The Health
Consequences
of Smoking

THE CHANGING CIGARETTE

a report of the
Surgeon General

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES
Public Health Service
Olfico WI Smoking and Health


The Honorable Thomas P. O'Neill, Jr.
Speaker of the House of Representatives
Waahingto". D. C.  20515

Dear Wr. Speaker:

  I hereby submit to YOU the Health Conmequencee of Smoking-
The Changing cigarette.  lhia report ie in re*pon.e to two
Co"gre8eio"al requirements.  The Public Health Cigarette Smoking
Act of 1969 call8 upon thin Department to iaaue annual reports on
the health consequence. of smoking and to submit legislative
ret-ndatione.  Section 403 of the Health Service8 and Canter8
Amendment, of 1978 asks for a 'ntudv or etudiee of (11 the
relative health risks aeeociated with lrmoking cigarettea of
varying level, of tar, nicotine, and carbon monoxide: and (2) the
health rinka aaeociated with mmoking cigarette8 containing any
substances ccuumonly added to c-rcially manufactured
cigarettem. * .

   In preparing this report, the ecientiets and scientific
agencies of thin Department have reviewed all current scientific
evidence and have concluded that the search for leea hazardous
cigarette8 hoe not yielded a product which CL" be considered
"mafe." The per.0" who changes to a cigarette with lower maaaured
yielda may reduce certain hazards of smoking, but the benefits
will be small coapared to the benefita of quitting entirely.

  The noat important conclusion of thin report is that
government and the private comuunity alike muat intensify their
effort8 to remind the public of the hazarda of emoking and to
ameiet thoee who do smoke to quit.  we mullt step up our programa
to pareuade young people not to take up the habit in the firat
place.

  This report also notes that we must continue to monitor the
changing cigarette to insure that when new cigarette products
appear they do not bring with them new hazard0 to health.
Throughout this report the need to knew about substances added to
cigarettem ia stated repeatedly.  At present. there is no
nschanian by which government or the scientific comrmnity can
require diacloeure of these additive*, which must obviously be a
firet step in aaaeeaing their health effects.  'his needs to be
corrected by voluntary action or, if "ece*~ary, by legislation.
   0" a "umber Of occasions previoue Secretaries of this

Department have called for new and stronger health warnings, the
eetablishment of maximum level6 of "tar" and nicotine and the
dimcloeure of more information about cigarette products.  ltlie
1981 report eatabliahea the need to move forward on these
ret-ndationa.  I" particular,  I believe the manufacturere
should list yields of "tar". nicotine and other harardoua
colPpo"e"ta on their packagee and in their advertising with
appropriate explanatory information on the health significance of
theee meamuremente.  Thin would be a minimum first 8tep in giving
cigarette coneumera full and adequate information about the
products they are buying.

Patricia Roberts Harrim

Enclosure


PREFACE

This is the fourteenth report on the health consequences of smoking
which the Public Health Service has issued since 1964 and the third to
be issued during my term as Surgeon General. By Congressional
directive it considers the relative health effects of cigarettes with
varying levels of "tar" and nicotine and the relative health effects of
cigarette additives.
At the present time, a third of all smokers, some 18 million persons,
are smoking cigarettes with measured yields of less than 15 mg "tar,"
and this number is increasing by approximately 5 percent per year.
Most of these persons have changed to lower yield cigarettes in the
expectation that this will somehow reduce the hazards of their
smoking. It is in the interest of these persons, and in the public
interest, to know to what extent these expectations are justified.

In 1966, the Public Health Service held that "The preponderance of
scientific evidence strongly suggests that the lower the tar and
nicotine content of cigarette smoke, the less harmful would be the
effect."

In 19'79, the Public Health Service confirmed this statement, citing
new evidence, but was more cautious. "In presenting information to
the public," I wrote in the Preface to the 1979 Report, "three caveats
are in order: consumers should be advised to consider not only levels of
tar and nicotine but also (when the evidence becomes available) levels
of other tobacco smoke constituents, including carbon monoxide, They
should be warned that, in shifting to a less hazardous cigarette, they
may in fact increase their hazard if they begin smoking more
cigarettes or inhaling more deeply. And, most of all, they should be
cautioned that even the lowest yield of cigarettes presents health
hazards very much higher than would be encountered if they smoked
no cigarettes at all, and that the single most effective way to reduce
the hazards associated with smoking is to quit."
In this 1981 Report, the Public Health Service has reviewed the
question again and in far greater depth than before. Overall, our
judgment is unchanged from that of 1966 and 1979: smokers who are
unwilling or as yet unable to quit are well advised to switch to
cigarettes yielding less "tar" and nicotine, provided they do not
increase their smoking or change their smoking in other ways. But our

V


new review raises new questions and suggests an even more cautious
approach to the issue.

Here are the basic findings of this Report:
1. There is no safe cigarette and no safe level of consumption.
2. Smoking cigarettes with lower yields of "tar" and nicotine reduces
the risk of lung cancer and, to some extent, improves the smoker's
chance for longer life, provided there is no compensatory increase
in the amount smoked. However, the benefits are minimal in
comparison with giving up cigarettes entirely. The single most
effective way to reduce hazards of smoking continues to be that of
quitting entirely.

3. It is not clear what reductions in risk may occur in the case of
diseases other than lung cancer. The evidence in the case of
cardiovascular disease is too limited to warrant a conclusion, nor is
there enough information on which to base a judgment in the case
of chronic obstructive lung disease. In the case of smoking's
effects on the fetus and newborn, there is no evidence that
changing to a lower "tar" and nicotine cigarette has any effect at
all on reducing risk.

4. Carbon monoxide has been impugned as a harmful constituent of
cigarette smoke. There is no evidence available, however, that
permits a determination of changes in the risk of diseases due to
variations in carbon monoxide levels.

5. Smokers may increase the number of cigarettes they smoke and
inhale more deeply when they switch to lower yield cigarettes.
Compensatory behavior may negate any advantage of the lower
yield product or even increase the health risk.
6. The "tar" and nicotine yields obtained by present testing methods
do not correspond to the dosages that the individual smokers
receive: in some cases they may seriously underestimate these
  dosages.
7. A final question is unresolved, whether the new cigarettes being
produced today introduce new risks through their design, filtering
mechanisms, tobacco ingredients, or additives. The chief concern is
  additives. The Public Health Service has been unable to assess the
relative risks of cigarette additives because information was not
  available from manufacturers as to what these additives are.
In evaluating the public health significance of the finding of reduced
risk of lung cancer, it is important to recognize that the largest
component of excess mortality caused by smoking is cardiovascular
disease deaths. There is not sufficient evidence to conclude that use of
lower "tar" and nicotine cigarettes causes any reduction in this burden.
The same is true of the other major diseases caused by cigarette
smoking, most notably chronic obstructive lung disease and adverse
effects on pregnancy.

vi


These findings raise important questions of public policy. Some
appear to be easily resolved. It should be possible to work out
procedures so that cigarette manufacturers can disclose the additives
they use while still protecting their legitimate interest in trade secrets;
an effort to accomplish this is now underway. It should also be possible
to develop better methodologies to measure smoke constituents,
although no machine will ever be able to duplicate human smoking
behavior exactly. And longitudinal surveys are now being carried on in
an effort to monitor smoking behavior, and to help answer some of the
behavioral questions raised in this Report.

  Other questions pose greater difficulty. A common thread running
through the sections of the Report is that too much reliance in the past
has been placed on the nonselective measure of "tar" as a measure of
risk to the neglect of other constituents and approaches to risk
assessment. Additional epidemiologic and bioassay work is required, as
is a better definition of the fundamental mechanisms of smoking-
related disease. Further study is necessary to examine the addictive
nature of smoking and its impact on initiation, maintenance, and
ozssation, especially in light of the recent statement of the National
DrugAbuse AdvisoryCouncil that cigarette smoking is addictive.These
questions cannot be answered quickly or without expenditure of
scientific resources.

The questions raised by this Report suggest action in both the public
and private sector.

In the research community, a research plan is needed to enable us to
monitor the changing cigarette and to answer the many research
questions put forth in this Report, with special emphasis on the issues
of initiation and cessation. New measures and markers of relative
toxicity are needed to supplement "tar" and nicotine. As stated, a
voluntary disclosure and testing program needs to be developed with
cigarette manufacturers to assess the relative health risks of cigarette
additives and to protect against new hazards.
In the regulatory area, this Report suggests the need to increase the
public's access to information about the product it buys. Advertise-
ments and packages alike should display yield figures more prominent+
ly, including measures of carbon monoxide and possibly other hazard-
ous ingredients. Marketing terms such as "low-low" and "ultra-low'
need to be standardized.
In the area of public information and education, much more needs to
be done both by the Government and by private health and educational
agencies. The overriding objective must be to persuade young people
not to take up smoking and to encourage present smokers to quit.
Smokers of the lower yield cigarettes should be warned not to begin
smoking more cigarettes or inhaling more deeply. Pregnant women
should be cautioned that lower yield cigarettes are not an alternative
to quitting.

vii


Since 1964, when the first Public Health Service Report was issued,
smoking has declined in the United States from 40.3 percent of the
population to 33.5 percent. Per capita consumption of cigarettes is now
at the lowest level since 1957. There is less smoking by boys than in
many years, and smoking by girls has declined from the higher levels
of the mid-1970s. This is a tribute to the educational efforts of our
teachers, of our health professionals, and of our educational and health
agencies. There is every reason to hope and believe these trends will
continue.

Yet 54 million Americans continue to smoke, unwilling or unable to
quit. This population is at extra risk of lung cancer, heart disease,
chronic lung disease, and other diseases; it is a population with a life
expectancy months and years less than the population of nonsmokers.
The evidence presented in this Report shows that there is no "safe"
cigarette available to these smokers, but that some cigarettes may be
less hazardous than others, reducing the risks of smoking in a limited
and selective fashion.

January 12, 1931

Julius B. Richmond, M.D.
Assistant Secretary for Health and
Surgeon General

. . .
VI11


ACKNOWLEDGEMENTS

This Report was prepared by the Department of Health and Human
Services under the general editorship of the Office on Smoking and
Health, John M. Pin'ney, Director. Medical Staff Director for the
Report was Joanne Luoto, M.D., M.P.H. Managing Editor was Donald
R. Shopland.
Consulting scientific editors were David M. Burns, M.D., Ellen R
Grits, Ph.D., Jeffrey E. Harris, M.D., Ph.D., and John H. Holbrook,
M.D.
The following individuals participated in working groups at the June
1980 conference on Research Needs on Low-Yield Cigarettes. Except
where otherwise indicated, the working group chairperson also au-
thored the corresponding working group report and was responsible
for incorporating comments from other members of the group.
phamnacologyand Toxicology
Fred G. Bock, Ph.D. (Chairman), Director, Orchard Park Laboratories,
Roswell Park Memorial Institute, Orchard Park, New York
S. P. Battista, Ph.D., Senior Staff Pharmacologist, Arthur D. Little,
Inc., Cambridge, Massachusetts
James F. Chaplin, Ph.D., Director, Oxford Tobacco Research Laborato-
ry, Oxford, North Carolina
0. T. Chortyk, Ph.D., Chief, Tobacco and Health Laboratory, Richard
Russell Research Center, Athens, Georgia
Louis Diamond, Ph.D., Professor and Director of the Pharmacodynam-
its and Toxicology Division, College of Pharmacy, University of
Kentucky, Lexington, Kentucky
M. R. Guerin, Ph.D., Section Head, Bio-Organic Analysis Section,
Analytical Chemistry Division, Oak Ridge National Laboratory, Oak
Ridge, Tennessee
Jeffrey E. Harris, M.D., Ph.D., Associate Professor, Department of
Economics, Massachusetts Institute of Technology, Cambridge,
Massachusetts
Dietrich Hoffmann, Ph.D., Chief, Division of Environmental Carcino-
genesis and Associate Director of Naylor-Dana Institute, American
Health Foundation, Valhalla, New York
Harold C. Pillsbury, B.S., Technical Director, Federal Trade Commis-
sion, Tobacco Research Laboratory, Washington, D.C.

ix


W. S. Rickert, Ph.D., Department of Statistics, University of Waterloo,
Waterloo, Ontario, Canada
T. C. Tso, Ph.D., Chief, Tobacco Laboratory, U.S. Department of
Agriculture, Beltsville, Maryland
Cancer

Jesse L. Steinfeld, M.D. (Chairman), Dean of the School of Medicine,
Medical College of Virginia, Richmond, Virginia
Lawrence Garfinkel, M.A., Vice President for Epidemiology and
Statistics, American Cancer Society, Inc., New York, New York
Michael Kunze, M.D., Professor of Social Medicine, Institute of
Hygiene, University of Vienna, Vienna, Austria
William Lijinsky, Ph.D., Director, Chemical Carcinogenesis Program,
Litton Bionetics, Frederick Cancer Research Center, Frederick,
Maryland
Donald H. Luecke, M.D., Chief of Special Programs Branch, Division of
Cancer Cause and Prevention, National Cancer Institute, Bethesda,
Maryland

Marvin A. Schneiderman, Ph.D., Bethesda, Maryland
William D. Terry, M.D., Acting Director, Division of Cancer Control
and Rehabilitation, National Cancer Institute, Bethesda, Maryland
Elizabeth Weisburger, Ph.D., Chief of Laboratory for Carcinogenesis
Metabolism Branch, Carcinogenesis Intramural Program, Division of
Cancer Cause and Prevention, National Cancer Institute, Bethesda,
Maryland
Ernst L. Wynder, M.D., President, American Health Foundation, New
York, New York
Dietrich Hoffmann, Ph.D. (Special Consultant), Chief, Division of
Environmental Carcinogenesis and Associate Director of Naylor-
Dana Institute, American Health Foundation, Valhalla, New York

William P. Castelli, M.D. (Chairman), Medical Director, Framingham
Heart Study, Framingham, Massachusetts
Poul Astrup, M.D., Professor of Clinical Chemistry, University of
Copenhagen, Copenhagen, Denmark
Manning Feinleib, M.D., Dr.P.H., Associate Director for Epidemiology
and Biometry, National Heart, Lung, and Blood Institute, Bethesda,
Maryland
William Friedewald, M.D., Associate Director, Clinical Applications
and Prevention Program, National Heart, Lung, and Blood Institute,
Bethesda, Maryland
Robert S. Gordon, Jr., M.D., Special Assistant to the Director, National
Institutes of Health, Bethesda, Maryland
William R. Harlan, M.D., Professor and Chairman, Department of
Postgraduate Medicine, University of Michigan, Ann Arbor, Michi-
gan

X


Richard J. Havlik, M.D., M.P.H., Chief, Clinical and Genetics Epide-
miology Section, National Heart, Lung, and Blood Institute, Bethes-
da, Maryland

John H. Holbrook, M.D., Associate Professor of Internal Medicine,
University of Utah, Salt Lake City, Utah
Stephen B. Hulley, M.D., M.P.H., University of California, School of
Medicine, San Francisco, California
Henry C. McGill, M.D., Professor, Department of Pathology, Universi-
ty of Texas Health Science Center, San Antonio, Texas
Gardner C. McMillan, M.D., Associate Director for Etiology, Arterio-
sclerosis and Hypertension, Division of Heart and Vascular Disease,
National Heart, Lung, and Blood Institute, Bethesda, Maryland
Douglas R. Rosing, M.D., Senior Investigator, Cardiology Branch,
National Heart, Lung, and Blood Institute, Bethesda, Maryland
Nicholas J. Wald, M.D., I.C.R.S., Cancer Epidemiology and Clinical
Trials Unit, Radcliffe Infirmary, Oxford, England
William J. Zukel, M.D., Associate Director for Program Coordination
and Planning, Division of Heart and Vascular Diseases, National
Heart, Lung, and Blood Institute, Bethesda, Maryland
Chronic Obstructive Lung Disease
Philip Kimbel, M.D. (Chairman), Chairman, Department of Medicine,
The Graduate Hospital, Philadelphia, Pennsylvania
A. Sonia Buist, M.D., Associate Professor, Department of Physiology,
School of Medicine, University of Oregon, Portland, Oregon
David M. Burns, M.D., Pulmonary Division, University Hospital, San
Diego, California

Jeffrey M. Drazen, M.D., Assistant Professor of Medicine, Harvard
Medical School, Peter Bent Brigham Hospital, Boston, Massachu-
setts
Eric R. Jurrus, Ph.D., Health Scientist Administrator, Airways Dis-
eases Branch, Division of Lung Diseases, National Heart, Lung, and
Blood Institute, Bethesda, Maryland
James F. Morris, M.D., Chief, Pulmonary Disease Section, Veterans
Administration Medical Center, Portland, Oregon
Clifford H. Patrick, Ph.D., Chief, Prevention, Education, and Manpow-
er Branch, Division of Lung Diseases, National Heart, Lung, and
Blood Institute, Bethesda, Maryland
Diana Petitti, M.D., Department of Medical Methods Research, Kaiser
Permanente Medical Care Program, Oakland, California
Pregnancy and Infant Health
Lawrence D. Longo, M.D. (Chairman), Professor of Physiology and
Perinatal Biology, Professor of Obstetrics and Gynecology, School of
Medicine, Loma Linda University, Loma Linda, California
Heinz W. Berendes, M.D., M.H.S., Director, Epidemiology and Biome-
try Research Program, National Institute of Child Health and
Human Development, Bethesda, Maryland

xi


William A. Blanc, M.D., Professor of Pathology, Head, Division of
Developmental Pathology, College of Physicians and Surgeons,
Columbia University, New York, New York
Alfred W. Brann, M.D., Professor, Department of Pediatrics, Director,
Division of Neonatal-Perinatal Medicine, Emory University School
of Medicine, Atlanta, Georgia
Charlotte S. Catz, M.D., Head, Pregnancy and Perinatology Section,
Clinical Nutrition and Early Development Branch, Center for
Research for Mothers and Children, National Institute of Child
Health and Human Development, Bethesda, Maryland
Eileen G. Hasselmeyer, Ph.D., Associate Director for Scientific Review,
National Institute of Child Health and Human Development,
Bethesda, Maryland

Mary B. Meyer, Sc.M., Associate Professor, Department of Epidemiolo
gy, School of Hygiene and Public Health, The Johns Hopkins
University, Baltimore, Maryland
David Rush, M.D., Ph.D., Associate Professor of Public Health
(Epidemiology) and Pediatrics, Faculty of Medicine, School of Public
Health, Columbia University, New York, New York
Zena Stein, M.D., Professor of Public Health (Epidemiology), Sergiev-
ski Center at Columbia University, New York, New York
Behawiwal Aspects
Charles R. Schuster, Ph.D. (Chairman), Departments of Psychiatry and
Pharmacological and Physiological Sciences, Pritzker School of
Medicine, University of Chicago, Chicago, Illinois
Lynn T. Kozlowski, Ph.D. (Author), Scientist, Clinical Institute of the
Addiction Research Foundation, Toronto, Ontario, Canada
Roland R. Griffiths, Ph.D., Associate Professor of Behavioral Biology,
School of Medicine, The Johns Hopkins University, Baltimore,
Maryland
Ellen R. Gritz, Ph.D., Associate Research Psychologist, Department of
Psychiatry and Pharmacology, University of California at Los
Angeles; Research Psychologist, Veterans Administration Medical
Center, Brentwood, Los Angeles, California
Murray E. Jarvik, M.D., Ph.D., Professor of Psychiatry and Pharmacol-
ogy, University of California at Los Angeles; Chief, Psychopharma-
cology Unit, Veterans Administration Medical Center, Brentwood,
Los Angeles, California
Chris-Ellyn Johanson, Ph.D., Research Associate (Associate Professor),
Department of Psychiatry, University of Chicago, Chicago, Illinois
Sandra Levy, Ph.D., Acting Chief, Behavioral Medicine Branch,
Division of Resources, Centers, and Community Activities, National
Cancer Institute, Bethesda, Maryland

Margaret E. Mattson, Ph.D., Program Scientist, Behavioral Medicine
Branch, Division of Heart and Vascular Diseases, National Heart,
Lung, and Blood Institute, Bethesda, Maryland

xii


David M. Monsees, -Ph.D., Program Director for State and Evaluation
Projects, Behavioral Medicine Branch, Division of Resources, Cen-
ters, and Community Activities, National Cancer Institute, Silver
Spring, Maryland

Edward J. Roccella, Ph.D., Deputy Branch Chief, Health Education
Branch, Office of Prevention, Education and Control, National
Heart, Lung, and Blood Institute, Bethesda, Maryland
Michael Russell, M.D., Institute of Psychiatry, Maudsley Hospital,
London, England

The editors acknowledge with gratitude the many distinguished
scientists, physicians, and others who lent their support in the
preparation of this Report by coordinating manuscript preparation,
contributing critical reviews of the manuscript, or assisting in other
ways.

Henry Blackburn, M.D., Professor and Director, Laboratory of Physic
logical Hygiene, School of Public Health, University .of Minnesota,
Minneapolis, Minnesota
Lester Breslow, M.D., M.P.H., Dean, School of Public Health, Center
for the Health Sciences, University of California, Los Angeles,
California

Benjamin Burrows, M.D., Director, Division of Respiratory Sciences,
Arizona Health Sciences Center, Tucson, Arizona
Vincent T. .DeVita, M.D., Director, National Cancer Institute, Bethes-
da, Maryland
Donald S. Fredrickson, M.D., Director, National Institutes of Health,
Bethesda, Maryland

Maureen Henderson, M.D., Associate Vice President for Health
Sciences, University of Washington, Seattle, Washington
Norman Kretchmer, M.D., Ph.D., Director, National Institute of Child
Health and Human Development, Bethesda, Maryland
Robert I. Levy, M.D., Director, National Heart, Lung, and Blood
Institute, Bethesda, Maryland

Abraham Lillienfeld, M.D., M.P.H., D.S.C., University Distinguished
Service Professor, Department of Epidemiology, School of Hygiene
and Public Health, The Johns Hopkins University, Baltimore,
Maryland
Kenneth Moser, M.D., Director, Pulmonary Division, University Hospi-
tal, San Diego, California
R. L. Naeye, M.D., Professor and Chairman, Department of Pathology,
M.S. Hershey Medical Center, Hershey, Pennsylvania
Richard Peto, M.A., M.S.C., I.C.R.S., Regius Assessor of Medicine,
Radcliffe Infirmary, Oxford, England
William Pollin, M.D., Director, National Institute on Drug Abuse,
Rockville, Maryland

. . .
Xl11


Richard D. Remington, Ph.D., Dean, School of Public Health, Universi-
ty of Michigan, Ann Arbor, Michigan
Robert Resnick, M.D., Associate Professor, Department of Reproduc-
tive Medicine, Medical Center, University of California, San Diego,
California

Dorothy P. Rice, Director, National Center for Health Statistics,
Hyattsville, Maryland

Marvin A. Sackner, M.D., Chairman, Department of Medicine, Mt.
Sinai Medical Center, Miami Beach, Florida
Irving J. Selikoff, M.D., Professor of Community Medicine, Professor
of Medicine, Mt. Sinai School of Medicine, City University of New
York, New York, New York

Jeremiah Stamler, M.D., Chairman, Department of Community Health
and Preventive Medicine, Northwestern University Medical School,
Chicago, Illinois
Ronald W. Wilson, M.A., Chief, Health Status and Demographic
Analysis Branch, Division of Analysis, National Center for Health
Statistics, Hyattsville, Maryland

The editors also acknowledge the contributions of the following staff
and others who assisted in the preparation of the Report.
Erica W. Adams, Copy Editor, Informatics Incorporated, Rockville,
Maryland
Richard H. Amacher, Director, Clearinghouse Projects Department,
Informatics Incorporated, Rockville, Maryland
John L. Bagrosky, Associate Director for Program Operations, Office
on Smoking and Health, Rockville, Maryland
Jacqueline 0. Blandford, Secretary, Office on Smoking and Health,
Rockville, Maryland

Tina K. Brubaker, Information Specialist, Clearinghouse Projects
Department, Informatics Incorporated, Rockville, Maryland
Betty Budd, Administrative Clerk, Office on Smoking and Health,
Rockville, Maryland
Marsha Clay, Clerk-Typist, Office on Smoking and Health, Rockville,
Maryland
Martha E. Davis, Technical Illustrator, Informatics Incorporated,
Rockville, Maryland

Wesley Dean, Clerk-Typist, Office on Smoking and Health, Rockville,
Maryland
Stephanie D. DeVoe, Data Entry Operator, Informatics Incorporated,
Rockville, Maryland
Steve A. Fairbairn, Applications Manager, Information Processing
Services Division, Informatics Incorporated, Rockville, Maryland
Rose M. Gerondakis, Secretary, Office on Smoking and Health,
Rockville, Maryland

xiv


John F. Hardesty, Jr., Public Information Officer, Office on Smoking
and Health, Rockville, Maryland
Rebecca C. Harmon, Manager, Graphics Unit, Informatics Incorporat-
ed, Rockville, Maryland
Reginald V. Hawkins, M.P.H., Public Health Analyst, Office on
Smoking and Health, Rockville, Maryland
Patricia E. Healy, Technical Information Clerk, Office on Smoking and
Health, Rockville, Maryland
Linda Herold, Information Specialist, Clearinghouse Projects Depart-
ment, Informatics Incorporated, Rockville, Maryland
Shirley K. Hickman, Lead Data Entry Operator, Informatics Incorpo-
rated, Rockville, Maryland
Cindi M. Holgash, Secretary, Clearinghouse Projects Department,
Informatics Incorporated, Rockville, Maryland
Robert S. Hutchings, Associate Director for Information and Program
Development, Office on Smoking and Health, Rockville, Maryland
Barbara Hyde, Editor, Biospherics, Incorporated, Rockville, Maryland
Lisa A. Katz, Graphic Artist, Informatics Incorporated, Rockville,
Maryland
Margaret E. Ketterman, Public Information and Publications Assis-
tant, Office on Smoking and Health, Rockville, Maryland
Julie Kurz, Graphic Artist, Informatics Incorporated, Rockville, Mary-
land

C. Yvonne Lee, Statistician, Informatics Incorporated, Rockville,
Maryland
William R. Lynn, Public Health Analyst, Office on Smoking and
Health, Rockville, Maryland
Jacquelene Mudrock, Technical Illustrator, Informatics Incorporated,
Rockville, Maryland
Judith L. Mullaney, M.L.S., Technical Information Specialist, Office on
Smoking and Health, Rockville, Maryland
Marjorie L. Olson, Secretary, Office on Smoking and Health, Rockville,
Maryland
Raymond K. Poole, Production Coordinator, Clearinghouse Projects
Department, Informatics Incorporated, Rockville, Maryland
Karen Robinson, Clerk-Typist, Office on Smoking and Health, Rock-
ville, Maryland
Roberta A. Roeder, Secretary, Informatics Incorporated, Rockville,
Maryland
Matthew J. Schudel, Editor, Biospherics, Incorporated, Rockville,
Maryland
Valsala Sekhar, Data Entry Operator, Informatics Incorporated,
Rockville, Maryland
Linda R. Sexton, Information Specialist, Clearinghouse Projects
Department, Informatics Incorporated, Rockville, Maryland
Scott Smith, Editor, Biospherics, Incorporated, Rockville, Maryland

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

Sol Su, Sc.D., Statistician, Office on Smoking and Health, Rockville,
Maryland

Carol M. Sussman, Writer-Editor, Office on Smoking and Health,
Rockville, Maryland

Selwyn Waingrow, Public Health Analyst, Office on Smoking and
Health, Rockville, Maryland

Melissa L. Yorks, M.L.S., Technical Information Specialist, Office on
Smoking and Health, Rockville, Maryland

Xvi


TABLE OF CONTENTS

Preface.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . v

Acknowledgements . . . . ..*............................................. ix

1. Introduction, Summary, and Research
Recommendations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1

2. Pharmacology and Toxicology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27

3. Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75

4. Cardiovascular Diseases ........................................ 111

5. Chronic Obstructive Lung Disease .......................... 131

6. Pregnancy and Infant Health . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 153

7. Behavioral Aspects ............................................... 173

8. Lower "Tar" and Nicotine Cigarettes: Product Choice
and Use .............................................................. 193

Index .................................................................... 239

xvii


Section 1.  INTRODUCTION,
      SUMMARY, AND
       RESEARCH
      RECOMMENDATIONS


CONTENTS

Introduction

Dose-Response Relationship
Relative Risks of Lower "Tar" Cigarettes for Specific
Disease8

Methodologies for Assessing Relative Risk
Conclusion

Summariefs

Pharmacology and Toxicology
Cancer

Cardiovascular Diseases
Chronic Obstructive Lung Disease
Pregnancy and Infant Health
Behavioral Aspects
Lower "Tar" and Nicotine Cigarettes: Product Choice
and Use

Reaearch Recommendations From the Working Meeting
"Research Needs on Low-Yield Cigarettea"


Introduction

Great changes have taken place in the cigarette product in recent
decades. In 1954, the average "tar" yield of the sales-weighted average
cigarette was 37 mg and average nicotine yield was 2 mg. In 1930, the
comparable figures are expected to be less than 14 mg of "tar" and leas
than 1 mg of nicotine. No cigarette marketed in the United States in
1979 yielded more than 30 mg of "tar."l
Smokers have turned to these new products because of health
concerns. In the 19509, cigarette manufacturers introduced cigarette
filters as "health protection" and advertised them widely. The 1964
Report of the Surgeon General's Advisory Committee on Smoking and
Health did not discuss cigarette smoke filtration, but in 1966 the Public
Health Service reviewed the issue of smoke constituents. That report
stated, "The preponderance of scientific evidence strongly suggests
that the lower the `tar' and nicotine content of cigarette smoke, the
less harmful would be the effect." Thereafter, Government and
tobacco industry scientists conducted studies of cigarette engineering
and tobacco cultivation that could lead to lower "tar" and nicotine
yields. Later, when new products appeared, cigarette manufacturers
aggressively promoted them through advertising.

The request by Congress for an assessment of the "relative health
risks associated with smoking cigarettes of varying levels of `tar,'
nicotine, and carbon monoxide," and "the health risks associated with
smoking cigarettes containing any substances commonly added to
commercially manufactured cigarettes" has come at an appropriate
time. In the 2 years since Congress called for the present study,
manufacturers have marketed cigarettes that yield as little as 0.01 mg
of "tar" when measured by present Federal Trade Commission
technology.
The technology of producing lower "tar" cigarettes has progressed
well beyond a simple reduction in the amount of tobacco in the
cigarette or the removal of a portion of the "tar" by filtration. Present
technology has achieved "tar" reduction by alterations in plant
genetics, changes in the cultivation and processing of the tobacco leaf,
and changes in cigarette paper and filtration of the cigarette.
The methods used in testing cigarettes by machine may not
correspond to the way persons actually smoke. There is evidence to
suggest that the cigarette yields measured by machine are very
different from the yields that the consumer actually obtains by
smoking the cigarette, due in part to the difference in patterns of
smoking between testing machines and individual smokers. Therefore,
"tar" measurements of current cigarettes may not reflect the same

5


estimate of risk provided by the "tar" measurement of cigarettes
manufactured at the time of the 1966 Public Health Service Review.
Another closely related concern about lower "tar" and nicotine
cigarettes is the use of flavorings and other chemical additives. In
order to enhance consumer acceptability, flavoring substances are
added to cigarettes; it may be that the lower the "tar" yield, the more
flavoring additives are used. It is impossible to make an assessment of
the risks of these additives, as cigarette manufacturers are not
required to reveal what additives they use. No agency of the Federal
Government currently exercises oversight or regulatory authority in
the manufacture of cigarette products. Further, no agency is empow-
ered to require public or confidential disclosure of the additives
actually in use by the cigarette manufacturers.

At the same time that changes have occurred in the cigarette,
marked changes have occurred in the smoking patterns of the U.S.
population that may have substantially altered the risk of smoking
lower "tar" cigarettes. Over recent years, smokers have been taking up
regular smoking at younger ages, and the number of women who
smoke currently far exceeds the number from several decades
previously. The multiplicative risks of smoking and oral contraceptive
use is an example of how changes in the population of smokers can
make both quantitative and qualitative changes in the nature of the
risk. The proportion of the population that smokes has declined, but the
average number of cigarettes smoked by each smoker appears to have
increased over several decades. Changes have occurred in the environ-
ment, dietary habits, and behavioral patterns of the population, which
may alter the interaction between cigarette smoking and other risk
factors for disease. Thus, we have a continually changing population of
smokers who smoke a continually changing cigarette in a continually
changing manner.

DoeResponse Relationship

A clear dose-response relationship has been established between
cigarette smoking and a number of disease states; this constitutes a
major part of the evidence suggesting that lower "tar" cigarettes may
be less hazardous. It is important to understand this dose-response
relationship and the limits of the data.

The major prospective studies on smoking and disease show that the
risk of coronary heart disease and lung cancer increases in a roughly
linear manner with increasing numbers of cigarettes smoked per day.
There is also a marked increase in the risk of death from chronic lung
disease with the number of cigarettes smoked per day, but problems in
classification of this disease make it unclear whether the relationship is
linear. There is no clear evidence of a threshold effect in any of these
studies. The relationship between number of cigarettes and disease is
strengthened by showing that the risk increases with longer duration

6


of the smoking habit and with younger age at initiation of regular
smoking. Risk is thus closely related to smoke dose as measured by
number of cigarettes consumed. The relationship may result from the
effect either of repetitive doses or of cumulative smoke dosage. The
effect on risk of the time interval between cigarettes has not been
thoroughly examined, but there is evidence to suggest that risk is
related to the total dose of smoke delivered to the smoker, regardless
of the time pattern of exposure. Overall, disease risk clearly increases
with increasing depth of cigarette smoke inhalation. Pipe and cigar
smokers who do not inhale have a lower risk of tobacco-related
diseases. Thus, it is logical to hypothesize that a reduction in the actual
dose of cigarette smoke to the smoker would be accompanied by a
reduction in the risk of developing heart and lung disease.

"Tar" is a major portion of the total particulate matter of cigarette
smoke. To the extent that the machine measurements of `Yar" yield of
cigarettes reflect the actual smoke exposure resulting from use of that
cigarette, a lower "tar" cigarette should be less hazardous. In order for
the measured "tar" yield of a cigarette to reflect smoke exposure, a
number of conditions would have to be met.

First, changing the "tar" yield should not change the pattern, or
style, of cigarette use. If the smoker compensates for reduced yield by
increasing the number of cigarettes, the depth of inhalation, or the
volume or frequency of puffs, a reduction in "tar" might not result in a
reduced smoke exposure. The possible increase in the average number
of cigarettes smoked by each smoker and the possibility that the depth
of inhalation and puff volume may also have increased as the average
"tar" yield of the cigarette has declined raise a real concern that the
shift to the use of lower "tar" cigarettes may not have resulted in a
proportionate drop in smoker exposure.

A second assumption in equating lower "tar" yield per cigarette with
lower smoke exposure, and therefore lower risks of disease, is that the
reduction in "tar" is accompanied by a similar reduction in all of the
constituents of smoke, or at least all of those constituents related to
disease. As long as the lowering of the "tar" yield was largely
secondary to a reduced amount of tobacco in the cigarette or a
filtration of the smoke, a reduced "tar" yield could be assumed to
represent a lower smoke exposure. Prior to 1971, the reduction in "tar"
yield was very similar to the reduction in weight of tobacco per
cigarette (see Figure 8, Section 8), but since that time the reduction in
"tar" has been proportionately somewhat greater than the reduction in
weight of tobacco per cigarette, and this difference appears to have
increased since 1975. As discussed in this Report, the recent reductions
in "tar" yield have been accomplished by altering tobacco growth and
processing and by changes in cigarette manufacture. These changes
may have produced a "tar" with a different composition from that of

7


old higher "tar" cigarettes, and may have changed the concentrations
of some of the constituents contained in the gas phase of the smoke.
An additional concern L that the production of cigarettes with lower
"tar" and nicotine yields may involve the increasing use of additives
for tobacco processing or flavoring. Some additives available for use
are either known or suspect carcinogens or give rise to carcinogenic
substances when burned. The use of these additives may negate
beneficial effects of the reduction of "tar" yield, or might pose
increased or new and different disease risks. Therefore, the "tar" yield
of cigarettes currently being manufactured probably cannot be used as
a precise measure of current smoke exposure risk, nor be compared
quantitatively with the smoke exposure risk of the older higher "tar"
cigarettes. The major prospective studies that provide the data for our
assessment of smoking-related health risks examined persons who
smoked these older, higher "tar" cigarettes.

A third assumption in equating "tar" yield with smoke exposure is
that the "tar" yield of a machine-smoked cigarette be equal to or at
least proportional to the yield of the same cigarette when it is
consumed by the smoker. Later sections of this Report clearly establish
that the "tar" yield of the current cigarette may vary markedly with
style of smoking, with much higher yields being produced by higher
puff volumes or occlusion of the perforations in the cigarette wrapper.
Thus, the manufacturing changes that have resulted in low "tar" yield
measurements may not have resulted in a comparable reduction in the
exposure of the individual cigarette smoker.

Relative Risks of Lower `Tar" Cigarettes for Specific Diseases

Having examined the nature of the dose-response relationship and
some of the limitations of using "tar" measurements as the measure of
dosage, we can now examine the evidence available that aases~~ the
relative risk of lower "tar" cigarettes for specific disease processes. An
understanding that the different health consequences of smoking may
be caused by different smoke constituents is pivotal to these assess-
ments of relative risk. Our understanding of the specific etiologic
mechanisms by which cigarette smoke constituents cause different
diseases remains incomplete at this time.
The individual sections of this Report review in detail evidence on
the relative health hazards of lower "tar" and nicotine cigarettes.
Assessment of the relative risk of these cigarettes requires the
integration of this information; final assessment of the overall relative
health hazard of these cigarettes has not been reached. The major issue
is the potential and actual health impact of the introduction of these
cigarettes into the marketplace. Assessment of thii requires under-
standing of the changes that have taken place in the cigarette product,
the effects of those changes on smoking initiation, cessation, and
patterns of cigarette use, and the probable health effects of the net


change in cigarette smoke dose. It also requires an understanding of
the changes in risk that occur secondary to switching to lower "tar"
cigarettes distinct from the risks of lifelong use of these products.

Lung cancer is the disease process in which the relative risk of lower
"tar" and nicotine cigarettes has been most clearly evaluated. Approxi-
mately 85 percent of the incidence of lung cancer can be directly
attributed to cigarette smoking; there are relatively few problems
with changing criteria for classification of cause of death, and there is
a clear, linear dose-response relationship. Moreover, the "tar" portion
of the smoke probably contains most of the carcinogenic activity of the
whole smoke. If the reduction in machine-measured "tar" yield is
accompanied by an actual reduction in smoker exposure dose, then
there should be a relatively proportionate reduction in lung cancer risk.

Lower "tar" cigarettes are associated with a reduction in the risk of
developing lung cancer, although the proportionate reduction in risk is
substantially less than that of "tar" yield.
A smaller percent reduction in lung cancer risk versus that of
measured cigarette "tar" yield could result from several factors,
including compensation (such as an increased depth of inhalation or a
greater number of cigarettes smoked per day), or from a lack of
comparable reductions in other carcinogens.

For several reasons, it is difficult to extrapolate these risk reduction
data to the current very low "tar" cigarettes. Because the lower "tar"
yield of the cigarettes evaluated in the published studies probably was
accomplished predominantly by reducing the weight of tobacco in the
cigarette and by removing "tar" through filtration, use of these
cigarettes might reasonably be expected to result in a lower smoke
exposure if compensation did not occur. It is not clear, however, that
the alterations in the techniques of tobacco processing and cigarette
manufacture that have produced the very low ma&me-measured "tar"
yields can be expected to result in similar reductions in actual smoker
exposure to toxic smoke constituents. In addition, the ptential
carcinogenic effect of the substances added to these cigarettes has not
been evaluated The demonstrated reduction in mouse skin tumorigen-
icity of "tar" has not, however, been accompanied by a reduction in the
incidence of or mortality rates due to lung cancer among humans.
Cigarette smoking is an independent risk factor for coronary heart
disease, one that interacts synergistically with other risk factors such
as hypertension and hypercholesterolemia. The effect of cigarette
smoking in coronary heart disease risk is clearly dose related, and
cessation of smoking reduces the risk. Estimation of the impact of
varying cigarettes on coronary heart disease risk is difficult, because
the exact etiologic agent(s) have not been identified. A number of
agents have been suggested to be active in the development of
coronary heart disease, including nicotine and carbon monoxide. Any
change in risk that might occur because of switching to lower "tar"

9


and nicotine cigarettes might be expected to become evident more
rapidly for coronary heart disease risk than for cancer risk, due to the
acute effects of cigarette smoke in causing adverse coronary heart
disease events such as sudden death.

As in the ease of cancer, the expectation that a risk reduction for
coronary heart disease would accompany the use of lower "tar" and
nicotine cigarettes is baaed on the premise that the use of lower %r"
cigarettes results in a reduction of exposure to the responsible smoke
constituents. This assumption is reasonable if nicotine is a major
etiologic agent, because there is a close relationship between the "tar"
and nicotine yields for individual cigarettes. That is, among the
cigarettes currently available in the United States, a lower "tar"
cigarette is also a lower nicotine cigarette.

The variations of the other constituents in the particulate phase of
the smoke in relation to "tar" yield is largely unknown, especially in
those cigarettes specially formulated to produce very low machine
measurements of "tar" yields.

Carbon monoxide is one gas in cigarette smoke that may be closely
associated with coronary heart disease risk, perhaps through interfer-
ence with myocardial oxygenation, enhancement of platelet adhesive
ness, or promotion of atherosclerosis. The relationship between carbon
monoxide yield and "tar" yield, however, has not been as thoroughly
examined as that between "tar" and nicotine. The factors that
influence the carbon monoxide yield are closely related to the
manufacturing process (e.g., porosity of the paper, filter ventilation,
etc.), and therefore may vary somewhat independently of "tar" yield.
In addition, the absorption of carbon monoxide is more dependent on
depth of inhalation than is the absorption of nicotine and, if the use of
lower "tar" products results in a compensatory increase in depth of
inhalation, smoker exposure to carbon monoxide may remain un-
changed or actually increase. The reality of this concern is home out by
those studies that show no lowering of carboxyhemoglobin levels in
smokers who switch to lower "tar" cigarettes. If carbon monoxide is an
active etiologic agent for cigarette-related coronary heart disease, and
if significant compensatory changes in the style of smoking occur with
use of lower "tar" cigarettes, then the risk of coronary heart d&ease
with lower "tar" cigarettes may be similar to, or possibly greater than,
the risk of smoking higher "tar" cigarettes.

Some other agents in the gas phase of cigarette smoke have also
been suggested as possible contributors to the development of coronary
heart disease. Little is known about the relationship between the yield
of the gas phase of the smoke and the "tar" yield The change in
formulation that allows the reduction in "tar" yield of the new lower
"tar" cigarettes has not been examined for its effect on the yield of
individual gas phase constituents. The potential for creating new
substances and for increasing the yields of existing gas phase

10


constituents by changes in formulation cannot be assessed from
existing data, but may well impact on the risk of coronary heart
disease produced by smoking lower "tar" cigarettes.

It is not surprising that the studies looking at the relative risk of
lower "tar" cigarettes reviewed in the cardiovascular section have not
produced a clear estimate of relative risk, given the difficulty in
relating a difference in "tar" yield to a difference in coronary heart
disease risk and the existence of gaps in our understanding of the
etiologic agents in smoke that cause coronary heart disease. Thus, the
impact of a reduction in the "tar" yield of cigarettes on the coronary
heart disease risk produced by smoking cannot be estimated at this
time.

