enforce the restrictions. Therefore, it is legitimate to favor voluntary
restraints over those that require formal policing. Syme and Alcalay
(1982) call for intervention and prevention efforts at the community
level using a public education agenda Such programs will seek to
increase public awareness of the health consequences or smoking,
create an atmosphere in which smoking is recognized as a minority
behavior, influence public policy, and increase antismoking adver-
t.isements.

Breslow (1982) has recently reviewed the environmental and
public policy approaches to smoking control and calls for a "compre-
hensive strategy that will mobilize all available resources most
effectively" (p. 149). He advocates Federal, State, and local legisla-
tion as the most important forms of social action directed t,oward
action alternatives as well as research. He states that "protection
and advancement of economic Interests wili gene;ally follow prevail-
ing ideology. Finding ways of cutting through the economic barriers,
as always, will pose a challenge to public health. Whi!e co.mprcmises
will be necessary, the objective of steady movement toward the g:naT
now seems attainable" :p. 149).

Cessation Studies

Controlled community studies otl smoking ressI.::on are stil!
relatively scarce. However, community trials for carciiovascuiar
disease prevention, in which cigarette smoking is ill+' major risk
factor, are providing son12 of the best examples of I 2 ". .: 1; in tl;is
area. These studies have tended to focus on cessation among adu!ts
because primary outcomes of the trials include possib!e short-tltrm
(5 to lo-year) effects on c,,lrdiovascular mortality and morbidity
rates that could hypothetically result from widespread adult cessa-
tion. These studies were reviewed ir. depth in the 1983 Report of the
Surgeon General T/z Health C'onsc:~u~nces of` ,!nlc;king (USDHHS
1983).

Stanford Three-Community Study

The most well known U.S. cardiovascular community study was
conducted in California by Farquhar, Maccob:r, and colleagues at
Stanford University (Farquhar et al. 1977; Maccoby and Alexander
1980; Meyer et al. 1980). Beginning in 1972 and ending in 1976, the

507


study was supported through the National Institutes of Health
research grant program and involved three small communities
(population of each was approximately 20,000) nonrandomly as-
signed to control, media-only, or media and face-to-face programs.
The three towns are all within 100 miles of Stanford University. The
control town, Tracy, is located in an inner valley and not exposed to
media sources common to the other two towns, Gilroy and Watson-
ville. Gilroy, assigned to the media-only condition, is situated in a
coastal valley, and Watsonville, receiving a small additional inter-
personal communication program, is on the coast. In Watsonville, a
cardiovascular high risk group including many smokers (n= 169) was
identified, and 113 cases were randomly assigned at a 2:l ratio for
face-to-face intervention. The three towns are demographically
similar, although the proximity of Watsonville and Gilroy to the
larger cities of Santa Cruz and San Jose gives them more cosmopoli-
tan features than Tracy. Nevertheless, the research design was
probably the best balance of feasibility and external and internal
validity that could have been achieved in that setting given the
limited available resources.

In each town, multistage probability samples of households were
contacted and invited to a survey station where questionnaires and
physiological measures were administered. These surveys were
applied in the autumn months, beginning in Watsonville in Septem-
ber and ending in Tracy in November. Approximately 600 persons
aged 35 to 59 were sampled at each location. The measurements
included questions about smoking, and serum samples from high risk
participants were analyzed to estimate thiocyanate concentrations
as a check on inaccurate reporting of smoking status (Meyer et al.
1980). These measurements were taken annually for 4 years,
yielding a picture of 3-year smoking trends among the survey
participants in the three communities.

The program of media communication was conducted over 3 years
(1973 to 1975), with greatest intensity in the first and second years of
work. Television, newspapers, radio, billboards, and direct mail
advertising were designed to provide information and to model
attitudes and skills that would promote behavioral changes associ-
ated with lowered cardiovascular risk, such as weight reduction,
lowered fat consumption, and increased exercise. To encourage
cessation of smoking, information about its harmful effects was
given, along with advice on how to stop smoking. In booklets mailed
to the sampled households in Gilroy and Watsonville, instructions
were provided for simple self-control skills (Meyer et al. 1980). In
brief television and radio communications, actors were shown
recommending or modeling cessation of smoking in a variety of
authoritative and entertaining ways.

508


The face-to-face, intensive instruction program was provided for
113 randomly assigned high risk participants in Watsonville, of
whom 107 started treatment, and 77 continued for the second annual
examination. Activities were based on principles of behavioral
psychology and group dynamics and were designed to reinforce and
train skills for behavior change (Meyer et al. 1980). The first-year
program consisted of classes and home visits, mostly during the
summer of 1973. During the summer of the following year, aggres-
sive followup activities were conducted to reinforce smokers who
reported cessation and to encourage and train those who were not
yet able to quit. This maintenance program included training in
stress management and other intensive, individual counseling for
those who consented to continuing contact. In the third year, the
activities were gradually reduced to telephone contacts and a small
"reunion" in the summer of 1975.

The results of the program among high risk participants in each of
the four surveys are displayed in Figure 1. Over the 3 years of study,
the prevalence of smoking decreased markedly among the group
receiving media and face-to-face communication. The group receiv-
ing media intervention showed an initial decline as compared with
the control group, but the change did not differ from the modest
reduction observed in Tracy over the entire 3-year period. Because
the high risk samples included most of the older smokers in the
survey samples from each community, the data on cessation in the
complete samples corresponded closely to that of the high risk group.
The serum thiocyanate tests indicated very slight overreporting of
cessation (Farquhar et al. 19771, but self-reported cessation rates
were not adjusted for thiocyanate findings (Kasl 1980). There was
some attrition in this longitudinal study, but not enough to account
for the clear differences in cessation rates between the intensively
instructed and the other participants. Adjust.ing for attrition, 32
percent reported sustained cessation in the intensive intervention
group (Meyer et al. 1980). This research supports the hypothesis that
face-to-face communication is a necessary part of a successful
community program to reduce smoking. Farquhar and his colleagues
(Farquhar et al. 1981) conclude that the question of how such
communication can be feasibly and cost-effectively provided on a
widespread basis remains to be answered by further studies, and this
conclusion will be noted in a later section. A number of critical
comments can be made in regard to the Stanford three-community
study, and these have been thoroughly discussed in numerous
publications (Leventhal and Cleary 1980; Meyer et al. 1980). The
primary shortcomings concern the quasi-experimental research
design and the inability to generalize from the longitudinally
followed study group to the entire community.

509


GIlroy-media only

3

FIGURE l.-Comparison of cessation rates among smokers
      in communities subjected to varied intensities
      of education, the Stanford three-community
       study
SOURCE Farquhar et al f 1981 I

Australian North Coast Program

A trial very similar to the Stanford three-community study was
conducted by the regional Health Department of New South Wales,
Australia (Egger et al. 19831, beginning in 1978 and, as in the
Stanford study, using small community populations of 12,000 to
27,000 persons. The towns of Tamworth, Coffs Harbor, and Lismore
were assigned to one of three conditions: control, media only, or
combined media and community programs. The three towns were all
between 300 and 400 miles from the research center in Sydney.
Coffs Harbor, the media-only town, was approximately half the size
of the other two communities. Tamworth was not served by the
regional administrative center in Sydney.

In each town, a series of random sample surveys was conducted.
Interviews and physiological examinations were requested from up
to two adults in randomly sampled households. Those who refused
appointments were given self-report questionnaires to be completed
at home. Separate samples were drawn in 1978, 1980, and 1981 with
the objective of measuring 600, 1,200, and 1,200 different persons in
the 3 respective years. Smoking behavior, attitudes, and knowledge

510


regarding smoking were measured, and in 1980 and 1981, serum
thiocyanate values were determined for a randomly selected 5
percent subsample. Measures were also made of other cardiovascular
disease risk factors in accordance with the program's primary goal.

The media program included output from a television station, a
radio station, and several small newspapers, supplemented by other
materials such as stickers, posters, T-shirts, and balloons. The three
stages of the media campaign were designed to sequentially raise
awareness, provide information, and stimulate action. Advertising
time was purchased to insure presentation of television commercials
during peak viewing periods. Beginning in October 1979, the print
advertisements were suspended for several months because of a
complaint to the Media Council of Australia. The overall campaign
continued for approximately 1 year. The community program.that
was applied in Lismore was varied. Several different kinds of groups,
clinics, workshops, and other interpersonal support systems were
organized; physicians were also involved. A total of 386 smokers
participated in these activities, most (150) joining a lday workshop.
The 3-month success rate in smoking cessation, measured by
telephone interview, was 16 percent for the workshop participants.
The highest success rate (48 percent) was found for the 40 persons
who received help kits from physicians. The community program
also included other programs (e.g., for physical fitness and stress
management), which may have facilitated the cessation of smoking.

The results of the project were based on the three independent
sample surveys. The authors point out that "there was substantial
confounding owing to age and sex differences between towns" (p.
1127). Analyzing results according to a multiple logistic model
controlling for age and sex differences, a significant treatment effect
(p=O.O5) was observed. Thiocyanate analyses showed no difference
between towns in the small estimated invalidity of self-reports (3
percent). Among men and women in various age groups, consistently
different rates of change in prevalence of smoking were found. In
Lismore, absolute percentage reductions ranged from 6 to 15
percent. In the media-only town (Coffs Harbor) absolute 6 to 11
percent reductions were estimated. In Tamworth (the control)
absolute reductions of only 2 to 5 percent were found. The research-
ers found no evidence of effects on knowledge or attitudes.

Many criticisms can be made from the standpoint of a clinical
scientist accustomed to dealing with individual subjects in highly
controlled settings. If limitations to inference are clearly acknowl-
edged, however, the Australian study provides a practical illustra-
tion of what may be achieved through community intervention. The
findings are based on independent samples, and thus represent
changes that seem to have occurred on a communitywide basis. The
magnitude of the apparent effect was particularly encouraging

511


among rhe youngest age groups I 18 to 25) where absolute reductions
in prevalence of smoking showed a threefold difference between the
maximrlm intervention (15.6 percent) and control towns (5.0 per-
cent 1. The most significant limitation arises out of the nonrandom
assignment of communities and problems with their comparability.

Swiss National Research Program

Another important community study was conducted in Switzer-
land (Autorengruppe Nationales Forschungsprogramm 1984; Gutz-
willer and Schweizer 1983). Four communities of 12,000 to 16,000
inhabitants were selected, two each from the German-speaking and
the French-speaking parts of the country. A fifth community in the
Italian-speaking region was also studied, but only for epidemiological
purposes. French-speaking and German-speaking pairs were ran-
domly assigned to intervention (Nyon) or regular care (Solothurn
and Vevey) conditions. This project was conducted over a 4-year
period with research support from the Swiss National Science
Foundation. A baseline assessment was made in late 1977 and early
1978 by stratified random sampling and examination of 2,000
persons aged 16 to 69 in each community. With attrition of
approximately 30 percent, this sample was resurveyed at the end of
1980, at which time another independent sample was drawn and
surveyed. A questionnaire was used to determine smoking behavior,
and plasma thiocyanate was measured on a subsample of respon-
dents. Other health-related factors such as blood pressure, lipid
fractions, exercise tolerance, and psychosocial adjustment were also
measured.

The community interventions were conducted over 2.5 years in
Nyon, with guiding principles of "active local participation" and
"integration into existing local health and social services." The
central feature was the establishment of a Citizen Health Action
Committee in each of the two towns, with a coordinator assigned to
guide local planning and implementation. Media and community
organizations were combined to promote a variety of programs in
each location, including classes, self-help groups, and meetings to
discuss topics such as environmental regulation via public non-
smoking areas.