Approximately 70 percent of chronic obstructive lung disease deaths
are attributable to cigarette smoking. The number of deaths attributed
to chronic obstructive lung disease is much smaller than the number of
lung cancer deaths. This fact, and the relatively long interval of time
between the onset of symptomatic chronic airflow limitation and death
from respiratory failure, reduce the usefulness of mortality data from
chronic lung disease in assessing the relative risks of lower "tar"
cigarettes. Therefore, attention has focused on the level of symptoms
and measured reductions in air flow for evaluating relative risk of
chronic obstructive lung disease.

As reviewed in the section on chronic obstructive lung disease, there
are three major aspects of cigarette-induced lung injury: chronic
mucous hypersecretion, airway inflammation and narrowing, and
alveolar septal destruction. The causal agents for each type of lung
injury may be different, and therefore each type may be affected quite
differently by a reduction in the "tar" yield of the cigarette.

The mucous hypersecretion and cough are a response of the lung to
the chronic irritant effects of cigarette smoke. To the extent that a
reduction in "tar" yield reflects a reduction in smoke exposure,
smoking lower "tar" cigarettes should result in reduced cough and
sputum production. In the studies that have looked at this question, the
expected decrease in cough and sputum production has indeed
accompanied the use of lower "tar" cigarettes.
Airflow limitation is not produced by mucous hypersecretion per se
but rather by airway narrowing and loss of parenchymal lung units.
The same studies that showed a reduction in symptoms with the use of
lower "tar" cigarettes failed to show a similarly reduced effect on air
flow limitation. This finding may indicate that tests of air flow
limitation are not sufficiently sensitive to measure the differences in
extent of disease. It could also result from a failure to produce lower
exposure to the causative agent(s) with the use of lower "tar"
cigarettes, either due to a lack of reduction in concentration of the
agent(s) or to compensatory changes in smoking behavior.

11


The loss of parenchymal lung units that is the hallmark of
emphysema is extremely difficult to measure during life, but there has
been substantial progress toward an understanding of how this disease
is produced by cigarette smoking. This work is reviewed in detail in the
section on chronic obstructive lung disease; it is suggested that
alveolar walls are destroyed by excess proteolytic activity. Cigarette
smoke may promote this excess activity through a combination of an
increased cellular release of proteolytic enzymes and the oxidative
inactivation of the inhibitor of these proteolytic enzymes. Since the
airways filter out most of the particulate matter in the smoke, it is felt
that the gas phase may be the component of smoke responsible for the
changes in enzymatic activity. The gas phase contains a number of
agents capable of oxidative inhibition of the enzyme inhibitor alphal-
antitrypsin. Therefore, the risk of developing emphysema may not be
related to the "tar" yield of the cigarette smoked. Even if the
reduction in "tar" yield results in a reduction in smoker exposure to
"tar," a pattern of compensation that produces a deeper inhalation
may deliver a greater dose of the gas phase of that smoke to the alveoli
where it produces a pathologic effect. In addition, the techniques used
in formulation of the newer very low "tar" cigarettes may result in an
increase in the concentrations of etiologic agents in the smoke.
Therefore, the relative risk for lower "tar" cigarette usage in the
development of chronic obstructive lung disease is highly problemati-
cal. The lower "tar" and nicotine cigarettes may well produce less of
the symptomatic component of this disease, but even if they do result
in a reduction of total smoke exposure, the pattern of that smoke
exposure may negate any reduction in risk.

The relative risks for both the mother and the fetus of smoking
lower "tar" and nicotine cigarettes during pregnancy are of great
concern, both because of the numbers of young women who smoke and
because of younger women's more frequent use of lower "tar"
cigarettes. The increased use of cigarettes with lower "tar" yields has
not been investigated for its effect on changes in risk of adverse
effects of smoking on pregnancy. Accordingly, no reduction in risk
relative to higher "tar" and nicotine cigarettes has been demonstrated.

Of particular concern is the potential teratogenic effect of additives
and their combustion products. Thus, it is not possible to assume that
switching to a lower "tar" cigarette would have an effect in reducing
risk during or after pregnancy. It is clear that the only recommenda-
tion that can be made to reduce risk in the smoking mother is for her to
quit smoking.

The ultimate assessment of risk is, of course, overall mortality. One
study examined the effect of smoking lower "tar" and nicotine
cigarettes on overall mortality. Persons smoking cigarettes with lower
"tar" and nicotine yield exhibited a decline in mortality rate from any
cause of approximately 15 percent in comparison with that of smokers

I.2


of higher "tar" cigarettes. Direct extrapolation of these overall
mortality results to current smoking exposure is not possible. The
lowest "tar" categories in that study included cigarettes that would be
considered higher "tar" products today; the mechanisms by which
subsequent reductions have been achieved may differ from earlier
techniques. There was no evidence available on the duration of use of
lower "tar" products in this population.

Methodologies for Ames&g Relative Risk

The task of monitoring the relative risks of lower "tar" cigarettes is
complex, but it is not impossible. Four approaches can be used:
constituent toxicology, bioassay systems, observational epidemiology,
and the study of fundamental mechanisms of disease production. Each
approach makes a unique contribution to our understanding of relative
risk. Each approach also has significant limitations to its contribution
to a complete assessment of risk. It is necessary to combine the
information gathered by each of these methods in order to understand
the risk. The final assessment of relative risk requires data from each
of these four methodologies. To the extent that information from any
one area is lacking, the estimation of relative risk is incomplete.
The first approach is that of constituent toxicology. A tremendous
amount of time and effort has been spent to characterize cigarette
smoke and to identify disease-producing smoke constituents. Several
thousand individual constituents have been identified. Much has been
learned about the effects of cigarette reformulation on the pyrolytic
process. Studies have led to a better understanding of human
absorption of these substances and how this is influenced by differing
patterns of puffing and inhalation. The identification of carcinogens,
oxidants, and ciliatoxic compounds represents an important advance in
understanding the risks of cigarette smoking. The fundamental
strength of this approach is that it might ultimately allow risk to be
measured by examining the chemical composition of the smoke and its
absorption. Thus, assessment of risk might be made prior to allowing
human exposure to the smoke. It could lead to the selective removal of
toxic substances from smoke.
The major limitation of this approach is the sheer magnitude of the
task. It would be necessary to identify each of the several thousand
substances, the site and amount of absorption with different patterns
of smoking, and the toxicity for each organ system. It would also be
necessary to address the more complicated question of the potential
interactions between smoke constituents, environmental and occupa-
tional exposures, and other exposures, such as medications. The
monumental nature of this task does not mean that constituent
toxicology is unable to contribute to our assessment of relative risk. It
simply means that it alone cannot solve the problem. The choice of
what substances to measure in order to assess risk must be guided by

13


an understanding of the basic mechanisms of disease production and
must be correlated with changes in disease occurrence in human
populations. In this way the search can be, and is being, focused on
those areas and substances that may provide the best measure of risk.

A second method of assessing risk is through the use of bioassay
systems. The term "bioassay" is used broadly to include animal models
as well as cellular or organ responses. This approach can also rapidly
provide information on risk without human exposure and has the
additional advantage that whole smoke or major fractions of smoke
can be tested rather than individual constituents. The limitation of this
method is that the estimate of risk is only as go& as the bioassay
system. Unless the system truly approximates the disease process of
concern, changes in that system may not reflect risk of disease. A
number of bioassay systems exist for the study of cigarette risk.
Unfortunately, none of them can be said to exactly duplicate human
disease. At the present time, estimates derived from these systems
cannot stand alone, but must be interpreted in the light of information
derived from other methods.

The ultimate "bioassay" is, of course, human exposure. The oeeur-
rence of disease in human populations would provide the most accurate
estimate of the relative risk of lower "tar" cigarette smoking. An
important drawback to this approach is that it permits the develop
ment of that disease in the population prior to measuring risk and
taking appropriate public health action. An additional limitation of the
observational epidemiology is that the risk being measured is caused by
a product and a pattern of use that occurred in the past. Because of the
long time lag between regular exposure to smoke and the development
of most cigarette-related diseases, and the time lag between develop
ment of disease and diagnosis of that disease, the relative risk
determined by observational epidemiologic methods may lag many
years behind the current risk. It may take 20 to 30 years before
smoking-related disease is observed. With a rapidly changing cigarette
product, it is necessary to estimate the risks of current exposures
rather than those of past exposures. This assessment is complicated by
the difficulty of defining and measuring any differences in individual
smoker exposure resulting from changes or individual variations in
styles of smoking. Nonetheless, despite these difficulties, the epidemio-
logic method remains the major tool in assessing the relative health
risks of differing cigarettes.

Some of the limitations of the observational epidemiologic method
can be overcome by incorporating information from the other ap
proaches to risk assessment. Information on the toxicology of cigarette
smoke might allow epidemiologists to sharpen their measurement of
actual smoker dosage, and might identify earlier tests of toxicity than
the traditional end points of disease occurrence or death. Information
on the basic mechanisms of disease production could improve the

14


estimation of relative risk by directed measurement of the basic
pathophysiologic processes or their biochemical or metabolic sequelae.
An excellent example of this kind of potential interaction is the testing
of populations of smokers for the byproducts of elastin degradation
suggested in the section on chronic obstructive lung disease.

The fourth method of assessing relative risk is the definition of the
fundamental mechanisms of disease production. An obvious attraction
of this approach is its potential to provide information that would
permit the prevention or cure of the disease process.

The difficulty with this method of risk assessment is our limited
understanding of these fundamental mechanisms. It is important to
incorporate what understanding we do have into the risk assessment
produced by other methods, and equally important to incorporate
information from other methods into the search for disease mecha-
nisms. As an example, it would be fruitless to examine the effect of a
given substance on the cell function in alveoli if it has been learned
from absorption studies that the substance is absorbed in the upper
airway and never reaches the alveoli.

Once the mechanism of disease is understood, however, an estimate
of relative risk might be made, not only by measuring the dose of
etiologic agents in smoke, but also those determinants of the disease
process preexisting in a given individual.

Conclusion

In summary, the final estimation of the relative risk of smoking
lower "tar" and nicotine cigarettes must be based on a synthesis of the
information derived from several methodologies. Despite the lack of
comprehensive and conclusive evidence currently available, the Public
Health Service policy on lower "tar" and nicotine cigarettes must
remain unchanged. The health risks of cigarette smoking can only be
eliminated by quitting. For those who continue to smoke, some risk
reduction may result from a switch to lower "tar" and nicotine
cigarettes, provided that no compensatory changes in style of smoking
occur.

This F&port of the relative risks of lower yields of "tar," nicotine,
and carbon monoxide has defined the following more clearly: the
conclusions warranted by present evidence; the difficulties and
importance of defining and monitoring changes in cigarette yields and
actual smoker exposure; and the major questions remaining unan-
swered, which constitute the major areas for future researc h efforts.
Summaries of the available data on the relative risks of cigarette-
related diseases among smokers of differing cigarettes follow. They
are grouped by topic.

Following these summaries are the research recommendations from
the Working Meeting, "Research Needs on Low-Yield Cigarettes."

15


These recommendations are combined, reflecting the common underly-
ing concerns among disciplines.

Summaries

Pharmacology and Toxicology

l! Several thousand constituents have been identified in tobacco
and tobacco smoke. Of these, nicotine appears to be the most
important acute-acting pharmacologic agent. Nicotine's physio-
logic effects include increased heart rate and blood pressure.
Nicotine also can permit the formation of tobacco-specific
nitrosamines, which are potent carcinogens, and nicotine itself
may be a significant cocarcinogen. The carcinogenic potency of
cigarette smoke condensates appears to depend on the nicotine
content of the "tar." This relationship may be due in part to the
conversion of nicotine to tobacco-specific nitrosamines or to the
coexistence of nicotine and some other unidentified carcinogen.
Whether the carcinogenic effects of nicotine as determined in
animal studies are directly applicable to humans is not known at
present.

2. In an important study to predict the carcinogenic activity of
cigarette smoke condensate, the amount of available nicotine
delivered to the mice was found to be a factor in every term but
one of the predictive model.

3. Polycyclic aromatic hydrocarbons and tobacco-specific nitrosa-
mines are two prominent classes of tumor initiators found in the
smoke condensates of commercial cigarettes. Of the polycyclic
aromatic  hydrocarbons formed during combustion, ben-
zo[a]pyrene (BaP) may be the most important and has been
studied the most extensively. A correlation has been found
between benzo[a]pyrene levels and the carcinogenic activity of
smoke condensates from several types of cigarettes, but other
studies have failed to show that carcinogenic potential is
significantly dependent on benzo[a]pyrene content. However, the
interaction of BaP with nicotine does appear important in
carcinogenesis.
4. The tobacco-specific nitrosamines (TSNA) are formed during
curing and fermentation of tobacco leaves and combustion of
cigarettes. TSNAs induce cancer in the lungs and trachea of
hamsters and may be of particular importance in the induction of
human laryngeal cancer. They may be active as contact carcino-
gens, or their metabolism at distant sites may produce carcino-
gens that are then transported to a target site.
5. It is not known whether the unidentified mutagens in cigarette
smoke are an important cause of lung cancer in humans, but

16


added exposure to any tumor initiators probably carries an
increased risk of cancer.

6. Cigarette smoke contains oxidants that have been shown to
reduce the activity of alphal-antitrypsin in animals and man. This
inhibitory function is distinct from the effect whole smoke has on
increasing levels of elastolytic enzymes released by neutrophils
and macrophages.

7. The great variety of tobacco types makes it possible to manipu-
late the plant genetically to change the content of the constitu-
ents of the leaf. The chemical content of the leaf is also affected
by agricultural practices and curing methods. The nicotine
content of tobacco, for example, is related to the amount of
nitrate fertilizer used in cultivation. Modification of tobacco as
reconstituted sheet incorporates substantial amounts of tobacco
stems that contain less nicotine than the leaf. The physical nature
of reconstituted sheets can be controlled to change their burning
characteristics and smoke composition.

3. Vapor-phase constituents of cigarette smoke inhibit ciliary
motility and mucous flow in experimental animals.

9. Cigarette smokers metabolize several compounds more rapidly
than do nonsmokers. This effect is believed to be caused by the
induction of microsomal oxidases, which include aryl hydrocarbon
hydroxylase (AHH). Induction of AHH activity appears to be
caused by systemic exposure to the smoke compounds themselves
or to the metabolites of those compounds. The AHH system may
be involved in the metabolic formation of ultimate carcinogens
from procarcinogen precursors.

10. In recent years, a number of flavoring additives or cellulose-
based tobacco substitutes may have been included in manufac-
tured cigarettes. The nature and amounts of such additives as
actually used are not known, nor is it known what influence these
additives may have on the chemical composition or subsequent
biological activity of cigarette smoke.

11. Cigarette design has a major effect on smoke composition. The
filter is the design characteristic that has the most impact on
"tar" yield; it can also selectively remove nitrosamines and
semivolatile phenols from smoke. The porosity of cigarette paper
and the presence of holes in the mouthpiece influence smoke
composition because ventilation reduces the quantity of "tar" and
dilutes the gas phase of smoke.

12. Because of the complexity of cigarette smoke, the total impact of
any cigarette modification on smoke composition will probably
never be fully known.

13. Many laboratory studies of the effects of smoke constituents
have been carried out using smoking machines that control puff
volume, frequency and duration, butt length, and other factors

17


according to standardized parameters. However, the most widely
used parameters were established in 1967, and the type of
cigarettes generally smoked today are substantially different
with respect to length, paper porosity, "tar" and nicotine content,
and concentration of gas phase constituents. Evaluation of the
toxicological and pharmacological properties of smoke from new
types of cigarettes requires detailed knowledge of the manner in
which those cigarettes are smoked, as well as of how smoking
patterns affect smoke composition.

Cancer

-1. Today's filter-tipped, lower "tar" and nicotine cigarettes produce
lower rates of lung cancer than do their higher "tar" and nicotine
predecessors. Nonetheless, smokers of lower "tar" and nicotine
cigarettes have much higher lung cancer incidence and mortality
than do nonsmokers.

2. Smokers of lower "tar" and nicotine cigarettes may tend to
smoke larger numbers of cigarettes, to inhale more deeply, to
have relatively higher amounts of carboxyhemoglobin than
predicted from machine measurements of carbon monoxide yield,
and to have higher than predicted carbon monoxide in exhaled
air.

3. In attempting to develop a "less hazardous" cigarette, singular
emphasis has been placed on reducing the "tar" yield of cigarette
smoke because of the early demonstration of a causal relationship
between "tar" and lung cancer. Comparable data on changes in
yield of constituents in the gas phase of smoke are not publicly
available.

4. The occurrence of laryngeal cancer has. been reported to be
reduced among smokers who use filtered cigarettes, compared
with those who use nonfiltered cigarettes.
d There is no epidemiologic evidence to prove or to di?yrove a
decreased occurrence of cancers of other sites in humans who
smoke lower "tar" and nicotine cigarettes.
6. In evaluating the effect of smoking lower "tar" and nicotine
cigarettes on histologic changes in the bronchial epithelium, it
was determined in one autopsy study that male smokers who died
between 1970 and 1977 had fewer histological changes than those
smokers who died between 1950 and 1955.
`7. Even among those who do not develop cancer, histologic changes
in the tracheobronchial tree are more advanced at autopsy in
smokers of cigarettes with higher "tar" and nicotine than among
smokers of cigarettes with lower yields.

8. The "tar" content of smoke condensate of today's cigarettes is
less tumorigenic to mouse skin than that of cigarettes of 30 years
ago. Levels of the known carcinogen benzo[akyrene are lower in

18


the smoke of today's cigarettes than in that of cigarettes of 30
years ago. Flavor additives used in lower "tar" and nicotine
cigarettes produce traces of mutagenic compounds.

9. Although studies point to polycyclic aromatic hydrocarbons in the
"tar" of inhaled cigarette smoke as potential carcinogens for
humans, additional work is needed to determine whether nicotine
plays a major role as a carcinogen. Definition of the role of
nicotine in carcinogenesis is necessary prior to advocacy of
cigarettes yielding less "tar" but more nicotine.

10. Animal studies have shown that a significant reduction of "tar"
and a selective reduction of tumor initiators and cocarcinogens
can markedly reduce the tumorigenic potency of cigarette smoke.

Cardiovascular' Dieeases

P&pidemiological studies show that the incidence of coronary
heart disease (CHD) increases as the daily number of cigarettes
smoked increases and that the incidence of CHD decreases among
those who quit smoking. These dose-related effects suggest that
lower "tar" and nicotine cigarettes might be associated with
lower risks of CHD. However, the overall changes in the
composition of cigarettes that have occurred during the last 10 to
15 years have not produced a clearly demonstrated effect on
cardiovascular disease, and some studies suggest that a decreased
risk of CHD may not have occurred.

2. Of the several thousand substances found in cigarette smoke,
only a few have been implicated in cardiovascular risk. A number
of substances have not yet been adequately assessed. Further, the
changes in smoke constituents that have resulted from changes in
the cigarette product have not been documented.
3. Linking cigarette smoke yields to cardiovascular disease is
complicated by the evidence that smokers of lower "tar" and
nicotine cigarettes may smoke more "intensively," although they
may not smoke a substantially greater number of cigarettes daily
than do smokers of higher "tar" and nicotine cigarettes. The net
result could be to decrease the actual intake of "tar," nicotine,
and carbon monoxide less than that expected on the basis of
machine measurements.

&Nicotine stimulates the sympathetic nervous system, producing a
rise in catecholamines that in turn increases heart rate, elevates
systolic blood pressure, constricts cutaneous blood vessels, and
increases levels of free fatty acids. The nicotine-stimulated
release of catecholamines has been suggested as the cause of
increased platelet stickiness and aggregation, pointing to a
potential role in coronary disease. There is some evidence that
these physiological effects may be dose related and somewhat
diminished with lower nicotine varieties of cigarettes.

19


5. Carbon monoxide has a negative inotropic effect on the myocar-
dium of patients with angina pectoris. When combined with
hemoglobin in the form of carboxyhemoglobin, carbon monoxide
may increase the permeability of the blood vessel walls to lipids,
thereby promoting atherosclerosis.
6. Cigarettes with unperforated filters yield lower "tar" and
nicotine levels than unfiltered cigarettes, but they yield more
carbon monoxide than do unfiltered cigarettes at the same "tar"
yield. Carbon monoxide yields are lower in cigarettes with
perforated filters, but as the composition of cigarettes has
changed, carbon monoxide yields have decreased much less in
proportion to the decrease in "tar" and nicotine yields.
7. In studies of patients with angina pectoris, increased carboxy-
hemoglobin levels significantly shorten exercise time until the
onset of angina pectoris.
8. Myocardial ultrastructural changes have been found in rabbits
exposed to carbon monoxide.
9. Most cardiovascular studies have focused on nicotine and carbon
monoxide rather than on "tar," which has not been shown to have
a major acute role in cardiovascular disease. Even less is known
about other constituents of cigarette smoke.

10. Not all cigarettes that produce a lower yield of one substance
necessarily provide a lower yield of other substances.

11. Evidence on the association between CHD and filter cigarettes is
  somewhat conflicting. One major study showed a reduction of 10
  to 20 percent in coronary deaths among persons smoking lower
  "tar" and nicotine cigarettes as compared with those who smoked
  higher yield cigarettes, but other surveys have shown a slightly
  increased risk of coronary mortality in people who smoked filter
  cigarettes relative to those who smoked nonfiltered cigarettes.
  Recent unpublished data from the Framingham Study do not
  show a lower CHD risk among smokers of filter cigarettes.
Chronic Obstructive Lung Disease

1. The relationship between cigarette smoking and chronic obstruc-
tive lung disease (COLD) is well documented. The constituents of
cigarette smoke that are responsible are currently not known.
Whether a difference in risk of COLD has occurred with lower
"tar" and nicotine cigarettes as compared with higher "tar" and
nicotine cigarettes is currently unknown.

2. Cigarette smoking is associated with the release by alveolar
macrophages of an increased amount of the elastolytic enzymes,
which degrade alveolar tissue, and with reduced activity of
alphal-antitrypsin, the primary elastase inhibitor. This mecha-
nism has not yet been directly related to the development of
human emphysema. To date there are no published studies that

20


compare the effects of higher versus lower "tar" and nicotine
cigarettes on elastolytic enzymes and inhibitor activity.

3. Cigarette smoke also contains relatively high levels of oxides of
nitrogen. The nitrogen oxides produce lung damage in animals
that is similar to that induced in humans by cigarette smoke. The
oxides of nitrogen may be responsible for the early lesions of
human emphysema.

4. An individual's smoking pattern is one of the most important
determinants of the relative concentration of smoke constituents
that reach the lungs and of the subsequent response of the
airways to smoke inhalation. Holding smoke in the mouth before
inhaling it into the lungs produces less response of the airways
than direct inhalation, which causes spirometric changes indica-
tive of bronchoconstriction. This effect is independent of the
"tar" content of the cigarette.
5. Pulmonary mucous hypersecretion and symptoms of cough and
phlegm appear to be affected by the "tar" content of cigarette
smoke. The development of airway obstruction is closely related
to the number of cigarettes smoked. Smokers of lower `Yar" and
nicotine cigarettes who compensate by smoking more or inhaling
more deeply might thereby increase their risk of developing
obstructive airway disease.
6. Population studies that have examined the rate of decline of lung
function in relation to the number of cigarettes smoked have
shown variable results, and most of the available data do not
relate lung function to cigarette yield. Overall, the mean
difference between the rate of decline of FEVl in asymptomatic
smokers and nonsmokers is very small, but there is a subgroup of
the smoking population that shows more rapid decline and is
apparently more likely to develop significant pulmonary disease.

Pregnancy and Infant Health

1. Cigarette smoking during pregnancy has been shown to have
adverse effects on the mother, the fetus, the placenta, the
newborn infant, and the child in later years. There is no evidence
available that lower "tar" and nicotine cigarettes decrease or
increase these health risks, relative to those posed by higher "tar"
and nicotine cigarettes.

2. Problems that have been linked to smoking during pregnancy
include placenta previa, abruptio placentae, vaginal bleeding, and
reduced average birthweight of newborn infants.
3. Smoking by pregnant women increases the risk of spontaneous
abortion, premature delivery, fetal death, and perinatal death.
Parental smoking is associated with the sudden infant death
syndrome.

21


4. The fetuses of smoking mothers have higher blood carboxyhemo-
globin levels and lower fetal arterial oxygen levels than do the
mothers.

5. Children of smoking mothers appear to show a greater suscepti-
bility to some adverse health effects, such as bronchitis, pneumo-
nia, and respiratory disease, during early childhood. Slight
differences in physical growth and other forms of behavioral and
intellectual development may be found in children as old as 11
years of age.
6. Although "tar," nicotine, carbon monoxide, and some other
constituents of cigarette smoke produce deleterious effeeta, the
specific etiologic agents and their mechanisms of action for
adverse effects on pregnancy are not clearly determined. Thus,
the relative importance of "tar" and nicotine, or carbon monoxide
and other constituents of tobacco smoke in the etiology of
adverse gestational and fetal events is not known.

Behavioral Aqtects

1. Nicotine appears to be the primary pharmacological reinforcer in
tobacco, but other pharmacological and psychosocial factors may
also contribute a reinforcing effect.
2. It appears that some smokers make compensatory adjustments in
their smoking behavior with cigarettes of different yields that
might increase the amounts of harmful substances entering the
body. The frequency and amount of spontaneous compensatory
changes in smoking style with different cigarettes require
further investigation.

3. Additional information is needed on the role of lower "tar" and
nicotine cigarettes in the initiation, maintenance, and cessation
of smoking.
4. Rigorous comparative behavioral studies involving animals are
needed to provide comprehensive, experimentally valid results on
behavioral aspects of smoking.

5. Laboratory techniques developed for study of opioids and alcohol
should be adapted for studies of tolerance and dependence on
nicotine.

6. Improved laboratory facilities are necessary for more tightly
controlled behavioral research. A particular need exists for
clinically acceptable cigarettes with standardii ingredients.
7. Smoking-machine measurements that more closely simulate the
practices of human smokers must be developed.

Lower `Tar" and Nicotine Cigarettes: Product Choice and Use
1. Public awareness of the dangers of smoking has steadily
  increased since 1965. In 1978, more than 99 percent of all
  Americans believed cigarette smoking to be hazardous to health.

22


2. Cigarette product choice has shifted dramatically since the 1950s.
In 1979, 91.7 percent of U.S. smokers used filter-tipped ciga-
rettes, compared with 1.4 percent in the early 1950s.
3. Lower "tar" cigarettes conventionally have been defined as
yielding 15 mg of "tar" or less per cigarette. The proportion of all
cigarettes consumed in the United States that are lower "tar"
has increased from 3.6 percent in 1970 to almost 50 percent in
1979. In 1979,58.5 percent of all cigarette brands marketed in the
United States yielded 15 or fewer mg of "tar."

4. Since 1968, the "tar" content of the "average cigarette" in the
United States has declined by 32.2 percent, and nicotine content
has fallen by 25.6 percent. These declines may be partially
amunted for by lower tobacco weight per cigarette-down 23.8
percent from 1968 to 1978-and by the greater length of the
filter and overwrap of the average cigarette, which could result
in a declining number of machine puffs per cigarette.
5. The prevalence of smoking in the U.S. adult and adolescent
populations has continued to decline. In 19'79,32.5 percent of the
adult population smoked cigarettes (36.1 percent of men and 29.4
percent of women). However, evidence suggests that the average
daily number of cigarettes consumed by those adults who
continue to smoke has increased over several decades. The
availability and use of lower "tar" cigarettes have increased over
recent years.
6. In 1979, 33.3 percent of adult regular smokers used cigarettes
yielding 15 mg "tar" or less. Studies show that women smokers
are more likely to use lower yield cigarettes than men are, and
white smokers use lower yield cigarettes in greater proportions
than do blacks. Smokers of higher income and education also
select lower yield cigarettes in a higher percent of cases.
7. A large national survey found that smokers in older aged cohorts
choose both the lowest and highest yield cigarettes in higher
proportions than do younger cohorts.
8. Although black smokers choose cigarettes of higher "tar" and
nicotine in greater proportions than do whites, the lower daily
number of cigarettes smoked by blacks suggests that their
average daily intake of "tar" and nicotine may be lower than that
of white smokers.

9. In 1979, 33.5 percent of adolescent smokers (age I2 to 18) used
lower "tar" cigarettes, compared with 6.7 percent in 1974. Boys
and girls smoke cigarettes of about the same level of "tar"
content.

10. Adult smokers started smoking regularly at the average age of
18 years. One survey showed that the higher the "tar" level of the
cigarette currently smoked, the younger the reported age of
beginning smoking.

23


11. Evidence from a large national survey does not support a
  correlation between a greater mean number of cigarettes smoked
  per day by users of lower "tar" and nicotine cigarettes than by
  higher "tar" users,
12. In a national survey, smokers of lower "tar" and nicotine
  cigarettes more frequently reported having attempted to quit at
  least once, and among these smokers, a higher proportion report
  having attempted unsuccessfully to quit multiple times. The
  applicability of these data to defining the role of "tar" or nicotine
  yields of cigarettes in quitting behavior is not clear in the absence
  of more detailed longitudinal data.
13. Although a greater proportion of unsuccessful quitters reported
  smoking the lowest "tar" and nicotine products than did recent
  successful quitters in one large survey, interpretation of these
  data is made difficult by the noncomparability of brand reported
  (i.e., unsuccessful quitters reported the brand smoked after an
  attempt, successful quitters reported the brand smoked prior to
  the attempt).
14. In a large national survey, the mean duration of the latest
  unsuccessful attempt to quit shows no clear relationship to "tar"
  or nicotine yields.
Research Recommendations From the Working Meeting
"Research Needs on Low-Yield Cigarettes"
The following list is an overview of research recommendations
submitted as a result of the working group reports from the June 1930
conference "Working Meeting: Research Needs on Low-Yield Ciga-
rettes." No attempt has been made to place them in order of priority.
o It must be determined whether lower "tar" and nicotine
  cigarettes change smoking behavior. For instance, compensatory
  adjustment, such as deeper, longer, and more frequent puffs,
  may turn a nominally lower yield cigarette into a higher yield
  cigarette. Studies am needed to determine whether adjustments
  made by smokers of lower "tar" and nicotine cigarettes may
  inadvertently increase their exposure to "tar" and carbon
  monoxide beyond that expected from a less intensively smoked
   higher yield cigarette.
o  Because of changes in cigarette composition, further retrospec-
  tive and prospective epidemiologic studies are needed to assess
  the health effects of these changes. A primary need is to
  establish whether there are measurable differences in morbidity
  between smokers of higher "tar" and nicotine cigarettes and
  smokers of lower "tar" and nicotine cigarettes. Efforts should
  include ongoing long-term studies that are adaptable to such
   epidemiologic inquiry.

24


o  The increased use of nonhuman primate models might permit
comparison of the effects of lower "tar" and nicotine cigarettes
with those of higher "tar" and nicotine cigarettes under
  controlled conditions.
0  More indepth studies on the mechanisms of cardiovascular and
pulmonary disease are needed to assess new brands of lower
"tar" and nicotine cigarettes. With improved noninvasive tech-
niques, scientists will be better able to determine how a
particular cigarette affects cardiac function and other physio-
logical activities. Genetic markers should be explored as a
possible method of identifying high-risk groups who are more
likely to develop tobacco-related diseases if they smoke.
0  Additional emphasis should be given to both human and animal
research models for the developmental mechanism of chronic
obstructive pulmonary disease and its possible alteration by
lower "tar" and nicotine cigarettes. The elastase-inhibitor
imbalance hypothesis of emphysema pathogenesis needs confir-
mation for human disease. Recently developed tests that
measure lung elastin degradation products in plasma and urine
need rapid clinical evaluation.

0 Emphasis should be placed on studies that determine the
character and magnitude of the health hazards that lower "tar"
and nicotine cigarettes pose for pregnant women and their
offspring. Specifically, the smoking habits of pregnant women
should be analyzed in prospective epidemiologic studies to
determine the effect of varying cigarettes on the course and
outcome of pregnancy. Careful laboratory measurements of
various physical capacities and functions of newborn infants and
pregnant women should be performed in case-control and
prospective studies to determine the influence of smoking on
pregnancy outcome. Clinical and experimental studies using
  animals should be conducted to evaluate the effect of individual
constituents of cigarette smoke on tissues and physical re-
sponses. Direct intervention strategies should be aimed at
pregnant adolescents who smoke.

0 Another research need is routine, frequent surveillance of
current and future lower "tar" and nicotine cigarettes for
specific chemical constituents and biological activity. In addition
to "tar," nicotine, and carbon monoxide yield, new types of
cigarettes should be monitored regularly for delivery of other
potentially harmful constituents, such as benzda]pyrene, phe-
nols, catechols, nitrosamines, nitrogen oxides, volatile aldehydes,
and radionuclides. More frequently updated ratings of "tar,"
nicotine, and carbon monoxide content would permit more
accurate studies on the potential impact of cigarette components
  on health.

25


o  More data are also needed on cigarette flavor additives and their
combustion products. Flavoring agents and additives should be
studied by cigarette companies for carcinogenicity and toxicity
before their commercial use is permitted, and the results of such
  studies should be made available.

o  Research should be done on the distribution, partitioning, and
penetration of lower "tar" and nicotine cigarette smoke in the
lung, with consideration of potential changes in smoking
patterns by those who smoke lower "tar" and nicotine ciga-
  rettes. Cigarette smoking-machines currently in use and the
techniques by which animals inhale cigarette smoke in research
models may not be representative of the human situation
because human smokers are able to take larger, more frequent,
and higher velocity puffs. To conduct meaningful assays of
cigarette yields and the biological activity of cigarette smoke, it
must be determined how smokers actually smoke various types
of commercial cigarettes. When this information is available, it
  will be possible to design smoking-machines that yield more
  accurate estimates of human risk.

o  Controlled studies are needed to determine the role of nicotine
  as a primary reinforcer in cigarette smoking and to determine
  whether there are other chemicals in addition to nicotine that
may contribute to or reinforce the smoking habit. By analyzing
  the mechanisms whereby nicotine reinforces smoking behavior,
  it may be possible to design more efficacious methods of
  smoking cessation.
o  Research should be conducted to define what effects modifica-
  tions of the physical and chemical properties of leaf tobaccos
  have on the pharmacology of cigarette smoke. Since tobacco
  culturing and curing practices are continually changing, it is
  important to determine whether such changes as the use of new
  pesticides also alter the composition and biological activity of
  cigarette smoke.

o Standardized experimental cigarettes have frequently proved
unpalatable and unacceptable for behavioral research. Proto-
type cigarettes should be especially designed to deliver a wide
range of constituent concentrations, particularly those that
approximate commercial cigarettes. This would allow research-
ers to predict the behavior of smokers of new types of cigarettes
more accurately.

26


Section 2. PHARMACOLOGY AND
       TOXICOLOGY


CONTENTS

Introduction

Experimental Systems for Assay of Relative Risks of
Cigarette Smoking
Lung Cancer
     Animal Models

Lung Carcinogens in Cigarette Smoke
Polycyclic Aromatic Hydrocarbons
Tobacco-Specific N-Nitrosamines
Other Mutagenic or Co-mutagenic Agents
Weak Acids
Nicotine
Polonium 210

    Volatile N-Nitrosamines
Bladder Cancer
Laryngeal Cancer
Other Cancers

Early End Points Suggestive of Carcinogenic Potential
Chronic Obstructive Lung Disease
Sudden Death Due to Cardiovascular Disease
   Animal Models
   Nicotine
  Carbon Monoxide
  Other Agents

Complications of Pregnancy and Early Childhood
Nonspecific End Points of Toxicologic Significance
  Reduction of Lung Defense Mechanisms
  Induction of Microsomal Oxidase
  Changes in Genetic Status
  Changes in Immune Status

composition of Smokes From Various Types of Cigarettes
Smoking-Machine Design
Dependence of Smoke Composition on Cigarette Design
     Filters
     Ventilation
    Tobacco Variety
    Agricultural Practice
    Reconstituted Sheet and Modified Tobaccos

29


Additives

Variations in Human Smoking Behavior

Research Needs

Surveillance of New Cigarettes
Determination of Parameters of Human Cigarette
Smoking

Evaluation of Health Effects of Nicotine
The Effects of Smoking-Machine Parameters on
Relative and Absolute Yields of Smoke Components
From Various Types of Cigarettes
Influence of Raw Product Modification on
Pharmacology of Cigarette Smoke
Physical and Chemical Properties of Smoke From
Cigarettes Delivering Less Than 10 mg of "Tar"
Development and Validation of Analytical Methods
Other Research Needs

Summary

References

LIST OF FIGURES

Figure l.-Effect of cigarette smoke differing in selected
chemical components on pancreatic elastase levels in
beagle dogs after a f5OO-day exposure protocol of 12
cigarettes per day, 7 days per week

LIST OF TABLES

Table I.-Major toxic agents in the gas phase of cigarette
smoke (unaged)

Table 2.-Major toxic agents in the particulate matter of
cigarette smoke (unaged)


Table 3.Ahefficient.a and standard deviations of
coefficients for Prediction Model 10

Table 4.-Comparison of mutagenic and tumor-promoting
activity of fractions of cigarette smoke condensate

31


lntroductlon

Tobacco and tobacco smoke are very complex mixtures. In 1968,
Stedman (155) reported that they contained more than 1,200 clearly
identified substances in addition to a number of polymer classes, such
as pigments, resins, and proteins, that were not resolved into specific
compounds. Since that time, many additional compounds have been
isolated; at least a thousand additional constituents were found in
tobacco and tobacco smoke in the following 10 years (67). Cigarette
smoke components arise through distillation of volatile and semivola-
tile materials from the leaf and from the pyrolytic decomposition of
leaf constituents. In addition, nonvolatile components of tobacco leaf
can be transferred to the smoke without degradation. Thus, the
components of smoke are very diverse. Many suspected or proved toxic
agents have been identified in the gas phase (Table 1) or in the
particulate matter (Table 2) of smoke (290). It is not surprising that
chronic exposure to such a complex mixture will lead to a variety of
pharmacologic and toxicologic responses.

TABLE l.-Major toxic agents in the gas pham of cigarette
      smoke (unaged)*

Di~thylnitmaamine
EthYlmethytnitroMmine
Diethylnitmsandne
Nitnxopyrrdidine
other nitmoaminen
(4 compotmde)
Hydrrdw
Vinyl chloride
urethane
Folldd&@
Hydmseneyanide
Aaolein
Aeetaldehyde
Nitrogen oxides (NO&
Ammonia
Pyridii
Carton monoxide

C
C
TI
CT Qc
`X T
Ei
T
T?d
TM
T


TABLE 2.-Major toxic agents in the particulate matter of
     cigarette smoke (unaged)*

B-+h~
bbiethmne
Ber&jjuonulthene
Bellr+~thInceDe
other polymlclear erometic hydm
carbons (>26 compound@
JXben&jJecridhe
Diben&h~dine
Dibe.nz&gJcuhemie
m=
Fl~OthlX
B-ofaimw
other polymldsv -tic by&o-
carbons (>lO compounds)
NapMtmlenea
l-Methylindokd
MbhthylarbsFales
Other neutrel compoundn
catechol
b & CMethyka~
0th c&e&oh (>4 mmpounde)
U&OtWlphC3ldSIWldhd6
N'-Nitmmnombtine
other nonvoletik nitmeeminea
&N~htbyluniM
OthW-tiCMUilE8
Unknown nitro compound8
Polonium-210
Niid mmpour&
Cedmium compounds
Aneaic
Nkotine
Mioor t4baan 8lkabida
I%mol
Crcaols (3 eompouoda)

TI
TI
TI
TI

TI
TI
TI
TI
ac
cot
ccc

cd:
cot
COG
cd2
cot
cd2
ccc
cot
cd2
C
C
Bc
Bc
Bc
C
C
C
C
T
T
CT
CT

  ?
l-10 M
0.349 H
o.m.2 pg
  ?

u)-r16ocB
80-4oM
?
?
loo-250 !q
?
o-26 w
?
?
0.62-1.2 pci
1@600 w
9-70 ng
l-26 M
0.1-20 mg
0.01-02 mg
l&206 #tg
10-166 R

?
6 M
0s P2
0.1 pg

Experimental Systems for Assay of Relative Risks of Cigarette
Smoklng
Lung Cancer

Animul Models

The mouse skin carcinogenesis assay is thus far the most fruitful
method of evaluating smoke condensates from different types of
cigarettes for carcinogenic potency for the human lung (46,51,89,106).

34


This model for the development of cancer dates back to 1915 (191). A
large body of laboratory experience has provided consistent evidence
for the quantitative validity of this relationship. Procedures providing
good dose-response relationships are in use in many laboratories.
Assays can be standardized to give relatively consistent results within
a laboratory, and probably among laboratories (62, 63,64, 65).
The assay depends on a number of similarities between the
laboratory model and human experience. The epithelium of both the
skin and lung is directly exposed to the presumptive carcinogenic
agent-in this case, cigarette smoke or cigarette smoke condensate.
Babbit and mouse skin develop tumors after exposure to coal tar, a
known occupational carcinogen. Mouse skin assays have predicted
occupational induction of human lung cancer by bis-chloromethyl ether
w, 170.

It is conceivable that the mouse skin carcinogenesis assay may give a
misleading measure of the relative risk of various types of cigarettes.
Skin is covered with a lipid film, and the pilo-sebaceous apparatus is
particularly suited for penetration of lipid materials into the skin. In
contrast, the airway surface is covered by an aqueous film and might
be less readily penetrated by fat-soluble materials. There is no
evidence, however, that such a difference is important. Indeed, the
response of mouse skin to different types of experimental cigarettes is
roughly parallel to the response of hamster larynx to the same
materials (49,50,189).
The hamster larynx has been used for comparative studies of
different types of cigarettes (17, 50, 52). Invasive carcinomas of the
larynx were induced in 37 percent of inbred hamsters exposed to
cigarette smoke for 59 to 30 weeks. Both the cancer incidence and the
incidence of other epithelial changes were dose related. Exposure of
rats and mice to cigarette smoke for up to 21/2 years resulted in a small
incidence of respiratory tract tumors, primarily pulmonary adenomas
(44, 68, 72). Cigarette smoke `produced changes in cultured human
gastric epithelial cells suggestive of malignancy (158).

Experience in man and with the mouse skin system indicates that
two or more distinct classes of carcinogenic stimuli lead to the
occurrence of tumors (16, 26, 48). Tumor initiators appear to alter the
genetic constitution of the cell; tumor promoters accelerate and
enhance the neoplastic expression of previously initiated cells. Both
may play a role in the induction of tumors. Other types of coca&n+
gens may also play a role in the induction of mouse skin tumors by
cigarette smoke condensate (16, 74,89,176). If similar mechanisms act
in man, it may not be possible to differentiate between a human
carcinogen in the conventional sense and a cocarcinogen or tumor

35


promoter acting on a diverse population already exposed to low levels
of a variety of tumor initiators.

Two prominent classes of tumor initiators are found in smoke
condensates of commercial cigarettes-polycyclic aromatic hydrocar-
bons (PAH) and tobacco-specific nitrosamines (TSNA), Other car&+
gens or tumor initiators are present in cigarette smoke as well;
however, they appear to be less significant because they either are less
potent or are present at lower concentrations than are PAH or TSNA.

Polycyclic Aromatic Hydrocarbons

A large variety of PAH molecules are formed by the pyrolytic
process during combustion of the cigarette (87, 105). Of the PAHs,
be&a&rene (BaP) is the most prominent and has been studied most
intensively. Chemical assays for BaP in smoke condensates are well
established, and it has been suggested that such assays can serve as
indicators of production of all of the PAHs. This appears to be
generally true. Among smoke condensates from 98 experimental
cigarettes,  the correlation  coefficient between BaP and
bem$a]anthracene content was 0.78 (15). Although highly signiicant,
the value is sufficiently low to indicate that real differences do exist in
the ratios of these cyclic molecules in the various cigarette smokes.
Nevertheless, BaP appears to be the most important single member of
this class of compounds, taking into consideration both its concentra-
tion and its relative carcinogenic potency.

The contribution of BaP or PAH in general to mouse skin
carcinogenesis by cigarette smoke condensate cannot be fully mea-
sured at this time. Wynder and Hoffmann (188) found a correlation
between BaP levels and carcinogenic activity of smoke condensates
from several types of cigarettes. A much larger series of experimental
cigarettes was studied in the smoking and health program of the
National Cancer Institute. No significant dependence of carcinogenic
potency on BaP content was observed (6&63,64,65). The relationship
between chemical composition of the experimental smoke condensates
and the biological activity of this series was examined extensively by
Bayne (15). He employed the linear terms, squared terms, and all
interaction terms between any 2 of 10 independent variables. Starting
with a 66-&m regression equation, he searched for simpler prediction
models that would provide useful estimates of carcinogenic activity.
The simplest model (Table 3) that retained good predictability
contained nine terms. The interaction of BaP with the nicotine term
was one that appeared important.

BaP and other tumor initiators are particularly important because
humans are already exposed to a number of initiators in the
environment. The effect of initiators is cumulative and irreversible.
Hence, any additional exposure to initiators such as the PAH might be
expected to increase tumor incidence in smokers.

36


TABLE 3.-Coeffkienta and standard deviations of coefficients
      for Prediction Model 10

                                        t3taDdIud deviatioo
       Terms.             Coefficienta            of aleffiientd

   1 Intercept                2.667                 0292
   2C                   4.792 E-2              0.234 Is2
    2cI                   4.66s E-4               0.406 El
   1 PH                   4.464 E-l              OMO El-1
    5vwA                  1.242 E-l               0.555 Fe-1
    6NxN                245oEl-5              0.668E-5
   7 pH x pH               2.662 J3-2              0.875 E-2
   8NxpH                -7.078 E-t               1.664 E-4
    9NxBAP               -1.T70 EL9              0.2TIE4
bs:; Cbmmhdon (m&&y); VWA-very wed mcih (u&g); N-nicoh (n@g); and BAP-bearo[+ymm

Born Bayme (26).

Tobacco-Specific N-Nitrosamines

During tobacco curing, fermentation, and burning, nornicotine gives
rise to N'-nitrosonomicotine (NNN), nicotine to NNN and to 4-(N-
methyl-N-nitrosamino)-l-(3-pyridil)-1-butanone (NNK), and anatabine
to N'-nitrosoanatabine (NAT). NNN is a moderately active carcinogen,
inducing tumors in the respiratory tract of mice, rats, and hamsters.
NNK is a strong carcinogen, inducing lung carcinoma in each of the
three animal species (75, 84, 86). The concentration of these carcino-
gens in cigarette smoke is very high in comparison with usual
environmental exposures, being 1 to 35 ppm in tobacco and 1 to 9 erg in
the smoke of a cigarette (57). These tobacco-specific N-nitrosamines
may play a role in the development of several types of human cancer.
NNN is metabolically activated by human liver microsomes (76) and,
together with NNK and NAT, may be formed in wivo from the tobacco
alkaloids.

Other Mutagenic or Co-mutagenic Agents

It is generally believed that tumor initiators are mutagens that can
be detected by one or more short-term biological assays (2, 103). A
number of fractions of cigarette smoke condensate are positive in the
Ames assay system (93, 101). The agents responsible for this activity
have not been fully identified, but probably include products of protein
pyrolysis (119). Ames test activity, however, does not predict the
activity of fractions in the mouse skin carcinogenesis assay. Fractions
of smoke condensate that show activity as complete carcinogens (89) or
in a promotion assay that would detect skin carcinogens as well as
tumor promoters (24) are not correspondingly active in the Ames
system (Table 4). It cannot be determined whether the unidentified
mutagens in cigarette smoke are an important cause of lung cancer in

37


TABLE 4.-Comparison of mutagenic and tumor-promoting
     activity of fractions of cigarette smoke condensate

whole eondeneate
Beeollatiblted
Bmea before, insoluble
Baaee after, iduble
Bmen, ether soluble
Bass, water soluble
week acid.9$ iMobible
Weak ad4 e&r soluble
Strong acidq iaaohble
Strong aci4 ether soluble
strong aei& water Eoluble
Neutrala, 80% methuwl dubie
Neutde, cyclobexane mluble
Neutrala, nitrome~ duble

100
89
21
26
11
1
30
5
2
<1
<2
2
51
2

humans; however, added exposure to any tumor initiators probably
carries an incremental risk of cancer.

Weak Acids

Cigarette smoke contains weak organic acids that exhibit tumor-
promoting or cocarcinogenic activity (24,74,176). The concentration of
very weak acids in cigarette smoke condensates was one of the terms
predictive of the skin carcinogenic activity of smoke condensates
(Table 3). Of the weak acids, catechol appears to be the most important
on the basis of concentration and activity (74,176).

It is probable that the weakly acidic constituents of smoke act as
tumor promoters or cocarcinogens rather than as tumor initiators, This
is true for phenols and for catechol (27, 176). There is no reason to
believe that tumor promoters or other types of cocarcinogens exhibit
either a cumulative or an irreversible effect. Indeed, for tumor
promotion in mouse skin by croton oil, clear thresholds for frequency of
application and for the amount of promoter in each applied dose are
apparent (26). If this is also true for man, the risk of very small doses
of weak acids might be negligible. Phenol (1.26, 188), but not catechol
(29), can be selectively removed by filters. The extent to which the
cocarcinogenic weak acids are reduced by selective filtration cannot be
determined at this time.

33


Nicotine

Nicotine exhibits neither complete carcinogenic activity nor tumor-
promoting activity. The nicotine content of cigarette smoke condensate
did not affect its carcinogenic activity when suspended in beeswax-
tricaprylin pellets implanted in rat lungs (48); however, in mouse skin
bioassays, this alkaloid is an important cocarcinogen (20). Not only is
nicotine active in models with other compounds such as BaP and 12-O-
tetradecanoylphorbol-X%-acetate (TPA), but also the measured carcino-
genic potency of cigarette smoke condensates appears to depend on the
nicotine content of the "tar." Of all of the individual compounds of
smoke condensates assayed in the smoking and health program of the
National Cancer Institute, nicotine was most closely related to
carcinogenic activity (62, 63, 64, 65). In the simplest predictive model
developed by Bayne, every term but one involved nicotine concentra-
tion, pH, or the concentration of crude condensate (Table 3). The
availability of nicotine to the tissues depends on the pH and concentra-
tion of condensate. Hence, available nicotine was a factor of all but one
term of the prediction model.

Nicotine may also play a role in the development of oral cancer in
tobacco chewers. Aqueous extracts or unburned tobacco exhibit tumor-
promoting activity when tested on mouse skin. This activity depends
on the presence of nicotine acting together with a fraction having a
molecular weight greater than 13,000 daltons (21). In addition, nicotine
gives rise to carcinogenic N-nitrosamines during tobacco chewing (84).

Data of Morosco and Coeringer (122) suggest that nicotine reduced
serum alpharantitrypsin activity and elevated pancreatic elastase
levels in dogs exposed to cigarette smoke. These workers believe that
interference with the protease-protease inhibitor balance may be a
factor in carcinogenesis (123).

It must be pointed out that the relationship between carcinogenic
activity of smoke condensates and their nicotine contents may be
caused in part by the conversion of nicotine to tobacco-specific
nitrosamines or to the co-occurrence of nicotine and some other
unidentified carcinogen. For example, the nicotine level of tobacco is
dependent on the amount of nitrate fertilizer used in tobacco culture
(166). High levels of tobacco-specific nitrosamines were found in the
unburned tobaccos usually raised with high levels of nitrogen fertilizer
(77). The level of volatile nitrosamines in cigarette smoke also depends
on nitrate fertilizer (170). One may postulate that the nicotine level of
cigarette smoke condensates is an indicator of such nitrogenous
carcinogens that were not measured directly. At present, however,
there is no direct evidence that this is the case. In any event, the
carcinogenic activity of mixtures of pure BaP and TPA are enhanced
by the concomitant application of nicotine under conditions such that
nitrosamine formation would not be expected (20).

39


Whether the cocarcinogenic effects of nicotine are important for
man is a matter of speculation. Tumor-promoting activity of croton oil
exhibits a threshold both for frequency of application and for the
quantity of agent present with any given treatment (26). The animal
studies in which nicotine acts as a cocarcinogen employ nearly lethal
levels of nicotine administered once or twice a day. In contrast,
smokers are exposed to a large number of low doses of nicotine daily. If
a threshold amount of nicotine per dose is required for cocarcinogenic
activity, human smokers may not be affected in a manner similar to
that of the mouse skin system.

Polonium 210

There have been repeated suggestions that "PO might contribute to
the carcinogenic activity of cigarette smoke in man (137). Polonium
levels in tobacco result primarily from the use of phosphate fertilizers
that are contaminated with radium decay products, particularly mPb,
a precursor of ~OPO (162,168). Very little uOPo is found in tobacco leaf,
but some is transferred to the smoke. Yields of 10 to 15 fCi of alpha
emitters were recently reported for experimental cigarettes and 490
fCi/gm for commercial cigarette smoke condensate (36). Most of the
radioactivity was due to insoluble forms of ~Po. Cancer may arise
from a single affected cell. It has been suggested that small amounts
of insoluble nOPo concentrated in small areas might deliver an effective
carcinogenic dose to a target cell (112). Harley et al. (71), however,
found very few "hot spots" in the lungs of deceased smokers. Based on
human experience with radon daughters, they assumed a lifetime risk
of lung cancer of 1 x 10-Z for a dose of one rad/year. At most, the
radioactivity they detected was estimated to explain only 10 percent of
the lung cancers suffered by cigarette smokers. They consider
polonium 210 a questionable risk factor in human carcinogenesis.

Polonium 210 contamination of tobacco can be effectively reduced by
selection of plant types and sources of phosphate fertilizer, and by
removal using chelating agents (71,171).

Volatile N-Nitrosamines

Tobacco smoke contains a number of secondary and tertiary amines.
These amines, together with nitrogen oxides, may give rise to the in
&uo formation of nitrosamines. Although the formation of most
nitrosamines is favored at low pH (llO), a small amount of volatile
nitrosamines is found in cigarette smoke and may be formed in the
lungs under normal conditions (30, 84, 170). The volatile N-nitrosa-
mines are organ-specific carcinogens, which in mice give rise to tumors
of the liver and kidney. At present, there is no reason to assume that
volatile nitrosamines cause lung cancer in smokers. Nevertheless, it is
prudent to limit the presence of any carcinogen in cigarette smoke.


Volatile nitrosamines in smoke can be reduced by selective filtration
and by limiting the nitrate content of tobaccos (SO, 121).

Bladder Cancer

The induction of bladder cancer in animals has been studied
intensively over the past several decades. The bladder appears to be a
particularly sensitive target for agents that are metabolized in the
liver and excreted in the urine. Among the compounds known to
produce bladder cancer in both man and animals is P-naphthylamine.
The presence of Snaphthylamine in cigarette smoke has been demon-
strated (85), along with other carcinogenic aromatic amines (129). The
yield was so low, however, that they did not believe these agents
contributed significantly to the risk of bladder cancer in smokers.
The urine of 10 smokers and 21 nonsmokers was examined by
Yamasaki and Ames (192) for mutagens or for substances that were
converted to mutagens by rat liver microsomes. Increased levels of
mutagens were found in the urine of seven smokers, but in none of the
nonsmokers. If promutagens in urine are responsible for the bladder
cancers occurring in cigarette smokers, it is possible that certain
individuals are particularly sensitive to bladder carcinogenesis by
cigarette smoke. If true, this sensitivity may be exploited for disease
prevention. Large quantities of mutagen-containing urine can be
collected from sensitive individuals. Isolation and identification of the
promutagens might permit removal of the precursors from cigarette
smoke.

Laryngeal Cancer

Hamsters develop laryngeal cancer after long-term inhalation of
diluted cigarette smoke (17, 50, 52). The effect is dose related and has
been used to compare different cigarettes. Tobacco-specific nitrosa-
mines induce cancer in the trachea and lungs of hamsters and may be
of particular importance in the induction of human cancer of the
larynx (84). Other carcinogens and cocarcinogens of cigarette smoke
that are active in the mouse skin bioassay system may also contribute
to induction of laryngeal cancer. Both organ systems involve epithelial
tissue directly exposed to the carcinogenic mixture.

Other Cancers

Cigarette smoking is also associated with cancer of the kidney,
pancreas, oral cavity, and esophagus (173). No animal model of these
cancers has been developed to the point where it could be used for
quantitative comparisons of different types of cigarettes. Oral cavity
and esophageal tumors may be induced by direct exposure to smoke
carcinogens. NNN, when given in the drinking water of rats, induces
cancer of the esophagus (84). This finding suggests that tobacc+

41


specific nitrosamines may be active as "contact" carcinogens. Alterna-
tively, the carcinogens might be produced through metabolism at
distant sites, such as the liver, and then transported to the target site,
where they can be further activated. Pancreatic cancer was induced in
hamsters with diisopropylnitrosamine (134). This observation suggests
the possibility of a similar action of smoke nitrosamines. Any
carcinogen in cigarette smoke might contribute to induction of cancer
distant from the exposure site. To this extent, elimination of the
carcinogens causing lung cancer or bladder cancer would reduce the
induction of cancer in other organs as well.

Alcohol usage and cigarette smoking show synergistic effects in the
induction of cancer in the upper digestive tract (113,172). The effect of
alcohol in this circumstance may result from the induction of
microsomal enzymes, which are believed to metabolize carcinogens to
their active forms (213).

Early End Points Suggestive of Carcinogenic Potential

It is generally considered that the induction of cancer requires a
specific genotoxic event that may be preceded or followed by ill-
defined and less specific epigenetic changes that enhance the manifea-
tation of the genetic event (182). In the two-stage carcinogenesis
system of mouse skin, the first step-initiation-appears to be
genotoxic, and the second step-promotion-appears to be epigenetic.
Several other forms of cocarcinogenesis have been described (16).
Tobacco smoke owes its carcinogenic activity to several carcinogens
and cocarcinogens (24,87,176,188).

Agents capable of producing genetic change can often be detected
by mutagenesis assay systems (2). Most carcinogens are mutagens.
Conversely, agents capable of inducing mutations are suspect as
possible carcinogens. Cigarette smoke condensates and some of their
fractions are mutagenic in the Ames salmonella assay systems (93,
119). These fractions are clearly of interest because they possess the
capability of inducing genetic changes that might lead to tumor
formation. Mutagenesis assays may provide a basis for the quantita-
tive comparisons of new cigarettes when the relative importance of the
genetic and epigenetic factors in smoke-induced cancer is understood.
The Ames test gives poor results for fractions of smoke condensate
that appear to be most active in systems designed to detect tumor-
promoting activity (Table 4). Furthermore, mutagenesis assays of a
series of experimental cigarettes have not provided consistent results
(167). The complexity of carcinogenesis by tobacco smoke condensates
renders mutagenesis assays of uncertain value for quantitative
comparisons of relative carcinogenicity.

Several in vitro systems measure the transformation of normal cells
into malignant cells after exposure to carcinogens. These systems are
sensitive to both genetic and epigenetic processe s (90,186). Such assays

42


may prove to be useful short-term indicators of the relative potency of
different types of cigarette smoke. The toxicity of most experimental
smoke condensates may interfere with the conduct of such studi=,
however. Experimental cigarettes that yield smoke condensates with a
wide range of carcinogenic activity are now available. It should be
possible to determine the usefulness of in vitro systems with this
material. For organ-specific carcinogens, the DNA repair test is a good
predictor of relative carcinogenic activity (186).

Most chemicals that are carcinogenic to mouse skin selectively
destroy the sebaceous glands of the treated skin (23). The sebaceous
gland suppression assay is a good predictor of the activity of
experimental smoke condensates as carcinogens in mouse skin (22).

Chronic Obstructive Lung Disease

No animal models for chronic obstructive lung disease are
available to measure the potency of smoke from various types of
cigarettes. Long-term inhalation studies with hamsters, dogs, and
primates have not given rise to disease states comparable to emphyse-
ma observed in humans (17,50,52,114). In two experiments, Sprague-
Dawley and CD rats exposed to cigarette smoke for 6 to 26 months
developed emphysematous changes (104,12d. Similar results were not
reported in other long-term studies with rats (44,68).

A number of pulmonary function tests have been evaluated as
measures of early lung disease in man (31, 61, 73, 100, 135, 154. Thus
far, similar tests have not proved useful as animal assays. They might,
however, be useful in comparing the effects of different types of
cigarettes on human smokers. Exposure of CD rats to whole tobacco
smoke for 6 months led to a loss of lung parenchymal tissue distal to
the terminal airways (124). This was indicated by a 21 percent decrease
in parenchymal tissue and 12 percent decrease in alveolar surface area.
Recent evidence suggests that emphysema results from a shift in the
balance of elastase production and elastase inhibition in the lung (97).
A few individuals with genetically determined very low levels of
alphal-antitrypsin, an elastase inhibitor, are particularly prone to
develop the disease (58). When purified elastase is instilled into the
lungs of dogs, emphysematous changes appear in as little as 96 minutes
(96,98).

Cigarette smoke can act on this system in two ways. In vitro tests
with cigarette smoke condensate show that this material suppressed
the antiprotease activity of human serum, pulmonary lavage fluid, and
purified human alphal-antitrypsin (94). The suppression of protease
inhibitors by cigarette smoke is blocked by the presence of phenolic
antioxidants, suggesting that oxidants or free radicals of the smoke
were responsible for the effect (107). In one study, the serum levels of
alphal-antitrypsin in smokers were higher than in nonsmokers (76).
Another study found, however, that immediately after smoking, serum


alphal-antitrypsin activity was reduced in smokers (95). Likewise, the
activity of alphai-antitrypsin in lung lavage fluid from Sprague
Dawley rats was reduced by 30 to 40 percent after 3 to 6 puffs of
cigarette smoke. Similar reductions were observed in lavage fluid from
the lower respiratory tract of asymptomatic smokers (58). Even
greater differences were seen between smokers and nonsmokers with
idiopathic pulmonary fibrosis. Cigarette smoke also stimulates the
release of elastase from macrophages in vitro and in &VU and from
polymorphonuclear leukocytes in vitro (19,1&9,185). Thus, smoke may
increase the elaboration of elastase in the lung and at the same time
suppress its inactivation. The techniques used in these studies could he
applied to smoke from various types of cigarettes; they might then
serve as short-term end points to evaluate relative cigarette risk.

Dogs exposed to cigarette smoke through tracheostomies for 600
days had significantly higher levels of pancreatic elastase than sham-
smoked controls (122). The greatest effects were seen in animals
exposed to higher nicotine cigarettes, although the blood carboxyhem-
oglobin levels were the same for both higher and lower nicotine
smokers (Figure 1). The lower nicotine cigarettes in this study were
produced by removal of the alkaloid by a commercial process (65). It
cannot he stated with confidence that other constituents were not
removed as well.

Sudden Death Due to Cardiovascular Disease

Animal Models

No animal model permitting the quantitative comparison of death
rates due to cardiovascular disease induced by different types of
cigarettes is presently available. Long-term inhalation studies using
smoke-exposed rats, hamsters, dogs, and primates have been conducted
(17,& 50,52,68,104,114). None has provided an end point comparable
to sudden death observed in human smokers. There are, however,
several avenues of investigation whose intermediate experimental
observations might indicate a mechanism for mortality caused by
cardiovascular effects. Much attention has been given to changes
induced by nicotine-induced catecholamine release (138, 156, 160).
Methods to follow these effects in animals are well established. Other
short-term end points being studied include lipoprotein levels (79),
alteration of arterial morphology (9, 10, 32, 111), and changes in
arachidonic acid metabolism (12, 82). These procedures might be
adapted for estimation of the relative potency of various types of
cigarettes, but there is no direct evidence that any of these changes are
either necessary or sufficient indicators of the risk of sudden death due
to heart disease.

44


  30-

-z
5  25-
g          Y
2
5  20-
Y
g  15-
?!
f `O-

   5-

   0

oooE32

    -
I   1,  I      t     I     1
   CODE13           colm?OL

FIGURE l.-Effect of cigarette smoke differing in selected
chemical components on pancreatic elastase levels in beagle dogs
after a 6OOday exposure protocol of 12 cigarettes per day, 7 days
per week. Bars indicate mean *SD. Animals exposed to code 32
(hiih-nicotine) and code 13 (low-nicotine) cigarettes diff'ered
significantly (p<O.O!5) in pancreatic elastase levels from
corresponding sham-posed controls. Sign&ant differences were
also observed (p<O.O5) between code 32 and code 13 cigarette
smokers (Student t-teat).

Nicotine

It has long been known that nicotine elevates blood pressure and
heart rate and may increase the onset of angina pectoris attacks. These
effects were summarized in the 1976 report, Tke Health Gmaquences
of Smoking (175). Nicotine readily passes through, biological mem-
branes. The level in the breast fluid of smoking women is similar to
that found in the plasma (81). The heart rate of fetuses of smoking
women is elevated, apparently caused by transplacental passage of
nicotine (127, 186). Thus, nicotine causes widespread effects in the
smoker.

An estimate of the relative potency of various cigarettes with
respect to the acute cardiovascular effects of nicotine can be deter-
mined by direct chemical assay of relative levels of nicotine in the
smoke. By measurement of urinary excretion of nicotine and its major

45


metabolite, cotinine, it is possible to estimate the individual smoker's
actual exposure to nicotine.

Nicotine appears to have measurable effects on performance by
smokers (149, 183). This may account for the apparent role of nicotine
in the reported tendency of some individuals to compensate when
switched from higher to lower "tar" and nicotine cigarettes (60, 136,
14.4 146,147').

The effects of carbon monoxide in reducing the oxygen-carrying
capacity of the blood are well known. More recently a body of evidence
has linked carbon monoxide directly to disease states and to early end
points that might be predictive of disease (11,109). Aronow has shown
that carbon monoxide, along with nicotine, decreased the duration of
exercise achieved before angina (6, 7, 8). In his studies, a non-nicotine
cigarette made of Indian herbal leaves was employed. Smoke from
these cigarettes was more active than expected on the basis of its
carbon monoxide content. Aronow (6) attributed this effect to a
"tobacco component" other than nicotine or carbon monoxide. The
effect, however, could well have been caused by a specific herb
constituent. Models using pigeons, rabbits, pigs, and primates have
been employed to study early end points for carbon monoxide effects
(4, 11, 114). To the extent that carbon monoxide is responsible for
cardiovascular disease, determination of the relative potency of various
cigarettes in affecting cardiovascular disease can be made by chemical
assay of cigarette carbon monoxide yield.

Other Agents

It has been suggested that agents of tobacco smoke other than
nicotine and carbon monoxide contribute to its cardiovascular effects
(4,116). Until these agents are identified or an alternative explanation
for tobacco effects is established, animal models predictive of cardi+
vascular death in smokers will be important.

Complications of Pregnancy and Early Childhood

A full understanding of the potential effects of smoking on
pregnancy and early infancy is still being developed. Most of the
current information available was reviewed in the 1980 report, The
Health Cbnsequences of Smoti~ for Women (174). Maternal smoking
causes changes in the vascular structure of the placenta and increased
fetal heart rate (9,10,127,136). Maternal carboxyhemoglobin (HbCO)
is elevated in smokers, leading to an elevated fetal HbCO and thus to a
reduced oxygen content of the fetal blood (108).

Some, if not all, of the smoking-related complications of pregnancy
are attributed to nicotine and carbon monoxide (108). The relative

46


hazards of lower "tar" and nicotine cigarettes with respect to these
agents can be determined by chemical assays of carbon monoxide and
nicotine. Actual disease risk, however, will be affected by the delivered
dose of these constituents, which in turn depends upon the individual's
style of smoking. Other constituents of smoke might also contribute to
complications of pregnancy. Comparisons of various types of cigarettes
should be possible through epidemiological study, coupled perhaps with
evaluation of the vasculature of human placenta (9, IO).

Recent reports indicate that cigarette smoke might contain active
transplacental carcinogens (54, 125, 140). The importance of this in
human cancer will probably not be determined soon. No animal assays
have yet been applied to assess the relative health hazard of varying
cigarettes in transplacental carcinogenesis.

Nonspecific End Points of Toxicologic Siignificsnce

Cigarette smoke and its components cause several conditions that
may relate to human disease in nonspecific ways. Using assays with
these end points may provide useful measures of potential risks due to
smoking.

Reduction of Lung Lkfeme Mechanisms

Vapor-phase constituents of cigarette smoke inhibit ciliary motility
and mucous flow in experimental animals (IS, 14). With ciliary
paralysis, removal of other toxic materials from the lung will be
inhibited. Animal models suffer some limitations in attempts to
duplicate the human situation. For example, many of the ciliastatic
agents in the gas phase of smoke are absorbed in the upper airways of
man and may not reach areas in the lung where they could affect
bronchial cilia (45). Furthermore, the concentration of ciliatoxic agents
in cigarette smoke will depend on the amount of dilution of smoke by
air that occurs during inhalation. Accordingly, the interpretation of
animal studies requires care. Similar effects occur in humans, however.
Clearance of FesOc dust from the lungs of smokers is dramatically
slower than from the lungs of nonsmokers (97).

Induction of Mi.cmwmd o;cidase

Cigarette smokers metabolize several compounds more rapidly than
nonsmokers (58, 39, 99, 187). This effect is believed caused by the
induction of microsomal oxidases, which include aryl hydrocarbon
hydroxylase (AHH). The level of AHH itself is much higher in
placentas from smoking women than from nonsmokers (190, MI, 178).
Activation of these enzymes has also been observed in the lungs of
rata, hamsters, and mice exposed to cigarette smoke (1, 59). Guinea
pigs, in contrast, showed a reduction in pulmonary AHH after smoke
exposure (18). Induction of AHH activity appears to result from

47


systemic exposure to the smoke compounds themselves or to the
metabolites of those compounds. Some carcinogens, including PAI&
induce AHH (38). More important, the AHH system is involved in the
metabolic formation of ultimate carcinogens from procarcinogen
precursors (118). Cigarette smoke may play an indirect role in
carcinogenesis among smokers through this mechanism. Assay of the
inducibility of AHH as a measure of individual sensitivity to cigarette
smoke has not proved useful (115,128); however, screening of enzyme
activity in tissues of human or animal smokers of different types of
cigarettes might prove useful for indicating the relative potency of the
different cigarettes.

Changes in Genetic Status

To the extent that an early step of carcinogenesis involves genetic
change, one would expect that exposure to cigarette smoke might
cause detectable changes in genetic material. It is reported that heavy
smokers have higher incidences of chromosomal aberrations and higher
rates of sister chromatid exchange than do nonsmokers (91). Animal
models with such end points are feasible, but have not heen applied to
assays of the toxicity of various cigarettes.

Ch.anges in Immune Status

Recent reports suggest that smoking causes changes in immune
function (56, 69, l&), but the contribution of these effects to major
disease states is unclear. Men with malignant melanoma who smoke
are more likely to develop metastases than are nonsmokers, perhaps as
a consequence of impaired immune systems (159).

ComposMon of Smokes From Various Types ot Cigarettes
Smoking-Machine Deign

Laboratory smoking-machine parameters historically have been
standardized to permit interlaboratory comparisons and to provide
reproducible baselines with which modified cigarettes can be com-
pared. Somewhat different parameters are used in different countries
(28). In the United States, the most widely used standards are those
employed by the Federal Trade Commission (163). The machines
deliver a 35 ml puff from the cigarette over a 2-second period with a
hell-shaped puff profile. The cigarettes are puffed once each minute to
the defined butt length of 23 mm (nonfiltered cigarettes), or to a butt
length 3 mm longer than the filter overwrap (filter-tipped cigarettes).
The butt length is different from cigarette to cigarette, according to
the length of the overwrap.

These parameters were established in 1967 when the great majority
of cigarettes consumed in the United States were nonfiltered and 70 or


85 mm in length. They were based, in part, on observed smoking
patterns in a limited number of human smokers. The types of
cigarettes smoked today are substantially different with respect to
length, paper porosity, pressure drop, "tar" and nicotine yield, and the
concentration of gas phase constituents.

Cigarette smoking-machines can be designed, however, to control
puff volume, frequency of puffing, duration of puff, the profile of puff
pressure over time, butt length, position of cigarette during and
between puffs (e.g., horizontal or vertical), and "restricted" or "free"
smoking between puffs (i.e., whether the butt end is closed or open).
The puff volume can be measured in terms of the air entering the
cigarette or the air plus combustion gases leaving the cigarette.
Smoking-machines could be designed to change the puff frequency and
the nature of the puffs during the course of smoking a single cigarette
(41,4a.

Human smoking patterns are diverse and span a wide range from
one individual to another (40,78,139). Some individuals compensate for
lower yield cigarettes by changing their style of smoking (80,139,1&
146,180). These changes can include increasing puff volume, duration,
or frequency, or changing the puff pressure profile. In summary,
human smoking behavior may be quite different from standard
smoking-machine behavior. Furthermore, the average smoker may
have a different smoking pattern for each different type of cigarette.
The chemical composition of smoke is affected by smoking-machine
parameters. "Tar" yield per puff depends on puff volume, puff
frequency, butt length, and the frequency of puffing at different
stages of cigarette consumption (188, 193,194). The concentrations of
several specific chemical constituents of "tar" are controlled by the
puff frequency, volume, and duration (Chortyk, O.T., and Schlot-
zhauer, W.S.S., personal communication). If the human smoking
pattern varies systematically with the type of cigarette, the relative
yield of various chemical constituents delivered to the smoker may
vary substantially from that measured by machine. Accordingly,
evaluation of the toxicological and pharmacologic potential of the
smokes from new types of cigarettes will require knowledge of the
manner in which those cigarettes are smoked by the consumer and of
the effect of smoking patterns on the composition of smoke.

Dependence of Smoke Composition on Cigarette Design

The composition of smokes from different types of cigarettes can be
described by absolute yields per cigarette or per puff, or by the
concentration of constituents per unit weight of "tar" or per unit
volume of smoke. Modifications of cigarette design can affect yield
(quantitative change) or composition of the smoke (qualitative
change). Information with respect to individual constituents is avail-
able for many modifications. However, modifications affecting the


concentration of one substance will also affect the levels of other
substances as well.

Because of the complexity of cigarette smoke, the full impact of any
cigarette modification on the composition of the smoke in either
absolute or relative terms can never be ascertained. For this reason,
bioassays with appropriate end points are essential to determine the
relative toxicities of new types of cigarettes. Several modifications of
cigarettes reduce the mouse skin carcinogenic activity of the smoke
condensate. These include choice of leaf variety, use of reconstituted
sheet, and use of tobacco substitutes.

The design characteristic of commercial cigarettes that most affects
the cigarette yield is the filter. In 1930, the "tar" yield of cigarettes, as
reported by the Federal Trade Commission or by advertisements,
ranged from 30 mg for unfiltered, king-sine cigarettes to as low as 0.1
mg for some filter-tipped brands (55). Filters selectively remove
nitrosamines and semivolatile phenols from the smoke (88, 120, 126,
188). Thus, not only the absolute delivery of these constituents but also
their relative concentration in cigarette "tar" depend on the filter.

A second major influence on the composition of cigarette smoke is
ventilation of the cigarette by the use of paper with a high degree of
porosity or by the presence of holes in the mouthpiece. When more air
is drawn through the paper or through the mouthpiece, the amount of
air drawn through the burning coal of the cigarette is reduced. This
effect will reduce the quantity of "tar." By altering the burn
temperature, it will also change the combustion process and thus the
composition of the smoke. Ventilation also dilutes the gas phase of the
smoke with air, causing a marked reduction in the concentration of gas
phase constituents in the smoke (66,83,126).

Tobacco Vark ty

A substantial collection of tobacco lines is available to plant
geneticists. These include 63 species related to tobacco and about 1,000
different tobacco varieties (164). The wealth of this material permita
genetic manipulation of the leaf, which could be used selectively to
enhance or to reduce the content of specific constituents. Among flue-
cured tobacco lines available at present, the nicotine concentration
varies from 0.2 to 4.75 percent (34). Among various burley lines the
concentration varies from 0.3 to 4.58 percent. The ranges could be
extended by agronomists, should that be desired. Changes in yield of
many other smoke constituents might be achieved by genetic modifica-
tion.

60


The chemical composition of tobacco leaf is also affected by
agricultural practice and by curing methods (161, 163). High levels of
nitrogen fertilizer increase nicotine and nitrate levels of the leaf.
Growing plants more closely together reduces the nicotine content of
the leaf. Flue-cured tobaccos are harvested, leaf by leaf, as each is ripe,
but the entire plant of burley tobacco is harvested at once. Changes
associated with leaf maturity depend on the harvesting practice.
Enzymatic degradation of leaf constituents is halted by heat during
flue curing. In contrast, burley, Maryland, and oriental tobaccos are
not heated to this extent, so that more extensive enzymatic changes
occur. As a consequence, there is a markedly lower sugar content in
burley tobacco along with a markedly higher content of pigment
polymers. Homogenized leaf curing (HLC), if commercially developed,
could permit better control over these chemical changes. Furthermore,
specific leaf constituents such as soluble proteins may be removed
during homogenized leaf processing. Cigarettes made with HLC
tobacco yielded smoke containing significantly less dimethylnitrosa-
mine and condensate having significantly less sebaceous gland sup
pression activity (165,169).

Rtmmstituted Sheet and Modi.d Tobaccos

The composition of cigarette smoke is also affected by the use of
reconstituted tobacco sheet and modified tobaccos (62, 69, 6.4, 65).
Reconstituted sheet can contain substantial amounts of the tobacco
%.em," which has a different composition from that of the leaf lamina.
The stem is noteworthy for having a low nicotine content. In addition,
the physical nature of reconstituted sheet can be controlled to change
its burning characteristics and hence the composition of the smoke.

In recent years, some cigarette tobacco has been "expanded" or
"puffed." Using this material, less tobacco is required to fill the
cigarette. The manner in which the tobacco is shredded also affects the
burning rate and therefore the composition of the smoke (47').
Cellulose-based substitutes have been used as a replacement for
tobacco (17, 35). These materials cause substantial differences in the
total yield and chemical composition of the smoke.

Additives

Humectants and flavoring agents have long been used as additives
in cigarette manufacture. The advent of reconstituted tobacco sheet
(RTS) technology expanded the possibilities for the addition of
substances to the sheet during the processing of tobacco for the
manufacture of cigarettes (174,188). It is possible to add substances to
the tobacco slung or suspension for extraction of specific constituents,
for dilution of the sheet, for burn rate acceleration or retardation, for

51


ash cohesion, and for enhancement of flavor (smoke aroma and taste)
(65,151). Additionally, one process for curing tobacco leaf calls for the
addition of exogenous enzymes to tobacco (169), and as noted above,
artificial tobacco substitutes are also available. In recent years,
cigarette manufacturers' advertisements have focused on the flavor of
new lower "tar" and nicotine cigarettes, enhanced presumably by the
addition of tobacco constituents or by the addition of new flavoring
materials, such as natural or synthetic chemicals. The identities and
amounts of the additives actually used in the manufacture of U.S.
cigarettes are not known. Systematic information has not been
published or made available on the influence of these additives on the
composition or biological activity of cigarette smoke.

Variatiom3 in Human Smoking Behavior

It does not appear possible to fully monitor smoking behavior in
humans without the subjects' knowledge. Butt lengths can be mea-
sured in a variety of settings, and puff frequency can be observed
without distorting smoking behavior. Measurement of puff volume and
duration and of intensity of inhalation, however, requires instrumenta-
tion that may lead to alteration of usual smoking behavior. Neverthe-
less, despite these limitations in objectivity, recent studies provide
better data than those available in the past.

Smoking measurements reported from England, Germany, and
Canada differ from those used for smoking-machines in the United
States (189, 141, 150). If the average American smoker, as well, is
taking larger puffs with a greater frequency than is the machine, the
absolute yields of smoke constituents are under-reported in the United
States. This is not to say that the relative yield of "tar" between
cigarettes is compromised; however, if smokers puff different types of
cigarettes in different ways, the relative yields may be grossly
distorted. For example, some smokers block the perforations in the
mouthpiece of ventilated cigarettes (102). These smokers receive
substantially more "tar," nicotine, and gas phase constituents than
would be predicted from machine-smoked cigarette yields. Because this
action would affect the yield only of ventilated filter cigarettes, the
relative ranking of cigarettes by yields would be affected. Similarly,
smokers' behavioral compensation for low nicotine delivery can affect
the relative yields of filter-tipped cigarettes (80,142).

Research Needs

Many gaps in our assessment of the pharmac ological properties of
cigarette smoke can be filled by a coordinated, welldirect.ed research
program. In comparison with the economic and medical costs of
cigarette smoking, the size of the required program is modest.
Resources sufficient for implementation of a meaningful program are

52


available. For example, except for assays of "tar," nicotine, and carbon
monoxide yield, new types of cigarettes are not being monitored
regularly for the delivery of potentially harmful smoke constituents.
Scientists currently conducting sophisticated assays of cigarette deliv-
ery of various smoke constituents could serve as resource personnel in
the design of an appropriate approach to assays of new cigarettes for
suspected toxic agents. Other scientists are investigating short-term
end points indicative of long-term risk from many diseases. These
laboratories could assist in modifying these procedures specifically for
cigarette smoke and its constituents.

Surveillance of New Cigarettes

The chief research need for the study of reduced "tar" and nicotine
cigarettes is the routine and frequent surveillance of current and new
cigarettes for specific chemical constituents and biological activity.
The chemical constituents should include nicotine, be&a]pyrene,
phenols, catechols, nitrosamines, carbon monoxide, nitrogen oxides,
volatile aldehydes, and radionuclides. The biological assays should
include sebaceous gland suppression assays, mutagenesis assays,
studies of the effects of smoke on airway and ciliary function and on
the increase of urinary metabolites related to the activity of elastase,
and such other biological assays as may appear predictive of human
disease in the future.

Inherent in this recommendation is the use of quantitative short-
term end points for various conditions associated with human disease.
We do not have proven animal models for quantitative evaluation of
risks of chronic obstructive pulmonary disease, sudden death due to
cardiovascular disease, or complications of pregnancy and infancy.
Emphasis should be given to developing short- and long-term bioassays
aimed particularly at these diseases.

Determination of Parameters of Human Cigarette Smoking

Smokers may smoke different types of cigarettes differently with
respect to puff volume, duration, and frequency, inhalation profiles,
and the manner in which the cigarette is held by the fingers and in the
mouth. To conduct meaningful assays of cigarette yields and of the
biological activity of cigarette smoke, it is important to know how
smokers consume each type of commercial cigarette. Only when this
information is available can smoking-machines be designed to yield the
most accurate estimate of human dose. We must know both the
average and the range of variation in smoking pattern.
The available studies compare smokers' behavior with commercial
cigarettes found to deliver different amounts of "tar" or nicotine.
Other changes that occur in the product are often unknown. A second
type of study should use prototype cigarettes specifically designed to
deliver a wide range of concentrations of a desired constituent; for

53


example, with high or low nicotine to "tar" ratios. Such a study would
define the behavior of smokers of new types of cigarettes before or as
they are marketed. These studies, however, would require a particular
resource that is not accessible to most investigators. There are a large
number of experimental cigarettes differing widely in several respects
(6.9, 69, 64, 65). Unfortunately, they were developed without concern
for smoker acceptability and cannot be used to evaluate human
response to design changes. A coordinated program should be eatab
lished to develop a series of clinically acceptable experimental eiga-
rettes that resemble a "reference standard" as closely as possible,
differing only in one or two well-defined characteristics. These should
then be made available to appropriate investigators for the study of
human smoking behavior.

Evaluation of Health Effects of Nicotine

Nicotine has pharmacological significance for man and animals (92).
The alkaloid is suspected of playing a role in sudden death due to
cardiovascular disease, to the complications of pregnancy and infancy,
and possibly to chronic obstructive pulmonary disease. Nicotine in
cigarettes leads to the formation of tobacco-specific nitrosamines in
the smoke. These are potent carcinogens. Nicotine itself is a significant
cocarcinogen in mouse skin carcinogenesis assays of smoke condensate.
It is important to determine whether nicotine acts as a cocarcinogen
under the conditions of dosage achieved by cigarette smokers and
whether the levels of nicotine-derived nitrosamines play a role in
human malignant disease. Resources for such study are available and
should be employed in a comprehensive evaluation of the potential
carcinogenic effects of new types of cigarettes.
Nicotine should be tested alone, and in the presence of other noxious
agents such as carbon monoxide, in animal systems designed to serve
as models for nonmalignant diseases associated with cigarette smoke.
Experimental cigarettes with a range of nicotine content have been
produced for studies of carcinogenesis. Many of these cigarettes are
still available. Those experimental cigarettes that might be needed for
pharmacological studies of nicotine should be identified and distributed
to appropriate laboratories as the need develops.

The Effecta of Smoking-Machiie Parame ters on Relative ad
Ab~~lute Yields of Smoke Components F'rom Various Types of
Cigarettes

Smoking-machine assays of cigarettes fulfill two needs. The FTC
ratings of "tar" and nicotine yields measure an implied risk to the
smoker. Smoking-machine data guide experimenters in elucidating the
mechanisms of induction of smoking-related disease. Absolute levels of
smoke constituents may be very important for experiments, so the
experimenter must have reliable information about the comparability


of machine and human smoking. The use of machine data to monitor
risk has somewhat different requirements. If the relative yields of
different cigarettes are not greatly affected by smoking conditions,
present smoking-machine standards will be adequate to indicate
relative risk of new cigarettes. We know, however, that the relative
yield of many constituents is affected by butt length, puff frequency,
and degree of ventilation. We need to determine how the variations in
these smoking parameters affect relative yields of the several sub
stances in smoke that are of toxicological interest.

Influence of Raw Product Modification on the Pharmacology of
Cigarette Smokfz

The composition of smoke is determined by the physical and chemical
properties of leaf tobacco. Modification of the raw product therefore
changes the pharmacology of cigarette smoke. The diversity of
available tobacco germplasm along with known genetic techniques
permits reduction of hazards in cigarettes through plant breeding and
selection. Cultural and curing practices are constantly changing in
response to market demands and the needs of farmers. Pesticides
currently registered for use on tobacco have been tested as contribu-
tors to the carcinogenic activity of cigarette smoke condensates. When
used as directed, these materials caused no significant change in
biological activity (65, 166). However, the pesticides used in tobacco
farming change from time to time in response to the occurrence of new
plant pests; for example, the recent spread of blue mold in tobacco-
growing regions has led to the use of a new pesticide. It is not known
whether the use of such materials may result in changes in the hazards
of cigarette smoke.

Present tobacco curing processes .may vary somewhat from farm to
farm. Furthermore, marked differences in agricultural practices such
as close spacing of tobacco plants, bulk curing, and homogenized leaf
curing might be introduced in the future. We need to determine the
consequences of changes (genetic, cultural, and curing methodologies)
on both the chemical composition and the biological effect of cigarette
smoke.

PhysicaI and Chemical F'roperties of Smoke From Cigar&tea
Delivering Less Than 10 mg of `Tar"

In the past few years, cigarettes delivering less than 10 mg of "tar"
by FTC test have been placed on the market. These cigarettes
apparently employ efficient filters together with various degrees of
smoke dilution. The extreme reduction of "tar" and nicotine delivery
by these cigarettes suggests significant differences in combustion
processes. Substantial differences in the chemical nature of both
mainstream and sidestream smoke might result from such changes.

55


Some or all of the new lower "tar" and nicotine cigarettes are
manufactured by processes that involve the use of chemicals or flavor
additives to improve consumer acceptability. The nature of these
additives, and their combustion products, that are currently used in
marketed cigarettes is not available to the public or to the Govern-
ment. Likewise, there are no published data on the biologic effects of
these additives or their combustion products.