The results of this study are moderately encouraging. Within the
sample population surveyed at baseline and followup, 26 percent of
the regular smokers in the intervention communities reported
cessation. In the control areas, 18 percent of the corresponding group
reported cessation. The investigators also report effects on other
cardiovascular disease risk factors, although plasma cholesterol
reductions were significant only for women in the German-speaking
region. A cost-benefit estimation model has been applied to the data
and results indicate a twofold cost-benefit ratio. The use of indepen-

512


dent surveys and the random assignment of communities represent
significant methodological strengths as compared with the Stanford
and Australian studies. However, the rural communities in this
study were very small. and only four were included. The final report
has been presented to formal decisionmakers to determine whether
broader national efforts are warranted.

The North Karelia Project

The best documented long-term community study is being conduct-
ed in Finland by Puska and colleagues (Puska et al. 1979, 1981,
1983a; Puska and Koskela 1983; McAlister et al. 19821. Also
beginning in 1972 and continuing to the present, the research is
comparing changes in cardiovascular disease risk factors in two
neighboring counties of eastern Finiand, Kuopio and North Karelia.
Both are large rural areas with numerous small farming, lumber. or
mining communities and a single major town. North Karelia is
representative of eastern Finland as a whole in having one of the
world's highest rates of cardiovascular disease (Pyorala 1974; World
Health Organization 1975). Financial support for the intervention
came from the Finnish Ministry of Health, following a formal
request from leaders in North Karelia for help in reducing the high
mortality and morbidity levels. Research funds were awarded by the
Academy of Finland. The neighboring county of Kuopio was selected
as a reference or control location. In North Karelia, a broad program
was implemented to provide new services, education, and training
through community health centers, the mass media, and a variety of
community organizations. During the second 5 years of the project,
media programs were carried out on a national level, with special
organizing and support for activities in North Karelia.

In both counties, independent samples of households were drawn
in 1972,1977, and 1982, with approximately 5,000 persons aged 25 to
59 in 1972 sampled in each area in the first two surveys and about
4,000 aged 25 to 64 sampled in the 1982 measurement. Response
rates were generally excellent, and nearly 90 percent of the sample
participated by attending local survey centers in the spring of each
of the survey years (1972, 1977, 1982). Self-reported cigarette-smok-
ing behavior was measured in all three surveys. In the 1977 survey,
serum thiocyanate values were estimated for a subsample, and in the
1982 survey, for all participants. For the 1977 sample, there was 99
percent agreement in smoking status (smoker/nonsmoker), and
when classified by intervals of 5 or 10 cigarettes, the agreement
between results was 93 and 97 percent, respectively (Puska et al.
1979). The age-adjusted partial correlation between daily reported
number of cigarettes and serum thiocyanate in 1982 was approxi-
mately 0.7 among men and women in both areas. In the years when
the larger surveys were not conducted, smaller samples (1,200 to

513


3,500) were selected yearly for a postal survey of North Karelia.
Together, these measurements provide a comparative view of trends
over 10 years in the populations of both counties and a year-to-year
picture of the changes in North Karelia.

The program of service, education, and training was very broad in
scope. Initially, an intensive educational campaign was conducted
for reduction of cigarette smoking with cooperation from the news
media. Physicians and public health nurses staffing community
health centers were provided special training and were encouraged
to recommend cessation to all patients visiting the centers. Tens of
thousands of leaflets and posters were distributed to encourage
nonsmoking. With assistance from Heart Association volunteers in
each small community, informal restrictions on smoking and point-
of-purchase advertising were adopted. During 1976 and 1977, these
measures became part of a package of national legislation that
increased cigarette tax revenue, directed health services to provide
information services, limited public smoking, and banned tobacco
advertising.

During the second 5-year period, an effort was made to provide
nationwide applications, while maintaining intensive community
work in North Karelia. A series of programs was broadcast national-
ly on television to demonstration how "average" people stop smoking
(Puska et al. 19811. In association with these broadcasts, special
organizing campaigns were conducted in North Karelia to increase
social support for people attempting to quit. These activities
occurred in the winters of 1978, 1979, 1980, and 1982 and were seen
nationally by a majority of the population, with higher viewership in
North Karelia. During the first broadcast series, an effort was made
to encourage the formation of informal volunteer-led self-help
groups to view the broadcasts together. Very few volunteers succeed-
ed in establishing groups, however, and focus in subsequent years
has been on training volunteers to provide even less formal cueing,
reinforcement, and support in their incidental, day-today contacts
with cigarette smokers (Puska et al. 1981).

The results to date (Puska and Koskela 1983) are presented in
Table 1. Over the lo-year period, self-reported numbers of cigarettes
smoked per day fell by more than one-third among men in North
Karelia. In the control or reference area, a less than 10 percent
reduction was observed. Changes in prevalence of smoking account
for most of this difference. No evidence of an effect occurred among
women, with rates of smoking going up in both areas. In Figure 2,
the year-to-year data for 25- to 29-year-old men and women in North
Karelia show an interesting pattern, with the sharpest declines
among men associated with the first year of work and with the
television broadcasts and associated activities in 1978 to 1980 and in
1982. Since 1978, when new antismoking laws were passed, the

514


proportion of male smokers aged 15 to 64 has changed from 44 to 31
percent in North Karelia, and from 39 to 35 percent in the rest of the
country, a difference of 9 percent in absolute rates of change over
that 4-year period. Although the effect of changes in smoking cannot
be separated from the effects of new hypertension services and other
measures to prevent cardiovascular disease, there is some early
indication that mortality rates may have been influenced by the
program: a 24 percent decline in cardiovascular deaths has been
observed in North Karelia, compared with a 12 percent decline
nationally in Finland (Puska et al. 1983a, bj.

The North Karelia Project has received much attention, and
various points of controversy have been widely discussed. The
methodology of the study does not compare with that achieved in
controlled clinical trials, but it may have been the optimal design
that was feasible in the circumstances. Puska and his colleagues
point out that "it is easy to say that the North Karelia Project was
successful because of the unique historical background and because
the conditions in North Karelia were favorable for the program.
However, at the planning stage, great concern was expressed
because the area was rural, of low socioeconomic status with high
unemployment, and so forth." Because a large number of indepen-
dent units were not randomly assigned to experimental and control
conditions, the Finnish study cannot be taken as a conclusive test of
the effects of community programs, but it does provide a promising
illustration and evaluation of what can be achieved through broad
and vigorous intervention to reduce smoking behavior. Its major
strengths are the relatively large number of different communities
that were studied and the lo-year followup interval.

Other Large-Scale Studies

There have been a number of other large-scale controlled studies,
single and multifactor clinical trials, and worksite trials that provide
a context for the consideration of the community-level intervention
studies described above. These studies were discussed in the 1983
Report of the Surgeon General The Health Consequences of Smoking
and include the London Civil Servants Smoking Trial (Rose and
Hamilton 1978; Rose et al. 1980, 19821, the Gijteborg (Sweden) study
(Werko 1979; Wilhelmsen 1981; Wilhelmsen et al. 19721, the Oslo
(Norway) study (Hjermann et al. 1981; Holme et al. 19811, the World
Health Organization European Collaborative Trials (WHO European
Collaborative Group 1974; Kornitzer et al. 1980a, b) and the Multiple
Risk Factor Intervention Trial (MRFIT) (Hughes et al. 1981;
MRFIRG 1982). In the sole American study (MRFIT), 12,866 men, 35
to 57 years old and at high risk for coronary heart disease (CHD),
were entered into a randomized clinical trial designed to test the
effect of a multifactor intervention program on CHD morbidity and

515


TABLE l.-Mean amount of reported daily smoking (*SD) in North Karelia and the reference area, in
     independent baseline (1972) and byear (1977) and IO-year (1982) followup survey samples,
      by sex and age

Sex and age

(Y-d

1972

North Karelia

  1977

1982

1972

Reference area

   1977

1982

Net difference, percentf@e '

197P1977   19721982

Men
3049
40-49
w.59
Total

Women
30-3
4@49
5049
Total

10.6 + 11.7    9.0 f 12.5    7.2 + 10.7
10.2 * 11.2    6.5 + 11.6    7.0 + 10.3
9.0 t 10.7    7.9 + 11.5    5.7 +  9.7
10.0 + 11.3    8.5 + 11.9    6.6 2 10.2



1.4 +  4.2    1.6 +  5.1    2.6 zk  5.8
1.2 +  4.0    1.1 +  4.0    1.5 *  4.4
0.7 +  3.2    0.7 +  3.4    0.9 f  3.6
1.1 +  3.8    1.1 +  4.2    1.7 +  4.7

8.5 + 11.0    9.0 t 11.9    8.6 + 11.5             16       33
9.0 + 10.7    8.6 ~fr 11.4    8.0 + 11.7             10       21
7.7 +-  9.9    7.7 + 10.5    6.5 +  9.6             16       23
6.5 f 10.6    8.5 + 11.4    7.8 f 11.1             13       28

1.5 f  4.5    2.0 +  4.6    2.8 k  6.2             15        2
1.0 +  3.2    1.2 +  5.0    1.7 -t  4.9             23       36
1.0 +  3.6    0.8 +  3.2    1.2 *  4.0             43       41
1.2 *  3.8    1.3 k  4.4    1.9 +  5.1              8       14

Four-way ANOVA'       19721977

Area            P<O.O5
Time               n.a.
Area-time          p<O.Ol
Area-tim~X        p<o.m

19721982

".8.
p<O.OOl
p<O.ool
p<O.ool

ANOVA for linear
trend 1972. 1977, 1982

   Men
   Women

North Karelia

p<O.OOl
p<O.all

Reference area

n.a.
p<o.au

`(North Karelia. 1982/1977-1972) - (Reference area, 1982/1977-1972)
~ANOVA=Ady~isofvariance.
SOUKCE: Puska and Kmkela (19a7).


FIGURE 2.-Prevalence of smoking among men and
     women, aged 25-29, North Karelia, 19721982
SOURCE- Puska and Kcakela f 19831

mortality. They were followed for an average of 7 years. At intake,

517


TABLE 2.-Results of community studies compared with
      other large-scale studies

Study

Years of   Net percent reduction
study      in smcking '

Strengths

Stanford Three
Community study

3

l&20

Matched
communities

Panel study
OtIlY

Australian
North Coast
study

3

15

Independent
samples

Problems with
comparability
of groups

Swiss National
Research
swam

3

8

Randomization,
independent
S4%lllpl@3

Small size and
number of
study sites

North Karelia
project

10

25'

Numerous
communities,
independent
samples

Nonrandom
assignment

Other large
scale studies 3

2-10

.w5

Internal
validity

EXtHlk31
validity

I Difference between percent reductmn in proportion of smokers m the maximum interventnn verws control
condlLrons.
*Difference between percent reductum m the mean number of cigarette smoked per day among men.
`Clmical and work-site tnals: the London CIVI! Servants Smokmg Trial, the Gotebarg study. the Oslo study, the
WHO Collaborative Trml. and the Multiple Rlak Factor Intervention Trml.

the self-reported prevalence of smoking was 64 percent. The 6,428
men randomized into the Special Intervention (SI) group received
intensive group sessions, personal instruction, and other followup to
encourage and support cessation of smoking, as well as intensive
assistance to alter other CHD risk factors. There were 6,438 men in
the group randomly assigned to Usual Care WC). At 6-year followup,
self-reported cessation rates were 43 percent in the SI group and 25
percent in the UC group. Thiocyanate analyses showed a necessity
for small adjustments in these figures to 42 percent and 24 percent,
respectively, a statistically significant difference (p < 0.01). Compari-
son of the results from the four community studies with those from
the large-scale studies, as shown in Table 2, indicates distinct
similarities. The individual studies each have somewhat different
weaknesses, but all indicate that absolute reductions in smoking
prevalence in intervention communities are about 12 percent
greater than reductions in comparison communities.