Very low yield cigarettes may add to present concerns with respect
to sidestream smoke (5, 157, 184). While these cigarettes may deliver
such low levels of "tar," nicotine, and gas phase constituents that
smokers cannot compensate completely, the delivery of sidestream
smoke may not be reduced. Indeed, the sidestream smoke might
contain more of some substances (e.g., pyrolytic products of flavor
additives) than does the sidestream smoke of higher yield cigarettes.
For very low yield cigarettes, the risk of the sidestream smoke may
equal that of the mainstream smoke. The chemical and physical nature
of sidestream smoke should be determined on new cigarettes.

Development and Validation of Analytical Methods

Methods for determining "tar" and nicotine yield were developed
before very low yield cigarettes were an important segment of the
market. It is questionable whether existing procedures can measure
accurately the "tar" delivery of the cigarettes yielding 0.1 mg of "tar."
Other techniques giving acceptable results must be developed. F'roce-
dures for determining "tar" yields of low magnitude through measure-
ment of fluorescence have been recommended (159). These methods
must be validated by determining intra- and inter-laboratory reprodue
ibility. Furthermore, fluorescence measurements may be compromised
by additives that interfere with fluorescence, either directly or through
the behavior of their pyrolytic products. Fluorescence measurements
may not be satisfactory for use with new commercial cigarettes.
Analytical procedures must also be validated for a number of
chemical constituents in smoke such as aldehydes, nitrogen oxides,
phenols and catechols, aromatic hydrocarbons, and nitrosamines.
Several laboratories are conducting such assays with favorable results.
However, coordinated comparisons among laboratories to measure the
degree of intra- and inter-laboratory variability have not been
reported.

Other Research Needs

A number of other research needs of lesser priority should be
addressed:

1. It is necessary to study the interaction of smoking with
occupational and environmental exposure to other noxious mate-
rials. The incidence of lung cancer is greatly increased in asbestos
workers or uranium miners who smoke cigarettes (8,70,117). The

56


risk of using contraceptive hormones is also greater in cigarette
smokers (~52,174). Laboratory models of wcarcinogenesis should
be used to measure the potential effect of combined smoking and
exposure to other environmental toxins. Animal models should be
developed to investigate the possible synergism of smoking and
the environment in causing other diseases.
2. It is necessary to determine the threshold, if any, for carbon
monoxide with respect to cardiovascular effects, pregnancy, and
psychological performance. Carbon monoxide delivery of ciga-
rettes can be controlled by ventilation (66,126). To determine the
carbon monoxide risk of lower "tar" and nicotine cigarettes, we
need to know whether thresholds for carbon monoxide activity
exist and whether these thresholds vary for individuals of
different ages, medical histories, or genetic backgrounds. Evalu-
ation of risk due to carbon monoxide must take environmental
exposure into consideration (152).
3. It is necessary to define the extent of smoker compensation for
differences in nicotine delivery of cigarettes. To the extent that
smokers compensate for lower nicotine delivery, they will
probably obtain more of other constituents from lower nicotine
than from higher nicotine cigarettes. For example, the smoker
might take more puffs to obtain the same dose of nicotine, and
thus receive a greater dose of carbon monoxide (80, 145). It
should be determined at what point smokers can no longer
compensate for lower nicotine levels and whether compensation
is a permanent behavior change of smokers who switch to lower
"tar" and nicotine cigarettes. To carry out such studies, standard-
ized noninvasive procedures to indicate smoke uptake from
cigarettes yielding various amounts of "tar," nicotine, and carbon
monoxide should be validated. Analyses of blood, urine, and
expired air have been used for these purposes (25, 179, 181).
Analysis of saliva for nicotine might also be useful. With any
procedure, inter-laboratory comparisons using standardized
methods are needed.

4. Many gas phase components of cigarette smoke are ciliatoxic in
the experimental setting. They may overwme physiologic de-
fense barriers against pulmonary toxins. To some extent, the
ciliatoxic agents are absorbed in the mouth and upper airways
and do not reach the deeper portions of the lung. Experimental
systems may not be capable of duplicating the anatomic and
behavioral factors that may affect human response to ciliatoxic
agents. Nevertheless, short-term sequellae of smoking can be
measured in human smokers of different types of cigarettes.
Further evaluation of these effects in man should be undertaken.
5. Attention to chemical habituation evoked by cigarette smoking is
centered on nicotine, which is the most active acute pharmacolog-

57


ic agent in cigarette smoke. It is necessary to determine whether
there may be other chemicals present in cigarette smoke that
contribute to cigarette smoking reinforcement.

6. A variety of short-term animal models with quantitative end
points predictive of the development of tobacc+aasociated dis-
easea should be developed. Fzcept for cancer, long-term animal
models suitable for quantitative comparisons of disease risk are
not adequate. Even if successful long-term animal models are
developed, the costs in time and resources may prevent the timely
evaluation of new cigarettes.
`7. It is necessary to develop methods for dissemination of informa-
tion regarding the delivery of various noxious agents by ciga-
rettes. The smoke content of "tar," niwtine, carbon monoxide,
phenolic constituents, volatile aldehydes, nitrogen oxides, are-
matic hydrocarbons, and nitrosamines may all contribute to the
risks incurred by smokers. The Federal Trade Commission
releases its findings of "tar" and niwtine yields of cigarettes and
has announced its intention to assay carbon monoxide delivery.
As additional monitoring assays are conducted, it will be
necessary to present the new information to the public and to
health professionals in a meaningful way.

8. It is neceSSBTy to evaluate the health hasard posed by passive
inhalation by nonsmokers of the sidestream smoke from new
types of cigarettes. Lower Yar" and nicotine cigarettes are
designed to reduce the mainstream smoke received by the
smoker. There is no evidence that the amount of sidestream
smoke or its quality is improved by these design changes. Indeed,
if additives are used to insure acceptability of the cigarettes by
the smoker, their pyrolytic products may occur in the side&ream
smoke. New types of cigarettes should be monitored for the
qualitative and quantitative risks they might impose on the
nonsmoker.
9. It is n ecessary to evaluate cigarettes with lower "tar" to nicotine
ratios than are currently found in the market place. Compensa-
tion by smokers of lower "tar" and nicotine cigarettes appears to
be baaed on niwtine delivery. The "tar" to nicotine ratio may
limit the delivery of smoke constituents to the smoker. A low
ratio might be a desirable strategy for lower risk cigarettes. It
should be determined whether smoke from cigarettes with
unusually low "tar" to nicotine ratios has unusual pharmacologic
or toxiwlogic properties.

10. It is necessary to develop a low "tar" and nicotine reference
cigarette. Several laboratories will need these reference ciga-
rettes as a standard for wmparisons of lower "tar" and nicotine
commercial cigarettes. Commercial products cannot serve as a
reference because design changes are made without announce-

5s


ment and because the identity of additives is not disclosed.
Without a stable reference, intra-laboratory wmparisons con-
ducted at different periods of time and many inter-laboratory
studies will be wmpromised. Reference cigarettes are available
for a limited range of "tar" and nicotine deliveries. A reference
cigarette delivering very low levels of "tar," niwtine, and gas
phase constituents is needed. To produce a reference of sufficient
quality, large numbers of cigarettes must be made. Because an
effort of this magnitude cannot be undertaken by individual
researchers, a centralized facility to provide reference cigarettes
to appropriate scientists is desirable.

Summary

1. Several thousand constituents have been identified in tobacco
and tobacw smoke. Of these, niwtine appears to be the most
important acute-acting pharmacologic agent. Nicotine's physic
logic effects include increased heart rate and blood pressure.
Nicotine also can permit the formation of tobacco-specific
nitrosamines, which are potent carcinogens, and nicotine itself
may be a significant wcarcinogen. The carcinogenic potency of
cigarette smoke condensates appears to depend on the nicotine
content of the "tar." This relationship may be due in part to the
conversion of niwtine to tobacco-specific nitrosamines or to the
coexistence of nicotine and some other unidentified carcinogen.
Whether the carcinogenic effects of niwtine as determined in
animal studies are directly applicable to humans is not known at
present.

2. In an important study to predict the carcinogenic activity of
cigarette smoke condensate, the amount of available nicotine
delivered to the mice was found to be a factor in every term but
one of the predictive model.
3. Polycyclic aromatic hydrocarbons and tobaccospecific nitrosa-
mines are two prominent classes of tumor initiators found in the
smoke condensates of commercial cigarettes. Of the polycyclic
aromatic hydrocarbons formed during combustion, ben-
zo[alpyrene (BaP) may be the most important and has been
studied the most extensively. A wrrelation has been found
between be@a]pyrene levels and the carcinogenic activity of
smoke condensates from several types of cigarettes, but other
studies have failed to show that carcinogenic potential is
significantly dependent on beHa]pyrene content. However, the
interaction of BaP with niwtine does appear important in
carcinogenesis.

4.The tobacco-specific nitrosamines (TSNA) are formed during
curing and fermentation of tobacco leaves and combustion of

59


cigarettes. TSNAs induce cancer in the lungs and trachea of
hamsters and may be of particular importance in the induction of
human laryngeal cancer. They may be active as contact car&+
gens, or their metabolism at distant sites may produce carcino-
gens that are then transported to a target site.
5. It is not known whether the unidentified mutagens in cigarette
smoke are an important cause of lung cancer in humans, but
added exposure to any tumor initiators probably carries an
increased risk of cancer.

6. Cigarette smoke contains oxidants that have been shown to
reduce the activity of alphal-antitrypsin in animals and man. This
inhibitory function is distinct from the effect whole smoke has on
increasing levels of elastolytic enzymes released by neutrophils
and macrophages.

7. The great variety of tobacco types makes it possible to manipu-
late the plant genetically to change the content of the constitu-
ents of the leaf. The chemical content of the leaf is also affected
by agricultural practices and curing methods. The nicotine
content of tobacco, for example, is related to the amount of
nitrate fertilizer used in cultivation. Modification of tobacco as
reconstituted sheet incorporates substantial amounts of tobacco
stems that contain less nicotine than the leaf. The physical nature
of reconstituted sheets can be controlled to change their burning
characteristics and smoke composition.
8. Vapor-phase constituents of cigarette smoke inhibit ciliary
motility and mucous flow in experimental animals.

9. Cigarette smokers metabolize several wmpounds more rapidly
than do nonsmokers. This effect is believed to be caused by the
induction of microsomal oxidases, which include aryl hydrocarbon
hydroxylase (AHH). Induction of AHH activity appears to be
caused by systemic exposure to the smoke compounds themselves
or to the metabolites of those compounds. The AHH system may
be involved in the metabolic formation of ultimate carcinogens
from procarc' inogen precursors.
10. In recent years, a number of flavoring additives or cellulose-
based tobacco substitutes may have been included in manufac-
tured cigarettes. The nature and amounts of such additives as
actually used are not known, nor is it known what influence these
additives may have on the chemical composition or subsequent
biological activity of cigarette smoke.

11. Cigarette design has a major effect on smoke composition. The
filter is the design characteristic that has the most impact on
"tar" yield; it can also selectively remove nitrosamines and
semivolatile phenols from smoke. The porosity of cigarette paper
and the presence of holes in the mouthpiece influence smoke

60


composition because ventilation reduces the quantity of "tar" and
dilutes the gas phase of smoke.

12. Because of the complexity of cigarette smoke, the total impact of
any cigarette modification on smoke composition will probably
never be fully known.

13. Many laboratory studies of the effects of smoke constituents
have been carried out using smoking machines that control puff
volume, frequency and duration, butt length, and other factors
according to standardized parameters. However, the most widely
used parameters were established in 196'7, and the type of
cigarettes generally smoked today are substantially different
with respect to length, paper porosity, "tar" and nicotine content,
and concentration of gas phase constituents. Evaluation of the
toxicological and pharmacological properties of smoke from new
types of cigarettes requires detailed knowledge of the manner in
which those cigarettes are smoked, as well as of how smoking
patterns affect smoke composition.

61


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73


Section 3. CANCER


CONTENTS

Introduction

Epidemiologic Studies
Background
Epidemiologic Studies
  Discussion

Pathologic Studies
  Discussion

Experimental Chemical Carcinogenesis

Tumor Initiation and &carcinogens

Organ-Specific Carcinogens

Carbon Monoxide in Cigarette Smoke

Smokers' Compensation

Transplacental Carcinogenesis

Flavor Additives

Conclusions and Recommendations

Summary

References

LIST OF FIGURES

Figure l.-Lung cancer mortality ratios, by amount of
"tar" and nicotine in cigarette smoke


Figure 2.-Lung cancer mortality ratios, by number of
cigarettes smoked per day and amount of "tar" and
nicotine in cigarette smoke

Figure 3.-Relative risks of lung cancer in long-term filter
smokers (LTF) compared with nonfilter smokers (NF) by
number of cigarettes smoked per day, males

Figure I.-Decrease of be@a]pyrene in the smoke of
U.S. nonfilter cigarettes (36 mm)

Figure &-Percent of sections with advanced lesions by
smoking habit in two periods

LIST OF TABLES

Table l.-American Cancer Society Matched Groups Study

Table 2.-Known carcinogenic agents in the gas phase of
cigarette smoke

Table 3.-Tumor-initiating agents in the particulate phase
of tobacco smoke

Table I.-&carcinogenic agents in the particulate matter
of tobacco smoke

Table 5.-Organ-specific carcinogens in the particulate
matter of cigarette smoke

Table 6.-Carbon monoxide in smoke of cigarettes

78


lntroductlm

Research indicates that cigarette smoking causes cancer of the lung,
larynx, oral cavity, and esophagus, and is significantly associated with
pancreas, urinary bladder, and kidney cancer in both men and women
(102, 108, 104. This conclusion is based on epidemiologic, pathologic,
and experimental evidence collected over the past half-century.
A quarter-century ago lung cancer was found to be related
quantitatively to cigarette "tar" cumulatively inhaled. This finding,
along with much other evidence, led to the production and widespread
use of today's lower "tar" and nicotine cigarettes.2
The evidence summarized in this section demonstrates that lower
"tar" and nicotine cigarettes produce lower rates of lung cancer than
do their higher "tar," higher nicotine predecessors, but smokers of
lower "tar" and nicotine cigarettes still have much higher cancer
morbidity and mortality rates than do nonsmokers, as well as a higher
incidence of other diseases associated with smoking.

One important research concern is to identify the human carcinogen-
ic chemical or chemicals in the particulate and gas phases of cigarette
smoke. Multiple metabolic transformations are available in the human
body for the several thousand chemicals in cigarette smoke, a number
of which could lead to carcinogenic activity in model animal systems.
Another important research concern is that changes in cigarette
composition to reduce "tar," nicotine, and possibly even total smoke
exposure may inadvertently increase, or fail to decrease, those
chemical constituents still largely unidentified that contribute to
cardiovascular and pulmonary diseases, pregnancy complications, and
fetal and perinatal deaths.

A third area of concern is that the animal model systems used to
predict human disease from cigarette smoking require additional study
and correlation with the human situation, if these models are to serve
as a basis for modifying cigarette composition. When disease-produc-
ing chemicals are identified, their reduction or elimination should be
associated in the animal models with a decrease in the disease(s)
predicted and without untoward effects.

This section summarizes data on the human cancers associated with
lower "tar" and nicotine cigarettes, as compared with the "standard"
cigarette of the 1939s or 1949s. In addition, it compares pathologic
(autopsy) studies on bronchi of cigarette smokers of a quartercentury
ago with bronchi of lower "tar" and nicotine cigarette smokers.
Further, the section describes the identification, metabolism, and
possible mechanisms of action of certain carcinogenic chemicals in both
the particulate and the gas phases of cigarette smoke. Finally, the

79


section presents a series of conclusions and recommendations for
research.

Epldemlologic Studies
Background

It has been established that cigarette smoking causes cancer of
various organs including the lung, oral cavity, esophagus, and larynx,
as well as exhibiting a significant association with cancer of the pan-
creas, bladder and kidney (102). Epidemiological studies, both retrospec-
tive and prospective, have shown a dose-response effect; that is, risk
increases with the length of time the individual has smoked and with
the number of cigarettes consumed. Such studies have demonstrated
that, upon cessation of the smoking habit, risk for developing these
cancers declines; the slope of the decline depends on the duration and
extent of the former habit. For an individual who has smoked more
than 20 cigarettes per day for more than 20 years, no reduction in risk
of cancer development is noted for at least 3 years; however, the risk
decreases thereafter and, after 10 years of cessation, begins to
approach that of one who has never smoked.

From these epidemiological observations, it has been predicted that a
smoker's caner risk would be reduced if the "tar" yield of a cigarette
were reduced, provided that the individual does not compensate by
more frequent and deeper inhalation of lower "tar" cigarettes.

The trend toward cigarettes with lower "tar" and nicotine started
more than 25 years ago with the introduction of a number of filter
brands. This trend continued over the years with a greater number of
filter brands on the market. Since the early 1970s there has been a
rapid increase in production of cigarettes with 15 mg or less "tar" and
1.0 mg or less nicotine. By 1930, brands with these characteristics are
expected to account for more than 40 percent of total sales (70). In
1950, the average cigarette had 40 mg "tar" and 2.2 mg nicotine.
Today's filter cigarettes average about 14 mg "tar" and 1.0 mg
nicotine. The downward trend, particularly in terms of "tar" in filter
cigarettes, is continuing. There are increasing numbers of cigarettes
yielding 10 mg "tar" or less, and these have only one-fourth the "tar"
yields common 30 years ago. Although total consumption has increased
from 365 billion cigarettes in 1950 to 620 billion cigarettes in 1979,
consumption per capita by persons 18 years of age and over has
decreased by 5 percent in recent years-from 4,143 cigarettes in 1973
to 3,924 cigarettes in 19'79 (101), reflecting the 30 million smokers who
have quit (75). On the other hand, the proportion of smokers who
reported that they smoke 26 or more cigarettes per day increased from
23 percent in 1970 to 28 percent in 1978.


Epidemiologic Studies

Three epidemiologic studies-by the American Cancer Society, the
American Health Foundation, and the National Cancer Institute-
have evaluated the effect of lower "tar" and nicotine cigarettes on
lung cancer mortality.

The American Cancer Society conducted a prospective study in
which more than a million men and women in 25 States were enrolled
in 1959 and traced for 13 years. Subjects completed a questionnaire on
smoking habits upon enrollment, and the survivors completed another
questionnaire in 1965. An analysis of mortality from lung cancer was
made for two 6-year periods: July 1960 to June 1966 and July 1966 to
June 1972. The analysis included males and females who, in 1959-69
and in 1965, reported either that they had never smoked regularly or
that they smoked cigarettes regularly but never smoked cigars or pipes
regularly (36).

On each questionnaire, subjects reported the brand that they usually
smoked. From this information and from various reports of "tar" and
nicotine published in the years in which the questionnaires were
completed, subjects were classified as high "tar" and nicotine (T/N)
smokers, medium T/N smokers, and low T/N smokers. In the first
period, high T/N brands were defined as cigarettes with 26.8 or more
mg of "tar" and 2.0 or more mg of nicotine. Low T/N was defined as
brands with less than 17.6 mg "tar" and less than 1.2 mg nicotine. The
medium T/N category was between these two groups. By the time the
second questionnaire was distributed, there had been an increase in the
number of filter brands on the market and a general lowering of T/N
levels. Low T/N was defined in the same way as in the first period, but
the high T/N category had to be reset at a somewhat lower level.
Smokers in the three groups were compared by a matched groups
analysis. In this procedure, the groups were matched by age and other
factors, including number of cigarettes smoked per day, age at which
smoking began, race, urban or rural residence, occupational exposures,
education, income, and prior history of lung cancer or heart disease.
To be counted in the study, at least one person in each of the three
T/N groups had to be matched on all the variables mentioned above.
The adjusted number of lung cancer deaths was obtained by dividing
the number of deaths in each triad by the lowest number in each of the
three groups. The adjusted numbers of deaths were then summarized
for each of the three T/N groups.
Table 1 shows the number of subjects and the unadjusted and
adjusted number of lung cancer deaths in the high, medium, and low
T/N groups by sex and time period. In both sexes, deaths were fewest
in the low T/N group.
Figure 1 shows the lung cancer mortality ratios based upon the
adjusted number of lung cancer deaths. The number of adjusted deaths
for high T/N smokers was set at 1.00, and the adjusted number of lung

81


TABLE I.-American Cancer Society Matched Groupa Study

                 fw        Medium        LQW
sex           Period         T/N          T/N         T/N

Male
Male
Female
Female

Male         l960-l666         567          466          166
Mele        1666-1672         437          666           7s
Female        1960-1966          66          82           al
Female        1%&1972          89          149           44

  Male         196&11)86        l22.4         117.4         lOL0
  Awe         196&1m         S.6          a.6         76.6
  Female        1960-1966         4s.3          41.4          27.4
  Female       l9M-1972         68.1          42.2          lx2

SOURCE: Eemmoed et al. (ss).

cancer deaths for medium and low T/N smokers was compared with it.
The mortality ratio for male low T/N smokers was 0.83 and 0.79 in the
two time periods; for females, it was 0.57 and 0.62. The mortality from
lung cancer in low T/N cigarette smokers for both sexes over the
combined time periods was 26 percent lower than for high T/N
smokers. The mortality ratio for smokers of medium T/N cigarettes
was lower than for high T/N, but greater than for the low T/N
smokers.

Low T/N smokers had mortality ratios considerably higher than men
and women who had never smoked. In men, the mortality ratio of
nonsmokers for lung cancer was only 9 percent of that of the low T/N
smokers; in women, the nonsmoker rate was 49 percent as high in the
fit 6-year period and 22 percent as high in the second 6year period.

It is important to note that the T/N level of the brand of cigarettes
smoked was not as significant as the number of cigarettes smoked. The
adjusted number of deaths in men and women who smoked fewer than
20 high T/N cigarettes per day was compared with those who smoked
20 or more low T/N cigarettes per day. Figure 2 shows the mortality
ratios. The less-than-2O-cigarettes-perday high T/N smokers had
mortality ratios from 67 percent to 27 percent lower than the men and
women who smoked 20 or more low T/N cigarettes per day.

A retrospective study of lower "tar" and nicotine cigarettes was
conducted by the American Health Foundation (111). Data on lung
cancer cases in white males and females were collected, and interviews
were conducted in hospitals in six U.S. cities between 1969 and 1976.
Control cases were selected from patients in the same hospitals on the
basis of an absence of a history of tobacco-related diseases.

82


           Men
  Period1           Peliod2
1.00             1.00

         women
  Period1           Period2
1.00             1.00

"TAR" AND NICOTINE IN CIGARETTE WOKE

FIGURE l.-Lung cancer mortality ratios, by amount of "tar"
and nicotine in cigarette smoke
NOTE:H-hi&Y-msdnm;L-br.
SOUBCE: lid at al. (se).

Cigarette smokers were classified as long-term filter smokers (those
who smoked filter cigarettes currently and for at least 10 years) and
nonfilter smokers (current smokers of nonfilter brands).

Relative risks for filter smokers and nonfilter smokers were
computed by number of cigarettes smoked per day. Figure 3 shows the
relative risk of the male filter smokers as a percent of the risk for
nonfilter smokers. The percentages ranged from 61 to 39. Females
showed the same pattern, with the relative risk for long-term filter
smokers ranging from 33 to 79 percent of the nonfilter group. Only in
the heaviest smoking category (a small number of cases) ware the
relative risks the same.
This risk ratio of filter smokers to nonfilter smokers remained low
when the data were adjusted for factors such as duration of smoking,
amount of cigarette smoking, age, and alcohol consumption.
The American Health Foundation study also analyzed the risk of
larynx cancer for long-term filter smokers versus that for nonsmokers.
There were many fewer cases of larynx cancer than of lung cancer, but
the same general pattern was observed. In men, the relative risk for
long-term filter smokers was between 50 percent and 75 percent of the

83


Perk41
1.00

Park42

20+ <20
A DAY   A DAY

LOW    HIQH
TIN    TIN

20+ <20
A DAY   A DAY

LOW    HIQH
TIH    TIN

20+ <20      20+ <2tl
A DAY   A DAY     A DAY   A DAY

LOW    HIQH      LOW    HIQH
TIN    TIN       TIN    TIN

FIGURE t.-Lung cancer mortality ratios, by number of
cigarettes smoked per day and amount of "Yar" and &tine in
cigarette smoke
mJEcE: Elelemd et al. (.3@.

risk for nonfilter smokers in various number-of-cigarettmoked-per-
day categories. Women showed the same pattern.

A third epidemiologic study was conducted in Austria (63). This
project, part of an international study of smoking by the National
Cancer Institute, analyzed data on a sample of 414 lung cancer patients
and 823 controls. Cigarettes were categorized into three groups by T/N
level: Group I, cigarettes with "tar" yields below 15 mg; Group II, 15 to
24 mg "tar"; and Group III, 25 mg or more "tar." These groups were
assigned values of 1, 2, and 3, respectively, to indicate average
exposure.

The average "tar" exposure in cancer patients (2.596) was signifi-
cantly higher than for controls (2.026). Scores for total "tar" exposure
were computed as the product of the number of cigarettes smoked per
day, the number of years smoked, and the "tar" level (1, 2, or 3).

84


LTF NF      LTF Ns      LTF NF      LTF NF      LTF NF

l-10        11-20        21-30        314         41 +

AMY        AMY        A DAY        AMY        A DAY

FIGURE 3

I.-Relative risks of hmg cancer in long-term filter

smokers (LTF) compared with nonfilter smokers (NF) by number
of cigarettes smoked per day, ndea
SOUIOCIE: wyedw aed &elhM (my

Relative risks were then computed by these scores. These risks
increased directly with "tar" exposure scores, from 1.6 for scares lower
than 566 to a relative risk of 6.1 for scores higher than 5,600.

Cigarette smoke condensate of present cigarettes pro&as fewer
tumors on mouse skin than did that of cigarettes tested some 30 yeam
ago (109). This difference is probably because today's cigarettes
contain more tobacco stems and more reconstituted tobaccos and have
cigarette paper with higher porosity, all contributing to smoke
condensate that is less tumorigenic to the experimental animal.
Changes in chemical composition of the smoke may be a factor. Using
just one chemical component as a carcinogenic indicator, researchers
have shown that benzo[ajpyrene (BaP) content is significantly lower in
today's cigarettes than in cigarettes of 36 years ago (Figure 4) (49).

85


r

12-

E 1.0-
E
8
&
? 0.6-
%
P

0.6 -

I      I      I       I      I      I
1955      1960      1965      1970      1975      1960
              YEARS OF PURCHASE

FIGURE 4.-Decream of benzo[a]pyrene in the smoke of U.S.
nonfilter cigadtm (&I!5 mm)
SOUECE: Hoffmule std. (4s).

Many brands of cigarettes classified as lower "tar" and nicotine were
introduced in the 1970s and had a remarkable growth in sales. The
average "tar" in lower "tar" and nicotine brands in 1978 was about 10
mg. Many brands of cigarettes classified as lower "tar" and nicotine in
studies reported in the 1960s and early 1970s would be classified as
medium "tar" and nicotine cigarettes in the 1980s. Therefore, it might
be assumed that cigarettes with lower "tar" and nicotine yields afford
even lower cancer risks. But this is not necessarily true. Studies of
smoking patterns suggest that smokers of the lower "tar" and nicotine
cigarettes tend to inhale more deeply (44,98), have higher amounts of
carboxyhemoglobin than predicted (106), and have higher than expe&
ed carbon monoxide in their exhaled breath (54). On the other hand,
the lower "tar" and nicotine cigarettes of 1980 have as little as one-
fourth the "tar" and nicotine of the cigarettes of 1950, and even if
some compensation takes place, actual net smoker exposure is probably
much lower.

There is evidence that machines that measure "tar" and nicotine
content are not suitable for measurements of smoke from lower "tar"
and nicotine cigarettes with perforated filter tips (62) and that the

86


"tar" and nicotine in the inhaled smoke may be more than indicated by
the test proc43dures.
Epidemiological studies thus far have only studied cohorts who
began their smoking careers with the old nonfilter, high "tar" and
nicotine cigarette. Only in the years to come can we determine the risk
of those individuals who began smoking with lower "tar" and nicotine
cigarettes, and it is important to study this risk.
As the "tar" yields of cigarettes decrease further, it is probable that
flavor additives will be increasingly used. Their potential biologic
activities need to be investigated and monitored on an ongoing basis.
Epidemiological data in addition to chemical and biological findings
show the reduced risk among lower "tar" and nicotine cigarette
smokers, which was predicted because of chemical and biological data
previously known. No such clear demonstration of effect exists,
however, for cardiovascular disease, chronic obstructive pulmonary
dii, or pregnancy. The character and mechanisms of smoke
components causing these diseases probably differ significantly from
those acting in carcinogenesis.

Pathologic Studier

Histological changes in the tracheobronchial tree in noncancer
patients can be observed at autopsy in direct proportion to the number
of cigarettes smoked per day during life. Lung cancer patients have
the most advanced histological changes in their remaining epithelium
(4, 6). Ex-smok ers who quit for at least 5 years show greatly reduced
histologic changes. This finding, together with the observation of cells
with disintegrating nuclei in the epithelial lining, suggests that a
healing process has taken place in these cases (5).
To evaluate the effect of smoking lower "tar" and nicotine
cigarettes on histologic changes in bronchial epithelium, male patients
who died of causes other than lung cancer in 1970-77 were compared
with those who died in 195569 (3). None of the men who died in the
later period could have, in the last 5 to 10 years of their lives, smoked
cigarettes that were as high in "tar" and nicotine content as the
cigarettes smoked by men who died in the earlier period. Sections from
the tracheobronchial tree of 211 men who died in the earlier period and
of 234 men who died in the later period were put in random order for
microscopic study. A total of 20,424 sections were read, an average of
46 sections per patient. Histologic changes studied included basal cell
hyperplasia, loss of cilia, and occurrence of cells with atypical nuclei.
Smokers had these changes far more frequently than did nonsmokers,
and within each group the percent with these changes increased with
the reported number of cigarettes smoked per day. Nonsmokers in both
time periods had about the same proportion of these changes. But in
each smoking category (adjusted for age), the men who died in 1970-77

87


NEVER <l    l-2    2+

NEVER <1     l-2    2+

SMOKED PACK PACKS PACKS        SMOKED PACK  PACKS PACKS
REG.   ADAY ADAY ADAY          REG.   A DAY   ADAY ADAY

FIGURE a--Percent of sections with advanced lesiona by
smoking habit in two periods

had far fewer histological changes than those who died in 1955-69.
Figure 5 shows the percentages with the most advanced histologic
change recorded (carcinoma-in-situ) in the 1955-69 and 1979-7'7 groups.
These changes were not found in nonsmokers in either group, and they
were found far more frequently in smokers in the 195569 cases than in
the 19'70-77 cases. In two-pack-aday smokers, 225 percent of the
195540 group had this advanced change, compared with only 2.2
percent of the twopack-aday smokers in the 19'7&77 group.

Discussion

Epidemiologic and experimental pathologic studies yield some
evidence that filter, lower "tar" and nicotine cigarettes produce fewer
neoplasms than the nonfilter cigarettes of 25 to 39 years ago. While it
is not always possible to directly extrapolate data on animal experi-
mental carcinogenesis studies to man, the data summarized in this
section show the predicted lower mouse skin tumorigenesis of filtered,
lower "tar" and nicotine cigarette "tar" on an equal weight basis. Po&


mortem studies of the human lung further support the finding that the
filter, lower "tar" and nicotine cigarettes are less oncogenic than the
nonfilter cigarettes of 25 to 50 years ago.

Experlmental Chemical Carcinogenesls

While epidemiologic, pathologic, and experimental studies all point
to polycyclic hydrocarbons within the "tar" moiety of inhaled cigarette
smoke as potential carcinogens for man, additional work is needed to
determine whether nicotine plays a major role as a cocarcinogen.
Further, nicotine and nor-nicotine give rise to two carcinogenic
nitrosamines that are found only in tobacco products. Tables 2,3,4, and
5 list known carcinogenic agents in both the particulate and the gas
phases of cigarette smoke.

Russell (90) recently suggested that a lower "tar," medium nicotine
cigarette would be more attractive to smokers and tend to promote
their use while minimizing health risk. This action cannot be supported
without further research on nicotine's effects in carcinogenesis.
Studies should address not only nicotine carcinogenesis, but also the
chemical's effects on the cardiovascular, gastrointestinal, endocrine,
and central nervous systems. Nicotine has been found to have potent
physiologic effects on these systems.

The following discussion briefly considers the probable routes of
metabolism and binding to critical cellular components of the chemi-
cals in the particulate and gas phases of cigarette smoke thought most
likely to be carcinogenic for man.

Most procarcinogens are metabolized through a mixed function
oxidase system, which is composed of the hemoprotein cytochrome P-
450, NADPHdependent cytochrome P-450 reductase, and phospholip-
id. Various forms of P-450 have been characterized immunologically
(99), and some have been separated electrophoretically (78). The amino
acid composition and partial sequences of some forms of P-450 have
been elucidated recently (15). A treatise on the physicochemical
characteristics and physiological function of P-450 has also appeared
(78). The different forms of P-450 may have differential effects in the
production of metabolites (99, 81, 91). Metabolic activation of most
carcinogens by the P-450 mediated oxygenases is considered to afford
structures that are strong electrophilea and thus prone to attach to
cellular nucleophiles, including proteins, nucleic acids, and other
macromolecules (21, 72, 73).

Polycyclic aromatic hydrocarbons present in tobacco smoke are
typified by ben@a]pyrene (BaP). BaP is found in the soil and
atmospheric particulates of cities, with relatively high concentrations
around highways, airports, factories, and similar installations (51).
Since it occurs in pyrolysis products, such materials as soot, tar, and
charcoal-broiled or thoroughly roasted foods all have measurable

a9


levels. BaP also has been identified in forest soils, in volcano effluents
(50), in marine sediments, and even in the deeper layers of soil from the
permafrost regions of the earth (52).
BaP was among the first polycyclic aromatic hydrocarbons isolated
from coal tar and has been used for various experimental purposes for
50 years.
On the basis of metabolic studies with phenanthrene, Boyland (16)
hypothesized that hydrocarbons were metabolized through arene oxide
or epoxide intermediates. Such intermediates could account for the
identification of phenols, dihydrodiols, premercapturic acids, and
mercapturic acids as metabolites of phenanthrene or naphthalene, all
depending on whether the epoxide reacted with water or glutathione
or rearranged nonenzymatically.
The information gathered from various experiment-a in vitro with
metabolites of BaP, DNA adducts, and presumed intermediates led to
the conclusion that both the dihydrodiol and epoxide moieties were
required for carcinogenic activation of BsP and other polycyclic
hydrocarbons. In the case of BaP, the potent carcinogenicity of the `I,%
dihydrodiol indicated that it was probably an intermediate toward the
final activated carcinogen (57).
A number of studies have substantiated the concept that a "hay"
region is involved in transformation of most polycyclic hydrocarbons to
the activated intermediate (7496,108).
The diol epoxide of BaP thus appears to be the metabolically derived
strong electmphile that is capable of reacting with critical constituents
in the cell. The reaction of this activated intermediate with nucleic
acids has been followed both in tivo and in vitro (59,61,76).
P1-450 is also a component of the enzyme system called aryl
hydrocarbon hydroxylase (AHH) (2). The major phenolic detoxification
product, 3-hydroxybe&a]pyrene, results from nonenzymatic rear-
rangement of the initial 2,3-epoxide formed by the P&i0 (112). The
phenols are amenable to conjugation by glucuronyl transferase or
sulfotransferase, leading to solubilization and more rapid excretion.
The available evidence suggests that in different strains of mice high
AHH inducibility leads to increased susceptibility to hydrocarbon-
induced tumors. The genetics of AHH inducibility in mice have been
thoroughly discussed (77, 78, 79). Attempts have been made to extend
some aspects of the AHH work to humans, despite the variability in
results noted in human populations (2).
Although there is currently more emphasis on the reactions of the
electrophilic species from carcinogens with nucleic acids, the binding of
carcinogens to proteins had been noted many years earlier (72). More
recent efforts have shown that ligandin, a hepatic protein that binds
anionic metabolites of glucocorticoids (67), also binds some carcinogens
such as polycyclic aromatic hydrocarbons and aminoazo dyes but not
aromatic amides (68).


Aromatic amines are found in tobacco smoke. These compounds are
formed during the burning of tobacco, including toludines, Znaphthyl-
amine, and unknown aminofluorenes. These compounds are also
activated through the P-450 system similar to that for the aromatic
hydrocarbons. Ring-hydroxylated products of aromatic amines appar-
ently are detoxification products. For most of the carcinogenic
aromatic amines or amides investigated, N-hydroxylation apparently
was the activation route.

Further reaction of the N-hydroxy compounds was found necessary
to afford forms capable of reacting with nucleic acids or proteins.
Acetate, glucuronide, sulfate, or even phosphate esters of the N-
hydroxy amide had the required characteristics; the products from in
vitro reactions with nucleic acid were the same as those isolated from
reactions in viva. In some but not all cases, the carcinogenicity of the
parent amide or amine roughly correlated with the enzyme levels in a
target organ.

One of the most readily obtained of the activated esters, N-acetoxy-
N-24luorenylacetamide (N-AcO-FAA) has been employed in many
model experiments to study effects on the structure and function of
nucleic acids. N-A&-FM forms a major adduct with DNA where
approximately 84 percent of the fluorene residue was linked to the C-g
of guanine by arylamidation, affording N-(deoxyguanosin43-yl)-2
fluorenylacetamide, which retained the N-a&y1 group (28).
An additional means for activation and adduct formation of
aromatic amine derivatives has been investigated by CM. King et al.
(58). An enzyme termed N-O-acyltransferase forms derivatives that
are quite reactive and readily form adducts with RNA.
More recent work points toward attachment by the activated
aromatic amines and amides to still other positions on the bases of
nucleic acids (10,55,56).

Numerous model studies with N-A&-FAA modified nucleic acids
have shown a change in function of the altered nucleic acid. However,
none has shown the exact role in the process of carcinogenesis; this
remains an area for further investigation (94).
Although the aminoazo dyes and aromatic amines or amides are
activated in a similar fashion and both bind to proteins, the proteins
involved differed somewhat (8,9, 68,97).

Relatively less emphasis has been placed recently on carcinogen-
protein interactions than on carcinogen-nucleic acid interactions. In
view of the essential function of the proteins, it seems their interac-
tions with carcinogens require more investigation.

N-Nitroso compounds found in tobacco smoke include those derived
from nicotine, nitrosonornicotine and related compounds, N-nitroso-
diethanolamine, and nitrosodimethylamine. Metabolic activation of
dialkylnitrosamines is necessary for expression of their toxic and
hepatocarcinogenic effects. Oxidative metabolism of dimethylnitrosa-

91


mine, for example, is accomplished by the liver microsomal P-450
system yielding an unstable (a-hydroxymethyl)methylnitrosamine,
which forms formaldehyde and an unstable methylnitrosamine. In
turn, this molecular species collapses with release of nitrogen and
formation of the methyl carbonium ion, CHa+, which alkylates
proteins, nucleic acids, and probably other cellular constituents. The
intermediacy of the (a-hydroxymethyl)methylnitrosamine is substanti-
ated by the potent mutagenicity and outstanding carcinogenicity of
the more stable (a-acetoxymethyl)methylnitrosamine (11). More recent
studies suggest that other oxidation pathways may also be involved
(66).

Tobacco and its resultant smoke contain two carcinogenic N-nitrosa-
mines that are formed from nicotine and nornicotine (Table 2) (46,47).
N-Nitrosonornicotine (NNN) gives rise to cw-hydroxy N-nitrosamines,
which are unstable and decompose finally to oxocarbonium ions, the
suspected ultimate carcinogenic forms of NNN. Most of the oxocarb+
nium ions react with water, yielding a keto alcohol and a hydroxyal-
dehyde (19). The other carcinogenic and tobacco specific N-nitrosamine
is 4-(N-methyl-N-nitrosamino)-l-(3-pyridyl)-1-butanone (NNK), which
is also a-hydroxylated. The methyl hydroxylation product gives rise via
an oxodiazohydroxide to the same carbonium ion as the 2'-hydroxyl-
ation of NNN (42).

Alkylnitrosoureas afford alkylating moieties without the need for
metabolic activation; spontaneous decomposition occurs at alkaline pH
values. However, the organs affected by alkylnitrosoureas may vary,
depending on the route of administration and the animal model.

Nitrosomethylurea, most widely used in model experiments, can
cause tumors in brain, breast, stomach, liver, heart, skin, kidney,
intestinal tract, bladder, trachea, and peripheral nervous system (107);
administration to pregnant animals often leads to tumors of the
nervous system in the offspring many months later (SO).
The alkylating moiety (carbonium ion) formed from a nitroso
compound may attach to a variety of positions in the nucleic acids
bases, on the phosphate backbone, or on the ribose portion of the RNA.

Environmentally, nitrosamines and related structures represent a
problem, since they may be formed endogenously from secondary or
tertiary amines, amides, or ureas and nitrite, available from reduction
of nitrate by bacteria of the salivary plaque. Nitrate has a widespread
distribution in dietary vegetables and grains. Although each individual
has therefore the capacity to form nitroso compounds, endogenous
nitrosation can sometimes be inhibited by ascorbic acid, propyl gallate,
or other compounds that compete with the amine or amide for nitrous
acid. This is not a panacea, for ascorbic acid may enhance nitrosation of
certain amines (18). Furthermore, innocuous nitroso compounds, such
as nitrosoproline, or even some aliphatic nitro alcohols, can provide a
nitroso group to form carcinogenic nitrosamines or amides by transm-

92


trosation (26, 95). Although certain bacteria are instrumental in
formation of nitrosamines within the organism (.@), bacteria also
degrade nitrosamines (89), leading to a balance between endogenous
formation and decomposition of nitroso compounds. During the
chewing of tobacco, N-nitrosonornicotine is formed in the oral cavity
(41). Although it has not been demonstrated, it may be assumed that
under certain conditions the carcinogens NNN and NNK can also be
formed from nicotine in other organs or sites in man.

Another carcinogen, vinyl chloride, has also been identified in
tobacco smoke. Metabolically, vinyl chloride is activated through the P-
450 system by formation of a halogenated epoxide (7,.@, 113). Such an
epoxide may yield halogenated aldehydes or alcohols through rear-
rangement (45, 118) or through derivatives of glutathione through S-
transferase (4.5).

In summary, most of the identified carcinogens found in tobacco
smoke are activated through the P-450 system to electrophilic corn
pounds, which react with proteins, nucleic acids, perhaps lipids, and
other cellular constituents. Since there are many constituents of
tobacco smoke, only the activation pathways of BaP, typical aromatic
amines, nitrosamines, and vinyl chloride have been presented here. The
activation pathways of the other carcinogens found in tobacco smoke
may be similar.
Although the pathogenesis of several types of cancer, chronic
obstructive pulmonary diseases, and cardiovascular diseases is linked to
different tobacco smoke constituents, the epidemiologic associations
with cigarette smoking are dose related for each of these diseases (84,
86, S7, 58, 102). Thus, the first goal in production of a "less hazardous
cigarette" was to reduce total smoke delivery. Because the causal
relation between smoking and lung cancer was the first established,
primary emphasis was placed on reducing the carcinogenic "tar" of
cigarette smoke (110).

Tumor lnltlation and Cocarcinoge~~s

Inhalation studies with Syrian golden hamstem and bioassays on
mouse skin, rabbit ears, and the connective tissue of mice and rats have
clearly indicated that the major carcinogenicity of cigarette smoke
resides in its particulate phase (28, 18,109). Although the presence of
volatile carcinogens in the gas phase has been well established (Table
2), the models available at present do not allow detection of a
carcinogenic effect of the gas phase because of the low sensitivity of
the systems (98).

Extensive fractionation studies combined with bioassays have
supported the concept that the concentration in cigarette "tar" of
certain polynuclear aromatic hydrocarbons (PAH), which are known
human carcinogens (85, 69, 86), is too low to account for their activity


TABLE 2.-Known carcinogenic agents in the gas phsae of
     cigarette smoke*

DitMthytIli-
EthylmethylnitmsMine
Dbth~llti~ltt!
Nitmwpydiine
mher nirnd'
Hydrazine
Vinyl chloride
Aerylonitde
ZNhpropme
UMhlM

1
0.1
0
2
0
24
1
82
0.72
`al

as complete carcinogens. These PAH, however, are active as tumor
initiators and thus contribute to the induction of tumors by tobacco
"tar," which contains an abundance of cocarcinogens (2U, 49). Tables 3
and 4 list the tumor initiators and cocarcinogens in cigarette smoke
known at this time. Large-scale model studies on mouse skin and
inhalation studies with Syrian golden hamsters have shown that a
significant reduction of "tar" and a selective reduction of tumor
initiators and cocarcinogens will lead to a significant reduction of the
carcinogenic potential of cigarette smoke (IS, ZS, 24,29, SO, 91, 92, 48).
Recently, a study has indicated that nicotine (and possibly other
tobacco alkaloids) may be active as a cocarcinogen (14), while another
study did not show acrolein to have cocarcinogenic properties (27').
Further detailed investigations are required.

Organ-Specific Carcinogens

This approach toward the less hazardous cigarette has been criticized
by several groups as one-sided because it has been concerned only with
"tar," nicotine, and tumor initiators such as PAH and with coca&n+
gens, rather than with organ-specific carcinogens (85,88,102).
Table 5 lists the known organ-specific carcinogens. In the case of
polonium-210, a recent indepth study raises doubts on the significance
of =OPo as a factor contributing to lung cancer in smokers. Neverthe-
less, it may be prudent to reduce the =OPo content of tobacco products
w

Among the aromatic amines, certain individual compounds are
known human bladder carcinogens (e.g., Z-naphthylamine, 4-biphenyla-

94


TABLE 3.-Tumor-initiating agenta in the particulate phase of
       tobacco smoke*

CompoutKl

Relative activity aa
amplete eareiaogelP

NgAiguette

+++
+++
++
++
++
++
++
++

1040
  0.6
r10
a,
60
2
s-10
G
40-70
404
MO
  7
10
34
s
  0.1
  0.7

mine, and henzidine) (83). Doll (22) has discussed the aromatic amines
as likely contributors to the increased risk of cigarette smokers for
bladder cancer. These carcinogenic compounds are primarily pyrosyn-
thesized from the tobacco proteins (8492). Except,for the development
of a process to reduce the protein content of tobacco (IOO), no efforts
toward the reduction of aromatic amines in cigarette smoke have been
reported.

A major group of organ-specific carcinogens in cigarette smoke are
the N-nitrosamines. The volatile nitrosamines, for which protein and
nitrate are precursors, can be selectively reduced by filtration (I 7). The
tobacco-specific N-nitrosamines in tobacco and in smoke are formed
during tobacco curing as well as during smoking. So far, N'-nitrosonor-
nicotine (NNN), 4-(N-methyl-N-nitrosamine)-l-(3-pyridyl)-l-butanone
(NNK), and N'mitrosoanatabine (NAT) have been identified. These
compounds are formed from the major tobacco alkaloids: nicotine
(NNN and NNK), nomicotine (NNN), and anatabine (NAT). The total
concentration of these three nitrosamines varies between 0.7 and 10.0
Irg/cigarette (47). NNN is a moderately active carcinogen in mice, rata,
and Syrian golden hamsters, whereas NNK is a strong carcinogen in
the respiratory tract of all three species; NAT has so far not been

95


TABLE 4.-Cocarcinogenic agents in the particulate matter of
       ~.~MCCO smoke*

L Neutral fraction
  pyreae 6)
  MethYlPyreaea (I)
  Fluomotheoe (-)
  Methylfluoraotheoed (+ ;I)
  ~tiAi,~~~~ (4
  B-mPP~ (+I
  other PAEra (+)
  Napbthalenen (-)
  1-Metbylinddea (-)
  BMethylcarhamlea (-)
  4#-Dichloraetilb (-)
  Other oeutral eompotmd8 (7)
IL Acidic fmetioo
  ~teelml (4
  ~Methyldechol (-)
  4aethylLxt4uM (-)
  cEkhykda?hol (-)
  4-o-Ropylateehd (7)

+
?
+
?
+
+
?
+
+
+
+
?

bioassayed. Although conclusive epidemiologic data are not available,
"NNN should be regarded for practical purposes as if it were
carcinogenic to humans" (53). Ftesearch programs on the reduction of
these tobacco-specific carcinogens in cigarette smoke and their possible
in tivo formation in the smoker from nicotine, nornicotine, anatabine,
and other tobacco alkaloids need to be undertaken.

A neglected area may be the reduction of other organ-specific
carcinogens in cigarette smoke, such as nitro-arenes and pesticides that
may give rise to carcinogens such aa maleic hydrazide diethanolamine
(MH-30).

Carbon Yonoxlde in Cigarette Smoke

Until a few years ago the reduction of carbon monoxide in cigarette
smoke had not been seriously studied. In fact, in 1976 a report from the
United Kingdom demonstrated that unperforated filter cigarettes can
deliver higher carbon monoxide values (13-18 mg/cig) than nonfilter


TABLE 5.-Orgamfic aucinogens in the particulate matter
      of cigarette smoke

L -
   N'-Ni~WlVliCOtiO8
  44.N.Me-thyl-N-oh-m-
   mino~l-(Myridyl~l.
   butaoooe
   N'-Nitmmnatabine
  Nitmsopiperidiw
  uokoowo u08yometrical

   Polollium-210
  Nickel mmpouoda
  tkdmim eompouod8
   UUkWWM
III. PImcrm
   Nitmmmbm
   UUkBOWM
IV. Kidney and bladder
  BNapbthyhine
  .&nioofluoreae
  x--h
   o-Toluidine
   uokoowo aroom& Mliuea
   o-Nitrotduene
  uokoowo oitm eootpouod8
  Di-n.butylniW
   otter oi-e8

0.14.0 *
1-m w

0.1-0.4 pg
0.24.6 erg
mne

?

0.03-1.3 pci
0-6oow
S-IO og
?

?
?

+
+
+

+

+
+
?
?

cigarettes (9-16 mg/cig) (105). This finding has been confirmed in both
Germany and the United States (49). An increasing number of the
cigarette brands sold in the United States have perforated filter tips,
at present amounting to approximately 50 percent. The filter perfora-
tion leads to air dilution of the smoke and to changes in the burning
profile of the cigarette, and thus, to a significant reduction of the
carbon monoxide content of the smoke (Table 6). Filter tip perforation
similarly reduces the nitrogen oxides in cigarette smoke (82).

Smokers' Compensation

Studies by Russell and his group (90, 98) and recently by Hill and
Marquardt (4.4) have demonstrated that many smokers who switch to
lower "tar" and nicotine cigarettes will compensate for the loss in
smoke nicotine (and possibly other agents) by intensifying their smoke
intake, puffing more frequently, and drawing larger volumes per puff.
In the case of cigarettes with perforated filter tips, the occlusion of the
filter vents by the fingertips may be an additional compensation

97


TABLE B.-Carbon monoxide in smoke of dgareth
                    carbon onmmide (olgk!igade)

                                             Pafaated
                   Nonfilter           nlter           filter

19Tl/1976       11.6-17.0
         (N * 8)
             9-16
         (N - 9)
            16-n
         (N - 7)
            14iw9.9
         W - le)

14.4-20.0
W - 28)
lal8
(N - 10)
las-23            -
0 - 17)
8.&las
W - W    (EJ)

technique that smokers may develop either intentionally or subcons-
ciously (62). These factors of "smoker compensation" must be consid-
ered in the evaluation of lower "tar" and nicotine cigarettes. Filtered,
lower "tar" and nicotine cigarettes that are less vulnerable to
increasing the smoke and nicotine deliveries are needed. Such producta
are envisioned by scientists in the tobacco health field. Attempting to
minimize smoker compensation by selectively reducing `%ar" and other
smoke compounds while maintaining nicotine yield may carry serious
disadvantages. First, maintaining nicotine delivery may reinforce
physiologic habituation, and interfere with smoking cessation attempts
(98). Second, nicotine gives rise to the tobacco-specific carcinogenic N-
nitrosamines, NNN and NNK, and nicotine itself may be carcinogenic
(see Experimental Chemical Carcinogenesis within this section). F'inal-
ly, nicotine is suspected to bc a major smoke constituent correlated
with the increased risk of cardiovascular disease among cigarette
smokers.

Transplacental Carclnogenesfs

The possible transplacental effect of cigarette smoking on carcino-
genesis should be investigated. Recently, it has been shown that
cigarette "tar" is an active transplacental carcinogen in Syrian golden
hamsters (80). Furthermore, a number of smoke constituents are active
as transplacental carcinogens in the experimental animal (25). These
include volatile N-nitrosamines, bewaJpyrene, o-toluidine, ethyl
carbamate, and vinyl chloride (87). Other major tobacco carcinogens
including the benzofluoranthenes, NNN, and NNK need to be bioas-

98


sayed for their transplacental activity and to be considered with
respect to lower "tar" cigarettes.

Flavor Additives

The development of lower "tar" and nicotine cigarettes has tended
to yield products that lacked the taste components to which the smoker
had become accustomed. In order to keep such products acceptable to
the consumer, the manufacturers reconstitute aroma or flavor. There
are several ways in which this can be achieved. Flavor extracts of
tobacco can be added to the lower-yield blends. Other plant extracts
can be used to supplement the flavor spectrum, synthetic flavors can
be added, or a combination of techniques can bc applied (64, 65).
Powdered cocoa, one flavoring additive that is probably used in U.S.
cigarettes, has been found to increase mouse skin tumorigenicity of the
"tar" from a standard experimental cigarette at each of two dose
levels (31).

The burning of cigarettes with flavor additives produced increased
and perhaps novel types of semivolatile agents, including traces of
mutagenic compounds. The mutagenic agents were found in the basic
fraction of the semivolatile portion obtained from heating the tobacco
mixtures. Chemically, the agents thus far identified were substituted
pyrazines and other aza-arenes with and without amino groups (64).

The exact delineation of the chemical structure of additives, their
pyrolytic products, the possible carcinogenic properties, and the
quantities found in smoke of lower "tar" cigarettes is urgently needed
in order to assure the consumer that the filter, lower "tar" and nicotine
cigarette does not carry additional or new health risks.

Conclusions and Recommendations

1. Both retrospective and prospective epidemiologic studies in man
have shown a dose-response relationship between cigarette smok-
ing and the occurrence of cancer of the lung, larynx, esophagus,
oral cavity, and bladder with a less clear quantitative relationship
to cancers of the pancreas and kidney. Smoke dose was measured
by various parameters, including numbers of cigarettes (daily or
lifetime), duration of habit, depth of inhalation, and number of
puffs per cigarette.

  The highest priority in the field of public health is that
individuals who have not started smoking should not begin and
that those who currently smoke should quit.
2. Those individuals who start smoking with a filter-tipped, lower
?ar" and nicotine cigarette, or who switch after a period of time
from high "tar" and nicotine cigarettes to the lower "tar" and
nicotine cigarettes, will have a lower incidence of lung cancer, but
an incidence far in excess of the nonsmoker.

99


  Specifically, high priority should be given to continued and
long-term retrospective and prospective epidemiologic studies on
all tobaccorelated diseases, with specific reference to brand of
cigarettes smoked, number of cigarettes, manner of smoking,
inhalation, etc., along with generation of data on "tar," nicotine,
carbon monoxide, and other chemical content, as determined by
the most up-to-date scientific methods. This same epidemiologic
survey should include studies of individuals in high-risk occupa-
tions, of groups such as teenagers, minorities, and people of
varying socioeconomic status, of men compared with women, and
of different ages at which smoking began. Concern expressed by
the group was, because cigarette composition in the United States
is changing rapidly, without continued, well-planned, long-term
studies, it will be difficult to know what effect the changing
composition is having on the health of the American people.
3. An administrative mechanism to focus major interest on tobacco
and the diseases caused by smoking tobacco should bc established.
Such a mechanism should include involvement of basic scientists,
epidemiologists, physicians, statisticians, social scientists, and
related experts concerned with smoking. There should be a stable
source of funding for both new and established investigators to
work together on tobacco and health problems over a period of
time, since the answers to the questions raised over the past
quarter-century will not come quickly, considering the magnitude
and duration of the problem in the United States.
  Moreover, institutions and programs should be encouraged to
train scientists for smoking research and to maintain a core group
of physicians, scientists, and educators to consider various aspects
of smoking research issues.
4. Additional work in carcinogenesis should be performed:
a. It should be determined whether nitrosamines are formed from
  cigarette smoke in the human body and, if so, whether they are
  formed in significant concentrations. A key concern is whether
  nicotine itself forms nitrosamines in biologically significant
  quantities following reaction with nitrous oxides. The role of
  nicotine in human carcinogenesis should be identified.
b. Tobacco additives and flavoring agents should be studied by
  appropriate methods for carcinogenicity and other toxicities,
  before their commercial use is permitted, and study data should
  bc made available to the appropriate agencies.
c. A continuing study of lower Yar" and nicotine cigarettes for
  carcinogenicity might detect changes resulting from new or
  different manufacturing practices or from new additives or
  flavoring agents that might act synergistically.
d. The gas phase of cigarette smoke should bc examined more fully
for carcinogenicity.


e. Several carcinogens from cigarette smoke should be studied for
synergistic, additive, or antagonistic effects on carcinogenesis
because tobacco constituents are inhaled or swallowed as a
mixture, not individually.

f. Further investigations of promoters, cocarcinogens, and initia-
tors of cancer in cigarette smoke are necessary.
g. New models for carcinogenicity should be developed with
emphasis on in V&W or short-term experiments.
h. Nicotine itself should be investigated for carcinogenic or
cocarcinogenic action in animals even though it is a very toxic
chemical. Similarly, acrolein should be tested for carcinogenic
and cocarcinogenic action.

i. Anti-carcinogens or preventive compounds, such as vitamin A,
retinoids, or other chemicals that may prevent carcinogenesis
deserve further investigation.
j. There should be a registry for listing all the different chemicals
identified in cigarette smoke, along with known properties of
those chemicals.

5. Cooperative international epidemiologic studies should examine
different tobaccos, ethnic groups, diets, and smoking habits. Such
studies would describe the differences in development of tobacco-
related cancers and elucidate the etiologic roles of differing
cigarettes.

6. Genetic markers such as HLA or other indices should be sought to
identify high-risk groups prone to tobacco-related diseases if they
smoke. Genetically susceptible individuals should be counseled
about their high-risk status.

Summary

1. Today's filter-tipped, lower "tar" and nicotine cigarettes produce
lower rates of lung cancer than do their higher "tar" and nicotine
predecessors. Nonetheless, smokers of lower "tar" and nicotine
cigarettes have much higher lung cancer incidence and mortality
than do nonsmokers.

2. Smokers of lower "tar" and nicotine cigarettes may tend to
smoke larger numbers of cigarettes, to inhale more deeply, to
have relatively higher amounts of carboxyhemoglobin than
predicted from machine measurements of carbon monoxide yield,
and to have higher than predicted carbon monoxide in exhaled
air.

3. In attempting to develop a "less hazardous" cigarette, singular
emphasis has been placed on reducing the "tar" yield of cigarette
smoke because of the early demonstration of a causal relationship
between "tar" and lung cancer. Comparable data on changes in

101


yield of constituents in the gas phase of smoke are not publicly
available.

4. The occurrence of laryngeal cancer has been reported to be
reduced among smokers who use filtered cigarettes, compared
with those who use nonfiltered cigarettes.

5. There is no epidemiologic evidence to prove or to disprove a
decreased occurrence of cancers of other sites in humans who
smoke lower "tar" and nicotine cigarettes.

6. In evaluating the effect of smoking lower "tar" and nicotine
cigarettes on histologic changes in the bronchial epithelium, it
was determined in one autopsy study that male smokers who died
between 1970 and 1977 had fewer histological changes than those
smokers who died between 1950 and 1955.

`7. Even among those who do not develop cancer, histologic changes
in the traeheobronchial tree are more advanced at autopsy in
smokers of cigarettes with higher "tar" and nicotine than among
smokers of cigarettes with lower yields.

8. The "tar" content of smoke condensate of today's cigarettes is
less tumorigenic to mouse skin than that of cigarettes of 30 years
ago. Levels of the known carcinogen bemalpyrene are lower in
the smoke of today's cigarettes than in that of cigarettes of 30
years ago. Flavor additives used in lower "tar" and nicotine
cigarettes produce traces of mutagenic compounds.

9. Although studies point to polycyclic aromatic hydrocarbons in the
"tar" of inhaled cigarette smoke as potential carcinogens for
humans, additional work is needed to determine whether nicotine
plays a major role as a carcinogen. Definition of the role of
nicotine in carcinogenesis is necessary prior to advocacy of
cigarettes yielding less "tar" but more nicotine.

10. Animal studies have shown that a significant reduction of "tar"
and a selective reduction of tumor initiators and cocarcinogens
can markedly reduce the tumorigenic potency of cigarette smoke.

102


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109


Section 4. CARDIOVASCULAR
       DISEASES


CONTENTS

Introduction

The Relation of Cigarette Smoking to Cardiovascular Risk

Factors in Cigarette Smoke Related to Cardiovascular
Function
  Nicotine
  Carbon Monoxide
Other Components

Studies of the Impact of Lower "Tar" and Nicotine
Cigarettes on Coronary Heart Disease

The Challenge of Future Research

--
Proposed Future Research
  Descriptive Studies
  Cohort Studies
     Observational Studies
     Clinical Trials
     Case-Control Studies
  Studies of Mechanisms
Animal Experimentation
  Technical Resource Center
  Behavioral Ramifications

Summary

References

LIST OF TABLES

Table l.-Coronary heart disease-mortality ratios

Table 2.-The effect of the cessation of cigarette smoking

113


on the incidence of coronary heart disease (CHD)-
morbidity ratios in males

Table 3.-Filter cigarettes and risk of coronary heart
disease in men

114


Introduction

The expectation that a lower "tar" and nicotine cigarette would be
associated with less cardiovascular disease is baaed on two well-known
epidemiological findings: (1) the strong dose-related association be-
tween cigarette use and coronary heart disease (CHD)-the largest
component of cardiovascular disease; and (2) the evidence that if one
quits smoking, the vascular consequences of smoking diminish. Table 1
shows that the more people smoke per day, the greater their risk of
coronary heart disease. Table 2 summarizes several studies indicating
that persons who quit have a lower risk of CHD.

These findings have been challenged (41) because the sample of
smokers who have voluntarily quit may be biased through self-
selection. Indeed, even prior to quitting, persons who stop smoking
differ from those who continue smoking (15); however, their major
cardiovascular risk factors do not differ (18).
A multivariate analysis of the impact of smoking on CHD that takes
into account all the major possible confounders shows smoking's
independent effect on CHD risk (32). In some studies (18), the quitters
were more sick than those who continued to smoke, but none of the
known major factors involved in CHD risk (disregarding cigarette
smoking) explains the difference in CHD rates between smokers and
nonsmokers. None of the factors distinguishing quitters from continu-

TABLE l.-Coronary heart disease-mortality ratios

Referenoe      NS      10    10-20 <20     P    >P    m-40 >40

Hemmond and    LOO    1~     L89                       2.20    241
&ml (f-9
Doyk et d. (24)   1.00                 200     1.70    250
Doll and Pet0     1.00                 129     121     1.4S
(14
Pooling Project    1.00    1.65                 1.70    6.06
@a
lmm w       LOO     1~     1.76                      L64    200

NOTE:NS-Noamdran

TABLE 2.-The effect of the cessation of cigarette smoking on
     the incidence of coronary heart disease (CHD)-
     morbidity ratios in males

lieference

Never        Former
smoked       smokeln       smokers

Hammond and Garfinkel @I)              1.00         1.16         1.62
Jenkins et al. (s-7)                    LOO         215         236
Shspiro et al. (42)                    1.00         0.76         1.67
Kmnel et al. (So)                    1.06         0.W         1.70

115


ing smokers clarifies why the risk of cardiovascular disease declines
rapidly following smoking cessation.

The effect of smoking on CHD risk fulfills many epidemiologic4
criteria for a causal association: powerful, independent, dose related,
and reversible. When the association of smoking with CHD is adjusted
by the other major risk factors, the coefficients are strengthened,
rather than weakened (19).

At present only a few of the several thousand substances found in
cigarette smoke have been implicated in cardiovascular risk; others
have yet to be fully assessed. In order to facilitate a complete analysis,
a study would have to measure the impact of each substance in
cigarette smoke and establish its independent contribution. However,
testing large fractions of cigarette smoke for cardiovascular risk might
allow the elimination of specific constituents.

Currently, one can define only part of the impact of smoking on
cardiovascular risk. What factors isolated in cigarette smoke are
known to have cardiovascular consequences? What, is already known of
the cardiovascular impact of smoking cigarettes with some of these
factors removed? In view of the rapidly changing variety of cigarettes
found in the market, how can one keep pace with studying the
cardiovascular impact of each new lower "tar," lower nicotine, lower
carbon monoxide cigarette?

The Relation of Cigarette Smoking to Cardiovascular Risk

Many exhaustive reviews of this issue exist, and only a brief account
of the essential findings is presented here. The chapter on cardiovascu-
lar disease in the 1979 Surgeon General's Report on Smoking and
Health amply documents that cigarette smoking is a major, indepen-
dent coronary heart disease risk factor in Western countries (46). There
is substantial evidence from autopsies that more atherosclerosis is
found in smokers than in nonsmokers (44. Hyaline thickening of
arterioles in the heart is more prevalent in smokers (6). Experiments
on atherosclerosis in animals, however, have not produced uniform
results.

In those parts of the world where serum cholesterol levels are low,
especially below 160 mg%, smoking is not as strong a risk factor as it is
in the United States (33). After the age of 65, smoking poses less of a
cardiovascular risk than it does in younger age groups (31). Study
results differ on whether smoking is a risk factor in coronary heart
disease following a myocardial infarction (46). The relationship of
smoking to angina pectoris is uncertain (27,31).

It is essential to emphasize these points because one could plan a
study of lower "tar" and nicotine cigarettes in developing countries,
with older subjects or with people who have already had a myocardial
infarction or angina pectoris and find that the excess risk of CHD

116


among smokers had disappeared. To establish that lower "tar" and
nicotine cigarettes cause less risk of CHD than higher yield cigarettes,
there should be studies of randomly selected American men, 40 to 60
years of age, for the development of sudden death, first myocardial
infarction, or peripheral vascular disease-endpoints with which
cigarettes are associated at more than double the normal risk.

All the other factors associated with CHD risk should be measured
simultaneously in a multivariate analysis so that any differences
caused by quitter self-selection can be eliminated as the explanation of
reduced risk. In this way, independent change in risk caused by the
change in smoking behavior could be accurately assessed.
In addition to its effect on coronary heart disease, smoking increases
the risk of arteriosclerotic peripheral vascular disease. Its impact on
cerebrovascular disease is less uniform (46).

Factors In Cigarette Smoke Related to Cardiovascular Functlon

Most of the studies on cardiovascular endpoints associated with
cigarette smoke have focused on nicotine and carbon monoxide rather
than on "tar," which has not been demonstrated to have a major acute
cardiovascular effect. Less is known about the effects of cadmium.,
zinc, chromium, carbon disulfide, carbon dioxide, tobacco antigens,
hydrogen cyanide, nitrous oxide, or polonium-210, among other
constituents of cigarette smoke.

Nicotine

Many studies have documented a dose effect of nicotine on
cardiovascular function (2,.&Q. Acute studies in humans indicate a rise
in heart rate, an elevation of systolic blood pressure, and cutaneous
vasoconstriction. Cardiac output generally rises, but not always. Since
stroke volume is generally not affected, or may fall, in patients with
angina pectoris (2), the observed rise in cardiac output has been
attributed to an increased heart rate.

Such changes have been attributed to a stimulation of sympathetic
ganglia by nicotine. This stimulation results in a rise in catecholamines,
which in turn produces variable degrees of positive chronotropic and
inotropic cardiac actions. Other effects include generalized peripheral
vasoconstriction and transient systemic (primarily systolic) hyperten-
sion (7).

Levels of free fatty acids rise in nicotine-treated subjects, possibly as
another consequence of the catecholamine release (32). Whether free
fatty acids affect cardiac function adversely, as some researchers have
proposed (39, or aid in fatty deposition as others have suggested (10)
has not yet been fully established.

Nicotine increases the diurnal secretion of cortisol (26). Plasma
cortisol levels have been found to be elevated during myocardial

117


infarction, but the increase may be an effect rather than a cause of this
condition. On the other hand, the cortisol rise has been implicated as a
precursor of ventricular arrhythmias (36).

Nicotine-stimulated release of catecholamines has also been suggest-
ed as a cause of increased platelet stickiness and aggregation (24); this
and other smoking-related hemostatic effects are potential mecha-
nisms by which smoking may contribute to increased cardiovascular
disease.

Although the evidence is meager, some of the acute effects of
nicotine on cardiovascular function, such as elevation of heart rate and
blood pressure, are dose related and apparently diminish in some
lower-nicotine varieties of cigarettes (2,&).

Carbon Monoxide

Carbon monoxide is inhaled in the form of a gas in cigarette smoke.
Its affinity for hemoglobin is approximately 210 times greater than
that of oxygen. The availability of oxygen to the myocardium is
further decreased by the tighter binding of oxygen to hemoglobin in
the presence of carboxyhemoglobin. Carbon monoxide also combines
with myoglobin, impairing the availability of oxygen to the mitochond-
ria. In addition, carbon monoxide can combine diitly with cyt+
chrome oxidase to slow the oxidation of reduced nicotinamide-adenine-
dinucleotide (55).

Carbon monoxide has a direct impact on cardiac function in patients
with angina pectoris, including a negative inotropic effect on the
myocardium. Aronow (1) demonstrated an increase in left ventricular
end-diastolic pressure, with a significant decrease in left ventricular
dp/dt and stroke index. Angina1 patients with increased carboxyheme
globin levels also experience significantly shortened exercise time until
the onset of angina pectoris (3). DeBias and co-workers (12) have also
shown in monkeys that exposure to carboxyhemoglobin lowers the
threshold for ventricular fibrillation.

Myocardial ultrastructural changes have been described in rabbits
exposed to carbon monoxide. Among the changes are myofibrillar
necrosis and mitochondrial degeneration (5).
Astrup (4 has proposed that c&oxyhemoglobin increases hypoxia
of vessel walls. Because this condition may increase the permeability to
lipids, including cholesterol-laden lipoproteins, it may promote the
process of atherosclerosis. It has been shown that exposure of humans
to carbon monoxide increases the rate of disappearance of radio-
iodinated serum albumin (43). Wald and Howard (49) have shown that
the earboxyhemoglobin level is more closely related to the prevalence
of coronary heart disease than is smoking history. They emphasize that
smokers who are physically active enhance their mechanisms for
releasing carboxyhemoglobin and have a much better CHD prognosis
than do sedentary smokers.

118


Other Components

McMillan ($5) has reviewed studies on a variety of other factors in
cigarette smoke and has concluded that much more data are needed.
He noted a possible association of cadmium with hypertension.
Smoking generally results in an acute rise in blood pressure, but has
not been proved to cause chronic hypertension. Whether tobacco
antigens play a role in increased endothelial cell damage is conjectural.
Finally, McMillan considered the hypothesis proposed by Benditt and
Benditt (18) that atherosclerosis is really caused by monoclonal smooth
muscle cellular proliferation. If so, one may be persuaded that "tar,"
which is mutagenic, is atherogenic after all.

Studies o? the impact of Lower "Tar" and Nicotine Cigarettes
on Coronary Heart Disease

Not all cigarettes that produce a lower yield of one substance
necessarily provide a lower yield of other substances. Indeed, research
suggests that cigarettes with unperforated filters ("unventilated"),
which yield lower "tar" and nicotine levels than do nonfiltered
cigarettes, may increase exposure to carbon monoxide (53) and lead to
higher levels of carboxyhemoglobin (52). Cigarettes with perforated
("ventilated") filters may produce lower carbon monoxide yields (52).

People who smoke lower "tar" and nicotine cigarettes do not
generally smoke substantially more cigarettes per day than smokers of
higher yield cigarettes (16, 40, 51); however, their intake of "tar,"
nicotine, and carbon monoxide is higher than would be predicted by
data from machine-smoked cigarettes. This suggests that these
cigarettes are smoked more intensively than higher yield cigarettes
(~0,50
There is evidence from four studies of the association between
cardiovascular disease and the use of lower "tar" and nicotine
cigarettes. Hammond et al. (22), in their prospective study of
volunteers of the American Cancer Society, have shown reductions of
10 to 20 percent in observed coronary deaths among persons smoking
lower "tar" and nicotine cigarettes when compared with those who
reported smoking similar numbers of regular cigarettes per day.
Hawthorne and Fry (25), in three prospective surveys of over 18,006
persons in west-central Scotland, showed a slightly increased relative
coronary mortality in persons who smoked filtered cigarettes com-
pared with persons who smoked unfiltered cigarettes. Dean et al. (II),
in a retrospective mortality study in northeast England published by
the Tobacco Research Council, showed relative risks of about 0.6 for
coronary heart disease and 0.4 for cerebrovascular disease in filter
cigarette users versus smokers of unfiltered cigarettes. Unfortunately,
smoking habits of cases and controls were obtained from different
sources and at different times, confounding the study design. Recent

119


TABLE 3.-Filter cigarettes and risk of coronary heart dieease
       in men

Reference
Hawthorne and Fry (95)
Hammond et al. (~8

Plain          Filter
LOO          LO4

  `1 "  Period 1
L0w tar (Period 2

LO9          0.92
1.00          082

        Period 1
Medium "tar" (period 2

1.99          0.91
1.00          Lo8

De-30 et al. (11)
Caddli et al (9)
<=
  55+

1.00           0.66

1.00           LO2
LOO           0.95

unpublished data from Framingham (9) have failed to show a lower
CHD risk among smokers of filter cigarettes, and in younger men
there was actually a slightly higher rate of coronary disease among
smokers of filtered cigarettes (Table 3).

This study took into account the other major CHD risk factors
(cholesterol, blood pressure, and age); the increased risk in filter
smokers is independent of effects attributed to these other factors.
Overall, use of lower "tar" and nicotine cigarettes has not produced a
consistent decrease in risk for cardiovascular disease; indeed, in some
studies a slight increase in risk has heen seen. Additional studies will be
needed to assess the actual impact of any changes in the composition of
cigarettes on subsequent CHD rates. Terms like "lower yield" may
describe only part of the change; other additives and the overall use of
the cigarette might actually increase risk. Wald (5.4 has shown that, in
the United Kingdom, while lung cancer mortality fell in men from
195&60 to 1969-73, with the change to filter cigarettes, CHD mortality
increased. The author wondered whether the decrease in "tar"
accounted for the lower lung cancer death rates, and whether
unchanged levels of carbon monoxide might have contributed to the
observed continuing rise in CHD death rates.

The Challenge of Future Research

In the United States, virtually no filtered cigarettes were smoked
before 1950; now 90 percent of the cigarettes sold are filtered. The
sales-weighted average "tar" composition per cigarette has decreased
from over 35 mg of "tar" per cigarette in the early 1950s to under 15
mg in 1979. Currently, nicotine has decreased from over 2.5 mg per
cigarette to about 1.0 mg per cigarette. Ultra low nicotine and "tar"
cigarettes are now increasingly available, with levels of under 1.0 mg
"tar" and 0.1 mg nicotine. Unfortunately, the amount of carbon
monoxide delivered by cigarettes has not been studied as intensively as
the "tar" and nicotine levels, although a recent United Kingdom

l.20


survey of old and current cigarettes indicates that carbon monoxide
yields have changed much less than "tar" or nicotine yields. This may
be the case in the United States as well. Linking cigarette carbon
monoxide yields to possible toxicity is further complicated by the fact
that patterns of smoke inhalation for lower "tar" and nicotine
cigarettes may differ from patterns for higher "tar" and nicotine
cigarettes (51).
A technique should be developed to monitor the effect of changes in
cigarette composition, particularly in nicotine and carbon monoxide
content, on cardiovascular risk.

Proposed Future Research
Descriptive Studies

Continued research into the changes in cigarette smoking is needed.
Surveys such as the National Health and Nutrition Examination
Survey (NHANES), prospective epidemiological field studies, and
prepaid hospital insurance group studies are needed to provide
comprehensive information on cardiovascular disease caused by
smoking. Such studies should include worldwide data surveillance.

Cohort Studies

Observational Studies

Observational studies are studies of large populations in which a
variety of factors related to cardiovascular disease are measured and
followed, permitting an independent analysis of variables such as a
given cigarette brand.
There are now a number of studies that follow a given population
over a period of time to assess prospectively the impact of smoking.
Some of these are traditional single-town studies in which a random
sample of a given population is followed over varying time intervals,
often every 2 to 5 years. Examples of such studies are those in
Framingham, Tecumseh, Puerto Rico, Evans County (Georgia), Hono-
lulu, and Goteborg and Stockholm, Sweden, where whole populations
or samples thereof are followed on a more or less continuous basis. In
addition, there are worksite studies, such aa the Albany civil servants,
People's Gas Company of Chicago employees, Western Electric work-
ers (Chicago), Minneapolis business executives, California longshore-
men, and British doctors, which call for repeated observations.
Questionnaire studies, such as the American Cancer Society's 25-State
Study or the g-State Study, the U.S. Veterans Study, the Canadian
Veterans Study, the Swedish Study, the Japanese 29 Health Districts
Study, and the Study of California Males, can observe as many as a
million subjects.

I21


In addition to measuring the risk for cardiovascular disease, most of
these studies also assess other consequences of smoking. They allow,
better than any other studies, the calculation of the independent effect
of smoking.

The shortcoming of these prospective studies has been that the
average turnaround time has been approximately 10 years. Occasional-
ly, a 4-year interval produces enough data for a meaningful analysis,
but with the rate of change in the composition of cigarettes, the
information could be outdated by the time the data are collected and
analyzed.

Clinical Trials

Several clinical trials of the effect of smoking intervention on
coronary heart disease are in progress. Perhaps the most promising of
these is the Multiple Risk Factor Intervention Trial (MRFIT) (28), in
which high-risk men were randomly assigned to a special-intervention
group and a usual-care group. The study, now in its 6th year, avoids
self-selection bias by contrasting the overall disease experience of the
two randomly assigned groups. Unfortunately, the inferences that may
be drawn about lower "tar" and nicotine cigarettes per se (which is
only a part of the intervention program) are somewhat limited and do
involve self-selection. Another problem is that this study directs its
intervention to serum cholesterol and blood pressure control as well as
to smoking cessation. Nevertheless, long-term studies like the MRFIT
are recommended because the followup of cohorts may provide
findings that differ qualitatively from those available in strictly
observational studies and because the measurement of other major risk
factors permits the estimation of the independent effect of smoking
behavior changes. All such clinical trials should incorporate the
conviction of the medical and public health communities that current
smokers ought to quit and that nonsmokers should not begin to smoke.

Case-Control Studies

Case-control studies have the advantage of relatively short turn-
around times and usually are less expensive than other studies.
Unfortunately, unless very carefully designed, they can suffer from a
partial and therefore less accurate assessment of the disease under
study. For example, in studying cigarettes, one must assess the death
endpoints of coronary disease. The problem in studies of this kind is
how to compile an objective smoking history of the deceased.
Obtaining information from a spouse or close associate introduces a
certain amount of error, but this error may be controlled somewhat by
interviewing close associates of the members of the control group.

122


In studies of nonfatal myocardial infarction, the survival of both the
cases and the controls allows more precise measures of the variables
under study.

Despite shortcomings, case-control studies represent the major
means for assessment of the relative cardiovascular risk of varying
cigarettes. Further, serial case-control studies, similarly designed,
performed, and analyzed, could provide information on changes in risk
over time. In such studies care must be taken to select appropriate
controls, to treat cases and controls alike, to avoid hospital-based
rosters, and to study well-defined and documented endpoints.

Studies of Mechanisms

In view of the difficulties involved in doing large population-baaed
studies and the need to know more about the mechanisms whereby
cigarettes cause damage, more studies are needed on the components
in cigarettes that affect cardiovascular risk. It may be that nicotine
and carbon monoxide are the chief toxic agents, but until more is
learned of the other constituents, judgements are based on scanty
information.

Perhaps the main reason to pursue the study of disease mechanisms
is to shorten the turnaround time for assessing any new brand of
cigarette; studies could be designed to measure particular constituents
of the cigarette smoke and characteristics of the subject at risk.
With better noninvasive cardiovascular techniques, studies of how a
particular cigarette affects cardiac function could be performed in
greater depth. Such studies would provide better measurement of the
biological effect of the cigarette smoke components in individual
smokers. Measurement of expired carbon monoxide, serum carboxy-
hemoglobin, thiocyanate, and cotinine would help resolve not only
differences in the composition of cigarettes, but also major differences
in the ways individuals smoke (47, 48). These more precise measure-
ments of smoke exposure and dosage of smoke constituents could be
correlated with a host of biochemical and physiological parameters.

The number of biochemical factors found to be affected by smoking
continues to grow. Lower HDL cholesterol levels are found in smokers
than in nonsmokers, an effect that is associated with an increased CHD
risk (17).

A variety of effects could be weighed to produce a multifactorial
analysis of how cigarettes produce atherosclerosis, sudden death, and
other cardiovascular problems.

Physiological studies using treadmill performance, scintillation
scanning-including gated pool studies-and Holter monitoring could
provide better clues to the action of cigarettes on cardiovascular
function. If such alterations in function could be more certainly tied to
later events, they might prove invaluable predictors of smoking-
related risk for a given individual.


Animal Experimentation

Most of the animal models used in studies of the effects of cigarette
smoke have been designed to test its carcinogenicity on the bronchial
epithelium or the skin of small animals, usually rodents. A few models
have been developed to examine the effects of inhalation on the
respiratory and cardiovascular systems of rodents, dogs, or nonhuman
primates (20). Very few animal studies have attempted to assess the
effects of different cigarette smokes in inhalation studies of experi-
mental atherosclerosis or on the styles of inhalation that may be
intervening variables in the pathogenesis of atherosclerosis. It is
feasible to induce nonhuman primates to inhale cigarette smoke (34.
Such primates frequently develop many of the physiologic changes
related to the atherosclerosis found in human smokers (39). The
further utilization of such animal models would permit a comparison of
the effects of proposed lower "tar" and nicotine cigarettes with the
effects of conventional higher yield cigarettes under controlled
conditions. Subjects could be assigned randomly to different types of
cigarettes to eliminate the self-selection bias.

The primates could be examined for effects of smoke from different
cigarettes on response variables such as serum lipids and lipoproteins.
At this time, the augmentation of experimental atherosclerosis by
exposure to cigarette smoke has not yet been demonstrated; further
development of an animal model must occur before definitive studies
in atherogenesis will be practical.

Technical Resource Center

In addition to monitoring research evidence on the impact of
smoking on health, further activities should focus on developing tools
for the conduct of studies on the impact of smoking on health in
several areas. A standard questionnaire on smoking should be refined
for use by the various studies in the United States and in foreign
countries.

In addition, techniques for measuring actual exposures to carbon
monoxide, cotinine, nicotine, and many other substances could be
evaluated to determine the most effective analytic techniques. Where
debate continues on the merits of one test versus another, studies
should be designed to resolve the issue. Control of test quality should
be instituted and could be ascertained, even from widely disparate
groups. Not only could a hierarchy of useful tests be provided, but a
quality-control mechanism should be developed to ensure continued
high performance.

Finally, frequent updated ratings of "tar," nicotine, and particularly
carbon monoxide yields would permit others to conduct better studies
of the impact of cigarette smoke components on cardiovascular
functions.


Behavioral Ramifications

It is important to determine the effect of lower "tar" and nicotine
cigarettes on cardiovascular disease risk reduction. A key unknown is
whether efforts to persuade people to switch to lower "tar" and
nicotine cigarettes interfere with other efforts to persuade people not
to begin smoking or to quit. Activities to provide a less hazardous
cigarette should not interfere with efforts to eliminate cigarette
smoking.

Finally, given the limitation in research funds, priorities for research
must be drawn. The research proposals outlined above are of high
priority. The combination of results from a variety of studies can
provide a consensus on the impact of a given innovation in lower "tar"
and nicotine cigarette composition. Ultimately, the effect of lower
"tar" and nicotine cigarettes will be measured in terms of smoker
morbidity and mortality.

Summary

.l. Epidemiological studies show that the incidence of coronary
heart disease (CHD) increases as the daily number of cigarettes
smoked increases and that the incidence of CHD decreases among
those who quit smoking. These dose-related effects suggest that
lower "tar" and nicotine cigarettes might be associated with
lower risks of CHD. However, the overall changes in the
composition of cigarettes that have occurred during the last 10 to
15 years have not produced a clearly demonstrated effect on
cardiovascular disease, and some studies suggest that a decreased
risk of CHD may not have occurred.

2. Of the several thousand substances found in cigarette smoke,
only a few have been implicated in cardiovascular risk. A number
of substances have not yet been adequately assessed. Further, the
changes in smoke constituents that have resulted from changes in
the cigarette product have not been documented.

3. Linking cigarette smoke yields to cardiovascular disease is
complicated by the evidence that smokers of lower "tar" and
nicotine cigarettes may smoke more "intensively," although they
may not smoke a substantially greater number of cigarettes daily
than do smokers of higher "tar" and nicotine cigarettes. The net
result could be to decrease the actual intake of "tar," nicotine,
and carbon monoxide less than that expected on the basis of
machine measurements.

4. Nicotine stimulates the sympathetic nervous system, producing a
rise in catecholamines that in turn increases heart rate, elevates
systolic blood pressure, constricts cutaneous blood vessels, and
increases levels of free fatty acids. The nicotine-stimulated
release of catecholamines has been suggested as the cause of

125


increased platelet stickiness and aggregation, pointing to a
potential role in coronary disease. There is some evidence that
these physiological effects may be dose related and somewhat
diminished with lower nicotine varieties of cigarettes.

5. Carbon monoxide has a negative inotropic effect on the myocar-
dium of patients with angina pectoris. When combined with
hemoglobin in the form of carboxyhemoglobin, carbon monoxide
may increase the permeability of the blood vessel walls to lipids,
thereby promoting atherosclerosis.

6. Cigarettes with unperforated filters yield lower "tar" and
nicotine levels than unfiltered cigarettes, but they yield more
carbon monoxide than do unfiltered cigarettes at the same "tar"
yield. Carbon monoxide yields are lower in cigarettes with
perforated filters, but as the composition of cigarettes has
changed, carbon monoxide yields have decreased much less in
proportion to the decrease in "tar" and nicotine yields.

`7. In studies of patients with angina pectoris, increased carboxy-
hemoglobin levels significantly shorten exercise time until the
onset of angina pectoris.

8. Myocardial ultrastructural changes have been found in rabbits
exposed to carbon monoxide.
9. Most cardiovascular studies have focused on nicotine and carbon
monoxide rather than on "tar," which has not been shown to have
a major acute role in cardiovascular disease. Even leas is known
about other constituents of cigarette smoke.

10. Not all cigarettes that produce a lower yield of one substance
necessarily provide a lower yield of other substances.

11. Evidence on the association between CHD and filter cigarettes is
somewhat conflicting. One major study showed a reduction of 10
to 20 percent in coronary deaths among persons smoking lower
"tar" and nicotine cigarettes as compared with those who smoked
higher yield cigarettes, but other surveys have shown a slightly
increased risk of coronary mortality in people who smoked filter
cigarettes relative to those who smoked nonfiltered cigarettes.
Recent unpublished data from the Framingham Study do not
show a lower CHD risk among smokers of filter cigarettes.