Several ambitious community studies of cardiovascular disease
prevention are currently in progress with support from the National
Heart, Lung, and Blood Institute, but no additional data on
community-level intervention are available. At Stanford University,
a large study of two intervention and three control towns with
several hundred thousand residents has been in progress since 1978
and is projected to continue for at least 10 years (Farquhar I978). A

51r


similar study, with three matched pairs of variously-sized towns and
cities, has been in progress in Minnesota since 1979 cRla:sk'aurn et
al., in press; Blackburn, in press; Blackburn and Pechacek, in press).
A smaller study of one Rhode Island town a.ld one town in a
neighboring State began in 1980 (Lasater 1983). Because it has
become clear that community studies are the most natural and cost-
effective method for testing new public health services to reduce
chronic disease (Farquhar 1978; Puska et al. 1983a. b), more of these
efforts may be useful, particularly if costs can be reduced and, where
possible, absorbed into existing services.

Related Studies of Cessation

A number of recent efforts have increased understanding of and
confidence in the methods employed in large-scale community
studies. Research on methods of stimulating interpersonal support
for mass media programming is particularly relevant (Colletti and
Brownell 1982). In quasi-experimzntal studies, McAlister et al. (1980)
and Puska et al. (1981) have reported methods for facilitating the
effectiveness of televised smoking cessation classes in Finland.
Formal self-help groups appear difficult to organize, but reorganiza-
tion of less formal social reinforcement in natural interaction
sett,ings appears feasible and effective. Related studies of television
and other media-based methods are described by Danaher et al.
(1983), Best (1980), Lerlthar (1981), and others. Dubren (1977a, b),
Brengelmann (1976), and the American Cancer Society (1981) found
that effects of media programs may be enhanced if a telephone
hotline is offered. Flay et al. (1983b) used a school-based, family-
oriented prevention program that included a five-segment television
Tomponent to be aired the following week to encourage participation
of cigarette-smoking parer& Overall, parents of students in exwri-
mental groups were over three times more likely to view the
cessation segment than parents of control students, with similar
differences observed for the proportions of successful parental
attempts to quit. Within the experimental groups, teacher training
had a significant effect (p< .Cl) on raising participation rates by
parents of program students. Considering only homes with smokers,
51 percent of the students with trzined teachers reported that at
least one cigarette smoking adult viewed one or more cessation
segments, compared with 37 percent of students with untrained
teachers. Furthermore, 38 percent of parents with trained teachers
attempted to quit smoking, compared with 24 percent of parents of
students with untrained teachers !p< .OOl). At l-year followup, the
cessation rates in the two groups were 19 and 13 percent, respective-
ly, according to children's reports of parental behavior. The validity
of the indicators of adult smoking behavior is at issue; student
reports could contain bias, which will be estimated in further

519


analyses. Nevertheless, these results suggest that children can
enhance the effectiveness of a media program in encouraging
parents to stop smoking, and that organized social reinforcement is
important in mass media smoking cessation programming (Flay et
al. 1983b). More research is needed on these and other methods of
large-scale social reinforcement and support for cessation of smok-
ing.

Some attention has been given to environmental changes that
might contribute to the cessation of cigarette smoking. Evidence
indicates that smoking can be regulated by counteradvertising,
restrictions on advertising, warning labels, and symbolic or govern-
mental actions such as the Surgeon General's Report of 1964
(Warner 1977). Complete prohibition of smoking is not an acceptable
alternative, but restrictions on smoking locations may be helpful for
people attempting to quit voluntarily (Horwitz et al. 1982). Taxation
of cigarettes has provided an effective deterrent in some population
groups, particularly among younger men (Lewit et al. 1981). In
Finland, cigarette taxes have been increased and a portion (0.5
percent) of the funds are dedicated to support services to reduce the
prevalence of smoking (Puska and Koskela 1983). Similarly, integrat-
ed environmental and educational interventions may be useful in
further large-scale efforts.

Prevention Studies

Although evidence increasingly indicates that it is more cost
effective to prevent the onset of smoking among young people than
to change the dependent behavior of adults, smoking prevention has
received far less attention than cessation in controlled community
research. This can be attributed to the complex processes involved in
the onset of smoking (e.g., Evans 1976; Leventhal and Cleary 19801.
to the extended timespan required for proper evaluation of preven-
tion studies, and to the overall tendency of the health sciences to
focus more on individual-level research than on primary prevention
studies in which whole populations must be followed. Research on
the prevention of smoking onset was considered in detail in the 1982
Report of the Surgeon General The Health Consequences of Smoking:
Cancer (USDHHS 1982), and only selective studies are reviewed
herein. Although there are no currently available published reports
on controlled community studies of smoking onset prevention in
whole populations, a number of school-based studies have been
conducted recently that involve large proportions of particular age-
grade cohorts in discrete communities.

520


Stanford Study

In one such study McAlister et al. (1979, 1980b) assigned the 1978
seventh grade cohorts in two similar suburban California towns to
control (receiving Usual Car: health education) or to a special peer
prevention program to deter the onset of smoking. The special
intervention program consisted of 7 classroom hours distributed over
the school year in which 15 to 17-year-old peer leaders led Socratic
dialogues, role plays, and simple contests to reinforce smoking
avoidance behavior among 12-year-old students and to promote the
social desirability of nonsmoking. Role plays and simple contests
were used to help students learn assertive ways of declining offers to
smoke, emphasizing counterarguments to the kinds of perceived peer
social pressures that may be associated with the onset of smoking
(McAlister et al. 1979). Several followup sessions were conducted
when the study cohort reached the eighth grade.

At baseline and three followup points, students in the control and
the environmental groups provided anonymous self-reports of smok-
ing through classroom surveys. Participation rates were close to 100
percent in all surveys, and the measures were supplemented by
collecting samples of exhaled breath at followup. These repeated
surveys provided good measures of smoking prevalence in the age-
grades studied in the two similar suburban communities, and
although attrition and replacement may have threatened inference,
the findings in Figure 3 indicate that the special intervention may
have had a preventive effect. Note that the dependent variable is the
percentage of participants who reported smoking during the previ-
ous week. Definitions of smoking in adolescents often differ, making
results difficult to compare. Over 2 years of initial followup, the rate
of self-reported smoking onset diverged sharply in the two age-grade
cohorts, and differences persisted over an additional year of followup
(Telch et al. 1982).

The North Karelia Youth Project

Stemming from the North Karelian project described in an early
section, a youth program was initiated in six rural communities in
eastern Finland (Vartiainen et al. 1983). Two urban and two rural
communities were assigned to intensive (direct contact with the
experimenter) or countywide (teacher-led) intervention programs in
North Karelia. Two matched communities were selected as controls
in the neighboring province of Kuopio, and subjects were seventh
grade students (average age of 13 years) in the autumn of 1978. From
a population of 897 available students, nearly all participated in the
baseline survey; 95 percent participated in a 2-year followup; and 88
percent participated in a second followup 30 months after the
program began. The survey included measurements of self-reported
smoking and related variables as well as serum thiocyanate levels.

521

480-144 0 - 85 - 18


20



15

10

Months of study

FIGURE 3.--Long-term effects of a peer group training
       course on smoking behavior of B-year-old
        students
SOURCE T&h et al (1981).

The special intervention spanned the seventh and eighth grade
years and included 10 hours of instruction in the intensive program
and 5 hours in the countywide program. The methods were based on
those employed by McAlister et al. (1980), as reported in the
preceding study. Peer leaders, students 1 to 2 years older than the
subjects, were the primary agents used to deliver the antismoking
message. The program used role play and other active learning
techniques to teach skills for resisting the social and psychological
pressures to smoke and to reinforce negative attitudes toward
smoking.

The results indicated a preventive effect from the special interven-
tion, as shown in Figure 4. Among boys, the followup rates of
smoking at least once a month were significantly lower in the four
intervention schools (21 to 24 percent) than in the reference area
communities (39 percent). Results for girls were less conclusive, but
the overall difference between groups at followup was significant: a
17 percent rate of smoking at followup in intervention schools and a
24 percent rate in control schools. Analysis of the serum thiocyanate
samples showed that 2 to 3 percent of the professed nonsmokers gave
inaccurate self-reports, but the slight underreporting was greater in
the control schools-indicating that inferences from the reported
findings were not significantly threatened by self-report biases.

Other Prevention Studies

In a more rigorous study, Flay et al. (1983a) assigned 22 schools in
Canada, some randomly, to receive special interventions or to serve
as controls. The smoking prevention curriculum consisted of three
major components, using the social psychological model delivered in

522


Autumn               Autumn Spnng
1970                 1983   1981

FIGURE 4.-Percentage of children who reported smoking
       at least once a month in baseline survey (1978)
      and two followup surveys (1980 and 1981)
SOURCE Vamamen et al (1983)

six l-hour weekly sessions during grade six. The social psychological
model aims at developing future attitude and behavior changes and
acquiring social skills, and involves eliciting information from
children rather than providing it for them. The three components
focused on smoking consequences and reasons for smoking, social
influences promoting smoking, and decisionmaking and public
commitment. Two booster sessions were delivered in both grades
seven and eight. Short-term findings show a preventive effect,
manifested in grade seven by an increased level of experimental
smoking in the control group compared with the experimental
group. In another study, Worden et al. (1983) tracked changes in
smoking rates in two towns receiving a mass media campaign and a
high-intensity program of adult communication skills related to
adolescent smoking prevention. Over 1 year of followup, onset rates
were markedly greater among a set of comparison towns receiving
only the media campaign and some low-intensity community inter-
vention.

523


?;lcAlister ;lYP:j: randomly assigned members of five matched
pairs of community and neighborhood schools to serve as controls or
to receive an experimental prevention program. The study included
students in the f'irst year of secondary school (sixth or seventh grade)
in 1979 in coastal and inland California towns and inner-city and
suburban locations near Boston, Massachusetts. Over 2 school years
of initial followup. sharply lower smoking onset rates were observed
in some of the schools receiving the experimental programs. The
findings are difficult to interpret and suggest that variability among
highly diverse community age-grade cohorts, inconsistent implemen-
tation. and other related factors threaten inferences that may be
drawn from studies of relatively small numbers of unique age-grade
cohorts. Preventive effects on smoking onset have been reported by
other investigators in Houston (Evans 19761, Minnesota (Hurd et al.
1980), New York (Botvin et al. 1980), and elsewhere; they were
reviewed extensively in the 1982 Report of the Surgeon General The
Health Consequences of Smoking (USDHHS 1982). These studies
have tended to show positive results for the nontraditional health
education methods, particularly those using peer teaching and role
plays of saying no or resisting social pressures toward smoking.
Currently, large-scale research on the prevention of smoking is in
progress in the community studies of cardiovascular disease preven-
tion that were cited in a previous section, as well as in other research
centers in the United States and abroad. Internationally, Sweder!
has declared the creation of a "Smoke-Free Generation," and other
countries have taken various steps to deter the onset of smoking
(Wake et al. 1982).

Although studies were not sufficient to confirm the hypothesis. it
is probable that young people not strongly dependent on tobacco are
most sensitive to the various "environmental" policy options for
smoking reduction. For example, the price elasticity of decisions to
smoke regularly (smoking status) is -1.4 for males aged 20 to 25, but
lower for older men (Lewit et al. 1981). This indicates that a 9
percent increase in the price of cigarettes might yield a 15 percent
decrease, in the proportion of male smokers in the younger age group.
Environmental changes related to the marketing, price, or availabili-
ty of cigarettes tend to be implemented in whole States or nations
and are not amenable to controlled demonstration research. How-
ever, as local authorities play an increasing role in various matters,
opportunities for innovative community level research may be
available.

Methodological Issues

In view of the high costs of clinical trials, such as those incurred by
the Multiple Risk Factor Intervention Trial, a strong argument can

524


be made for the cost effectiveness and generalizability of community
studies of chronic disease prevention (e.g.. Farquhar 19'iS~. However,
there are methodological problems with the community studies that
deserve careful consideration. In order to ensure strict adherence to
assumptions of the statistical theories supporting experimental
inference, independent units of observation must be sampled.
Because the behavior and disease rates of people within a communi-
ty are obviously not independent, the data from geographic units
must be aggregated at various levels, such as family, neighborhood,
community, and region. Thus, for example, smoking rates in three
communities assigned to three different experimental conditions
must be treated as three discrete observations, but having only one
observation per condition does not permit use of traditional statisti-
cal procedures for hypothesis testing. By assigning more than one
community to each condition, between-community variance can be
estimated to provide more valid tests of program effect. As the
statistical theory guiding community studies becomes more devel-
oped (Flay and Cook 19811, future research may be expected to
involve more sites, with fewer cases sampled in each site.
Another problem concerns the comparability of groups. Unless a
large number of communities are random1.y assigned to conditions,
the strict methodologist can identify obvious threats to experimental
validity. For example, it might be natural to expect a bias toward the
application of experimental programs in settings favorable to the
adoption of innovation, while using "less interested" communities
for the control group. This inevitably raises questions about the
comparability of communities with regard to socioeconomic status,
cosmopolitan features, or other hard-to-measure social characteris-
tics. If the experimental group has a favorable predisposition at
baseline, inferences about changes in health-related variables are
severely threatened. When a high degree of demographic similarity
between communities can be demonstrated, confidence in inferential
statistics is enhanced. If possible, the communities to be compared
should be assigned randomly to experimental groups or to control
groups.
Problems with comparability are also introduced by the possibili-
ties of experimental contamination or confounding effects of compet-
ing experimental programs. This issue must be thoroughly analyzed
with respect to the North Karelia Project, where it appears that
program results for dietary change and control of hypertension have
been diluted by program spillover and the establishment of new
health services in the reference (control) area.
Related to the issue of comparability of groups within a study is
the problem of generalization to broader populations. For example,
some groups that fall into the lower socioeconomic strata have not
followed the general population trend toward smoking cessation and


may also be at increased risk for smoking-related disease from
concurrent industrial exposures. Results of trials involving such
populations (WHO European Collaborative Trials) should be exam-
ined for overall outcome as well as evaluation of programmatic
elements wherever possible. Differential effectiveness of interven-
tion techniques with varying populations remains to be established.

Another methodological question is raised by studies that rely
primarily on self-reports that may be biased by intervention
programs (Evans et al. 1977; Benfari et al. 1977; Pechacek et al., in
press). Physiological indicators of cigarette smoking are expensive in
studies involving large numbers of individual measurements. Most
researchers take physiological measurements from a subsample of
the group providing self-reports. If there is no evidence of self-report
bias between groups, experimental comparisons can be based on the
self-report data. However, the usefulness of this procedure depends
upon the statistical power of the test comparing relationships
between self-reports and physiological measures in the different
experimental groups. Tests based on very small subsamples will
almost certainly show no statistically significant evidence of self-
report bias, but only because they lack the statistical power to detect
the relatively small differences that might confound inference.
Numerous other methodological points are pertinent to the review of
community studies. For example, cohort studies that track individu-
als over time may be much less generalizable than those that involve
repeated independent surveys, but are critical for studying develop
ment of certain behaviors, such as smoking onset. A great need
exists, therefore, for more focused awareness on the various method-
ological concerns that limit the interpretation of community studies.

Directions for Future Studies

There is a clear need for further research on community-level
intervention to reduce smoking. The challenge is to develop relative-
ly inexpensive methods that can be easily implemented on a large-
scale basis. This will involve refinements in three broad activity
categories: (11 education and instruction related to smoking, smoking
cessation, and smoking prevention; (2) social reinforcement in
support for nonsmoking behavior; and (3) environmental changes
related to cigarettes and cigarette smoking.

Education and instruction methods are needed to convey informa-
tion, attitudes, and skills more effectively as they relate to the
cessation and prevention of smoking. For example, as the factors
contributing to the process of smoking cessation and prevention are
identified (DiClemente and Prochaska 1982; McAlister 1983; Leven-
thal et al. 1980), they can be modeled via television or other forms of
mass communication. Although the schools have an obvious role in

526


smoking prevention, the kinds of educational activities that appear
to produce results are not easily adopted by traditional educators.
Innovative education and training programs can be marketed to
those willing to pay for therapeutic or consultative services related
to smoking cessation and prevention, but less costly methods need to
be developed for communitywide application. The establishment of
smoking cessation programs within existing health services and the
integration of chronic disease prevention with mental health promo-
tion are also needed to effect broad-scale societal education and
change.

Growing evidence indicates that the social reinforcement and
support provided in formal therapies can be effectively evoked at far
less expense by self-help groups and natural helping networks. In the
North Karelia Project, community volunteers were taught to rein-
force learning of smoking cessation skills from television (Puska et
al. 1981). Children may also be powerful, natural sources of social
reinforcement (Flay et al. 1983b). Related methods are being applied
in other ongoing community studies to harness the influence of
natural social networks for antismoking campaigns (Pechacek et al.,
in press). In addition to reinforcing specific behaviors and attitudes
related to smoking prevention and cessation, social environments
can give more general support and assistance to people trying to cope
with stress, strain, and conflict. Given the relationship between
chronic smoking, stress, and alienation, it is reasonable to expect a
positive effect from interventions that reduce stress, improve coping,
and increase social support (Colletti and Brownell 1982).

Other community efforts are being made in noncontrolled con-
texts, as in the following examples. First, the American Cancer
Society has introduced an "Adopt A Smoker" program to involve ex-
smokers in the annual Great American Smokeout Day. Second,
community physicians are being urged to increase the frequency and
intensity of cessation advice given to smokers. Finally, the television
and newspaper media have become involved in the antismoking
campaign, frequently including programming and articles that
feature behavioral scientists discussing smoking behavior and the
techniques of quitting.

Options for environmental change and public policy are varied and
complex (Farquhar et al. 1981). The outright prohibition of smoking
is not feasible, but limited prohibitions on smoking in public and
some private places can have desirable effects in shifting negative
attitudes. Restrictions on marketing are difficult on a local level, but
constraints on advertising or availability may have a powerful effect.
As indicated in a previous section, new taxes or other broad
environmental changes are more likely to affect young smokers
among whom dependence is not firmly established. Thus, they may
be expected to have cumulative, long-term effects on future smoking

527


rates. There is a role for research in clarifying optimal forms of
restriction, but is has not been implemented, even in worksites
where the effects of restrictions could be evaluated (Orleans and
Shipley 1982).

Future studies must also develop an integrated model for combin-
ing cessation and prevention activities. Although the processes
involved in the adoption of smoking are clearly different from those
involved in its discontinuance, there are commonalities to be
explored to find more efficient strategies for smoking reduction. The
research of Flay et al. (1983a) is particularly promising in this
regard. Any program that changes perceptions of social norms or
other environmental factors may influence nonadoption or discon-
tinuance of cigarette smoking, but effects will probably be greatest
on young people not dependent on tobacco or on older age groups
where the adverse health effects of smoking are already becoming
apparent.

Summary and Conclusions

1. Community studies of smoking cessation and prevention are
becoming an established paradigm for public health action
research. Such studies emphasize large-scale delivery systems,
such as the mass media, and include community organization
programs seeking to stimulate interpersonal communication in
ways that are feasible on a large-scale basis.

2. Although there, are methodological limitations to nearly all
communitywide studies, the results yield fairly consistent
positive results, indicating that large-scale`programs to reduce
smoking can be effective in whole populations. Person-to-
person communication appears to be a necessary part of a
successful community program to reduce smoking.

3. Further research is needed, with both improved methodology
and more emphasis on low socioeconomic status groups that
have not yet shown population trends toward reduced smoking.
4. Several promising directions for research are clear, but the
most important future trends will be toward the establishment
of smoking reduction programs within existing health services,
the combination of chronic disease prevention with mental
health promotion via mass media and community intervention,
and the development of social policy to establish integrated
strategies for smoking cessation and prevention.

528


References

AMERICAN CANCER SOCIETY. A Study of the Impact of the 1980 Great American
Smokeout. Summary Report. National program sponsored by Gallup Organization,
Inc., and analyzed by Lieberman Research, Inc., January 1981,7 pp.
ATKIN, C. Research evidence on mass mediated health communication campaigns.
In: Nimmo, D. (Editor). Communication Yearbook III. New Brunswick, New Jersey,
Transaction Books, 1979.

AUTORENGRUPPE NATIONALES FORSCHUNGSPROGRAMM. Wirksamkeit der
Gemeindeorientierten Pruvention Kardiovascularer Krunkheiten. [Effectiveness of
Community-Oriented Prevention of Cardiovascular Disease.] Bern, Hans Huber,
  1984.

BANDURA, A. Social Learning Theory. Englewood Cliffs, New Jersey, Prentice-Hall,
  1977.

BENFARI, R.C., MCINTYRE, K., BENFARI, M.J.F., BALDWIN A., OCKENE, J. The
use of thiocyanate determination for indication of cigarette smoking status.
Evaluation Quarterly l(4): 629438, November 1977
BERNSTEIN, D.S. Modification of smoking behavior: An evaluative review. Psycho-
logical Bulletin 71(6): 418-440, June 1969.

BERNSTEIN, D.A., McALISTER, A.L. The modification of smoking behavior:
Progress and problems. Addictive Behaviors l(2): 89-102, 1976.
BEST, J.A. Mass media, self-management, and smoking modification. In: Davidson,
P.O., Davidson, SM. (Editors). Behavioral Medicine: Changing Health Lifestyles.
New York, Brunner/Mazel, 1980, pp. 371-390.
BLACKBURN, H. Research and demonstration projects in community cardiovascular
disease prevention. Journal of Public Health Policy, in press.
BLACKBURN, H., LUEPKER, R., KLINE, F.G., BRACHT, N., CARLAW, R.,
JACOBS, D., MI'ITELMARK, M., STAUFFER, L., TAYLOR, H.L. The Minnesota
Heart Health Program: A demonstration project in cardiovascular disease
prevention. In: Weiss, S. 0Qlitor). Settings for Health Promotion in Behavioral
Health: A Handbook for Health Enhancement and Disease Prevention. Silver
Spring, Maryland, John Wiley & Sons, in press.
BLACKBURN, H.. PECHACEK, T. Smoking Cessation and the Minnesota Heart
Health Program. In: Nosbakken, D. (Editor). Proceedings of the Fifth World
Conference on Smoking and Health, in press.
BOTVIN, G.J., ENG, A., WILLIAMS, C.L. Preventing the onset of cigarette smoking
through life skills training. Preventive Medicine 9(l): 135-143, January 1980.
BRENGELMANN. J.L. Experimente zur Behandlung des Rauchens. [Experiments in
the Treatment of Smoking.] Stuttgart, Verlag W. Kohlhammer, 1976.
BRESLOW, L. Control of cigarette smoking from a public policy perspective. In:
Breslow, L., Fielding, J.E., Lave. L.B. &litors). Annual Review of Public Health.
Volume 3. Palo Alto, California, Annual Reviews Inc., 1982, pp. 129-151.
CAMPBELL, D.T., COOK, T.D. Quasi-Experimentation: Design and Analysis for Field
Settings. Chicago, Rand McNally College Publishing Company, 1979.
CAPLAN, R.D., COBB, S., FRENCH, J.R.P., Jr. Relationships of cessation of smoking
with job stress, personality, and social support. Journal of Applied Ps-ychology
6of2): 211-219, April 1975.

COLLE'ITI, G., BROWNELL, K.D. The physical and emotional benefits of social
support: Application to obesity, smoking, and alcoholism. In: Hersen, M., Eislee,
R.M., Miller, P.M. (Editors). Progress in Behavior Modification. Volume 13. New
York, Academic Press, 1982, pp. 109-178.
CRAIK, K.H. Environmental psychology. Annual Reuierc, of Ps.vchology 24: 403422,
  1973.

DANAHER. B.G., BERKANOVIC, E., GERBER, B. Smoking and television: Review of
extant literature. Addwtit,e BehaLllors 812): 173-182. 1983

529


DiCLEMENTE, CC., PROCHASKA, J.O. Selfchange and therapy change of smoking
behavior: A comparison of processes of change in cessation and maintenance.
Addictioe Behaviors 7(2): 133-142, 1982.