126


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Section 5. CHRONIC OBSTRUCTIVE
       LUNG DISEASE


CONTENTS

The Research Problem

Current Research Findings

Future Research Approaches

Epidemiologic Studies

Priorities for Research Recommendations

Research Recommendations

Summary

References

133


The Research Problem

The causal relationship between cigarette smoking and chronic
obstructive lung disease (COLD) (chronic bronchitis and chronic
obstructive pulmonary emphysema) is well documented (34). However,
the possible differences in the effects of higher versus lower "tar" and
nicotine cigarette smoke in the pathogenesis of chronic obstructive
lung disease are not known. COLD usually progresses slowly; physic
logic and pathologic abnormalities may exist for an extended period of
time prior to the development of disabling clinical manifestations. The
latter are usually associated with severe lung damage or destruction. It
is uncertain which of the many ingredients in cigarette smoke has a
role in the production of COLD. Lower "tar" and nicotine cigarettes
may have no impact, or indeed an untoward impact, on the develop
ment of COLD. Therefore, it is urgent that research be carried out to
resolve this complex problem.

Cigarette-related chronic lung disease may be subdivided into three
major components: (1) uncomplicated chronic bronchitis, a disease of
mucous hypersecretion and cough; (2) chronic bronchitis and bronchi+
lar inflammation, similar to (1) but with airflow limitation caused by
intrinsic airway pathology; and (3) emphysema, a disease associated
with anatomical hyperinflation of the distal air spaces and destruction
of lung parenchyma. Because cigarette smoking is associated with all
of these conditions, they commonly coexist. The factors causing one or
more of these diseases to develop in response to cigarette smoke in
some individuals and not in others are unknown. Cough and mucous
hypersecretion are common symptoms among cigarette smokers, while
evidence of airflow limitation is significantly less common. Recent
evidence suggests that the early stage of emphysema is associated with
cigarette smoking-related inflammation in airways less than two
millimeters in diameter (II).

Research on the response to inhaled irritants is usually focused on
one or more of the anatomical components of the lung: the airways, the
cellular and biochemical contents of the alveolar spaces, and the
contents and structure of the alveolar septa or interstitia. Responses in
the airways may consist of alterations in epithelial cell types, mucous
gland hyperplasia, hypersecretion of mucus, inflammation, impair-
ment of mucociliary function, abnormalities of immunologic factors or
other substances, smooth muscle hyperreactivity and hypertrophy, and
intrinsic narrowing fibrosis or destruction of small airways. Physiolog-
ic responses reflect airflow limitation, early closure of small airways,
and nonuniform distribution of inspired air.

In the alveolar spaces, free cells (including alveolar macrophages and
neutrophils), surfactant (a phospholipid secreted by the alveolar lining
cells), enzymes released or secreted by macrophages or neutrophils, and
protease inhibitors and other proteins that reach the alveolar spaces by
transudation from the circulation are all under study. The alveolar

135


septum or interstitium, consisting of alveolar lining cells, basement
membrane, capillary endothelial cells, other alveolar interstitial cells,
and the connective tissue framework composed primarily of collagen,
elastin, and proteoglycans is the focus of much research. Physiologic
alterations reflect decreased surface area for gas exchange and
alterations in the elastic recoil of the alveolar structures.

The lung plays an active role in the production and metabolism of
various bioactive substances such as angiotensin, prostaglandins, and
serotonin. This anatomically, physiologically, and biochemically corn
plex organ is exposed to the external environment and its agents,
including cigarette smoke and air pollution. Complicating host factors
also affect this system: age; sex; inherent reactivity of the airways;
genetic factors that predispose to emphysema, such as alpharantitryp.
sin deficiency; childhood infections; and as yet undefined familial
factors.

The design of experiments to determine the shortc or long-term
effects of cigarettes on smokers is made difficult because the
composition of cigarettes and the population of smokers have been
changing over the past 10 to 15 years. Further complicating this
problem is the large number of tobacco smoke components with
varying solubility and interactive capabilities. There is also a lack of
knowledge of the topography of cigarette smoking. Individual differ-
ences in the mechanics of smoking such as the volume of puff, holding
time in the oral cavity, depth of inhalation, time of retention in the
lung, and length of butt significantly influence the composition,
distribution, penetration, and retention of cigarette smoke components
in the lungs. The topography of smoking may vary depending on the
nicotine content. The composition and concentration of the gas phase
components that reach the small airways and alveoli may have a
significant role in the production of emphysema, while the particulate
matter that deposits in the larger airways may be more involved in the
development of chronic bronchitis. The target tissues, cells, or ultra-
structural components may be different in chronic bronchitis and
emphysema. Thus it is extremely important to develop a better
understanding of the topography of smoking so that appropriate
experiments can be designed to determine dose-response relationships
of pertinent smoke components and the reactions to them in the
different regions of the lung. The problem is that of assessing the
effects of continually changing cigarette products on a continually
changing population of smokers. The ultimate concern is for the
effects on smokers. For chronic lung disease, this effect can best be
assessed by the combination of epidemiologic evaluations of popula-
tions at risk and laboratory evaluations of the effects of smoke on the
mechanism of disease production.

136


Current Research Findings
Recent advances in research have led to a plausible hypothesis for
the etiology of pulmonary emphysema: If an imbalance between
endogenous elastolytic enzymes and protease inhibitors in the lungs
permits active enzymes to exist in the alveoli or alveolar walls,
degradation of the alveolar tissue components, primarily elastin, will
occur (25, 26). The sources of endogenous elastase are polymorphonu-
clear leukocytes and alveolar macrophages. The major source of the
inhibitor is the serum protein, alphal-antitrypsin, which reaches the
alveolar space by the process of transudation. This hypothesis is
reinforced by experimental data from a variety of sources. Humans
with a genetically transmitted deficiency of alphal-antitrypsin are
prone to develop emphysema (29). The instillation of elastolytic
enzymes into the lung, including human neutrophil elastase, will
produce experimental emphysema in animals (33). Cigarette smoke is
implicated in this process by mechanisms that may lead to the
development of emphysema.
Alveolar macrophages from smoke-exposed mice increase in number
and secrete significantly greater amounts of elastase than macro
phages from control mice (35). Human alveolar macrophages from
cigarette smokers also secrete significantly more elastase than macro
phages from nonsmokers (32). Alveolar macrophages exposed to
cigarette smoke produce a chemotactic substance for polymorphonucle-
ar leukocytes (I?). Mild exposure to cigarette smoke also increases the
release of elastase from human polymorphonuclear leukocytes (5).
Cigarette smoke inhalation decreases the alphal-antitrypsin activity
in the rat lung (22), and alveolar lavage from human smokers shows a
functional antiprotease deficiency (16). This effect of cigarette smoke
on alphal-antitrypsin is related to its oxidant effect (1, 8). The loss of
inhibitory activity of alphal-antitrypsin is induced by oxidation of
methionine residues at the reactive center of the molecule (23). A
chemical oxidant, chloramine-T, administered to dogs, also induces a
reduction in the elastase inhibitory capacity of both the serum and
alveolar lavage. fluid, and the animals develop morphologic changes of
mild emphysema (IS). This animal model simulates the human alphal-
antitrypsin deficiency state except that the deficiency is functional and
not in absolute quantity. Oxidants are also released when polymorpho-
nuclear leukocytes are exposed to exogenous elastase (27).
This in z&o and in vitro experimental evidence indicates that
cigarette smoke both increases the amount of elastase in the alveolar
tissue or air spaces and simultaneously reduces the functional capacity
of the primary elastase inhibitor, alphal-antitrypsin, and links the
action of cigarette smoke to the possible production of disease in
humans. Although there is general acceptance of the protease-inhibitor
imbalance hypothesis, it has yet to be directly related to human
emphysema. There are no available studies in which smoke from


regular and lower "tar" and nicotine cigarettes has been used to
determine if there are differences in their effects on elastase or
oxidant release or production, or concentrations of cigarette smoke
oxidants that could affect the functional capacity of alphal-antitryp
sin.

Small airway inflammation and bronchiolar inflammation develop
much more frequently in smokers than in nonsmokers (11). Findings in
the lungs of individuals 40 years of age or older who died suddenly of
nonrespiratory causes revealed inflammation, increased numbers of
goblet cells, and muscular hypertrophy in small airways. There was
also an increase in airways under 400 microns in diameter and in the
occurrence of respiratory bronchiolar inflammation in the smokers.
The lungs showing both the largest number of small (under 400
microns) airways and the most airway pathology had the most
centrilobular emphysema, the predominant type found in cigarette
smokers. The respiratory bronchiolar inflammation was characterized
by infiltration with macrophages that extended into adjacent alveolar
walls. Previous studies of resected lung from smokers showed that the
severity of similar small airway pathology in excised human lungs
correlated with impairment in ventilatory function (IO). The small
airway disease and severity of emphysema also correlated with
changes in small muscular pulmonary arteries that could be important
in the development of pulmonary hypertension (19). These studies
suggest that cigarette smoke produces small airway pathology, which
is a factor in ventilatory function impairment. The respiratory
bronchiolar inflammation may initiate an enzyme-inhibitor imbalance
in the centrilobular regions. The release of elastase from alveolar
macrophages and from neutrophils brought to the alveoli by increased
chemotaxis and the impairment of alphal-antitrypsin function could be
stimulated by cigarette smoke in the alveolar spaces. This leads to
destruction of alveolar wall elastin and then to the morphologic and
physiologic changes observed in emphysema.

The oxides of nitrogen occur at relatively high levels in cigarette
smoke and at lower levels as an ambient air pollutant. Exposure of
dogs to NOZ and NO for 68 months resulted in pulmonary function
changes characteristic of emphysema (18) that continued to progress
after cessation of exposure. Long-term exposure to oxides of nitrogen
results in airway and alveolar epithelial changes and parenchymal
damage that suggest an emphysema-like disease (14. Evidence
suggests that the damage is induced by an oxidant-type mechanism. In
addition, the most severely affected tissues are the terminal bron-
chioles, alveolar ducts, and adjacent alveoli, which are infiltrated with
inflammatory cells. The latter are primarily macrophages with other
mononuclear cells and occasional granulocytes. Interruption and
thickening of elastic fibers in alveolar walls were observed. These
lesions are similar to those induced by cigarette smoke and suggest

138


that the oxides of nitrogen may be one of the agents responsible for
the initiation of the early lesions of human emphysema.

As an outgrowth of the elastase-inhibitor imbalance hypothesis for
the etiology of emphysema, new potential markers or indicators of
disease are being investigated. Since lung elastin appears to be the
target substance for degradation, several laboratories are seeking a
method to identify products of elastin breakdown that would serve as
markers for the development of emphysema. In one study, peptide
breakdown products of lung elastin were identified in the serum of
dogs in which experimental emphysema was induced by the adminis-
tration of elastase (28).

Other investigators are measuring the urinary excretion of desmo
sine, the cross-linking amino acid of elastin that appears as a
breakdown product. If it can be demonstrated that elastin degradation
products are significantly elevated in the blood or urine of smokers
who have early emphysema, undetectable by other means, further
development and refinement of such tests may provide a sensitive
biochemical marker or screening test for the early detection of
emphysema. Such a measurement would simplify cross-sectional and
other epidemiologic studies in which the results in subjects who smoke
regular cigarettes could be compared with those of subjects who smoke
lower "tar" and nicotine cigarettes.

Studies of acute human responses to the different types of ciga-
rettes, which may be important in the pathogenesis of chronic lung
disease, are beginning to appear. The type of cigarette and the amount
of smoke inhaled into the lungs, measured by changes in blood nicotine
level or carboxyhemoglobin level, are not related to the occurrence of
acute airway responses to smoke inhalation (21). The authors found
that individual susceptibility is a factor, but even more important is
the smoking pattern. Holding the smoke in the mouth prior to
inhalation into the lungs reduced the response, whereas direct
inhalation from the cigarette into the lungs caused an increased
number of smokers to develop spirometric changes indicative of
bronchoconstriction. This was independent of "tar" yield and rein-
forces the importance of the cigarette smoking pattern in the dose-
response relationship. The study showed that the habitual cigarette
smoker avoids the direct irritant effect of cigarette smoke by
temporarily storing the smoke in the mouth before inhaling it into the
lungs and also demonstrated that the smoke inhalation pattern is
important in determining the relevant concentration of the constitu-
ents of smoke that reach the lungs.
There are few epidemiologic studies, either cross-sectional or
longitudinal, that deal with differences relating to the "tar" and
nicotine yield of cigarettes smoked. In a survey of over 18,000 civil
servants (20), the "tar" yield and the number of cigarettes smoked
daily were correlated to respiratory symptoms and spirometry. Sputum

139


production and air flow obstruction increased as cigarette consumption
increased. "Tar" yield influenced sputum production, but not the
degree of air flow obstruction. When subjects smoking lower "tar"
cigarettes smoked over 20 per day, their sputum production was the
same as that of the higher "tar" cigarette smokers. In this study of
asymptomatic men, the air flow obstruction was related to the daily
cigarette consumption. Higher "tar" cigarette smokers did not have a
greater air flow obstruction than those using lower "tar" cigarettes. If
there was a compensating increase in the number of cigarettes smoked
by the smokers of lower "tar" and nicotine cigarettes, the advantage of
reduced mucous hypersecretion was lost. Ex-smokers had better lung
function than current smokers with comparable total cigarette con-
sumption. The authors conclude that mucous hypersecretion depends
on the "tar" fraction of the cigarette's smoke and that the develop
ment of air flow obstruction depends on the number of cigarettes
smoked. They reason that the gas phase of the smoke, particularly the
volatile compounds, was responsible for damage leading to air flow
obstruction. They hypothesize that "tar" droplets and soluble gases,
such as sulfur dioxide and hydrogen cyanide, are more likely to be
deposited or absorbed in the larger bronchi where mucus is produced.
The smaller bronchi, which are the site of airway obstruction, and the
alveoli are exposed to a lower concentration of "tar," but to a full
concentration of insoluble gases, such as the nitrogen oxides and ozone.
Higenbottam and coworkers (20) did not differentiate between
emphysema and chronic bronchitis as a cause of airway obstruction.
The authors conclude that smokers of lower "tar" cigarettes who
compensate by smoking more cigarettes or inhaling more deeply may
increase the risk of obstructive airway disease. They suggest that more
information is needed about the nature and concentrations of irritants
in the gaseous phase of smoke and their relation to concentrations of
"tar" and respiratory damage.

Another British study (15) indicates that filter cigarette smokers
report less cough. The difference between the groups of smokers was
relatively small, however, and the filter cigarettes that were smoked
are probably dissimilar to those currently smoked in this country. Dean
et al. (1.2) reported the results of two retrospective studies, separated
by an interval of 10 years but carried out in the same area, to
determine whether the increasing use of filter cigarettes produced less
risk of dying of four diseases, including chronic bronchitis. In the
second study, relatives of those who had died were interviewed to
obtain the information about the smoking habits of the deceased
individuals. The cause of death was determined from death certifi-
cates. A living population was selected as the control sample. The
investigators found that mortality from chronic bronchitis was related
to age, to the number of cigarettes smoked, and to the level of
inhalation. The estimated risk of mortality from chronic bronchitis of

140


the population who smoked filter cigarettes since 1954 was about half
that of the continuing regular cigarette smokers. Many features of this
study could cause bias or misinterpretation: information was collected
from relatives of deceased individuals; the information on the living
and the deceased populations related to different points in time; and
changes in air pollution levels and in the population probably occurred
during the period of the study. From the epidemiologic standpoint,
firm conclusions cannot be drawn from this study.

In an ongoing study of a healthy population, the rates of decline of
pulmonary function in smokers and nonsmokers show only a very small
difference (6). However, 8 to 12 percent of smokers have a distinctly
more rapid decline in the FEVl. These are primarily male smokers and
may represent the group who will ultimately develop symptomatic
obstructive lung disease. In the entire population, the tests of "small
airway function," such as closing capacity, show no difference in the
rate of change between smokers and nonsmokers. These tests tend to
be abnormal in those individuals who develop an abnormal FEVl, but
at the same time, a large number of subjects with abnormal tests of
small airway function will not develop a rapidly decreasing FEVl. Data
about differences in the type of cigarettes smoked were not obtained,
but the extremely small difference between healthy smokers and
nonsmokers, except for the small group of rapid decliners, suggests
that studies of large populations with this objective may not be
revealing.

Another longitudinal study suggests that a study of approximately 8
years is necessary to identify those asymptomatic smokers who will
show a significantly accelerated rate of lung function deterioration
(15). This study also finds that, in spite of frequent smoking-induced
cough and expectoration, only a relatively small percentage of smokers
show a greater than average decline in respiratory function. The
authors report that when a group of asymptomatic middle-aged
smokers who had subnormal FEVl levels and rapid decline stopped
smoking, the rate of deterioration reverted to that of nonsmokers
although there was no significant improvement' in the initially
determined abnormal lung function. This study did not distinguish
between the effects of lower "tar" and nicotine and regular cigarettes.

The traditional tests of airflow limitation such as FEVl are thought
to reflect changes relatively late in the course of disease. Some
investigators have demonstrated that flow measurements taken from
the near terminal part of the forced vital capacity tracing are more
sensitive, but these are not widely used to date (SO). Newer tests of
small airway function such as slope of phase III, closing capacity, and
volume of isoflow with helium and oxygen have not been established
for their specificity in indicating the development of significant
chronic lung disease (4).

141


A study carried out in two successive decades, in which successively
autopsied airways from lungs of smokers were studied for bronchial
epithelial changes, demonstrated a decrease in changes thought to be
related to carcinogenesis (2). This favorable change was thought to be
related to the increasing use of lower "tar" and nicotine cigarettes.
Unfortunately, this study did not examine the lungs for evidence of
chronic obstructive lung disease.

Future Research Approaches

Animal models in which emphysema has been induced by elastolytic
enzymes have been reported by a number of authors (24, but for
reasons that may reflect a combination of factors, such as the shorter
life span of animals, the method of smoke exposure, and species
resistance, there are no published studies that acceptably show in an
animal model that the development of emphysema is induced by
cigarette smoking. Thus, a successful animal model has not been
developed in which the relationship of different types of cigarettes to
the development of emphysema can be studied. One study in which
dogs received smoke directly through chronic tracheotomies reported
the development of emphysema (3). The lesions were not conclusive
and the results have not been confirmed by others. Therefore, to
elucidate more clearly the differences between regular and lower "tar"
and nicotine cigarette smoke exposure, it will be necessary to study
other aspects of lung function, either biochemical or physiological, that
may be altered by the cigarette smoke and that are projected to be
important pathogenetic mechanisms in humans.

As suggested in the preceding paragraphs, much new information
will be needed before conclusions can be drawn about the effect of
lower "tar" and nicotine cigarettes on the development of COLD.
Acute and subacute responses could be measured by physiologic
studies, although such responses may not be relevant to the develop
ment of chronic, irreversible lung disease. The quantity and composi-
tion of mucus secreted in the airways in response to different types of
cigarettes may be studied in animals or humans. The histology of the
bronchial mucosa may be evaluated in human material from lobes or
lungs resected for other reasons, from biopsy specimens, or from post
mortem findings in which changes related to chronic bronchitis or
emphysema are specifically quantitated. In autopsy or resected lungs
from smokers of regular and of lower "tar" and nicotine cigarettes,
factors in the small airways such as lumen size, number of airways, cell
types, goblet cells, muscle hypertrophy, and inflammation may be
evaluated. Enzyme inhibitors produced in the tracheobronchial tree
could also be evaluated, as could the secretion of immune globulins.
Effects of cigarette smoke on the mucociliary function of the bronchial
mucosa is another potential measurement.

142


The response of the alveolar region of the lung could be determined
by biochemical, morphologic, and physiological techniques. The cellular
content of the air spaces, the functional status of alphal-antitrypsin,
the presence of chemotactic factors, oxidant production by neutrophils
or macrophages, elastase production and inhibition, and degradation
products of lung elastin may be measured in response to smoke
exposure. Human studies would require bronchioalveolar lavage to
obtain these data, although the invasive nature of this technique may
preclude its use in large populations lacking other indications. Produc-
tion and turnover rates of lung elastin and collagen, the numbers and
types of interstitial cells, and the presence of free or bound elastase
may be evaluated in the interstitial tissue. Macrophage and neutrophil
responses to the whole smoke and selected fractions can be investi-
gated. These include phagocytosis and elaboration of elastases, chemo-
tactic factors, and oxidants. Surfactant production and alterations
might be evaluated. Many of these factors are deemed important in the
determination of the protease-antiprotease balance in the lungs. The
development of some measurements into standard biologic assays by
which the various types of cigarette smoke may be evaluated would be
a valuable advance. This research would not only aid in the develop
ment of techniques to assess the response to various types of smoke,
but also would add important information to our knowledge of the
pathogenesis of disabling chronic obstructive lung disease in humans.
Physiologic measurements of lung volumes, elastic recoil, and diffusing
capacity of the lungs may be studied in humans and animals, although
in published studies to date, the observed effect is minimal or negative.

The question of. which fraction of cigarette smoke contains the
agent(s) that alter the lung defense mechanisms to induce chronic lung
disease must be resolved. It is not feasible to evaluate each of the
several thousand substances in cigarette smoke, but the major
fractions that contain the offending agents and the distribution and
penetration of these fractions should be studied. Gas phase constitu-
ents should be evaluated by category, and the method of exposure
must be related to the actual smoking habits of humans. Cigarette
smoking-machines that produce 35 ml puffs and the techniques by
which animals inhale cigarette smoke in research models may not be
representative of the human situation. Research techniques must be
devised by individuals who are knowledgeable in the field of aerosol
distribution and deposition, in the chemistry of cigarette smoke, and in
the biophysics of the distribution of smoke in the airways. Patterns of
inhalation for the average smoker must be studied in more detail. If
individuals who switch from regular to lower "tar" and nicotine
cigarettes undergo a change in smoking pattern, such as deeper or
more frequent puffs, this must be taken into consideration because the
contents of the smoke, the size of the particulate matter, and the
distribution of smoke in the lung may change with the variations in

143


inhalation patterns. Such information must be applied to dosimetry in
short-term in &no and in vitro experiments as well as in epidemiologic
or population studies.

Epidemiologic Studies

Studies of populations of smokers with well-defined smoking
histories are a major tool in determining whether a real difference
exists between smokers of regular cigarettes and smokers of lower
"tar" and nicotine cigarettes. If, in well-planned epidemiologic studies,
there is no difference found in the human occurrence or severity of
chronic obstructive lung disease between smokers of different types of
cigarettes, more basic research involving humans, animals, or in vitro
systems to determine differences between the effects of smoke
products would be less useful.

The design of epidemiologic research for this purpose raises a
number of issues. Determining the true dose of smoke in cross-
sectional, retrospective, or prospective population studies is a difficult
problem. Most studies rely on patient histories to obtain dosage
information. The accuracy of recall, the design of the questionnaire,
and the skills of the interviewer all influence the accuracy of smoking
history. The cigarette itself presents a problem in studying the
significance of the lower "tar" and nicotine brands because changes in
the content and design of cigarettes have continued over the past 10 to
15 years. This "moving target" makes evaluation of the dose-response
in populations difficult, especially since a large proportion of current
smokers began their smoking careers with regular cigarettes and
switched after varying periods of time. The comparison of mortality
rates is a commonly used epidemiologic tool. There are well-known
problems in obtaining accurate mortality data on chronic lung disease,
particularly in retrospective studies in which death certificates ob
tamed 10 or more years ago are utilized. Morbidity, including hospital
days and days lost from work because of respiratory illnesses, might
also provide useful information but is limited because of the selective
nature of populations (31).

Population studies that investigate the rate of decline of lung
function proportionate to the number of cigarettes smoked have shown
variable results. Most of the available data apply to smoking without
regard to cigarette yield. Environmental factors such as air pollution
may change simultaneously, and corrections must be made for these
factors.

The mean differences between the rate of decline of the FEVl in
populations of nondiseased smokers and nonsmokers are very small. A
difference between the smokers of higher and of lower "tar" and
nicotine cigarettes may be impossible to detect. However, the subgroup
of the smoking population that shows a more rapid decline should

144


receive special attention, since it is probable that thii group of
smokers, for reasons yet unknown, is most likely to develop significant
disease. Random variations from year to year in the measured FEVl in
individual patients require an extended period of time before valid
data can be obtained (7'). Biochemical tests that may serve as new
markers for chronic lung disease are in the early research stage and
should be explored as soon as possible. Under the best of circumstances
they could replace the physiologic tests that measure air flow
limitation as the earliest practical mechanism to detect lung damage.
These measurements should be given high priority to determine their
ultimate usefulness. In the meantime, it would be reasonable to collect
and store for future use blood and/or urine samples from the screened
populations.

The lack of specific, detailed information about the human dose-
response to cigarette smoke and the mechanism that causes individual
susceptibility to more rapid deterioration of lung function results in
diificulty in predicting sample size and the length of time needed for a
population study to determine differences between the smokers of
higher and of lower "tar" and nicotine cigarettes. Current data suggest
that the time and effort required to mount new epidemiologic studies
may delay the acquisition of needed information. However, there are
several ongoing studies in which epidemiologic data, both cross-
sectional and longitudinal, are being collected with relevance to
chronic lung disease. It is appropriate to consider the utilization of
these current studies where populations are already identified. Data on
the history of brands smoked could be added. Available information
about the "tar," nicotine, and carbon monoxide yield of the various
brands offers one measure of dosage. A recently developed radioimmu-
noassay for plasma nicotine levels may also be a helpful tool (9),
although smoking patterns may be as important as the number of
cigarettes smoked in determining the actual dosage.

Additional questionnaire material involving brand data and history
of morbidity related to respiratory symptoms could be superimposed on
ongoing studies. The accuracy of historical data on cigarette smoking
must be verified to the best possible extent. If new indicators serving
as a screening test, such as blood or urine analysis for lung elastin
degradation products, become available, they should be incorporated
into the studies. Depending on their diagnostic reliability, it might be
possible to study a considerably smaller population than that required
for studies of morbidity, mortality, and lung function deterioration. All
studies yet to be initiated should include questions on brand history.
This would require the revisions in the standard questionnaires of the
American Thoracic Society and Medical Research Council of Britain.
An ideal longitudinal study will require the enrollment of younger
subjects who begin their smoking careers with regular or with lower
"tar" and nicotine cigarettes and continue to smoke them. Changes in

145


other constituents such as additives will have to be considered as will
data obtained on patterns of smoking. If population studies enroll
subjects who have switched to brands with varying smoke yields one or
more times, the probability of detecting differences in FEWi or other
parameters would be more difficult. Special efforts should focus on
observations made of asymptomatic and symptomatic individuals with
lung function abnormalities. It will probably be relatively easier to
detect differences in the rate of pulmonary function deterioration
between the regular and the lower "tar" and nicotine cigarette
smokers in this group.

Prloritles for Research Recommendations

The primary public health concern is the effect of the lower "tar"
and nicotine cigarette on the individual's health. The second concern is
the mechanism of the effect, and the third is the specific agent
involved in stimulating the mechanism. The first need is to establish
whether there is a measurable difference between smokers of regular
and of lower "tar" and nicotine cigarettes. The epidemiologic approach
to the problem may yield the greatest amount of valuable information
in the most rapid manner, but population studies may not. show
differences in the development of chronic lung disease, since it is not
known whether the etiologic component of smoke is altered in the
currently marketed lower "tar" and nicotine cigarettes. Therefore,
parallel research is nessary to a better understanding of the
pathogenesis of COLD and identification of the responsible smoke
component. A combination of epidemiologic studies designed to answer
broad questions and human, animal, and in vitro studies will be
required to define the entire problem. The epidemiologic studies will
determine whether or not the lower "tar" and nicotine cigarettes have
a health benefit or whether a potential benefit is negated either by
changes in smoking patterns or by ignoring the agents responsible for
inducing COLD. Topographic and dose-response information is re-
quired for the human studies. The final and perhaps most beneficial
aspect of the research would be the elimination of the offending agents
from cigarettes.

Investigation of the distal air spaces or lung parenchyma where the
destructive component occurs in emphysema has received recent
emphasis with new approaches and measurements. Therefore, investi-
gation of this area may offer a greater possibility for significant new
data. To date, studies of air flow characteristics, airway reactivity, and
morphology have provided data concerning the chronology of the
disease but have not pointed to the mechanism by which lung damage
in emphysema is produced. Much of the benefit of basic research
hinges on a better predictability of the topography of smoking and
dose-response relationships. Information learned in the basic studies

146


can be translated into or used in epidemiologic studies, while the data
obtained from epidemiologic studies can offer directions for the finer
tuning of basic research. All of this would provide more information
about the pathogenesis of chronic obstructive lung diseases and their
potential alteration by lower "tar" and nicotine cigarettes.
The problem of passive exposure to cigarette smoke of different
types of cigarettes also needs consideration. However, determination
of the impact of lower "tar" and nicotine cigarette smoke on active
smoke inhalation presents difficulties significant enough to render to
low priority the passive smoking investigation at this time. Future
dose-response data, especially determination of thresholds, would offer
a lead into the area of passive smoking.

Research Recommendations

1. High priority should be given to a study of the distribution,
partitioning, and penetration of regular and lower "tar" and
nicotine smoke into the lung, including quantitation of and
adjustment for any changes in the pattern of smoking by smokers
of lower "tar" and nicotine cigarettes. Individuals in the special-
ized fields of aerosol physics, pharmacology, and toxicology should
be involved in answering this question.

2. Parallel priority should be given to epidemiologic studies, prefera-
bly by adding to ongoing longitudinal and cross-sectional studies
the data necessary to determine brand-related history. Higher and
lower "tar" and nicotine cigarette smokers should be compared for
differences in symptoms, morbidity, physiologic measurements,
and mortality relating to COLD. Special attention should be given
to people with identified disease or whose pulmonary function is
deteriorating at an accelerated rate. New studies should be started
if it is not possible to supplement the ongoing studies.

Several ongoing epidemiological studies have been identified:
(1) the Tucson Epidemiologic Study of Obstructive Lung Disease
at the University of Arizona (Dr. Benjamin Burrows); (2) the
Emphysema Screening Center Study of smokers and nonsmokers
at the University of Oregon at Portland (Dr. Sonia Buist); (3) the
Johns Hopkins University study of risk factors in chronic lung
disease in Baltimore (Dr. Harold Menkes and colleagues); (4) the
study of smokers in the Kaiser Permanente Health Care Plan (Dr.
Diane Petitti); and (5) the Nurses Health Study at Harvard
University (Dr. Frank Speizer). Statistical data to be collected by
the National Center for Health Statistics, such as the Health and
Nutrition Examination Survey, should be oriented to the collection
of a detailed history of smoking, and followup studies should
include spirometry. Data from the National Health Interview
Survey and the National Death Index may also be useful.

147


3. The rapid clinical evaluation of the recently developed biochemical
tests that measure products of lung elaatin degradation and that
can be detected in the plasma or urine should be carried out. If
these prove both specific and sensitive, the time involved in
carrying out the human epidemiologic research could be shortened.
4. Human, animal, and in vitro research that studies the mechanisms
responsible for COLD and their possible alteration by lower "tar"
and nicotine smoke should receive emphasis. Although the elas-
tase-inhibitor imbalance hypothesis is well supported by experi-
mental studies, confirmation of this mechanism is required for
human disease. Verified animal models of emphysema induced by
cigarette smoke exposure are not available at thii time, but if such
a model can be identified, it should be exploited. Investigation
should involve airway factors, parenchymal alterations, and
alterations in defense mechanisms that can be studied in shortc
term or subacute experiments. Biochemical, histological, and
ultrastructural studies are required for correlation with exposure
to smoke products or components from regular or lower "tar" and
nicotine cigarettes. Dosimetry or exposure levels for these studies
can be drawn from topographic and epidemiologic studies. Re-
search on both animal and human tissue, cells, and lung lavage
fluid is required.

Much progress has been made in recent years in the study of the
mechanisms of lung damage relating to cigarette smoke. However,
chronic bronchitis and emphysema are potentially devastating illnesses
that have no curative treatment. Elimination of cigarette smoking
would significantly reduce their public health importance. It is
imperative that we define as soon as possible any differences in the
effect of currently manufactured lower "tar" and nicotine cigarettes in
the pathogenesis of these diseases.

Summary

1. The relationship between cigarette smoking and chronic obstruc-
tive lung disease (COLD) is well documented. The constituents of
cigarette smoke that are responsible are currently not known.
Whether a difference in risk of COLD has occurred with lower
"tar" and nicotine cigarettes as compared with higher "tar" and
nicotine cigarettes is currently unknown.

2. Cigarette smoking is associated with the release by alveolar
macrophages of an increased amount of the elastolytic enzymes,
which degrade alveolar tissue, and with reduced activity of alphal-
antitrypsin, the primary elastase inhibitor. This mechanism has
not yet been directly related to the development of human
emphysema. To date there are no published studies that compare

148


the effects of higher versus lower "tar" and nicotine cigarettes on
elastolytic enzymes and inhibitor activity.

3. Cigarette smoke also contains relatively high levels of oxides of
nitrogen. The nitrogen oxides produce lung damage in animals
that is similar to that induced in humans by cigarette smoke. The
oxides of nitrogen may be responsible for the early lesions of
human emphysema.

4. An individual's smoking pattern is one of the most important
determinants of the relative concentration of smoke constituents
that reach the lungs and of the subsequent response of the airways
to smoke inhalation. Holding smoke in the mouth before inhaling
it into the lungs produces less response of the airways than direct
inhalation, which causes spirometric changes indicative of bron-
choconstriction. This effect is independent of the "tar" content of
the cigarette.

5. Pulmonary mucous hypersecretion and symptoms of cough and
phlegm appear to be affected by the "tar" content of cigarette
smoke. The development of airway obstruction is closely related to
the number of cigarettes smoked. Smokers of lower "tar" and
nicotine cigarettes who compensate by smoking more or inhaling
more deeply might thereby increase their risk of developing
obstructive airway disease.

6. Population studies that have examined the rate of decline of lung
function in relation to the number of cigarettes smoked have
shown variable results, and most of the available data do not
relate lung function to cigarette yield. Overall, the mean differ-
ence between the rate of decline of FEVl in asymptomatic smokers
and nonsmokers is very small, but there is a subgroup of the
smoking population that shows more rapid decline and is appar-
ently more likely to develop significant pulmonary disease.

149


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(6) BUIST, A.S. The relative contributions of nature and nurture in chronic
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(7) BURROWS, B. Course and pro8nosis of patients with chronic airways obstruo
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(9) CASTRO, A, MONJI, N., ALI, H., YI, M., BOWMAN, ER, MCKENNIS, II.,
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(I 0) COSIO, M., GHEZZO, H., HOGG, J.C., CORBIN, R., LOVELAND, hf., DGS-
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(17) GADEK, J.E., HUNNINGHAKE, G., ZIMMERMAN, R., CRYSTAL, RG.
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(f8) GILLESPIE, J.R., BERRY, J.B., WHITE, L.L., LINDSAY, P. Effecti on
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(19) HALE, K.k, NIEWOEHNER, D.E., COSIO, M.G. Morphologic changes in the
   muscular pulmonary art&err: Relationship to cigarette smoking, airway
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   278, August 1989.
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(21) HIGENBOTTAM, T., FEYERABEND, C., CLARK, T.J.H. Cigarette smoke
   inhalation and the acute airway response. 7Xumx 35(4): 246254, April 1980.
(2%`) JANOFF, A., CARP, H., LEE, D.K., DREW, R.T. Cigarette smoke inhalation
   decreases alphai-antitrypsin activity in rat lung. Science 266(4424): 1313-1314,
   December 14,1979.

(33) JOHNSON, D., TRAVIS, J. The oxidative inactivation of human alphai
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(34) KARLINSKY, J.B., SNIDER, G.L. Animal models of emphysema American
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(25) KIMBEL, P. Proteolytic lung damage. Chest 77(Supplement 2): 274-276,
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(26) KIMBEL, P., KUEPPERS, F. The biochemical basis of emphysema: The oxidant
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(37) KITIGAWA, S., TAKAKU, F., SAKAMOTO, S. Evidence that proteaaes are
   involved in superoxide production by human polymorphonuclear leukocytea
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(39) LAURELL, C.-B., ERIKSSON, S. The electrophoretic alphai globulin pattern of
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(SO) MORRIS, J.F., KOSKI, A., BREESE, J.D. Normal values and evaluation of
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(8f) PATRICK, C.H. In: Hemphill, D.D. (Editor). Truce Su&anccs in Z&&vnm
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Section 6. PREGNANCY AND INFANT
        HEALTH


CONTENTS

Introduction

Evidence on the Effects of Smoking in Pregnancy

Health Effects of Lower "Tar" and Nicotine Cigarettes

Research Approaches
  Recommendations for Human Studies
  Recommendations for Behavioral Studies
  Recommendations for Clinical Studies
     General Studies
     Placental Studies
    Autopsy Studies
    Breast-Feeding Studies
Recommendations for Physiologic-Pharmacologic Studies
     Tobacco Smoke
     Nicotine
     Carbon Monoxide
    Polycyclic Aromatic Hydrocarbons
     Other Substances

Priorities for Research Recommendations

Summary

References

155


Introduction

Since Simpson (23) first reported that the newborn infants of women
who smoked during gestation were of significantly lower weight than
the infants of comparable nonsmokers, the adverse effects of maternal
smoking on pregnancy have been increasingly appreciated. In 1979 the
publication Smoking and Health: A Report of the Surgeon Germ-al (25)
documented the considerable body of epidemiological, clinical, and
laboratory evidence concerning the role of cigarette smoking in
complications for the pregnant woman, fetus, newborn infant, and
child. Although many of the effects on a pregnant woman and her
child of smoking "regular" cigarettes manufactured during the past
three or four decades are well known, possible differences between the
effects of higher versus lower "tar" and nicotine cigarettes on the
incidence and magnitude of these various complications are not known.
The relative importance of "tar" and nicotine (commonly assayed in
current cigarettes) versus the importance of carbon monoxide and
several thousand other constituents of tobacco smoke (usually not
measured) is not known. In fact, it is possible that compounds other
than "tar" or nicotine are important in producing these effects. It is
essential to elucidate these issues.

Evidence on the Effects of Smoking in Pregnancy

The complications of pregnancy ascribed to cigarette smoking may
be divided into those that affect (1) the mother, (2) the embryo and
fetus, (3) the placenta, and (4) the newborn infant and child. The
mother, fetus, and placenta constitute an integrated organic unit
rather than separate systems or organs. Thus, although separation of
effects into these categories is convenient, it is also somewhat
arbitrary. Some effects, such as spontaneous abortion and other
reproductive loss, affect both the mother and fetus. Complications in
different categories can occur concurrently. Cigarette smoking has
been demonstrated to exert effects on each category.

Maternal complications of pregnancy that show a greater incidence
among women who smoke cigarettes include placenta previa, abruptio
placentae, vaginal bleeding during pregnancy, and, possibly, prema-
ture rupture of the membranes (13,14). Lifetime smoking histories also
affect the occurrence of placenta previa, abruptio placentae, and
bleeding during pregnancy (17, 19). The incidence of amnionitis
(infection of the amniotic fluid and its membranes) also is increased
among women who smoke (16). The occurrence of the preceding
complications appears to increase with the number of cigarettes
smoked. For instance, the risk of placenta previa for mothers who
smoke less than one pack per day is 25 percent greater than that of
nonsmoking women, but is 92 percent greater in those who smoke one
or more packs of cigarettes per day (14). Additionally, the risk of

157


abruptio placentae is increased 23 percent and 86 percent, respectively,
in these two smoking-level groups compared with nonsmokers (14).

Virtually all of the more than 50 studies published, involving more
than half a million births from many countries and ethnic groups, have
been consistent in demonstrating that maternal smoking has an
adverse effect on birthweight (25). These newborn infants weigh on
the average 200 grams less than babies born to comparable women who
do not smoke, and the decrement in birthweight varies with the
number of cigarettes smoked (25). In an analysis of data from the
Ontario (Canada) Perinatal Mortality Study, the number of newborns
weighing less than 2,500 grams was 52 percent greater among women
smoking less than one pack per day and 130 percent greater among
women who smoked one pack or more per day, when compared with
the pregnancies of nonsmoking women (12, 13). The contribution of
this reduced birthweight to the occurrence of abruptio placentae or
placenta previa is not clear (18).

Several studies have shown that the placental ratio (placental
weight to fetal weight) is higher for the gestations of mothers who
smoke (~7'). This increase in the placental ratio results from a decreased
newborn birthweight and from a slight increase in absolute placental
weight in heavier smokers (25). Preliminary results from the Columbia
University study fail to show either smaller weight decreases in the
newborns of mothers who smoke lower "tar" and nicotine cigarettes or
a return to nonsmoker values in the placental to fetal weight ratios.

The risk of spontaneous abortion is 30 to `70 percent higher among
pregnant smokers than among nonsmokers and increases with the
number of cigarettes smoked (11). Rates of fetal deaths (occurring
after 20 weeks of gestation) also increase significantly with the level of
maternal smoking (3). The risk of premature delivery is 36 to 47
percent greater in mothers who smoke during pregnancy than in
nonsmoking mothers; about 13 percent of all preterm births can be
at,tributed to smoking (1, 3, 9, 13). This is an important factor in the
increased risk of neonatal mortality among the infants of smoking
mothers. Infants of women who smoke experience a mortality rate
ranging from less than 10 percent to almost 100 percent greater than
that among offspring of nonsmoking mothers. The excess risk of
perinatal mortality varies, depending upon the number of cigarettes
smoked and upon the presence of other high-risk factors (e.g., low
socioeconomic group, a previous low-weight birth, or anemia) (~5).

Several abnormalities of infancy and childhood occur more frequent-
ly among the offspring of mothers who smoke. Children of women who
smoke during and after pregnancy experience higher rates of morbidi-
ty and mortality up to the age of 5 years. In Finland, smokers' children
had more hospitalizations, more visits to the doctor, and more use of
specialized services (20, 21). Significantly more infants of smoking
parents are hospitalized for pneumonia and bronchitis (5, 6, 10). The

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sudden infant death syndrome (SIDS) occurs more frequently among
the children of parents who smoke (2,24). Other long-term sequelae of
maternal smoking during pregnancy are also of concern. Several
studies suggest that older children of mothers who smoke have slight
but measurable deficits in physical growth, intellectual ability, emo-
tional development, and behavior (25). For instance, in Great Britain
the physical growth of smokers' children remained less than that of
nonsmokers' offspring, at least until age ll(4). Associations have been
reported between maternal smoking and deficits in neurological and
intellectual development of the child. These include minimal cerebral
dysfunction and abnormal or borderline electroencephalograms (8),
hyperkinesis (r), and abnormal infant behavior patterns (22). These
long-term effects of maternal smoking require attention because of
their potential seriousness.

Thus, an excess risk of several disorders or death face the fetus and
infant of the mother who smokes.

Although "tar," nicotine, carbon monoxide, and some other constitu-
ents of cigarette smoke have been shown to produce various effects,
the specific etiologic agents and their mechanism(s) of action are not
clearly established for these adverse effects on pregnancy.

Health Effects of Lower "Tar" and Nicotine Cigarettes

Although use of lower "tar" and nicotine cigarettes has grown
markedly over the past decade, there are no data available that
suggest that the developing fetus, the infant, or the pregnant woman
are less harmed by cigarettes with lower levels of these constituents.
There has been no demonstration of decreased risk of complications of
pregnancy. There is no evidence of a decreased risk among smokers of
spontaneous abortion or preterm birth, nor of an increase in the
average weights of their babies. Newborn infants of smoking mothers
continue to have a mean weight of 200 grams less than those of
nonsmokers, a relation that is dose dependent. The risk of preterm
delivery remains much greater for smoking mothers. Further, there is
no evidence to date that maternal smoking of lower "tar" and nicotine
cigarettes decreases the risk of perinatal mortality.