DUBREN, R. Evaluation of a televised stopsmoking clinic. Public Health Reports
92(l): 81-84, January-February 1977a.

DUBREN, R. Self-reinforcement by recorded telephone messages to maintain
nonsmoking behavior. Journal of Consulting and Clinical Psychology 45(3): 35%
360, June 1977b.

EGGER, G., FITZGERALD, W., FRAPE, G., MONAEM, A., RUBINSTEIN, P.,
TYLER, C., MCKAY, B. Result of large scale media antismoking campaign in
Australia: North Coast "Quit For Life" Programme. British Medical Journal 286:
112~1128,1983.

EVANS, R.I. Smoking in children: Developing a social psychological strategy of
deterrence. Preventive Medicine 5(l): 122-127, March 1976.
EVANS, RI., HANSEN, W.E., MITTLEMARK, M.B. Increasing the validity of self-
reports of smoking behavior in children. Journal of Applied Psychology 62(4): 521-
523, April 1977.

FARQUHAR, J.W., WOOD, P.D., BREITROSE, H., HASKELL, W.L., MEYER, A.J.,
MACCOBY, N., ALEXANDER, J.K., BROWN, B.W., Jr., McALISTER, A.L.,
NASH, J.D., STERN, M.P. Community education for cardiovascular health. Luncet
l(8023): 1192-1195, June 4,1977.

FARQUHAR, J.W. The community-based model of life style intervention trials.
American Journal ofEpidemiology 108(2): 103-111, August 1978.
FARQUHAR, J.W., MAGNUS, P.F., MACCOBY, N. The role of public information
and education in cigarette smoking controls. Canadian Journal of Public Health
72(6): 412-420, November-December 1981.

FLAY, B.R., COOK, T.D. The evaluation of public communication campaigns. In: Rice,
R., Paisley, W. (Editors). Media Campaigns. Beverly Hills, Sage, 1981.
FLAY, B.R., d'AVERNAS, J.R., BEST, J.A., KERSALL, M.W., RYAN, K.B. Why
young people do it and ways of preventing it. In: McGrath, P., Firestone, P.
(Editors). Pediatric and Adolescent Behauioml Medicine. Springer Series on
Behavior Therapy and Behavioral Medicine, Volume 10. New York, Springer
Verlag, 1983a, pp. 132-183.

FLAY, B.R., DITECCO, D., SCHLEGEL, R.P. Mass media in health promotion. Health
Education Quarterly 7: 127-143,198O.

FLAY, B.R., HANSEN, W.B., JOHNSON, CA., SOBEL, J.L. Involvement of Children
in Motiuating Smoking Parents to Quit Smoking With a Television Progmm. Paper
presented at the Fifth World Conference on Smoking and Health, Winnipeg,
Manitoba, July 1983b.

FRITSCHLER, A.L. Smoking and Politics: Policy-Making and the Federal Bureau-
cracy. Second Edition). Englewood Cliffs, New Jersey, Prentice-Hall, 1975.
FUJI, E. The demand for cigarettes. Applied Economics 12: 479-489,1980.
GREEN, L.W. Identifying and overcoming barriers to the diffusion of knowledge
about family planning. Advances in Fertility Control X2): 21-29, 1970.
GRIFFITHS, W., KNUTSON, A.L. The role of maas media in public health. American
Journal of Public Health 50(4): 515-523, April 1960.
GUTZWILLER, F., SCHWEIZER, W. Intervention on smoking: An individual and
collective challenge. In: Schettler, F.G., Gotto, A.M., Middelhoff, G., Habenicht,
A.J.R., Jurutka, K.R. (Editors). Atherosclerosis: Proceedings of the Sixth Znterna-
tionnl Symposium. New York, Springer Verlag, 1983.
HJERMANN, I., VELVE BYRE, K., HOLME, I., LEREN, P. Effect of diet and
smoking intervention on the incidence of coronary heart disease. Report from the
Oslo study group of a randomized trial in healthy men. Lancet 2(82591: 1303-1310,
December 12,1981.

530


HOLME, I., HELGELAND, A., HJERMANN, I., LEREN, P. The Oslo study: Social
indicators, risk factors and mortality. In: Bostrom, H., Ljungstedt, N. (Editors).
Medical Aspects of Mortality Statistics. Skandia International Symposia. Stock-
holm, Sweden, Almquist and W&sell International, 1981, pp. 165-181.
HORWITZ, M.B., HINDI-ALEXANDER, M., WAGNER, T.J. Psychosocial Mediators
of Long-Term Abstinence Following Smoking Cessation. Paper presented at the
99th meeting of the American Psychological Association, Washington, D.C.,
August 2491982.

HUGHES, G.H., HYMOWITZ, N., OCKENE, J.K., SIMON, N., VOGT, T.M. The
Multiple Risk Factor Intervention Trial (MRFIT). V. Intervention on smoking.
Preuentiue Medicine lO(4): 476-500, July 1981.
HURD, P.D., JOHNSON, CA., PECHACEK, T.F., BAST, L.P., JACOBS, D.R.,
LUEPKER, R.V. Prevention of cigarette smoking in seventh grade students.
Journal of Behauioml Medicine 3(l): 15-28, March 1980.
KASL, S.V. Cardiovascular risk reduction in a community setting: Some comments.
Journal of Consulting and Clinical Psychology 48(2): 143-149, April 1980.
KLAPPER, J.T. The Effects ofMass Communication. New York, Free Press, 1960,302
  PP.

KORNITZER, M., DeBACKER, G., DRAMAIX, M., THILLY, C. The Belgian Heart
Disease Prevention Project: Modification of the coronary risk profile in an
industrial population. Circulation 61(l): 18-25, January 198Oa.
KORNITZER, M., DRAMAIX, M., KI'ITEL, F., DeBACKER. G. The Belgian Heart
Disease Prevention Project: Changes in smoking habits after two years of
intervention. Preuentiue Medicine 9(4): 496-503, July 198Ob.
LANDO, H.A., McGOVERN, P.G. Three-year data on a behavioral treatment for
smoking: A follow-up note. Addictiue Behaviors 7(2): 77-181, 1982.
LASATER, T. The Pawtucket Heart Program. Paper presented at ADAMHA Commu-
nity Prevention Research Technical Review, June 1983.
LEATHAR, D.S. The use of mass media health education campaigns in Scotland.
Journal of International Health Education 19(4): 122129,1981.
LEVENTHAL, H., CLEARY, P.D. The smoking problem: A review of the research and
theory in behavioral risk reduction. Psychological Bulletin B&2): 370-405, 1980.
LEVENTHAL, H., CLEARY, P., SAFER, M., GUTMANN, M. Cardiovascular risk
modification by community-based programs for life-style change: Comments on the
Stanford Study. Journal of Consulting and Clinical Psychology 48(2): 159-158,
April 1980.

LEWIT, E.. COATE, D., GROSSMAN, M. The effects of government regulation on
teenage smoking. Journal of Law and Economics 24: 545573, December 1981.
LICHTENSTEIN, E. The smoking problem: A behavioral perspective. Journal of
Consulting and Clinical Psychology W6): 804-819, 1982.
MACCOBY, N., ALEXANDER, J. Use of media in lifestyle programs. In: Davidson,
P.O., Davidson, SM. (Editors). Behavioral Medicine: Changing Health Lifestyles.
New York, Brunner/Mazel, 1980.

McALISTER, A. Social-psychological approaches. In: National Institute on Drug
Abuse. Preventing Adolescent Drug Abuse. Intervention Strategies. NIDA Research
Series, Volume 47. U.S. Department of Health and Human Services, Public Health
Service, Alcohol, Drug Abuse, and Mental Health Administration, DHHS Publica-
tion No. (ADM)83-1280,1983, pp. 36-50.

McALISTER, A.L., PERRY, C., MACCOBY, N. Adolescent smoking: Onset and
prevention. Pediatrics 63(4): 65&658, April 1979.
McALISTER, A., PUSKA, P., KOSKELA, K., PALLONEN, U., MACCOBY, N.
Psychology in action: Mass communication and community organization for public
health education. American Psychologist 35(4): 375-379, April 1980.

531


McALISTER, A.. PUSKA, P, SALONEN, J.T., TUOMILEHTO, J., KOSKELA, K.
Theory and action for health promotion: Illustrations from the North Karelia
Project. American Journal of Public Health 72~1): 43-50, January 1982.
McCOMBS, M.E., SHAW, D.L. The agenda-setting function of mass media. Public
Opinion Quarterly 36(2): 176187, Summer 1972.
MERMELSTEIN, R., LICHTENSTEIN, E., MCINTYRE, K. Partner support and
relapse in smoking-cessation programs. Journal of Consulting and Clinical
Psychology 51(3): 465-466, June 1983.

MEYER, A., MACCOBY, N., FARQUHAR, J. The role of opinion leadership in a
cardiovascular health education campaign. In: Ruben, B.D. (Editor). Communica-
tion Yearbook I. New Brunswick, New Jersey, Transaction Books, 1977.
MEYER, A.J., NASH, J.D.. McALISTER, A.L., MACCOBY, N., FARQUHAR, J.W.
Skills training in a cardiovascular health education campaign. Journal of
Consulting and CIznical Psychology 48(2): 129-142, April 1980.
MULTIPLE RISK FACTOR INTERVENTION RESEARCH GROUP. Multiple Risk
Factor Intervention Trial. Risk factor changes and mortality results. Journal of the
American Medical Association 248(12): 1465-1477, September 24,1982.
NATIONAL INSTITUTE ON EDUCATION. Teenage Smoking: Immediate and Long-
Term Patterns. US. Department of Health, Education, and Welfare, National
Institute on Education, November 1979,267 pp.
OCKENE, J.K., NUTALL, R., BENFARI, R.C., HURWITZ, I., OCKENE, I.S. A
psychosocial model of smoking cessation and maintenance of cessation. Preventive
Medicine lo(5): 623-638, September 1981.

ORLEANS, C.S., SHIPLEY, R.H. Worksite smoking cessation initiatives: Review and
recommendations. Addictive Behaviors 7(l): l-16, 1982.
PECHACEK, T.F., FOX, B.H., MURRAY, D.M., LUEPKER, R.V. Review of techniques
for measurement of smoking behavior. In: Mataraxzo, J.D., Miller, N.E., Weiss,
S.M., Herd, J.A. (Editors). Behauioral Health: A Handbook of Health Enhancement
and Disease Preuention. New York, John Wiley and Sons, in press.
PECHACEK, T.F., McALISTER, A. Strategies for the modification of smoking
behavior: Treatment and prevention. In: Ferguson, J.M., Taylor, C.B. (Editors).
Extended Applications and Issues. The Comprehensive Handbook of Behavioral
Medicine, Volume 3. Jamaica, New York, Spectrum Publications, 1980, pp. 257-
  298.

PUSKA, P., KOSKELA, K. Community-based strategies to fight smoking: Experiences
from the North Karelia Project in Finland. New York State Journal of Medicine
83(13): 1335-1338, December 1983.

PUSKA, P., McALISTER, A., PEKKOLA, J., KOSKELA, K. Television in health
promotion: Evaluation of a national programme in Finland. International Journal
of Health Education 24(4): 238250, October-December 1981.
PUSKA, P., NISSINEN, A., SALONEN, J.T., TUOMILEHTO, J. Ten years of the
North Karelia Project: Results with community-based prevention of coronary
heart disease. Scandinavian Journal of Social Medicine ll(3): 65-68,1983a.
PUSKA, P., SALONEN, J.T., NISSINEN, A., TUOMILEHTO, J., VARTIAINEN. E..
KORHONEN, H., TANSKANEN. A., RONNQVIST, P., KOSKELA, K., HU'ITU-
NEN, J. Coronary risk factor changes during ten years of a preventive community
programme, the North Karelia Project. British Medical Journal 287: 184G1844,
  1983b.

PUSKA. P., TUOMILEHTO. T., SALONEN, J., NEIITAANMAKI, L., MAKI, J.,
VIRTAMO, J., NISSINEN, A., KOSKELA, K., TAKALO, T. Changes in coronary
risk factors during comprehensive five-year community programme to control
cardiovascular diseases (North Karelia Project). British Medical Journal 2(6198):
1173-1178, November 10,1979.

PYRORALA, K. The epidemiology of coronary heart disease in Finland. A review.
Duodecim 90: 1605-1622.1974.

532


ROGERS, E., SHOEMAKER. F. Communication of Innotjations: A Cross-Cultural
Approach. New York, Free Press, 1971.

ROSE. G., HAMILTON, P.J.S. A randomised controlled trial of the effect on middle-
aged men of advice to stop smoking. Journal of Epidemiology and Communit:
Health 32(4): 275281, December 1978.

ROSE, G., HAMILTON, P.J.S., COLWELL, L., SHIPLEY, M.J. A randomised
controlled trial of anti-smoking advice: iLLyear results. Journal of Epzdemiology
and Community Health 36l21: 102-108. June 1982.
ROSE, G., HELLER, R.F., PEDOE. H.T., CHRISTIE, D.G.S. Heart disease prevention
project: A randomized controlled trial in industry. British Medzcal Journal 116216):
747-751, March 15,198O.

SAPOLSKY, H.M. The political obstacles to the control of cigarette smoking in the
United States. Journal of Health Politics. Polic? and Lnu 512): 277-290. Summer
  1980.

SYME, S.L., ALCALAY, R. Control of cigarette smoking from a social perspective. In:
Breslow, L., Fielding, J.E.. Lave, L.B. (Editors). Annual ReLiew of Public Health.
Volume 3. Palo Alto, California, Annual Reviews Inc.. 1982, pp. 179-199.
TELCH, M.J., KILLEN, J.D., McALISTER, A.L.. PERRY. C.L., MACCOBY. N. Long-
term follow-up of a pilot project on smoking prevention with adolescents. Journal
of Behavioral Medicine 5(1 I. l-8.1982.

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES. The Health Conse-
quences of Smoking: Cancer. A Report of the Surgeon General. U.S. Department of
Health and Human Services, Public Health Service. Office of the Assistant
Secretary for Health, Office on Smoking and Health. DHHS Publication No.
(PHS)82-50179,1982,302 pp.

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES. The Health Conse-
quences of Smoking: Cardioaascular Disease. A Report of the Surgeon General. U.S.
Department of Health and Human Services, Public Health Service, Office of the
Assistant Secretary for Health, Office on Smoking and Health. DHHS Publication
No. (PHS)84-50204,1983,388 pp.

VARTIAINEN, E., PALLONEN. U., McALISTER, A., KOSKELA, K., PUSKA, P.
Effect of two years of educational intervention on adolescent smoking (The North
Karelia Youth Project). Bulletin of the World Health Organization 61(31: 529-532.
  1983.

WAKE, R., McALISTER, A.. NOSTBAKKEN. D. A Manual on Smoking and Children
Technical Report Series, Volume 73. Geneva, International Union Against Cancer,
  1982.

WALLACK, L.M. Maas media campaigns: The odds against finding behavior change.
Health Education Quarterlv 8(3): 209-259, Fall 1981.
WARNER, K.E. The effects of the antismoking campaign on cigarette consumption.
American Journal ofPublic Health 67(7): 645-650, July 1977.
WARNER, K.E., MURT, H.A. Impact of the anti-smoking campaign on smoking
prevalence: A cohort analysis. Journal of Public Health Policy 3(4): 374-390.
December 1982.

WERKO, L. Prevention of heart attacks. A multifactoral preventive trial in
Gothenberg, Sweden. Annals of Clinical Research 1112): 71-79, April 1979.
WEST, D.W., GRAHAM, S., SWANSON, M., WILKINSON, G. Five year follow-up of a
smoking withdrawal clinic population. American Journal of Public Health 67~61:
536-544, June 1977.

WILHELMSEN, L. Risk factors for disease according to population studies in
ateborg, Sweden. Paper presented at Skandia International Symposia, September
2%25, 1980. In. Bostrom, H.. Ljungstedt. H. IEditors1. Medical Aspects of Mortaltt?
Statutics. Stockholm, Sweden, Almquist and Wiksell International. 1981, pp. 7%
  88.

533


WILHELMSEN, L.. TIBBLIN, G., WERKO, L. A primary preventive study in
Gothenburg, Sweden. Preuentiue Medicine lfl-2): 15%160, March 1972.
WORDEN, J.K., FLYNN, B.S., BRISSON, SF., McCAULIFFE, T.L. Adult Communi-
cation Skills Training to Preuent Adolescent Smoking. Paper presented at the
Annual Meeting of the American Public Health Association, Dallas, November 15,
  1983.

WORLD HEALTH ORGANIZATION. Vital Statistics and Causes of Death. 1972,
Volume 1. Geneva, 1975.

WORLD HEALTH ORGANIZATION EUROPEAN COLLABORATIVE GROUP. An
international controlled trial in the multifactorial prevention of coronary heart
disease. International Journal of Epidemiology X3): 219-224, September 1974.
WYNDER, E.L., HOFFMANN, D. Tobacco and health: A societal challenge. New
England Journal of Medicine 3OOf16): 894-903,1979.

534


INDEX

Chronic ?Auctive Lung Disease is abbreviated as COLD throughout this index.

ACROLEIN

alpha,-antitrypsin effect, 436
alveolar macrophage effects, 432
cilioinhibitory effect, 295
gas phase component, 294, 417
ADDICTION

cessation of smoking, relationship,
  468, 461, 485
ADDITIVES

(See also MENTHOL; PHENOL)
low yield cigarettes, increasing use,
13, 352, 354

ADOLESCENTS
Gee also CHILDREN)
increased cough in smokers, 6
prevalence of cough and amount
  smoked, 64

sex differences in prevalence of
respiratory symptoms, 66
small airways dysfunction in smok-
ers, 37, 427

smoking rates with smoking and
  nonsmoking parents, 566
ADVERTISING
(See also MASS MEDIA)
government regulation of tobacco
  advertising, 506-507, 514, 520,
   527
promotion of cardiovascular risk re
  duction, 506
smoking cessation or reduction ef-
  fects, 457
AGE DIFFERENCES
airflow obstruction incidence, 103
cessation rates in post-MI patients,
   475
cessation success, 466
chronic airflow obstruction, preva-
  lence, 78
chronic bronchitis, prevalence, 46
   47
COLD mortality, 191-192, 197,
   203-205

AGE DIFFERENCES-Contd.
cough and phlegm, prevalence, 46,

emphysema, severity in smokers
and nonsmokers, 126, 241-242
initiation of smoking and COLD
mortality, 209

lung pathology in smokers, 124
125, 231

mucociliary transport, 233
pulmonary function, 6
pulmonary function in children of
  smoking parents, 398
pulmonary function, rate of de
  cline, 9, 137
reductions in smoking with commu-
  nity intervention studies, 511-
   512
small airways dysfunction, 9, 29-
  30, 32-35, 37-39, 136-137
AIR POLLUTION
(See also PASSIVE SMOKING)
airflow obstruction relationship,
   105
bronchitis morbidity factor, 212
COLD mortality factor, 192
lung clearance effect, 424
particulates exposure compared
  with smoking, 417
workplace levels and pulmonary
  function, 31
ALCOHOL CONSUMPTION
abstinence in pregnancy, 462
airflow obstruction relationship,
   105106
ALLERGY
atopy and pulmonary function, 106
lung hypersensitivity and airflow
  obstruction, 104-105, 118
skin test reactivity and incidence
  of airflow obstruction, 103

535


INDEX

Alpha,-antiprotease See ALPHA,-
  ANTITRYPSIN
ALPHA,-ANTITRYPSIN
antiprotease activity, 262-264
deficiency in panacinar emphyse
   ma, 234-235
elastase inhibition, 8, 11. 301
genetic deficiency, 9-10, 83, 104,
  118, 129-137, 261-262, 275
oxidants and decreased inhibitory
  capacity, 273-274, 435
papain elastolysis, inhibitor, 265
tar and nicotine content effect on
  elastase inhibition, 340
tobacco smoke effects, 434-437
Alpha,-proteinase inhibitor
See ALPHA,-ANTiTRYPSIN
ALVEOLAR MACROPHAGES
changes in smokers, 255257, 259,
   261, 27%279
changes induced by tobacco smoke,
   431-434
emphysema pathogenesis, role, 26%
   270
increased numbers in smokers, 11,
  270-271, 301
increased numbers with nitrogen
  dioxide, 276
lung clearance mechanisms, role,
   42-24
neutrophil chemotaxis, role, 258
toxicity of cigarette smoke, 279-280
ALVEOLITIS
smoking relationship, 255
AMISH
COLD mortality, 213
AMMONIA
gas phase component, 294, 417
ANGINA
contraindication for nicotine chew-
  ing gum, 477
Antibodies See IMMUNE SYSTEM
ANTISMOKING CAMPAIGNS
(See also SMOKING INTERVEN-
  TION STUDIES)
smoking behavior, effect, 457
smoking cessation at prenatal clin-
  ics, effect, 462-463
ASBESTOS
cessation success in exposed ship
  yard workers, 482-483

536

ASTHMA
bronchoconstrictive effect of smoke
  inhalation in asthmatics, 42%
   429
children of smoking parents, 389,
  392-393, 403
mortality in California physicians,
   211
nonsmokers exposed to tobacco
  smoke, 403, 405406
reversibility of airflow obstruction,
   75
ATROPINE
cilioinhibitory effect, 295
AVERSIVE SMOKING
cessation effectiveness, 469

BACTERIA
clearance from respiratory tract,
   281
macrophage bactericidal capacity in
  smokers and nonsmokers, 27%.
   279
reduced resistance to infection in
  smoke-exposed animals, 280
BEHAVIOR MODIFICATION
physicians' efforts to get patients
  to quit, 455
social reinforcement in community
  intervention trials, 506
BIRTHWEIGHT
maternal smoking relationship, 461,
   464-465
BRONCHIOLITIS
childhood, association with subse-
  quent panacinar emphysema,
   236
COLD, role in pathogenesis, 11
pathology, 223, 230-231
smoking relationship, 242, 255-256
BRONCHITIS
(See also MUCUS HYPERSECRE
  TION)
abnormalities in regional gas ex-
  change, 22
aerosol clearance effects, 292-293
childhood, association with panaci-
  nar emphysema, 236
children of smoking parents, 13,
  393, 405
definition, 45-46, 224
excessive morbidity in Britain, 212
mortality and age of smoking initi-
   ation. 209-210


BRONCHITIS-Contd.
mortality and depth of inhalation,
   208

mortality and smoking habit, 201
mortality in physicians, 211
mucociliary dysfunction, 12, 233,
   297302
natural history, 115
particulate phase components, role,
   426
pathology, 227, 229
prevalence, 46
smoking relationship, 48, 255
BRONCHOCONSTRICTION
dogs exposed to cigarette smoke,
   429
induction by cigarette smoke, 428,
   430
inhalation pattern relationship,
   349-350
low yield cigarettes effect, 341

CADMIUM
induction of emphysematous lesions
  in animals, 276
tobacco smoke component, 426
CARBON DIOXIDE
gas phase component, 417
CARBON MONOXIDE
breath test to demonstrate smoking
  effects in pregnant women, 464
breath test to validate self-reported
  cessation, 460, 463
gas phase component, 417
increased alveolar epithelial perme-
  ability, role, 430
indoor air pollutant, 366, 383
low-tar and low-nicotine cigarettes,
  yields, 345-346
CARBOXYHEMOGLOBIN
asthmatics exposed to tobacco
  smoke, levels, 403
inhalation pattern relationship,
  345,349
measure of carbon monoxide at+
  sorption, 366, 383
nonsmokers exposed to tobacco
  smoke, levels, 384
cARclNOGElwS1s
consequence of mucociliary dysfunc-
  tion, 301
CASKIN
chemotaxis of polymorphonuclear
  leukocytes effect, 433