Most research reports to date have considered only the number of
cigarettes smoked per day in quantitating smoke exposure, without
adjusting for differences in yield of different cigarettes.

Research Approaches

Investigation into the effects of maternal cigarette smoking on
pregnancy, the fetus, and the young child should include the following
types of studies: (1) prospective epidemiologic studies comparing the
course and outcome of pregnancy by maternal smoking habits; (2)

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case-control studies of pregnancy complications including laboratory
measurements of various body functions and constituents and a
prospective study of pregnancy outcome; and (3) clinical and experi-
mental research, often using laboratory animals, in which tobacco
smoke or some of its constituents, commonly nicotine and carbon
monoxide, are administered to the subject, animal, tissue, cell, or
subcellular element, and the response quantified.

With numerous systems to be considered (the pregnant woman, the
fetus, the newborn, the young child), and with various organs, tissues,
cells, and subcellular elements potentially acted upon by a myriad of
tobacco smoke constituents, the selection of appropriate study designs
is a complex process. Further, the design of such studies is complicated
by continuous changes in the composition of cigarettes over the past
two decades. The spectrum of cigarette types, composition, and smoke
yield varies enormously. In addition, the individual smoker's lifestyle,
habits, and intake of other substances such as alcohol, caffeine, and
drugs must be considered.

In view of the multiple variables involved, the recommendations that
follow are those most likely to contribute significantly to an under-
standing of the character and magnitude of adverse effects of smoking
cigarettes with varying levels of "tar" and nicotine on pregnancy.
Research must define the relative importance of the several constitu-
ents, the impact of dose variations, and the mechanisms of action of the
toxins in cigarette smoke.

Recommendations for Human Studies

Studies of populations of individuals with defined smoking histories
have made an important contribution to elucidating the effects of
smoking on various aspects of pregnancy, childbirth, and infant health.
To date, no epidemiologic data exist to indicate lower risks of the
aforementioned conditions in the pregnant mother, fetus, or infant
resulting from the use of a lower "tar" and nicotine cigarette.

Present knowledge is sufficient that new, large prospective studies
specifically designed to evaluate smoking effects are not necessary;
rather, the approach should be, first, to encourage all prenatal care
facilities to record smoking information, preferably with measurement
of exhaled carbon monoxide. Second, the major source of information
should be centers where continuing prospective evaluation of pregnan-
cy is already being carried out in a systematic way, such as the Kaiser
Permanente Cohort Study.

These centers should adopt a uniform practice of keeping detailed
records of their patients' smoking habits, recording at each prenatal
visit the number of cigarettes smoked, brands, filters, "tar" and
nicotine content, and measured exhaled carbon monoxide (to estimate
maternal and fetal COHb). Records of other exposures such as alcohol,
coffee, and other drugs should also be kept. These and other relevant

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personal, medical, and demographic factors should be analyzed or
controlled in evaluating the outcome of these pregnancies (spontane-
ous abortions, later fetal deaths, complications of pregnancy, preterm
deliveries, duration of gestation, birthweight, and neonatal and later
conditions versus normal, live births).

These comprehensive, continuing studies are needed to elucidate the
interrelationships of factors already known to affect pregnancy
outcomes. It would be desirable to have several centers with large
numbers of births follow a standard protocol for such studies.

Within the context of such a protocol, or possibly separate from it,
case-control studies of spontaneous abortions, fetal death, preterm
births, and particularly abruptio placentae, placenta previa, and
premature rupture of membranes should be carried out. Patients who
have not delivered at the time of ascertainment should be followed
prospectively to delivery, together with their matched controls.
Biochemical tests should be included in these studies to elucidate the
mechanism of action of smoking in the increased incidence of these
events. Any possible modification of these outcomes that accompany
the use of lower "tar" and nicotine cigarettes should be examined.

A variety of other special clinical studies to test for differences in
adverse pregnancy outcome by use of different cigarettes during
pregnancy could be added to these larger monitoring operations or
could be set up independently, using infants of matched smokers and
nonsmokers. For example, (a) neonatal behavioral assessment (Brazel-
ton scale), (b) auditory response testing of newborns, (c) neonatal and
post-neonatal growth measurement, (d) special studies among very
heavy smokers, and (e) placental studies could be performed.

Several epidemiologic studies now in progress might provide an-
swers to some of these questions, for example, the study of spontane-
ous abortion at Columbia University in New York, or the Oakland
Kaiser Permanente Cohort Study, which prospectively links smoking
history and cigarette brand to all hospitalizations of approximately
50,000 women, many of childbearing age.

Studies have indicated that maternal smoking during pregnancy
may be associated with impairment of physical and intellectual
development, hyperkinesis, and changes in the infant's responsiveness
(25,26). The hypothesis that alterations in the constituents of cigarette
smoke might affect the risk of these conditions needs to be tested.
Differences in risk of long-term neurological consequences for a child
exposed to maternal smoking should continue to be examined in
existing data sets insofar as they contain appropriate information.
Data files include (a) the Collaborative Perinatal Project (U.S.), (b) the
1958 and 1970 British Perinatal Studies (U.K.), (c) the Kaiser
Permanente Cohort Study (Oakland), (d) the Finnish Perinatal Study
(Finland), and possibly (e) the University of Washington Study
(Seattle). Such studies must include consideration of possible confound-

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ing factors such as socioeconomic status, nutritional status, alcohol use,
and exposure to legal and illegal drugs.

In addition to studies documenting the maternal and fetal risks of
varying levels of "tar," nicotine, and other constituents in cigarette
smoke, there is need for study of the effect of cessation of smoking at
different times in gestation on subsequent adverse events of pregnan-
cy, including measures of birthweight, gestational age, perinatal
mortality, and long-term sequelae. It will be important also to
discriminate the effects of maternal smoking during gestation from
those of parental smoking during infancy and childhood.

The combined effect of such studies would be to define any
differences by cigarette "tar" or nicotine yield in the incidence of
maternal complications or fetal or newborn sequelae, relative to both
nonsmokers and smokers of different products.

F&commendations for Behavioral Studies

The factors and influences that lead an individual to start smoking
and to maintain the habit despite knowledge that it poses health risks
are complex. In view of the absence of evidence that lower "tar" and
nicotine products pose less risk to pregnancy outcome, the description
of smoking patterns among pregnant women and the investigation of
motivational factors in this population are critical to the design of
appropriate public health programs.

Some studies indicate that cessation of smoking early in gestation
results in a pregnancy and fetus with risks of low birthweight similar
to those among nonsmokers (25). Clinical studies could be conducted of
pregnant women who refuse to quit smoking, in order to define the
time intervals during which cessation of smoking results in a risk
indistinguishable from those of nonsmokers. In view of the demon-
strated effects of nicotine, carbon monoxide, and other tobacco
constituents, rapid smoking techniques for cessation are contraindicat-
ed in pregnant women. Exhaled carbon monoxide should be measured
at each visit, and the results used to explain to the mother that her
baby's oxygen supply as well as her own is reduced by carbon monoxide
from the cigarettes.

Further, considerable evidence indicates that the majority of women
initiate smoking during their teens and pre-teens. Therefore, behavior-
al studies should focus on the prevention of initiation of smoking in
this age group. Adolescents are a high risk group during pregnancy
because of many factors, such as inadequate nutrition, anemia,
inadequate prenatal care, and the use of illicit drugs. Adolescents who
smoke during pregnancy constitute a particularly important group
because of the coexistence of smoking and other risk factors. Interven-
tion techniques must be found that effectively illustrate to the
pregnant adolescent how smoking affects her body and fetus and that
assist in cessation attempts. Such demonstrations might include

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measurement of increases in fetal heart rate and decreases in fetal
respiratory rate after smoking.

Studies of lifetime smoking experience should describe the role of
pregnancy in changing smoking, such as cessation attempts and
successes, brand choices, and number of cigarettes smoked daily, A
logical extension of this study would define how the techniques of
smoking cessation during the course of gestation may differ for
pregnant women compared with those directed to smokers in general.
The applications of such studies are particularly important for women
who smoke heavily as well as for those women at high risk because of
other factors.

Recommendations for Clinical Studies

General Studies

The adverse health consequences of cigarette smoking for the
individual smoker extend beyond the pregnant smoker. As do the
taking of drugs, exposure to workplace chemicals, or voluntary
exposures to toxic substances such as alcohol, smoking by pregnant
women affects the health of her fetus. The implications of this
extended responsibility cannot be over-stressed.

The effects of heavy smoking (two or more packs a day) on the
pregnant woman, her fetus, and child have not been well defined. If
adequate numbers of pregnant women who are very heavy smokers
(two or more packs per day) could be identified, a special study should
be undertaken to compare them with nonsmokers matched on impor-
tant factors, e.g., time of registration, age, parity, and socioeconomic
status. A prospective study should examine heavy smokers, including
users of modified lower "tar" and nicotine cigarettes, as well as
nonsmokers. For these heavy smokers aa well as for light smokers,
maternal blood levels of nicotine, catecholamines, carboxyhemoglobin,
thiocyanate, cadmium, and other suspect compounds should be exam-
ined during pregnancy. Such a study should monitor several fetal
variables including cardiac electrical activity, breathing and other body
movements, cerebral electrical activity, and periodic measurements of
head growth (biparietal diameter). Following birth, placentas would be
examined for morphometric and/or pathologic abnormalities. Newborn
infants should be completely examined, including measurement of lung
volume and brain size and neonatal behavior assessment using the
Brazelton scale. Children should undergo long-term followup for
neurologic function (e.g., hearing and visual disorders). Alternatively,
certain aspects of neurological dysfunction should be examined by
case-control studies in which children with abnormalities are compared
with normal neonates, matched by such factors as time of birth,
gestational age, and socioeconomic status. Prenatal exposure to
smoking by amount, type of cigarette, and yield and exposure to other

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substances should then be compared to determine associations between
neurological abnormalities and these exposures.

The mechanism(s) by which maternal smoking increases complica-
tions of pregnancy, such as spontaneous abortion, abruptio placentae,
placenta previa, and premature rupture of the membranes are not
clearly defined, despite the fact that these complications account for a
significant portion of embryonic and fetal morbidity and mortality.
Abruptio placenta will continue to result in anoxic fetal deaths.
Preterm deliveries attributable to premature rupture of placental
membranes will continue to pose the attendant hazard of neonatal
death to the newborn infant.

Therefore, studies ought to test certain hypotheses about the
mechanisms of action of cigarette smoke in these events. Instances of
complications should be identified (i.e., placenta previa, abruptio
placentae, premature rupture of the membranes, and probably sponta-
neous abortions). Controls should be selected for each case (matched by
time of registration, gestational age at occurrence of complication,
social status, age, parity, and perhaps other factors), and demographic
factors and confounding exposure(s) to other compounds should be
examined. A number of variables quantitating smoke exposure should
be measured, including the concentrations of blood hemoglobin,
carboxyhemoglobin, thiocyanate, copper, and various vitamins (A, BE,
C, and folate). The subjects should be followed to delivery, and the
influence of measured factors related to outcome. Although at birth
one could measure variables such as the biomechanical properties of
membranes, tissue collagen concentrations, and cell number and size,
such measures are not known to elucidate the mechanism of action of
smoke constituents. Biopsies of the cervix from women with premature
rupture of the membranes should be examined for concentrations of
elastase or other enzymes that might play a role in premature dilation
of the cervix. In instances of abrupt@ placentae and placenta previa
(and in matched controls), that organ could be examined for morpho-
metric or morphologic alterations.

Piacentd Studtis

Placental morphology and morphometry are plagued by a lack of
information and understanding of the relation of villous structure to
the size (generation) of the associated blood vessels. Therefore, such
morphometric studies of the placenta should be carried out in a
laboratory dedicated to placental structure.

The ratio of placental weight to birthweight increases with numbers
of cigarettes smoked daily. bight smokers' placentas may be slightly
lighter and heavy smokers' placentas somewhat heavier than those of
nonsmokers. The diameter to thickness ratio is also somewhat in-
creased for smokers. Signs of "premature aging" are also seen in
smokers' placentas, characterized by early appearance of calcium and

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subchorionic fibrin (27'). The described changes were somewhat smaller
in magnitude than those described for high altitude or anemia. These
studies did not, however, include consideration of the type of cigarette
smoked. The factors that account for these changes and their
mechanism of action are unknown.

Morphometric studies should be designed to determine what fea-
tures of placental architecture are altered by maternal smoking and by
the type of cigarette used. These studies would include examination of
the trophoblast, blood vessels and their interrelations, relative matura-
tion of the placenta including the presence of calcium and subchorionic
fibrin, membrane thickness, relative size of the intervillous space, and
evidence of pathologic alterations. In addition, other studies should
examine ultrastructural features of the trophoblastic cells and blood
vessels. Further studies should examine biopsies of the placental bed,
including the decidua and endometrium of women who do and do not
smoke.

Studies indicate that the blood of smoking women has lower
concentrations of certain amino acids and vitamins A, Bw C, and folic
acid, among others, but the mechanism of these changes is unknown.
Placentas from smokers of different cigarettes and matched controls
should be studied for uptake kinetics and for intracellular to extracel-
lular concentration ratios of amino acids and other compounds.

Autopsy Studies

The fetus of the mother who smokes weighs less than the fetus of a
comparable nonsmoking mother, and this effect varies with the
number of cigarettes smoked. However, the mechanism(s) whereby
this change occurs is unknown. No evidence is available on how
different cigarettes affect the occurrence of low birthweights. In an
effort to determine whether decreased cell size, or cell number, or both,
account for this change, we recommend that studies examine DNA
concentrations (cell number) and DNA to protein ratios (cell size) in
infants of smoking mothers suffering perinatal death.

One large study, corroborated by others, showed that, among
perinatal deaths associated with maternal smoking, the largest catego-
ries of cause of death for stillborn infants were "unknown" causes or
"hypoxia." The largest number of neonatal deaths were ascribed to
"prematurity" alone. In an effort to elucidate specific causes and
possible mechanisms of these deaths and the implications for newer
cigarettes, dead fetuses and infants who die near the time of delivery,
of smoking and nonsmoking mothers, should be subjected to thorough
and careful autopsy by an experienced neonatal pathologist. Such
studies may help elucidate differences in the smoker's infant who dies.

Fetal lung weight is decreased preferentially in animals exposed
prenatally to carbon monoxide. Infants of smoking mothers experience
increased risk of respiratory infections and pulmonary disease, and the

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lungs may be altered in infants of smoking mothers who expire in the
"sudden infant death" syndrome. In an effort to determine the
morphologic basis and possible mechanism of these changes, the lungs
of stillborns, or of newborn infants who expire, should be examined for
morphologic and pathologic changes related to the smoking status of
the mother. Some specific indices to be examined include alveolar type
II cells, macrophages, and microcirculatory vascularization.

Fetal brain weight is increased (probably from edema) in animals
exposed prenatally to carbon monoxide. The infants of smoking
mothers experience increased risk of "minimal brain damage," hyper-
kinesis, and other neurologic disorders. In order to determine the
morphologic basis and possible mechanisms of these changes, the
brains of the dead fetuses or infants of this group should be examined
for morphologic and pathologic changes. Some specific indices to be
examined include neuronal and dendritic number and architecture. It
may be of special importance to examine the brainstem because of
altered respiratory control mechanisms.

Breast-Feeding Studies

Several products of tobacco smoke such as nicotine, cotinine, and
thiocyanate are known to be secreted in breast milk. However, little is
known about the dose-response relationship of smoking to the concen-
trations of these compounds. Breast milk of lactating mothers and the
blood of their newborns should be examined for concentrations of
nicotine, cotinine, thiocyanate, cadmium, and other toxins. In addition,
breast milk from smoking mothers should be analyzed for the
concentrations of leukocytes, monocytes, immune globulins, and other
immunologically important factors, in addition to protein, fat, carbohy-
drate, and other constituents that affect newborn growth. Again, dose-
response relationships should be explored.

Finally, breast-fed infants of smoking mothers should be examined
for evidence of nicotine addiction and withdrawal symptoms (irritabili-
ty, nervousness) at the time of weaning.
Some studies have indicated that maternal smoking suppresses
lactation. Milk production and ability to nurse should be studied in
smoking and nonsmoking women who want to breast feed their babies,
including evaluation of the effects of stopping smoking and the use of
lower "tar" and nicotine cigarettes.

Recommendations for Physiologic-Pharmacologic Studies

Laboratory studies in experimental animals have proved useful to
test various hypotheses regarding the specific effects of the individual
constituents of tobacco smoke, as well as mechanism(s) of action. Such
laboratory studies should be carried out in a well-organized and careful

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manner, and should consider exposure to tobacco smoke per se as well
as to its individual constituents.

Tobacco Smoke

The introduction of modified, lower "tar" and nicotine cigarettes
raises several questions regarding the effects of these tobacco products
on the pregnant woman, fetus, and infant. Although purportedly lower
in their yield of "tar" and nicotine, these cigarettes may still deliver a
threshold level or more of carbon monoxide or other toxic products.
Additionally, smokers may use certain techniques to increase the yield
so that the delivery of "tar," nicotine, carbon monoxide, or other
constituents is similar to, or perhaps in excess of, that of regular
cigarettes.

Further, the possibility exists that there is a systematic difference in
the style of smoking depending on "tar" or nicotine level. If smokers of
lower "tar" and nicotine products uniformly take more puffs, larger
puffs, or inhale more deeply, the actual dose of constituents experi-
enced by the smoker would not be as low as that predicted by machine
measurement. In addition, while the relative amounts of smoke
absorbed may vary, differences in smoking pattern might also affect
the relative proportions of constituents in the smoke inhaled, a fact
that might well influence the probability of developing smoking-
related health problems. Measurements of smoke constituents and
breakdown products in the smokers' exhalations, serum, and other
body fluids may provide better estimates of cigarette yield than
smoking-machine results. Levels also differ by sex and during
pregnancy.

Studies of the effect of tobacco smoke in animals present problems
as to the dose of smoke actually received by the animal, the specific
compound(s) responsible for the changes observed, and the concentra-
tion of these substances in blood or tissue. All such studies should
include measurements of blood concentrations of nicotine, carboxy-
hemoglobin, and perhaps other compounds, as well as tissue concentra-
tions where appropriate.

Numerous animals have been used for studies on the effects of
smoking. Ideally such studies should be carried out in subhuman
primates, such as baboons trained to smoke. However, the technical
difficulties and expense of such studies make this approach unrealistic.
Consideration must be given to whether there is, in fact, a particular
animal model that is optimal from the standpoint of relevance to
human studies, availability, and expense.

As noted previously, an almost universal phenomenon is the decrease
in birthweight of infants of smoking mothers. Animal studies must
explore which components of cigarette smoke are most important in
reducing the rate of fetal growth. Such studies should determine
whether it is the rate of mitosis or cell number that is reduced, and

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whether the smoking-associated reduction of fetal growth rate is
caused by retarded growth of only certain organs or tissues.

Following birth, many children of smoking parents are continuously
exposed to tobacco smoke. This may be a factor in the higher incidence
of sudden infant death syndrome, hyperkinesis, "minimal brain
dysfunction," and respiratory disorders in such children. Animal
studies should be performed to examine the effects of passive smoking
on newborn or young animals.

Nicotine

Nicotine is an important pharmacologic agent in tobacco smoke.
Studies suggest that some smokers titrate their nicotine dose by
altering the number of cigarettes smoked, the depth of inhalation, or
the degree of occlusion of pores (in the case of low "tar" and nicotine
cigarettes). The following major areas of inquiry should be studied:
1. Definition of the role of nicotine exposure during fetal life in
birthweight reduction, behavioral development, and childhood
  growth retardation

2. Examination of the effect of nicotine on individual organ growth,
including the fetal brain, adrenal glands, lungs, heart, and kidneys
3. Study of nicotine's contribution to neurologic disorders in children
4. Elucidation of the role of nicotine or its metabolites in carcinogen-
esis, alone or in combination with benzo[a]pyrene and other
carcinogens in smoke

5. Definition of the effect of nicotine on human fetal blood
catecholamine concentrations

Carbon Monoxide

Carbon monoxide, a product of incomplete combustion of carbona-
ceous compounds, is present in tobacco smoke in relatively high
concentrations (1 to 6 percent). Hemoglobin avidly binds carbon
monoxide as carboxyhemoglobin, decreasing the oxygen transport
capacity of blood. Because of the relatively higher affinity of fetal
hemoglobin for 02 and CO, as compared with adult hemoglobin, a given
carbon monoxide partial pressure results in a fetal blood carboxyhemo-
globin level 10 percent greater than that of the smoking mother, while
fetal arterial oxygen tension is only 20 to 36 percent that of the
mother. Thus, the fetus experiences higher carboxyhemoglobin levels
and a greater carbon monoxide-induced hypoxia than that occurring
simultaneously in the mother. Exploration of the following questions
should be undertaken:

1. Definition of the major physiological consequences of carbon
monoxide exposure on the developing fetus or newborn
2. Elucidation of the dose-response relationship of carbon monoxide
in disease occurrence

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3. Examination of fetal adaptation to low carbon monoxide concen-
trations, and the mechanisms of any such adaptation
4. Definition of the patterns of growth, development, and matura-
tion of the central nervous system and other organ systems
exposed to chronic low-level carbon monoxide
5. Study of the periods during gestation when the fetus is particular-
ly vulnerable to carbon monoxide

Polycyclic Aromatic Hydrocarbons
Benzo[a]pyrene (BaP) and other polycyclic aromatic hydrocarbons
(PAH) are potent carcinogens. Little is known about the transplacental
effects of these substances on the developing fetus. Examination of the
following questions is needed:

1. Definition of the transplacental passage of BaP and PAH
2. Description of BaP or PAH distribution in the fetal organs and
tissues

3. Examination of a possible role of BaP or PAH from maternal
smoking in the growth and development of the fetal brain and
  other organs
It should also be noted that BaP and PAH are known inducers of the
cytochrome oxidase (Pm) system, including aryl hydrocarbon hydroxyl-
ase (AHH). Such enzymes are involved in drug and steroid metabolism,
among other functions. Thus, the PAH should be investigated for
possible metabolic effects beyond those of carcinogenesis.

Other Substances

Numerous possibly toxic substances are present in cigarette smoke,
including cyanide and cadmium. Little is known about the role of these
compounds in altering fetal growth and development. Studies should
examine the effects and mechanism(s) of action of these substances.

Priorities for Research Recommendations

The preceding discussion has presented many research issues that
are major and valid questions. The primary emphasis, however, must
be placed upon studies that determine the character and magnitude of
the health hazards posed to the individual pregnant smoker and her
offspring by the modified lower "tar" and nicotine cigarettes. Research
to define the specific etiologic agents and their mechanism(s) of action
must take a priority second to that of defining the risks.

It is through epidemiologic research that the answers to the most
important questions will be reached. It is apparent that there is a need
for refining the measurement of cigarette dosage and the quantitation
of cigarette smoke exposure. A more accurate description of dosage
must be an intrinsic part of epidemiologic research efforts that deal
with smoking exposures. All obstetricians and prenatal clinics should

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be strongly urged to record details of their patients' smoking habits at
each visit.

Simultaneously, however, laboratory investigation should proceed in
parallel to examine the specific compounds involved and their mecha-
nisms of action. Research has contributed some knowledge of tissue,
cellular, and subcellular effects. Further studies at these levels hold
the promise of elucidating the mechanisms whereby these changes
occur. Such studies may lead to a greater understanding of specific
cigarette hazards by dosage and thereby suggest directions for
epidemiologic studies. Conversely, epidemiologic data will suggest
directions and specific questions for laboratory or clinical research.
These approaches should proceed in concert for maximal results in
understanding the problems of lower "tar" and nicotine cigarettes in
the medical, biological, and social environments.

Summary

1. Cigarette smoking during pregnancy has been shown to have
adverse effects on the mother, the fetus, the placenta, the
newborn infant, and the child in later years. There is no evidence
available that lower "tar" and nicotine cigarettes decrease or
increase these health risks, relative to those posed by higher "tar"
and nicotine cigarettes.

2. Problems that have been linked to smoking during pregnancy
include placenta previa, abruptio placentae, vaginal bleeding, and
reduced average birthweight of newborn infants.

3. Smoking by pregnant women increases the risk of spontaneous
abortion, premature delivery, fetal death, and perinatal death.
Parental smoking is associated with the sudden infant death
syndrome.

4. The fetuses of smoking mothers have higher blood carboxyhemo-
globin levels and lower fetal arterial oxygen levels than do the
mothers.

5. Children of smoking mothers appear to show a greater susceptibil-
ity to some adverse health effects, such as bronchitis, pneumonia,
and respiratory disease, during early childhood. Slight differences
in physical growth and other forms of behavioral and intellectual
development may be found in children as old as 11 years of age.
6. Although "tar," nicotine, carbon monoxide, and some other
constituents of cigarette smoke produce deleterious effects, the
specific etiologic agents and their mechanisms of action for
adverse effects on pregnancy are not clearly determined. Thus, the
relative importance of "tar" and nicotine, or carbon monoxide and
other constituents of tobacco smoke in the etiology of adverse
gestational and fetal events is not known.

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(.??) BERGMAN, A.B., WIESNER, LA. Relationship of passive cigarette-smoking to
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(3) BUTLER, N.R., ALBERMAN, E.D. (Editors). perinatal Pro&ms. The Second
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(4) BUTLER, N.R., GOLDSTEIN, H. Smoking in pregnancy and sulmequent child
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(5) COLLEY, J.R.T. Respiratory symptoms in children and parental smoking and
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(6) COLLEY, J.R.T., HOLLAND, W.W., CORKHILL, R.T. Influence of passive
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(7) DENSON, R, NANSON, J.L., MCWATTERS, MA. Hyperkinesis and maternal
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(8) DUNN, H.G., MCBURNEY, AK, INGRAM, S., HUNTER, C.M. Maternal
  cigarette smoking during pregnancy and the child's subsequent development:
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  Juumd of P&ti Health 68(l): 43-50, January/February 1977.
(9) FABL4, J. Cigarettes pendant la gmeseae, poids de naissance et mortalite
  perinatale. [Cigarette smoking during pregnancy, biih weight and perinatal
  mortality.] Canadian Medical Aseociation Jacrnal169(11): 1164-1169, Decem-
  ber 1,1973.

(10) HARLAP, S., DAVIES, A.M. Infant admissions to hoepital and maternal
   smoking. Lund l(7857): 527-532, March 361974.
(11) KLINE, J., STEIN, Z.A., SUSSER, M., WARBURTON, D. Smoking: A risk
  factor for spontaneous abortion. New England Journal of Medicin.e 297(15):
   793-796, October 13,1977.

(1%`) MEYER, M.B. How does maternal smoking affect biih weight and maternal
   weight gain? Evidence from the Ontario Perinatal Mortality Study. American
   Journal of Oh&tries and Gyneedogy 131(a): 888893, August 15,1978.
(18) MEYER, M.B., JONAS, B.S., TONASCIA, J.A. Perinatal events associated with
   maternal smoking during pregnancy. A mmimn Journal of Hpidemiology
   l&l(5): 464476, May 1976.

(14) MEYER, M.B., TONASCIA, J.A. Maternal smoking, pregnancy complications,
   and perinatal mortality. A mwimn Journd of &d&-ics and Gynecdogy
   l28(5): 494-502, July 1,1977.

(15) MEYER, M.B., TONASCIA, J.A., BUCK, C. The interrelationship of maternal
  smoking and increased perinatal mortality with other risk factors. Further
   analysis of the Ontario perinatal mortality study, 196&1961. Anwrkun
  Journal of Epidemidcgy loo(6): 443452, December 1974.
(16) NANE, R.L. Effects of maternal cigarette smoking on the fetus and placenta.
   British Journal of Obstetrics and Gyrzu~logy 85(10): 732737, October 1978.
(17) NAEYE, R.L. The duration of maternal cigarette smoking, fetal and placental
   disorders. .&rly Human hvdqmwnt 3(3): 229237, September 1979.
(18) NANE, R.L. Cigarette smoking and pregnancy weight gain. Land l(8171):
   765766, April 5,1989. (Letter)

(19) NAEYE, R.L. Abmptio placentae and placenta previa: Frequency, perinatal
   mortality, and cigarette smoking. Obstetrics and Gyneeub 55(6): 701-764,
    June 1989.

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(a0) RANTAKALLIO, P. Relationship of maternal smoking to morbidity and
  mortality of the child up to the age of five. Acta paediatrica Scandim&
   67(5): 621-631, September 1978.
(21) RANTAKALLIO, P., KRAUSE, U., KRAUSE, K. The use of the ophthalmologi-
  cal services during the preschool age, ocular findings and family background.
  Journal of pediatric Ophthalmology and Strabimnua 15(4): 253-258, July-
   August 1978.

(2%`) SAXTON, D.W. The behaviour of infants whose mothers smoke in pregnancy.
   Early Human hlopment 34): 363--369,1978.
(23) SIMPSON, W J. A preliminary report on cigarette smoking and the incidence of
   prematurity. A mericun Jvurnal of Obstetrics and Oynecdogy 73(4): 808-815,
   April 1957.

(34) STEELE, R., LANGWORTH, J.T. The relationship of antenatal and postnatal
  factor% to sudden unexpected death in infancy. Canadian Afed&& Asscciath
   Jownul94: 1165-1171, May 28,1966.

(35) U.S. DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE. &no&w
  and Health: A Report! of the Swgem Gewd. U.S. Department of Health,
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  Secretary for Health, Office on Smoking and Health, DHKW Publication No.
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(36) U.S. DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE. !l%c
  Health (3maeqmlece8 of Smoki~ for Women; A Repon! of the Swpon 6hemL
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   1980,359 pp.

($7') WINGERD, J., CHRISTIANSON, R, LOVITT, W.V., SCHOEN, K.J. Placental
   ratio in white and black women: Relation to smoking and anemia American
  Journal of Obstetrics and Gyneedogy M(7): 671-675, April 1,1976.

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Section 7. BEHAVIORAL ASPECTS


CONTENTS

Research Priorities

Controlled Studies To Determine the Role of Nicotine
as a Primary Reinforcer in Cigarette Smoking
  Animal Models of Nicotine Use
   The Self-Administration of Nicotine by Animals
   The Study of Tolerance and Physical
    Dependence

  Nicotine Research With Humans
Compensatory Behavior in Smoking
  Voluntary Switching
  Controlled Switching
   Additional Comments
Natural History of Smoking Along Both Biological and
Psychosocial Dimensions

Recommendations
Clinical Testing Facilities and Standardized Research
  Cigarettes

  Clinical Testing Facilities
  Research Cigarettes
Machine-Smoked Yields of Lower "Tar" and Nicotine
Cigarettes

Toxicology of Nicotine

Summary

References

175


This section outlines the futuw ,;lirections that research on lower
"tar" and nicotine cigarettes should take. These are: (1) to perform
additional laboratory studies under controlled experimental conditions;
(2) to conduct additional research on compensatory smoking; and (3) to
investigate both the biological and psychological factors involved in
smoking.

Research Prlorities

Controlled Studies To Determine the Role of Nicotine as a
Primary Reinforcer in Cigarette Smoking

Many important questions on the pharmacological importance of
nicotine in maintaining cigarette smoking remain unanswered, despite
a large number of studies on the topic (I, 2, 19,25, 36, 44, 46, 49, 65, 69,
73).

Nicotine is probably the primary source of the pharmacodynamic
appeal of tobacco, but not enough is known about its exact role in
smoking to determine whether it is the only source. (For reviews on
nicotine and smoking, see 18,21,31,57, 61.)

Tobacco without nicotine appears not to be sufficiently reinforcing
to support sustained use (18). There has never been an appropriately
designed study with a large number of subjects randomly assigned to
smoke flavor-balanced cigarettes of varying nicotine content over a
substantial (months) time period. The behavioral aspects of cigarette
smoking are of paramount importance in the evaluation of less
hazardous cigarettes. Behavior is the interface between cigarette
smoking, its pharmacological and physiological effects, and the
generation of disease. Compensation for nominally reduced machine-
measured `Yar" and nicotine yields of cigarettes by increased depth
and volume of inhalation as well as proportion of the burning cigarette
consumed has been demonstrated. Such a study would be necessary to
conclusively support this hypothesis of cigarette habituation.

Instead, we can only look at the distribution of smoking by nicotine
yield and the experimental literature. In 19'79, the percentage of
current regular smokers in the United States who smoked cigarettes
low in nicotine content (less than 0.5 mg nicotine and less than 5 mg
"tar") was very small, about 4 percent. Research studies using tobacco
cigarettes virtually free of nicotine show these to be rated as aversive
by smokers (36, 64). At the same time, it has been difficult to
demonstrate that smokers will use nicotine in a nontobacco medium. In
one study, lettuce leaf cigarettes injected with nicotine were smoked
for l-week periods at intake levels only approximately 50 percent the
rate of the subject's own brand, and with protest of much reduced
satisfaction (13). Considered a more direct route of administration,
injections of nicotine became a satisfying replacement for cigarettes

177


after repeated trials, but this early study was not conducted in a
"blind" fashion (38).

More recent studies of intravenously administered nicotine have
contained subjective reports of perceived pleasure (39), but also have
included reports of an inability to suppress subsequent smoking to a
major extent (39, 46, 49). Although the results were perceived as only
mildly pleasurable, nicotine administered in oral tablet form (85) or
embedded in chewing gum (44, 64) has decreased various measures of
smoking in individuals not trying to quit.

The major problem with giving nicotine in other than inhaled form is
that it lacks some of the biological as well as many of the behavioral
similarities to smoking. The nicotine bolus, when inhaled, reaches the
central nervous system in less than 8 seconds (58).

More information is needed to understand the pharmacological,
psychological, and situational cofactors that may contribute to the
reinforcing effects of nicotine. By analyzing the mechanisms whereby
nicotine reinforces smoking behavior, it may be possible to design more
efficacious treatments for cigarette dependence or to devise techniques
for maximizing the rewards of smoking while minimizing the risks to
health.

Animal Moo?els of Nicotine Use

Animal models have several advantages over human models in
studying the effects of nicotine. In the animal laboratory, environmen-
tal variables can be controlled to a much greater extent than they can
in the human laboratory. History of exposure to the drug can be
manipulated in a true experimental fashion. One of the greatest
limitations of much epidemiological and behavioral research on human
smoking behavior is that the subjects are self-selected. Consequently,
the research is inherently correlational rather than experimental.
Correlational research can describe associations between variables, but
it is often confounded by unmeasured variables (30).

Animal models have been used to study the dependence liability and
toxicity of many drugs (17, 75). The techniques used in analyzing
responses to other drugs should be developed further and applied to the
study of nicotine-and perhaps other substances in tobacco.

Methods of administration can have a large effect on the pharmaco-
kinetics of nicotine. Oral, intravenous, and inhalation modes of
administration should be employed, but since smokers receive nicotine
from inhaled smoke, the inhalation route is particularly important.
Unfortunately, animals do not inhale nebulized nicotine or cigarette
smoke in ways that are comparable to human inhalation patterns (53).
Until reliable inhalation methods for animals are perfected, intrave-
nous administration will have to be used in much of this research.

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The Self-Administration of Nicotine by Animals

Since people take nicotine on their own, an ideal animal model would
be one in which animals take nicotine on their own. Attempts to get
animals to administer nicotine to themselves have not been uniformly
successful (17, 21). Maintained self-administration has been found in
the monkey and the rat in some studies (6,22,47,50), but not in others
(82). Recent work has shown that under some schedules of reinforce-
ment, monkeys will self-administer injections of nicotine (12). In order
to discover precisely what variables are critical to the reinforcing
properties of nicotine, further studies are needed.

In addition to studying the parameters of self-administration,
toxicity should also be measured. For example, it is important to look
at the variables of physical dependenq food and water intake, and
morbidity, as well as necropsy findings.

The Study of Tolerance and Physical Dependence

Both tolerance and physical dependence can develop to nicotine or
other ingredients in tobacco (33, 48, 71, 78). Animal models have been
used successfully in research on opioids and alcohol (70) and could
prove effective in future research on nicotine and smoking.

Appropriate animal models would facilitate the study of the
pharmacokinetics of nicotine and would help in the evaluation of
pharmacological treatments for dependence. Since tolerance and
physical dependence can influence the reinforcing properties of drugs
of abuse, animal studies should investigate the extent to which
withdrawal phenomena may contribute to the reinforcing properties of
cigarette smoke. Methods developed for evaluation of opioid drugs
could be adopted for these purposes.

Nicotine Research With Humans

The scientific issues in human and animal research are similar,
although not all studies conducted on animals are practically and
ethically suitable for research on humans. A great amount of
preliminary data already exists on the role of nicotine in human
smoking behavior (see the reviews cited above), but the influence of
tolerance and dependence on nicotine on the initiation, maintenance,
and cessation of smoking behavior are still not resolved (27, 46, 59, 61,
68). Clearly, both biological and psychosocial factors influence human
cigarette intake (41), and it is in the human model of cigarette smoking
that the interplay of these factors can best be studied. There is no
known analog in animal behavior for future orientation and cognitive
factors, such as worrying about the risks of cancer or about weight
gain upon giving up smoking.

Progress to date in laboratory studies of smoking dependence has
been slowed by the lack of standardized test materials, such as

179


cigarettes made to research specifications, and of standardized, easily
accessible laboratory analyses, such as for plasma levels of nicotine.

Compensatory Behavior in Smoking

If, in the course of a standard assay for the "tar" and nicotine yields
of a cigarette (54, a smoking-machine derives relatively small amounts
of "tar" and nicotine, the cigarette can be called lower "tar" and
nicotine. Unfortunately the smoking-machine model is limited in
accurately reproducing human smoking behavior. The machines take a
2 second, 35 cc puff each minute until a predetermined butt length is
reached. Smokers, however, are able to take larger, more frequent, and
higher velocity puffs than the machines do. It appears that such
compensatory adjustments often turn nominally lower "tar" and
nicotine cigarettes into higher "tar" and nicotine cigarettes (1,4,9,%,
36, 46, 60, 62). Even if the compensations made in smoking a single
cigarette are small or nonexistent, smokers can increase their intake of
"tar" and nicotine by smoking more cigarettes (66).

Cigarettes of less than about 6 mg "tar" and 0.5 mg nicotine are also
subject to the influences of compensatory smoking. Most of these
cigarettes achieve their lower yields as a result of ventilation holes
placed in the filters, which cause each puff of smoke to be diluted with
air. These air-diluted puffs deliver relatively small amounts of "tar,"
nicotine, and carbon monoxide to the smoking-machines (29). Some.
smokers have learned to block the ventilation holes with their lips or
fingers-or sometimes with tape-and thereby, often unwittingly,
defeat the purpose of the holes. If the ventilation holes are blocked,
yields of nicotine, "tar," and carbon monoxide can increase by about
two, three, and four times, respectively (4.2). In 1979, ventilated-filter
cigarettes accounted for about 25 percent of total cigarette sales (29).

Many studies have used estimates of nicotine and smoke intake
based on direct observations (44), measurements of smoking topogra-
phy by means of special cigarette holders (24, 36), or analyses of
residual nicotine in cigarette filters (1, 9, 55). Only a few studies have
measured the levels of nicotine in plasma as a function of the nominal
smoking-machine yields (1, 63), but research indicates that some
smokers do compensate for reduced yields of nicotine.

By smoking more to compensate for lower nicotine intake, lower
"tar" and nicotine cigarette smokers can inadvertently increase their
exposure to "tar" and carbon monoxide beyond what might be
expected from a less intensively smoked higher "tar" and nicotine
cigarette (57, 67). Because less hazardous cigarettes may require the
delivery of moderate levels of nicotine while delivering lower levels of
"tar" and carbon monoxide, Russell (57) has proposed that lower "tar"
to nicotine ratios should be used to indicate less hazardous cigarettes.
These ratios may direct smokers to potentially less hazardous ciga-
rettes, but the way in which a cigarette is smoked can affect the ratio

180


examination of the advisability of encouraging people to switch to
milder cigarettes should be undertaken, (See Russell (60) for a brief
discussion of the possible role of self-selection biases in the epidemi+
logical finding that filter-tipped cigarettes are less hazardous (3, 81).
See Harris (23) for a summary discussion of behavioral and economic
factors affecting the promotion of lower "tar" and nicotine cigarettes.)

Controlled Switching

Very few studies on controlled switching have employed measures of
plasma nicotine (1, 28, 60). No large-scale studies have been conducted
that make use of plasma nicotine, carbon monoxide, and physiological
measures of smoke exposure.

The relationship between smoker satisfaction and compensatory
smoking appears to be complex. One forced switching study (74) has
shown that, even though the compensation was incomplete and did not
change for the few days of the study, satisfaction did improve during
the course of the experiment. We do not know if satisfaction with
lower "tar" and nicotine cigarettes increases with duration of their use,
if it decreases with time if compensation occurs initially, or if nicotine
yield alone determines cigarette acceptability.

Additional Comments

As noted earlier, progress in compensatory smoking research has
been hindered by the lack of research cigarettes varying systematically
in nicotine, "tar," and carbon monoxide, and by the shortage of
laboratory facilities in which to do needed analyses.

One byproduct of the proposed research on switching to lower "tar"
and nicotine cigarettes might be the development of practical diagnos-
tic techniques. Smokers and physicians have not determined whether
lower "tar" and nicotine cigarettes have produced "low-yield" smok-
ing, but simple measures such as expired air carbon monoxide (11, 26)
might help supply needed information concerning smoke exposure.

Natural History of Smoking Along Both Biological and
Psychosocial Dimensions

Since almost nothing is known about the role of lower "tar" and
nicotine cigarettes at crucial transition points in a smoker's history,
this issue cannot be considered in detail (7, 20, 40, 52, 56). One key
unanswered question is whether lower "tar" and nicotine cigarettes
tend to facilitate taking up the smoking habit. Presumably, initiation
of smoking is easier for those who first try lower "tar" and nicotine
cigarettes than for those who first try regular cigarettes. Thus, lower
"tar" and nicotine cigarettes can reduce aversive physical responses to
early smoking episodes that might otherwise deter taking up the habit
(44 56).

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Teenagers generally prefer moderately high-yield cigarettes (77),
but 2.5 percent of the boys and 12.3 percent of the girls who smoke use
lower "tar" and nicotine brands (here defined as 5 10 mg "tar").
Research has not addressed the question of what percentage of these
smokers may have been helped either in their initiation to smoking or
in their shift from casual to habitual smoking by the use of lower "tar"
and nicotine cigarettes. The incidence of smoking among teenage girls
has increased during the past 10 years (76, 77). Silverstein et al. (72)
present data supporting the hypothesis that the increasing availability
of lower "tar" and nicotine cigarettes has encouraged this increase in
smoking. Analysis of a survey of high school students suggests that
girls experience greater social pressure to smoke than do boys, and that
they also face greater physiological pressure not to smoke because of
their higher sensitivity to nicotine. Girls appear to resolve these
pressures by becoming lighter smokers than boys and by switching to
lower "tar" and nicotine cigarettes. Perhaps if lower "tar" and nicotine
cigarettes were less available, some girls would choose not to smoke
rather than to experience unpleasant nicotine reactions.

Most research on the initiation of smoking and casual smoking has
been psychosocial. No doubt there are practical, if not ethical,
constraints on studying biological influences on smoking among
teenagers. Whatever the reason, very little is known, for example,
about the role of nicotine in early smoking experiences. No one knows
how much exposure (days, months, years) to smoking is needed before
withdrawal symptoms appear. More balance is needed in research on
teenage smoking. Whenever possible, biological factors-both physic
logical and pharmacological-should be studied along with psychoso-
cial factors (27,41).