INDEX

CATALASE

reduction of smoke effects on al-
  pha,-protease inhibitor, 436
CERULOPLASMIN
prevention of alpha,-antitrypsin ox-
  idation, 274

CESSATION OF SMOKING
(See also REDUCTION OF
  SMOKING)

cardiopulmonary function improve-
ment, 465

COLD incidence and progression ef-
fects, 7-3

COLD mortality relationship, 10,
210-211, 214

community intervention studies, 15,
503-528

cough and phlegm reduction, 9, 48,
137

emphysema morbidity and mortali-
ty, 126

emphysema severity in ex-smokers,
241-242

emphysematous changes, effect,
127-129

lung clearance effects, 430
mechanical properties of lungs, ef-
fect, 123

morbidity and mortality reduction,
465

mucociliary transport effects, 293,
300

parents, effect on children's asth-
ma, 403

physicians, 456
pulmonary function effects, 9, 227,
232, 242

pulmonary function effects, rate of
decline, 9, 116-113, 137
reasons given by ex-smokers, 457
respiratory symptoms in ex-smok-
ers, 67

role of physicians, 14, 455-488
sex differences in pulmonary func-
  tion effects, 104
small airways function effects, 11,
  4042, 44, 137
CHEST INFECTIONS
airnow obstruction, role in etiology,
  83, 107
CHILDREN

(See also ADOLESCENTS)
influence on parental smoking cee-
sation, 468

537

480-144 0 - 85 - 19


INDEX

CHILDREN&&d.
pulmonary function effects of
  smoking, 398
respiratory illnesses and subsequent
  airflow obstruction, 104, 106, 118
respiratory infections and COLD
  susceptibility, 7
respiratory symptoms, parental
  smoking relationship, 13, 388-
  389, 392-393, 397-398, 402403,
   405
school-based prevention programs,
   519-524
CHLORAMINET
inhibitory capacity of alpha,-anti-
  trypsin, effect, 273-274, 436
Chronic airflow obstruction See
PULMONARY FUNCTION
CIGAR SMOKERS
COLD mortality, 10, 211-212, 214
cough and phlegm prevalence, 48
emphysema incidence at autopsy,
   240
former cigarette smokers, 460
Cilia See MUCO CILIARY TRANS-
PORT
CORONARY HEART DISEASE
contraindication for nicotine chew-
  ing gum, 477
COTININE
nicotine exposure in nonsmokers.
  measure, 13, 383, 405
urinary levels in children of smok-
  ing mothers, 397
COUGH
(See also MUCUS HYPERSECRE
  TION)
children of smoking parents, 388
contribution to pulmonary clear-
   ance, 300
increase in smokers, 6
low yield cigarettes effect, 336339,
   354
prevalence in smokers vs. nonsmok-
   ers, 9
tobacco smoke exposure as factor,
   386
CREATININE
urinary levels in children of smok-
  ing mothers, 397
CROSS-CULTURAL STUDIES
COLD mortality, l(r-11, 212-214

538

CYSTIC FIBROSIS
impairment of mucociliary trans-
  port, 283
submucosal gland enlargement, 225

DIABETES

contraindication for nicotine chew-
ing gum, 477

EDUCATIONAL ATTAINMENT
cessation of smoking, relationship,
  462, 468
ELASTASE

experimental induction of emphyse
ma, 8, 122-123, 134, 266270
increase in people deficient in al-
pha,-antitrypsin, 262
increased activity in smokers, 271,
301

inhibition by alpha,-antitrypsin,
301

inhibition by protease inhibitors,
434-435, 437

low yield cigarettes effects, 340
pathogenesis of COLD, role, 11
physiochemical conditions that
modify kinetics, 272-273
proximity in elastin degradation,
role, 272

release by macrophages and neu-
  trophils, 257-258, 271-272, 301,
   432-434
EIASTIN

chemoattractant for blood mono
  cytes, 258
degradation by elastase, 8
degradation by elastase, role of
  proximity, 272
degradation by papain, 265
synthesis and repair, cigarette
  smoke effect, 14, 4-39
EMPHYSEMA
age of smoking initiation and mor-
  tality, 209-210
amount smoked and severity, 11,
   137
animal models, 275-278, 433
bronchiolitis as precursor, 256
COLD disease process, 21
definition and characterization,
   119-120
detection, 120
gas phase components, role, 426
irreversibility, 75


INDEX

EMPHYSEMA-Contd.
lung clearance mechanisms effect,
   424
mechanical properties of lungs in
  etiology, 122-123
mortality in physicians, 211
oxidants in pathogenesis, 42-27
pathogenic mechanisms, 11-12, 261,
  275-301. 431, 435, 437
pathology, 223, 226, 230-242
peripheral airway resistance, 22
protease-antiprotease imbalances in
  pathogenesis, 11, 262, 270-278,
  301, 339-340
pulmonary function, 26, 121-122
quantification, 120-121
smoking relationship, 8, 10, 126
  135, 255
ESOPHAGITIS
contraindication for nicotine chew-
  ing gum, 477
EXERCISE
cessation in post-MI patients, ef-
  fect, 475
lung deposition of aerosols, effect,
   421
promotion in community interven-
  tion studies, 508

irritation following acute exposure
to tobacco smoke, 13, 386-367,
405

FAMILY

influence of support on smoking
cessation, 457, 485, 506
recidivism prevention in post-MI
patients, 475

FIBROBLASTS
membrane damage caused by ti
  bacco smoke, 436
FIBROSIS

lung clearance mechanisms, effect,
424

FILTER CIGARETTES
(See also LOW YIELD CIGAR-
  ETTES)

amount smoked and prevalence of
mucus hypersecretion, 65
cilioinhibitory capacity, 287
filter use and cessation probability.
469

mucociliary transport effects, 296-
297

FILTER CIGARETTES-Co&d.
pulmonary function effects, 116

GENETIC FACTORS
alpha,-antitrypsin deficiency, 9-10,
  83, 104, 118, 129-137, 261-262,
   275

development of airflow obstruction,
104, 106-107

GROUP COUNSELING
cessation rates in post-MI patients,

effect, 475

HEADACHE
after acute exposure
  smoke, 386
HEXAMETHONIUM
cilioinhibitory effect,
HISTAMINE

to tobacco

295

involvement in bronchoconstrictive
  response to smoking, 428
reactivity in smokers and nonsmok-
   ers, 430
release in animals exposed to ti
  bacco smoke, 429
HYDROGEN CYANIDE
ciliotoxicity, 263, 295
HYDROGEN PEROXIDE
alpha,-protease inhibition, effect,
   436
enhanced production in alveolar
  macrophages in smokers, 432
inactivation of alpha,-antitrypsin,
   274
HYPERRINESIS
maternal smoking relationship, 461
HYPERTENSION
cardiovascular risk reduction pre
  gram, factor, 515
contraindication for nicotine chew-
  ing gum, 477
pulmonary artery, association with
  chronic airflow obstruction, 232
HYPERTHYROIDISM
contraindication for nicotine chew-
  ing gum, 477

IMMUNE SYSTEM
ABH antigens and airflow obstruc-
  tion, 105

COLD susceptibility, factor, 7
smoking effects, 12. 255. 279-281,
301

539


                  INDEX

INFLUENZA
increased susceptibility in smokers,
   12, 280, 301
Involuntary smoking See PASSIVE
  SMOKING
ISOPRENE
mucociliary transport effects, 295
ISOPROTERENOL
reversal of airways reactivity, 105

LUNGS-Contd.
pulmonary epithelial permeability
  and smoking, 439.431, 439
tissue repair, cigarette smoking ef-
  fects, 437

LACTATION
inhibition by maternal smoking,
   461
LEAD
particulate phase component, 417
LEGISLATION
restrictions on smoking in public
  places, 507, 514, 520. 527
LOBELINE
nicotine substitute, 458
LOW YJELD CIGARETTES
(See also FILTER CIGARETTES)
additives, 13, 352354
cessation success and tar yield, 461
COLD mortality, 198, 201, 203
COLD risk, 12-13, 336-341, 354
lung cancer mortality relationship,
   339
mucociliary transport effects, 294
particulate concentrations and size,
   41%419
research recommendations, 353
respiratory symptoms, 66
smoking behavior effects, 341-348,
   354
tar yield and respiratory symp-
   toms, 65
LUNG CANCER
aerosol deposition at bronchogenic
  carcinoma sites, 422
low yield cigarettes relationship,
   339
mortality in smokers, 336
polonium deposition and site of
  bronchogenic carcinoma, 424
smoking behavior relationship, 333
smoking relationship, 255
LUNGS
cigarette-induced disease, pathology,
   11
growth in children of smoking
   mothers, 398
localization of emphysematous le
   sions, 275

Macrophages See ALVEOLAR
  MACROPHAGES
MARITAL STATUS
cessation of smoking, relationship,
   468-469
MASS MEDIA
(See also ADVERTISING)
antismoking educational campaigns,
   486
community intervention studies, 15,
  505506, 508-514, 523, 526, 528
televised smoking cessation classes,
   519
MATERNAL SMOKING
(See also PARENTAL SMOKING;
  PREGNANCY)
fetal and childhood effects, 461
prenatal smoking and respiratory
  infections in children, 393
METHACHOLINE
responsiveness and airways reactiv-
  ity, 105
responsiveness and smoking, 428
   429
METHOL
mucociliary transport effects, 295
Minority groups See RACIAL/
ETHNIC DIFFERENCES
MORBIDITY
bronchitis in Britain, 212
chronic airflow obstruction, 68-118
chronic mucus hypersecretion, 45-
   73
COLD prevalence and inhalation
  practices, 209
emphysema, 119-135
improvement following cessation of
  smoking, 465
small airways dysfunction, 22-44
smoking and COLD morbidity, 8-10
MORTALITY
cardiovascular diseases, declines re-
  lated to risk factor reduction
  program, 515
cessation of smoking relationship,
   465
COLD, airflow obstruction relation-
  ship, 339

540


INDEX

MORTALITY&ntd.
COLD, mucus hypersecretion rela-
  tionship, 339

COLD, smoking relationship, 8, lO-
11, 189-214, 336
fetal and neonatal, maternal smok-
ing effect, 461

myocardial infarction patients who
  quit smoking, 470
predictive effectiveness of FEV,, 72
MUCOCILIARY TRANSPORT
chronic bronchitis, 297-301
filters, effect, 296297
lung clearance of deposited particu-
  lates, 423-424

normal function, 28%286
smoke constituents, effect, 293-296,
426

tobacco smoke, effect, 12, 290-296,
  301302, 418, 431
MUCUS HYPERSECRETION
cigarette smoke effects, 11, 107,
  292, 302

COLD disease process, 21
COLD mortality relationship, 339
cough and phlegm, relationship to
airflow obstruction, 68-73
cough and phlegm, relationship to
sex and age, 6S68
cough and phlegm, relationship to
smoking, 47-48, 63-65
inhalation depth relationship, 349
low yield cigarettes, effect, 336-339,
354

measurement of cough and phlegm,
4546

phlegm in smokers vs. nonsmokers,
9

prevalence and amount smoked,
137

prevalence of cough and phlegm,
46-47

MYELOPEROXIDAS
inactivation of alpha,-antitrypsin,
  274, 436-437

MYOCARDIAL INFARCTION
cessation of smoking in post-MI pa-
  tients, 15, 470, 475476, 480-481,
   487

contraindication for nicotine chew-
ing gum, 477

N-CHLORSUCCINIMIDE
reduction of activity of alpha,-anti-
  trypsin, 436

NEUTROPHILS
changes induced by tobacco smoke,
   25S261, 432-434
chemotaxis inhibition by cigarette
   smoke, 269-270
decrease following elastase instilla-
   tion, 266
elastase source, 257-258, 267-268,
   271-272
increased numbers in smokers, 11,
   256-257, 27&271. 301
increased numbers with nitrogen
   dioxide, 276
migration in response to macro-
  phage chemotactic factor, 258
toxicity of cigarette smoke, 279-280
NICOTINE
alpha,-protease inhibitor effect, 436
alveolar epithelial permeability ef-
   fect, 430
blood levels with nicotine chewing
   gum, 476
bronchial reactivity effect in ba-
  boons, 430
bronchoconstriction effect, 428
chemokinetic factor for neutrophils,
   258, 432-433
compensatory behavior in smokers
  of low nicotine cigarettes, 421
DNA synthesis effect, 280
indoor air pollutant, 366
machine-determined yields and ac-
  tual intake, 335-336, 346-347
mucociliary transport effects, 295
nonsmokers exposed to tobacco
  smoke, levels, 383
particulate phase component, 417
reinforcer of smoking behavior, 13
saliva levels to validate cessation
   reports, 459
NICOTINE CHEWING GUM
cessation aid, 14, 460, 476478, 487
NITRIC OXIDE
mucociliary transport effects, 295
NITROGEN DIOXIDE
effect on macrophages, 279
emphysematous lesions in animals,
  role in induction, 276
gas phase component, 294
mucociliary transport effects, 295

541


INDEX

NITROGEN OXIDES
acute bronchospasm effects, 428
epithelial permeability effects, 436-
   431
gas phase component, 417
indoor air pollutant, 366
lung clearance mechanisms, toxic
  effecta, 424
NrrRosAMINE3
indoor air pollutants, 366
Nonsmokers See PASSIVE
SMOKING
NOSE
irritation following acute exposure
  to tobacco smoke, 386
NURSES
involvement in community inter-
  vention studies, 514

OCCUPATIONS
(See also WORKPLACE)
coal miners, 230, 234, 240
grain elevator workers, 31
industrial workers, 277
iron foundry workers, 42
physicians, 14-15, 194, 198, 206,
  208, 21&211, 45=, 511, 514,
   527
shipyard workers, 482-483
steelworkers, 30, 43
textile workers, 225, 242
OZONE
lung clearance mechanisms, toxic
  effects, 424
preexposure and cigarette smoke
  effect.9 in animals, 437

PAPAIN
emphysema pathogenesis, role, 26%
   266
PARENTAL SMOKING
(See also MATERNAL SMOKING)
children's encouragement to quit,
  effect, 519-520
influence on adolescent smoking
  rates, 506
pulmonary function in children,
   397-398, 405
respiratory infections in children,
  393, 397, 405
respiratory symptoms in children,
   13, 388-389, 392, 403, 405
PARTICULATRS
(See also TARS, TOBACCO)

PARTRXXATRS-ConM.
aerodynamic diameter, 418-420,
   438
exposure measurement, 383
indoor air pollutants, 366
ingestion by pulmonary macro-
  phages, 259
lung deposition, 420-422, 425, 438
lung retention, 423-424
PASSIVE SMOKING
acute airway response, 384, 386
children, respiratory infections re-
  lated to parental smoking, 393,
   397
children, subsequent susceptibility
  to COLD, 7
COLD risk effect, 13
deposition of particulates in lungs,
   425
exposure measurement, 316, 383-
   384
patients with preexisting pulmo
  nary disease, 403-405
prevalence of respiratory symp
  tams, 66
pulmonary function in children, pa-
  rental smoking relationship,
   397402
pulmonary function relationship,
   402-403
sidestream vs. mainstream smoke,
   365-366
symptomatic responses, 386-392
PEPSIN
emphysema induction in experi-
  mental animals, 123
PEPTIC ULCER
contraindication for nicotine chew-
  ing gum, 477
PEROKIDASE
transfer across tracheal epithelium,
   431
PERSONALITY
cessation of smoking factor, 469,
  481-482,485
PHENOL
mucociliary transport effects, 295-
   296
PHENYLMETHYLOXADIOZOLE
anticiliotoxic effects, 296
PHENYLVINYLOXADIOZOLE
anticiliotoxic effects, 296

542


INDEX

   PULMONARY FUNCTIONA!antd.
   children of smoking parents, 13,
     393, 397-398, 405
    chronic airflow obstruction, 42-44,
     68-118, 223-232
    cigarette smoke effects, 6, 9, 191,
     427-430, 438
    emphysema, 121-122
   expiratory airflow obstruction as
     COLD disease process, 21
   inflammation and small airways
     dysfunction, 11
   inhalation depth relationship, 349
   low yield cigarettes relationship,
     337-338, 354
    occupational exposure relationship,
      107
    passive smoking effects, 13, 384-
      386, 402-403, 405
   people deficient in alpha,-antitryp
      sin, 262
    small airways dysfunction, 22-44,
      136-137, 227

Phlegm See MUCUS HYPER-
SECRETION
PHYSICIANS
cessation of smoking and COLD
  mortality, 216211
COLD mortality, 194, 198, 206, 208
involvement in community inter-
  vention studies, 511, 514, 527
smoking cessation in patients, role,
   14-15, 455-488
smoking prevalence, 14, 456
PIPE SMOKERS
COLD mortality, 10, 211-212, 214
cough and phlegm prevalence, 48
emphysema incidence at autopsy,
   240
former cigarette smokers, 460
PNEUMOCONIOSIS
pathology, 225, 234
PNEUMONIA
children of smoking parents, 13,
  393, 405
POLONIUM
deposition at site of bronchogenic
  carcinoma, 424
particulate phase component, 417
POLYCYCLIC AROMATIC
  HYDROCARBONS
flbroblast membrane effects, 438
Polymorphonuclear leukocytea See
NEUTROPHILS
PREGNANCY
(See also MATERNAL SMOKING)
antibody production in pregnant
  smokers, 280
cessation of smoking, 14, 479-480,
   487
motivation for quitting, 484
physician intervention and ceasa-
  tion of smoking, 461-465
PREVENTION OF SMOKING
community intervention studies, 15,
   520-524
PROTEASEANTIPROTEASE
  IMBALANCE
alpha,-antitrypsin deficiency, 130
effect of oxidants, 275
emphysema pathogen&s, 11, 262,
  27@-278, 301, 339-340
smoke exposure effect, 277-278
PULMONARY FUNCTION
airway lesions relationship, 227,
   229
asthma patients, 13. 403, 405-406

RACIAL/ETHNIC DIFFERENCES
cessation of smoking during preg
  nancy, 462
chronic airflow obstruction, preva-
  lence, 78
COLD mortality, 11, 191, 214
COLD risk, 212-213
serum concentrations of alpha,-an-
  titrypsin, 263
smoking prevalence trends, 504
RECIDMSM
post-MI patients, environmental
  factors, 475
pregnant smokers, before end of
  pregnancy, 463
REDUCTION OF SMOKING
(See also CESSATION OF
  SMOKING)
physician intervention, effec-
  tiveness, 458-459
pregnant women, 463A65
psychologist's advice, effectiveness,
   468-469
RESPIRATORY SYNCYTIAL
VIRUS INFECTION
children of smoking mothers, 393,
   397

SEX DIFFERENCES
airflow obstruction prevalence, 78,
   83

543


INDEX

SEX DIFFERENCuntd.
cessation of smoking, 468
cessation rates in post-MI patients,
   475

cholesterol reduction, 512
chronic bronchitis mortality, 210
chronic bronchitis prevalence, 46-
47

COLD mortality, 10, 189, 192, 203-
207, 213-214

community intervention effec-
tiveness, 511, 514
cough and phlegm prevalence, 48,

emphysema incidence at autopsy,
24&241

emphysema severity at autopsy,
241-242

particulates deposition, 423
preventive effect of school-based
smoking interventions, 522
pulmonary function after passive
smoking, 384-386
reduction of smoking following phy-
sician intervention, 45-59
small airways dysfunction, 9, 28,
3740, 137

smoking patterns and pulmonary
  function, 32-33, 35, 104
smoking prevalence, 504
Small airways disease See PULMO-
NARY FUNCTION
SMOKING BEHAVIOR
cigarette yields, effect, 13, 64, 33P
   335

inhalation pattern and cessation
  probability, 469
inhalation pattern and COLD mor-
  tality, 203-209, 214
inhalation pattern and COLD sus-
  ceptibility, 7, 348-352, 354
low yield cigarettes relationship,
  12-13, 341-348, 354
lung deposition of particulates, ef-
  fect, 420-423, 425
lung injury relationship, 341
SMOKING INTERVENTION
  STUDIES
(See also ANTISMOKING CAM-
   PAIGNS)
cessation and prevention effects, 15
community cessation studies, .504-
  505, 507320, 528

544

SMOKING INTERVENTION STUDIES
community prevention studies, 526
  524, 528
methodological issues, 524-526, 528
research needs, 526-528
theoretical basis, 505-507
SMOKING-MACHINES
comparability to actual smoking be-
  havior, 12, 64, 333-336, 341, 354,
   420-421
SMOKING PATTERNS
age of initiation and COLD mortal-
  ity, 209-210
alveolar macrophage changes and
  amount smoked, 256
cessation probability and amount
  smoked, 459, 469, 481
COLD morbidity relationship, 9
COLD mortality and amount
  smoked, 10, 198, 201, 203, 205-
  208, 210-211, 213-214
COLD severity relationship, 336
cough and phlegm prevalence, 9,
  47-48, 137
determinants of airflow obstruction,
  92, 10%104
emphysema at autopsy and amount
  smoked, 240-241
emphysema severity, 10, 137
emphysematous changes and
  amount smoked, 126-127
mucus hypersecretion and amount
  smoked, 63-65
pulmonary function and amount
  smoked, 6-7, 9, 69, 115, 117,
  131, 137
respiratory symptoms prevalence,
   73
small airways dysfunction and
  amount smoked, 32-35, 39, 43,
   136137
SMOKING PREVALENCE
physicians, 456, 487
trends in various demographic
  groups, 503-504
SOCIOECONOMIC STATUS
cessation of smoking, relationship,
   466469
pulmonary function relationship,
   108
reduction in tobacco consumption
  in higher income groups, 503
smoking prevalence, 525-526, 528
trend toward reduced smoking, 15


INDEX

Sputum See MUCUS HYPER-
SECRETION
STRESS
cessation success relationship, 481-
   482
chronic smoking relationship, 527
management training to maintain
  nonsmoking, 509
SUPEROXIDE DISMUTASE
activity depression by tobacco
  smoke, 434
reduction of smoke effects on al-
  pha,-protease inhibitor, 436
SUPEROXIDE RADICALS
alphal-protease inhibitor activity,
  effect, 436
generation by alveolar macrophages
  in smokers, 259, 432
release from neutrophils in smok-
  ers, 433

TARS, TOBACCO
(See also PARTICULATES)
ciliotoxic effect, 295
cough and phlegm production rela-
  tionship, 337
exposure in nonsmokers, 384
mucus hypersecretion relationship
  12, 339
pulmonary function relationship,
   338
respiratory symptoms effect, 65
smoking behavior relationship, 13,
  347-348, 354
TAXES
increases as part of community in-
  tervention trials, 514

TAXES-C&M.
revenues contributed by tobacco in-
  dustry, 503

smoking deterrent effectiveness,
  457, 507, 520, 527
THIOCYANATE
plasma levels to validate self-re
  ports of cessation, 512
saliva levels to validate self-reports
  of cessation, 464
serum levels to validate self-reports
  of cessation, 508-509, 511, 513,
  518. 521522
TOBACCO SMOKE
aerosol characterization, 417420,
   438
deposition and toxicity, 14
mainstream vs. sidestream smoke,
   365-366
toxicology, 426439
TRACHEA
epithelial permeability in smoke-ex-
  posed animals, 430-431

WHEEZING
children of smoking parents, 388-
  389, 392-393
WOOD SMOKE
airflow obstruction, etiologic factor,
   83
WORKPLACE
(See also OCCUPATIONS)
air pollution and pulmonary func-
  tion, 31
smoking prohibitions and cessation,
   457

545