There has been little research on the effects of lower "tar" and
nicotine cigarettes on maintenance or cessation of smoking. There are
studies on the effects of using decreasing amounts of "tar" and
nicotine as a cessation or reduction aid (lo), but these studies do not
include biochemical or physiological measures of change in smoke
exposure. It seems plausible that the alternative of a supposedly less-
hazardous cigarette might make some smokers less likely to try to
abstain completely. By the same token, the example of a satisfied,
though perhaps fully compensating, smoker of lower "tar" and nicotine
cigarettes might make a former smoker more likely to relapse. The
former smoker might view the lower "tar" and nicotine cigarettes as
both acceptable and safe (14,15). Answers to these questions can have
immediate implications for smoking treatment. Research in this area
should include such crucial variables as gender (72). Both experimental
and epidemiological data are needed in these studies. Perhaps large-
scale smoking surveys can be expanded to include more questions that
would help characterize the natural histories of smokers.

183


Recommendations

Clinical Testing Facilities and Standardized Research Cigarettes

There has been an active research effort in this country on the
behavioral aspects of smoking. To further its productivity and to refine
the scientific questions that this research can address, especially with
regard to lower "tar" and nicotine cigarettes, the facilities and
research cigarettes described here are needed.

CZinical Testing Facilities

These facilities should be able to provide biochemical and pharmaco-
logical analyses of assays for plasma nicotine, cotinine, carboxyhemo
globin, and salivary thiocyanate. (Jarvik (34) reviews the use of these
assays.) Each of these assays can be used to measure a smoker's
exposure to some of the toxic and/or reinforcing ingredients in tobacco
smoke. Plasma assays for nicotine (8) are available in a few laborato-
ries; these assays can require special facilities to avoid problems of
contamination. For example, a laboratory that is used part of the time
by a worker who smokes may be unacceptable for the evaluation of
plasma nicotine levels. Few behavioral researchers have access to or
sufficient control over the needed laboratory facilities. Laboratories of
this nature would be a great boon to behavioral research and would
help to standardize assays in this area.

Research Cigarettes

A supply of clinically acceptable cigarettes that vary in nicotine,
"tar," and carbon monoxide yield should be made available to
behavioral researchers. Although some standardized cigarettes have
been available for years from the Tobacco and Health Research
Institute of the University of Kentucky, these cigarettes have no
filters, and their lack of palatability and acceptability almost complete-
ly precludes their use in behavioral research. Cigarette technology has
several ways of altering "tar," nicotine, and carbon monoxide yields.
Ideally, different strategies would be employed to produce cigarettes
with identical machine-smoked yields. Consider two examples. A fast-
burning, strong-tobacco cigarette might have the same yields as a
slow-burning, mild-tobacco cigarette, but it is not clear how human
smoking behavior might change as a function of these modes of yield
reduction. A cigarette low in carbon monoxide could be made with
either vented cigarette paper or a vented filter. The vented filter can
be closed by smokers accidentally or intentionally, thereby increasing
the actual yield to the smoker (42), but the effect of porous cigarette
papers cannot readily be circumvented by the smoker.

Variations in "tar" to nicotine ratios should be of special concern
(57). It is important to determine the lowest ratios that still produce a
satisfying cigarette. Obviously, identical "tar" and nicotine ratios can

184


occur in cigarettes that have very different standard nicotine yields.
Research could show if there is an optimum combination of standard
yield and ratio that leads to maximum satisfaction and minimal
exposure to toxic products. Cigarettes that, vary systematically in "tar"
to nicotine ratios are needed for this research.

Machine-Smoked Yields of Lower "Tar" and Nicotine Cigarettes

The standard smoking-machine assay of "tar" and nicotine yields
provides inadequate information to the tobacco consumer as well as to
the researcher (16, 4.5, 74). The published yields do not indicate how
many puffs were taken on a particular brand (4.5); assays at the Oak
Ridge National Laboratory (37) reveal that from 6.9 to 11.5 puffs are
taken on different brands of king-size filter cigarettes during standard
assays.

The current smoking-machine standards are meant to represent an
average smoker, but it is probable that the standard puff volume (35
cc) is too small (5,51) and that the puff interval (one puff per minute)
is too long (4, 74). Since compensatory smoking occurs with lower "tar"
and nicotine cigarettes, larger and more frequent puffs tend to be
taken. Smokers sometimes interfere with ventilation holes on lower
"tar" and nicotine cigarettes (45); smoking-machines do not.

In addition to the standard assays, there should be maximum-yield
assays of "tar," nicotine, and carbon monoxide. These assays would be
based on puffing parameters of volume, rate, and duration for the
95th-or even the `75th-percentile of heavy smokers smoking lower
"tar" and nicotine ventilated cigarettes up to the tip overwrap. These
parameters would be used in smoking-machines, with these same
ventilated brands, to derive yields with ventilation holes in both
blocked and unblocked conditions. This procedure would produce much
higher yields than does the standard assay, and these values would
better represent the possible maximum risks of the lower "tar" and
nicotine cigarettes to smokers who engage in compensatory smoking.
Without access to information about how much the standard yields can
change with intensive smoking, there can be only a limited understand-
ing of possible reductions in actual smoking exposure. Using research
in the British-American Tobacco Company Laboratories in the United
Kingdom, Green (16) has argued that intensive smoking can make
middle "tar" cigarettes (11 to 16 mg) deliver as much as high "tar"
cigarettes (31 to 35 mg). Green could not demonstrate that low "tar"
cigarettes (0.4 to 9 mg) can be made to deliver high "tar" levels, but
this study did not consider the effect of blocking the ventilation holes
on these cigarettes.

Toxicology of Nicotine

A probable outcome of behavioral research will be that nicotine is
the primary pharmacological reinforcer for cigarette smoking. If this

185


prediction is correct, a lower "tar" and nicotine cigarette that will be
used by smokers and that will minimize the exposure to other toxic
components of smoke may require substantial yields of nicotine (57,
62). Consideration of the toxicity of nicotine, then, may become crucial
in determining whether the benefits of lower "tar" and nicotine
cigarette smoking outweigh the costs.

Summary

1. Nicotine appears to be the primary pharmacological reinforcer in
tobacco, but other pharmacological and psychosocial factors may
also contribute a reinforcing effect.
2. It appears that some smokers make compensatory adjustments in
their smoking behavior with cigarettes of different yields that
might increase the amounts of harmful substances entering the
body. The frequency and amount of spontaneous compensatory
changes in smoking style with different cigarettes require further
investigation.

3. Additional information is needed on the role of lower "tar" and
nicotine cigarettes in the initiation, maintenance, and cessation of
smoking.

4. Rigorous comparative behavioral studies involving animals are
needed to provide comprehensive, experimentally valid results on
behavioral aspects of smoking.

5. Laboratory techniques developed for study of opioids and alcohol
should be adapted for studies of tolerance and dependence on
nicotine.

6. Improved laboratory facilities are necessary for more tightly
controlled behavioral research. A particular need exists for
clinically acceptable cigarettes with standardized ingredients.
`7. Smoking-machine measurements that more closely simulate the
practices of human smokers must be developed.

186


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192


Section 8. LOWER "TAR" AND
      NICOTINE CIGARETTES:
      PRODUCT CHOICE AND
       USE


Introduction

The Growth in the Use of Lower "Tar" and Nicotine
Cigarettes

An Increasing Public Awareness of the Health
Hazards of Cigarette Smoking
Public Attitudes
The Cigarette Profile

Cigarette Choice and Smoking Behavior
  Overview
Relationship of "Tar" and Nicotine Yields to Smoking
   Behavior

Consumption Patterns
Cessation

Summary

Addendum: Comparison of "Tar" and Nicotine Yields of
Cigarettes in 19'78 and 1979
  Yields of "Tar" and Nicotine
  Correlation of Varieties Reported in 1978 and 1979
  "Tar" and Nicotine Yields of New Brands in 19'79
Applications to the Discussion

References

LIST OF FIGURES

Figure l--Market share of dollars expended in the U.S.
on advertising and promotion of cigarettes yielding 115
mg "tar" compared with total domestic cigarette
advertising and promotional expenditures for years 1970,
1975, 1976, 1977, and 1978

195


Figure 2.-Domestic market share of cigarettes yielding
515 mg "tar," 1967-1978

Figure 3.-Sales-weighted averages of "tar" and nicotine
per cigarette consumed in the U.S., 195419'75

Figure 4.-Sales-weighted averages of "tar" and nicotine
per cigarette consumed in the U.S., 1968-1978

Figure 5.-Ratio of "tar" to nicotine based on sales-
weighted averages of cigarettes consumed in the U.S.,
1968-1978

Figure 6.-Delivery of nicotine as a function of "tar" of
commercial cigarettes, U.S.

Figure `I.-Delivery of carbon monoxide as a function of
"tar" of selected U.S. commercial cigarettes

Figure K-Index of average "tar" and tobacco per
cigarette, annually, 1967-1979

Figure 9.-Annual per capita consumption of total
cigarettes and filter-tipped cigarettes in the U.S., for
persons aged 18 and older, 1900-1979

Figure lO.-Annual per capita consumption of tobacco
products in the U.S. (including overseas forces) for
persons aged 18 and older, 1925-1979

Figure Il.-Annual per capita consumption of cigarettes in
the U.S. (including overseas forces) for persons aged 18
and older, 1963-1978

LIST OF TABLES

Table l.-Estimated percentage distribution of current
regular smokers by "tar" yield of primary brand of
cigarette, by sex, race, age, and education, adults, U.S.,
1979

1%


Table 2.-Mean daily dose of "tar" or nicotine for current
regular smokers by race, sex, and age, U.S., 1979

Table 3.-Estimated percentage distribution of current
regular smokers by "tar" and nicotine yield of primary
cigarette used, U.S., 1978 and 1979

Table 4.-Estimated percentage distribution of regular
smokers by "tar" yield, adolescents aged 12-18, U.S.,
1974 and 1979

Table L-Percent distribution of adolescent regular
smokers by "tar" yield of primary brand, by sex and
age, U.S., 1979

Table 6.-Mean age at onset of regular smoking by "tar"
or nicotine yield of primary brand, by age at interview,
current regular smokers, U.S., 1979

Table `I.-Estimated percentage distribution of current
regular smokers by number of cigarettes smoked daily
by approximate quintiles of "tar" or nicotine yield,
adults, U.S., 1979

Table &-Mean number of cigarettes smoked daily by
"tar" or nicotine yield, by age groups, current regular
smokers, adults, U.S., 1979

Table 9.-Estimated percent of current regular smokers
who have tried seriously at least once to quit, by "tar"
or nicotine level and age, U.S., 1979

Table lO.-Estimated percentage distribution of recent
smokers by status of recent attempt to quit, by "tar" or
nicotine yield of primary brand, July 1978 through
December 1979

Table Il.-Estimated percentage distribution of current
regular smokers by number of serious attempts to quit
smoking, by "tar" or nicotine level, U.S., 1979

Table 12.-Mean duration of most recent attempt to quit,
by "tar" or nicotine yield of current primary brand,
current regular smokers, 1979

197


Table 13.-Mean yield of "tar" and nicotine of cigarettes,
by type of modifier, all and filter-tip varieties, U.S., 1978
and 1979

Table 14.-Mean yield of "tar" and nicotine of the
varieties of cigarette marketed in both 1978 and 1979,
by type of modifier, all and filtertip varieties, U.S.

Table 15.-Comparison of "tar" and nicotine yield on the
varieties of cigarette marketed in both 1978 and 1979,
U.S.

Table 16.-Mean yield of "tar', and nicotine of the new
varieties of cigarette marketed in 1979, by type of
modifier, U.S.

Table 17.-Distribution of "tar" and nicotine yield of the
new varieties of cigarette marketed in 1979, U.S.

198


Introduction

This section discusses changes in cigarette smoking over recent years
in the United States. Currently available evidence indicates that, while
the prevalence of cigarette smoking is at its lowest point in several
decades among both adults and adolescents, there are significant
differences in the cigarettes being used by those persons who do
smoke.

The discussion does not attempt to describe comprehensively the
patterns of cigarette smoking; such reviews have been published
previously (25, 26). Rather, it focuses on the information that describes
the cigarette products currently being used by smokers and the role
that such modified products may play in the smoking habit. It includes
examination of (1) the growth of the lower "tar" and nicotine
cigarette, including social and marketplace activity in recent years,
and (2) cigarette product choice and use by the smoking population.

This consideration of changes in the cigarette is restricted to that of
"tar" and nicotine yields of various cigarette brands, because of the
availability of systematic measures of these constituents through the
annual reports of the Federal Trade Commission (FTC). Note should be
taken, however, that the extensive discussion of "tar" yields in this
Report ought not to be construed as implying a primary or singular
role of "tar" in causation of all the adverse health effects associated
with cigarette smoking. Rather, "tar" yields are used because they are
readily available and correlate closely to nicotine levels. No comparable
measurements are available for carbon monoxide or other constituents
of cigarette smoke, such as acrolein, hydrogen cyanide, or the nitrogen
oxides, which are identified as probable contributors to smoking-
related disease. Further, there are no systematic data available
regarding the effects of commercially used cigarette additives on the
yields of any of these constituents.

Although the data cited here are derived from multiple sources,
much of it represents the first analysis of a large, ongoing national
survey. At the request of the Office on Smoking and Health, a smoking
supplement was added to the continuing National Health Interview
Survey (NHIS) by the National Center for Health Statistics. Begun in
July 1978 and continued through 1979, the smoking supplement was
designed to provide data on the prevalence of smoking, amount
smoked, and attempts to quit smoking. Representing a random one-
third subsample of the NHIS interviews of noninstitutionalized
persons aged 17 or older, the M-month data included approximately
36,000 individuals interviewed. Unless otherwise indicated, the data
cited represent analysis of the approximately 24,000 interviews on
smoking conducted during calendar year 1979. Lifetime smoking status
(i.e., never, regular, occasional, and former smoker), age at onset,
brand choice, amount smoked, and data on the attempt(s) to quit were
collected for recent and current smokers. The "tar" and nicotine yields

199


for the 1978 and 1979 NHIS data sets are based on the FTC listing of
cigarette varieties, sampled in 1977 and published in May 1978, and
updated to include cigarettes identified by the FTC as marketed in
July 1978.

Three major conclusions can be elicited. First, Government and other
agency activities in recent decades have led to widespread public
recognition of the health hazards of smoking cigarettes. tind, the
marked increase in the use of filter-tipped cigarettes in the late 1950s
has been followed by a reduction in the "tar" and nicotine content of
the cigarette products actually being selected and used by the smoking
population. Third, the role of cigarettes of varying levels of "tar" and
nicotine in the initiation, maintenance, or cessation of smoking is
unknown. The data from the National Center for Health Statistics
presented here neither prove nor disprove a role of lower "tar" and
nicotine cigarettes in easing initiation, increasing daily consumption
among regular smokers, or decreasing the probability of attempting to
quit or of succeeding in the attempt. Much further work remains to be
done to clarify and define the effects of lower "tar" and nicotine
cigarettes on these behaviors, and thus their effect on total lifetime
patterns of cigarette smoke exposure.

The Growth in the Use of Lower "Tar" and Nicotine Cigarettes
An Increasing Public Awareness of the Health Hazards of
Cigarette Smoking

The decades since the first medical reports of a link between lung
cancer and smoking in the 1950s have seen multiple changes in the
cigarette products being used by the smoking population (11,14,15,16,
25). A number of factors may have encouraged these changes.
The U.S. Public Health Service (PHS) has been active in assessing
and attempting to reduce the excess burden of preventable illness
related to cigarette smoking. Its first comprehensive review of the
evidence linking cigarette smoking and adverse health effects by the
Advisory Committee to the Surgeon General of the Public Health
Service in 1964 was followed by regularly issued reports from 1966
through 1980, each of which continued and extended the PHS concern.
In 1966, the PHS submitted to Congress (42) the Technical &pm-t on
"Tar" and Nicotine. On the basis of the clear demonstration of
cigarette dose-dependent risks of several diseases, the PHS concluded:

The preponderance of scientific evidence strongly suggests that the
lower the "tar" and nicotine content of cigarette smoke, the less
harmful would be the effect.

We recommend . . . the progressive reduction of the "tar" and
nicotine content of cigarette smoke.


At the same time, Secretary of Health, Education, and Welfare John
W. Gardner urged the Congress to require "tar" and nicotine levels on
packages and advertisements, with provision for adding to the label
any ingredients subsequently identified as hazardous (4.2).
The PHS then began transmitting this information to the public.
The PHS policy formulated on the evidence available was that there is
no safe cigarette; the single best way to avoid the health hazards of
smoking is to quit smoking, but for those unable to quit, a lower "tar"
and nicotine cigarette would probably pose lower risks.
In 1972, the PHS classified some of the known chemical constituents
of cigarette smoke into different risk categories. The compounds
classified as "most likely" contributors to health hazards-"tar,"
nicotine, and carbon monoxide-were recommended as primary targets
for reduction (3.4).
In 1974 and again in 1975, Secretary of Health, Education, and
Welfare Caspar W. Weinberger formally requested legislation author-
izing the regulation of cigarettes by formulation of maximum
permissible levels of hazardous ingredients (38, 39).
During this time, a number of health professional societies, volun-
tary health agencies, and concerned citizens' groups also conducted
public education activities on the health hazards of cigarette smoking.
The cigarette industry's activities during this period probably also
influenced changes in cigarette choice. In 1952 only 1.4 percent of
cigarettes sold in the United States were filter tipped; by 1956, 29.9
percent of all cigarettes were filtered (27). In 1979, filtered cigarettes
represented 89.2 percent of all brands marketed (24), and were used by
91.7 percent of regular smokers, according to data from the 1979
Smoking Supplement of the National Health Interview Survey.
Advertising probably contributed to this rapid growth of filter-tipped
cigarettes. As early as 1954, one brand's advertising slogan read, " . . ,
filter gives greater protection against nicotine and tars than any other
cigarette on the market today. It is the greatest health protection in
cigarette history" (27). Another brand advertised the "Miracle of the
Modern Miracle Tip" (even while the "tar" yield of that product
increased 40 percent and the nicotine increased 70 percent over the 2-
year period after the filter had been introduced) (27).
During the last decade, when systematic data on "tar" and nicotine
yields of marketed cigarettes have been available, lower "tar" brands
have been marketed in increasing proportions. Federal Trade Commis-
sion data show that cigarettes yielding 15 mg or less of "tar"
constituted 15 percent of all brands in 1968, 20.4 percent in 1972, 30
percent in 1976, and 58.5 percent in 1979 (1,2,3,5). Over the same time
period, the proportion of all marketed brands that yielded 10 mg or less
of "tar" increased from 4.7 percent in 1968, 9.9 percent in 1972, 124
percent in 1976, to 33.0 percent in 1979.


L
    10.5%~

    1970

L
      ,5:
    19.9%

    1975

-

1

FIGURE L-Market share of dollars expended in the U.S. on
advertising and promotion of cigarettes yielding 115 mg Yar"
compared with total domestic cigarette advertising and
promotional expenditures for years 1970, 1975, 1976, 1977, and
1978

NOTE: Percentagw (ahaded area) refer to percent of each individd bar.
SOURCE: Derived from Federal Trade Gmmimion (6).

Further, the marked increase in the last 5 years in the proportion of
all cigarette sales accounted for by brands yielding 2 15 mg `Yar"
coincides with an increased percentage of total dollars spent for
advertising and promotion of cigarettes yielding 15 mg or less of "tar"
per cigarette. Figure 1 shows this increasing promotional effort. Since
1970, the absolute amount as well as the percent of all advertising
dollars spent that went to advertising of "low tar" cigarettes has
increased from approximately $37,900,000, or 10.5 percent, in 1970 to
$421,300,000, or 48.1 percent, in 1978 (4). This increase occurred over
the same period as the greatest increase in the lower "tar" brands'
proportion of market sales.

Public Attitudes
Several surveys have examined the opinions of the general public
about cigarette smoking.

202


Public surveys conducted by the National Clearinghouse on Smoking
and Health examined the beliefs and attitudes of the U.S. public
relative to cigarette smoking (28, 29, 36, 39, 41). These surveys
indicated that the belief that cigarette smoking poses health hazards
was increasing, not only among the general public but also among
persons who continued to smoke. For example, in response to the
statement "Smoking cigarettes is harmful to health," in 1964, 81.3
percent of the persons interviewed agreed and 13.1 disagreed, but in
1975, 84.9 percent agreed and 11.3 percent disagreed, with intermedi-
ate figures occurring in 1970 (29, 35,39). Substantial differences were
apparent when smoking history was considered. In 1964, former
smokers believed smoking to be harmful in 99.5 percent of interviews,
while only 69.5 percent of the current smokers believed smoking
harmful; only 7.4 percent of former smokers did not agree that
smoking is harmful, but 21.9 percent of smokers did not agree (29).
This difference by smoking status in the percentage of interview
subjects who believed smoking to be harmful persisted in 1975, but the
difference narrowed (78 percent of current smokers agreed and 91.6
percent of former smokers agreed) (39). Very similar results were
reported in a large survey in 1978, which found that 90 percent of all
persons and 83 percent of smokers believed smoking to be harmful to
health (7).
The percentage of smokers who agreed that "cigarette smoking
frequently causes disease and death" increased from 52.2 percent in
1966 to 70.7 percent in 1975; the proportion of smokers who disagreed
declined from 37.6 percent in 1966 to 22.3 percent in 1975. The
percentage of the total population who had no opinion on this question
and the preceding question declined from 9.1 percent to 5.3 percent and
from 4.7 percent to 3.4 percent, respectively. This suggests that
educational efforts may have reduced the size of the "undecided"
population.
Other questions assessed the personal impact of beliefs about the
health hazards of cigarette smoking. Although the percentage of
smokers who reported being "slightly" concerned about the possible
effects of smoking on their own health remained fairly constant from
1966 (18.1 percent) to 1975 (18.9 percent), the proportion of smokers
who were "fairly" or "very" concerned increased from 29.1 percent in
1966 to 47.6 percent in 1975. The number of smokers "not concerned"
declined from 52.5 percent in 1966 to 31.5 percent in 1975.
For the entire population, the proportion of interviewees who agreed
that "smoking (is) enough of a hazard for something to be done about
it" increased from 76.3 percent in 1966 to 84.0 percent in 1975.
Additionally, one question asked of current smokers in 1966, 1970,
and 1975 provides information on smokers' perceptions of varying
hazards by cigarette type (29, 36,40). The number of smokers who felt
that "all cigarettes (are) probably equally hazardous" declined from


57.8 percent in 1966 to 40.6 percent in 1975, while the number of
smokers who believed that "some cigarettes (are) more hazardous than
others" increased from 29.9 percent in 1966 to 49.1 percent in 1975.
Among smokers who believed there was a difference among cigarette
brands in health hazard, current smokers who believed their own
cigarette brand was less hazarti' than other kinds declined from 59.9
percent in 1966 to 49.7 percent in 1975, and smokers who believed their
cigarette brand was more hazardous increased from 12.6 percent to
20.4 percent. Thus in the period from 1966 to 1975, there was an
increasing proportion of smokers who believed different cigarettes
posed varying health risks, but among these smokers the proportion
who felt their cigarette was more dangerous to health than other
cigarettes also increased. Unfortunately, identical large surveys to
assess subsequent trends either in smokers' beliefs about differences in
health risks or about the role of such beliefs in affecting cigarette
product choice have not been published since 1975.

The Tobacco Institute, which represents the cigarette manufactur-
ers, has also supported periodic surveys of attitudes. Their most recent
survey is publicly available. Conducted in 1978 (18), this survey found
that more than 90 percent of the U.S. population believed cigarette
smoking is hazardous to the health of the smoker. Fully 61 percent
believed that any amount of smoking is hazardous, up from 47 percent
in 1970. This is in close agreement with surveys performed by the PHS
in 1970. Further, in 1970 and 1978, 42 percent and 50 percent,
respectively, of the population c,urveyed believed that smoking "makes
a great deal of difference in longevity," a higher percentage than those
believing the same thing about fatty diets (43 percent), alcohol
consumption (39 percent), lack of exercise (34 percent), and overweight
(24 percent).

The proportion of all persons who believe smokers "have" or
"probably have" more of "certain illnesses" has increased from 56
percent in 1970 to 62 percent in 1978, when only 11 percent believed
that smokers do not suffer more illness. Only 3 percent of people
surveyed did not believe that cigarette smoking is a cause of disease, a
figure that has not changed appreciably since 1970.

The 1978 Roper Survey found that the proportion of the population
who believed others' smoking is hazardous to the nonsmoker's health
had increased from 46 percent in 1974 to 58 percent in 1978. In 1978,
the number who believed passive or involuntary smoking to be harmful
was 69 percent among nonsmokers; while among smokers it was 40
percent. For the first time, the health effect of involuntary smoking
was cited most frequently as a reason for legislation to ban cigarette
smoking in public places.

204


The Cigarette Profile
The definition of cigarettes as "lower `tar' " at 5 15 mg is arbitrary.
Nonetheless, this breakpoint has gained general acceptance. The
separation of 5 15 mg "tar" was meaningful when the vast majority of
cigarettes were of higher "tar" yields; now, however, more than half of
all the cigarettes sold in this country are at or below the level of 15 mg
"tar" per cigarette. Many of the following measures use this break-
point ( < 15 mg). Special note should be taken, however, of the fact that
both "tar" and nicotine yields vary continuously, and groupings by
relative yield measurements do not automatically imply differences
either in the type or in the magnitude of their biologic effects.
As discussed previously, the proportion of domestic commercially
marketed cigarette brands that yield 15 mg or less of "tar" has
increased over the last two decades to 58.5 percent in 1979 (1,5). These
figures, however, reflect industry marketing decisions and do not
directly measure the smoking public's selection of a cigarette product.
The market share of unit sales, however, reflects both the "tar" yield
of each brand marketed and the smoking population's actual use of
that product. Figure 2 shows the percentage of all U.S. cigarette sales
(the "market share") represented by cigarettes containing 15 mg or
less of "tar." Over the last decade the market share of sales accounted
for by lower "tar" products has increased consistently since 1971.
Cigarettes yielding <15 mg "tar" accounted for only 2 percent of the
cigarette market sales in 1967, but the comparable figure is projected
to approach 50 percent in 1980 (24). This represents an almost 23-fold
increase over 13 years. There has been a threefold increase over the
last 5 years in the proportion of all cigarettes purchased and
presumably consumed that are lower in "tar." Thus, cigarettes of 15
mg or less are not only available in the market, but they are also being
chosen by the smoking population.
A different measure of cigarette choice is the sales-weighted
average of "tar" or nicotine. The sales-weighted average is derived
from the "tar" or nicotine yield of each cigarette available in the
United States, weighted by the numbers of packages of each brand
sold annually. The sales-weighted average values for "tar" and
nicotine thus represent a hypothetical "average cigarette" smoked in
the United States. Figure 3 shows the trend over time of the sales-
weighted average cigarette's "tar" or nicotine content (43).
The yield of "tar" declined from 38 mg in 1954 to 19 mg in 1975,
while that of nicotine declined from 2.3 to 1.3 mg per cigarette. The
decline in both "tar" and nicotine approximated 50 percent over this
20-year period. Data provided from a single source of continuous
measurement as shown in Figure 4 indicate that the decline in "tar"
has continued in recent years, although at a slower rate than that
observed from 1954 to 1965. It is projected that the sales-weighted


FIGURE 2.-Domestic market share of cigarettea yielding 215
mg "tar," X467-1978
NOTE: 1919 data unavailable.

SOURCE: Derived from Federal Trade `hnmtion (6).

average "tar" and nicotine in 1980 will be less than 14 mg and 1 mg,
respectively.

Examination of the ratio of "tar" yield to nicotine yield per cigarette
is interesting in light of the hypothesis that nicotine, perhaps in
combination with organoleptic compounds, exhibits a threshold value
for acceptability to the consumer. This threshold may have been

206


rng NICOTINE

c

FIGURE 3.--Sales-weighted averages of Yar" and nicotine per
cigarette consumed in the U.S., 1954-1975
SOURCE: wakeham (46).


-1.5

-1.4

-1.3

   i
  Ls
-'.2 y
i

-1.1

-1.0
+

OlIO
    1966 1969 1970 1971 1972 1973 1974 1975 1976  1977 1976

                        YEAR

FIGURE I.-Sales-weighted averages of "tar" and nicotine per
cigarette consumed in the U.S., KHZ-1978

SOURCE: Derived from Federal Trade Commission (6).

reached (at 1.4 mg nicotine) in certain countries (e.g., England) (19). In
the United States, the sales-weighted average nicotine yield per
cigarette has continued to decline below the level of 1.4 mg (Figures 3
and 4). Figure 5 presents the "tar" to nicotine ratio of the sales-
weighted "average cigarette" annually from 1968 to 1978. The "tar" to
nicotine ratio has ranged from 16 to 14.3, with a maximum variation of
less than 10 percent of the ratio's absolute value. There has been no
systematic difference observed between the declines of "tar" and
nicotine of the average cigarette product over the last decade.

The previous discussion has focused on "tar" yields and, to a lesser
extent, on nicotine yields. The relationship between "tar" and nicotine
is a direct one, as is shown in Figure 6 (5). The correlation coefficient
for these two variables is 0.967, based on data from the Federal Trade
Commission report (5). Similarly, the correlation coefficient reported
by the Oak Ridge National Laboratory was 0.917 (12). The description


16-

  15-

P
2
z
;:

  14-

0      I    I    I    I    I    I    I     I    I     I    I
     1968   1969   1970   1971   1972   1973   1974   1975   1976   1977   1970

                             YEAR

FIGURE 5.-Ratio of **tar" to nicotine based on sales-weighted
averages of cigarettes consumed in the U.S., 1968-1978

SOURCE: Derived from Federal Trade Ccmmiehn (6).

of cigarette products by "tar" yield can thus be assumed to approxi-
mate closely the pattern that would result from a similar analysis by
nicotine yield. There appears to be a similar relationship between "tar"
and carbon monoxide yields, as Figure 7 shows. There is, however, a
systematic difference between the "tar" and carbon monoxide yields of
filtered and nonfiltered cigarettes (12). Filtered cigarettes tend to have
a higher carbon monoxide yield than do nonfiltered cigarettes of the
same "tar" yield. Nonetheless, there appears to be a strong association
between "tar" and carbon monoxide yield by cigarette variety, with a
correlation coefficient for "tar" and carbon monoxide of 0.803.

Data from the Department of Agriculture describe tobacco weight
per cigarette over time (24). Figure 8 shows tobacco weight per
cigarette in relation to "tar" yield, with both values shown as a percent
of its value in calendar year 1967. While "tar" content per cigarette
declined by 32.2 percent and nicotine declined by 25.6 percent since
1963, the weight of tobacco per cigarette declined by 23.8 percent over
the same period (24). This suggests that a significant portion of the


2.5                                            4

2.0 -                                  0  0
                               QO  0
                                  00
                                 0   0
1.5 -                     0 0 0
         &lo T ..":
                 006 0

1.0 -

0.5 -                  0 Filter cigarette brand
I 8 C$O         o Nonfilter cigarette brand

o,,,,,,,,,, ,,,(,(,, I ,,(,,,,,,,,

0        5       `IO       15       20       25       30

  "TAR"
(mg/cigarette)

FIGURE C.-Delivery of nicotine as a function of "tar" of
commercial cigarettes, U.S.
SOURCE: Federal Trade Commission (5).

decline in the "tar" and nicotine yield in recent decades may have
resulted directly from a decrease in the amount of organic material
(tobacco) available to be burned in the cigarette.

Data available from Canada suggest that the observed decline in
that country's officially measured "tar" and nicotine yields per
cigarette at least in part results from a decline in the total number of
puffs taken per cigarette during machine measurements of smoke
yield (13). Although detailed information on the number of puffs taken
per cigarette is not available for U.S. cigarettes, the FTC reports on
"tar" and nicotine yields of 1J.S. cigarette brands suggest a similar
factor may be operating in the decline of "tar" and nicotine yield
measurements. The FTC testing method specifies that cigarette "tar"
and nicotine yields be determined by smoking the cigarette to a
minimum butt length of 23 mm, or to the filter and overwrap length
plus 3 mm if in excess of 23 mm, while holding constant the puff
volume, duration, and interval. Since 1967, the filter and overwrap
length of U.S. cigarettes appears to have increased. In 1967, the
proportion of cigarette brands that were smoked down to a butt length

210


40 -

36-

36-

34-

32 -

26 -                      00
                     0
24 -

22 -

zo-

12 -

10 -

a-

6-                                0 Filter
                                  . Nonfiiter
4- 08
,`-P O   I I I I I I I I I I I I I I I I 1
  0  2 4  6  a  10  12  14  16  16  20 22  24  26  26  30  32 34  36 36  40

                        "TAR"
                   (mg/cigarane)

FIGURE 7.-Delivery of carbon monoxide as a function of
`*tar" of sekcted U.S. commercial cigarettes
SOURCE: Derived from Jenkins (19).

of 23 mm was 26 percent, but in 1979 the comparable figure was only
10 percent. Conversely, the number of all brands tested that were
smoked to a butt length 30 mm or longer increased from 21 percent in
1967 to 77 percent in 1979. Thus, the butt and over-wrap lengths of U.S.
brands appear to have increased. The absolute contribution of this
factor in the total decline in "tar" and nicotine yields over recent years,
however, is undetermined.

Cigarette Choice and Smoking Behavior
Overview

Previous examinations of many parameters measuring the patterns
of cigarette smoking in the United States have been published (25, 26).
They documented the continuing decline over the last several decades

211


o-Ylll-rlll-rl-rll-
    1967  1969  1969  1970  197'   1972  1973  ,974  1975  1976  1977  1978  1979.
                            YEAR

FIGURE 8.-Index of average %r" and tobacco per cigarette+
annually, 1967-1979
o Data estimated or unavailable.
NOTE:FJeyeu1967-100.

SOURCE: U.S. Departmat of Agriculture (24).

in the proportion of men who were regular cigarette smokers, from
52.6 percent in 1955 to 37.0 percent in 1978. These publications also
reported a similar but smaller decline since 1965 in the proportion of
women who were current regular smokers, varying between 32 and 33
percent from 1965 to 1976, but declining to less than 30 percent in 1978.
These trends continued through 1979, with a total prevalence of
smoking at 32.5 percent of all adults, or 36.1 percent for males and 29.4

212


percent for females, according to data from the 1979 Smoking
Supplement of the National Health Interview Survey. Interpretation
of these cross-sectional data is difficult since changes in prevalence
figures represent the net effect of several variables, including the
entry of new smokers, the removal of smokers who quit, the reentry of
"relapsing" smokers, and the removal of smokers by death or
emigration. The data show an increasing proportion of former smokers
among the population, suggesting a significant role of cessation of
smoking in the observed decline in the prevalence of adult smoking,
particularly among males (25). The 1979 prevalence of regular smoking
at 32.5 percent of all adults represents the lowest total figure in more
than four decades.

Accompanying this decline in the prevalence of smoking among
adults has been a decrease in the per capita consumption of cigarettes
in recent years (Figure 9) and in the per capita consumption of pounds
of tobacco in any form or as cigarettes (Figure 10). After peaking at
4,336 in 1963, the consumption of cigarettes per adult decreased
(Figure 11) and is estimated to be 3,880 in 1980, its lowest point since
1950 (24). The decrease in per capita consumption of pounds of tobacco
began in the 1940s and continues to the present. The relatively greater
decrease in total pounds of tobacco consumed per capita in the form of
cigarettes than in tobacco consumed per capita in any form since 1978
may result from an increasing use of tobacco in other forms, such as
snuff or chewing tobacco, in addition to the previously mentioned
decline in the estimated weight of tobacco per cigarette.

The preceding parameters are aggregate measurements. Other more
detailed sources of evidence, however, suggest that the average
number of cigarettes smoked daily by regular smokers may, in fact, be
increasing. These data include evidence suggesting that the propor-
tionate decrease in percentage of the adult population who smoke
exceeds the reported decrease in per capita cigarette consumption for
the total population (25). Further, when figures on total annual per
capita cigarette consumption are divided by the estimated number of
smokers in the United States as derived from reported prevalence
figures, the estimated average daily intake for regular adult smokers
was 11.5 cigarettes in 1935, 26.2 cigarettes in 1955, and 33.3 cigarettes
in 1979 (26). These data should be interpreted in light of a strong
tendency for smokers to round off their reported number of cigarettes
smoked to one pack per day. Of the approximately 24,000 persons
surveyed for the Smoking Supplement of the National Health
Insurance Survey, fully 35.2 percent of all regular smokers reported
smoking one pack, or exactly 20 cigarettes per day. Nonetheless, the
proportion of all current regular smokers who consume 2.5 or more
cigarettes per day has increased for both sexes (26). These findings
could result from a higher rate of quitting by light smokers, from an
actual increase in the number of cigarettes consumed by continuing

213


1900    1910    1920    1930   1940    1950   1960    1970   19ea

                      YEAR

FIGURE 9.-Annual per capita consumption of total cigarettes
and filter-tipped cigarettes in the U.S., for persons aged 18 and
older, 19tML1979

SOURCE: U.S. Department of HealtJl, EIducatim, and welfare (26).

smokers, from the entry of new smokers who consume more cigarettes
per day, or from some combination of these factors. A number of
sources of information exist on the issue of the role of nicotine as the
major pharmacologic agent in maintenance of smoking, including
prospective studies (8, 9, IO) and short-term experimental studies (20,
21), A more detailed discussion of the possible role of lower nicotine
yields in increasing the daily number of cigarettes smoked can be
found in the Behavioral Aspects section of this Report. To summarize,
the available evidence is consistent with the conclusion that the
average daily number of cigarettes smoked by current regular smokers
has increased. Although a role for "tar" or nicotine yields in this
change has been postulated, whether the role is primary and by what
mode of action are not clearly understood.

Several surveys in the 1970s examined the percentages of recent
smokers who recently attempted to quit and of those who succeeded.
Data from the National Center for Health Statistics indicate that men
and women were not only similar in the probability of attempting to
quit but also indistinguishable in the probability of quitting successful-
ly (26).

214


3

2

1925 30  35  40  45  50  55  60  65  70  71  72  73  74  75  76  77  78 1979'

                         YEAR

FIGURE lO.-Annual per capita consumption of tobacco
products in the U.S. (including overseas forces) for persons aged
18 and older, 19254979
o 1879 data subject to rminicm.

SOURCE: U.S. D-Ep&meIlt of Agriculture (Es, 2.9, 2,).

Relationship of "Tar" and Nicotine Yields to Smoking Behavior

As indicated previously, this section focuses upon the currently
available "tar" and nicotine data for adults. The discussion presents (1)
a description by demographic characteristics of the current use of
cigarettes of different yields, as well as changes over time where
available; (2) data on the effect of varying "tar" or nicotine yields on
consumption patterns; and (3) data defining the role of varying yields
of "tar" and nicotine in cessation of smoking. The following data are
from the National Center for Health Statistics' Smoking Supplement
to the Health Interview Survey and include discussion of the informa-
tion on "tar" and nicotine levels of the cigarettes smoked by
adolescents, as collected by the National Institute of Education (17).

As noted previously, the selection of categories of "tar" or nicotine
yields is arbitrary; in fact, both are continuous variables. The
categories of yield used in the following analysis do not imply that the
cigarettes within those categories differ either qualitatively or quanti-
tatively from the cigarettes in other categories. Rather, the groupings
permit convenient presentation of data on a cigarette's yield of "tar"
and nicotine relative to other available cigarettes.

215


(
    I    I    I    I     I    I     I    I    I    I    I    I
   1963 1964 1965 1966                                    I     I
                    1967 1969                                     I    I
                    1969 1970 1971 1972 1973 1974 1975 1976 1977 197e
                                  YEAR


TABLE L-Estimated percentage distribution of current regular
     smokers by %r" yield of primary brand of cigarette,
     by sex, race, age., and education, adults, U.S., 1979

<lo         l&l4         1,%19        >m
mg          w          %!          mg

Total                13.0         20.3         57.3          9.4

sex
Males               11.1          17.3         59.1         125
Females              15.0         23.6         55.4          6.0

Sex and race
M&3,
  white
Males,
  black
Females,
  white
Females,
  black

l!2.2          18.0         57.4         125

3.2          12.1          71.5          132

16.0         24.5         53.6          5.9

7.6          15.0         89.8          7.6

Age in years
17-24                9.6         22.6         68.9          1.0
25-44               13.5         20.8         58.9          6.9
45-64               13.9          18.2         59.0         17.8
3-5                15.6         19.4         50.0          15.0

Years of education
o-a                 7.0          16.0         61.0         16.0
9-11                8.6          16.3         65.4          9.6
12                 126         21.2         57.8          8.4
l&l5               18.3         24.8         49.4          7.4
216                23.9         24.7         45.0          6.4

SOURCE: Bawd on data from the 19'79 Smoking Supplement of the National Health Interview Survey.

The percentage distribution of current regular smokers by "tar"
level of their primary brand of cigarettes is presented in Table 1.
Although not shown, the same patterns are observed among five
arbitrary categories of nicotine yield (based on data from the 1979
Smoking Supplement of the National Health Interview Survey).

As noted previously, both 1978 and 1979 data on brands were coded
to 1978 FTC values for "tar" and nicotine yield. For this reason, and
because the cigarette samples tested in 19'78 were obtained in 1977, the
data that follow probably report slightly higher values of "tar" and
nicotine yields than were actually being used during these periods. A
further discussion of the differences in "tar" and nicotine yields of
cigarette varieties reported by the FTC in 1978 and 1979 appears in the
addendum to this section. Overall, 33.3 percent of current smokers use
lower "tar" cigarettes (yielding less than 15 mg of "tar") and 66.7
percent use higher "tar" cigarettes. Females smoke lower "tar"

217


cigarettes in higher proportions than do males. This difference in
choice of product by "tar" or nicotine level also persists when examined
by race. Whites smoke lower "tar" products in greater proportions
than do blacks, regardless of sex. For both sexes, white smokers choose
lower "tar" products approximately twice as frequently as do black
smokers of the same sex. While the percentage of all smokers using
cigarettes yielding <lO mg of "tar" increases within age cohorts, there
is no clear relationship of age cohort to those smoking cigarettes
yielding 10 to 14 mg of "tar." Among smokers of the two highest "tar"
categories, there is a clear difference by age; the proportion of smokers
choosing cigarettes yielding 15 to 19 mg of "tar" decreases with age,
but the percentage using the highest "tar" (220 mg) cigarettes
increases with age. The trend to increasing use of highest yield
products among older cohorts is clearer than the corresponding trend
to higher proportions using the lowest "tar" yield products. The
correlation of older ages and more frequent use of the highest "tar"
products could result from a cohort effect among older smokers who
continue to use the higher "tar" cigarettes that they used when they
first began to smoke.

Educational level, as measured in years of education completed, is
strongly associated with the percentage of smokers who use low "tar"
products. In considering products of 15 to 19 mg "tar" yield, an inverse
relationship with educational level in the proportion of smokers using
that product is observed, and a similar pattern is observed for the
extremely high "tar" products, yielding 20 mg or more of "tar" per
cigarette. (This inverse relationship persists even when age is con-
trolled, although the data are not shown in the table.) A similar though
less clear trend is observed with an increasing proportion of smokers
choosing lower "tar" products among higher income groups (data are
not shown).

The lack of correlated health endpoint information or detailed data
on knowledge and beliefs precludes interpretation of these data as
cause or effect, but the data do provide a description of the observed
differences in product choice by "tar" or nicotine yields.

The percentage of adults of both sexes who use lower "tar" products
has increased over time. These increases are observed in both races for
the time period shown. This is consistent with the previously cited
market data on the sales of lower "tar" products. The finding that only
33.3 percent of adult smokers in 1979 used cigarettes yielding less than
15 mg "tar," although these products accounted for almost 40 percent
of the market, does not establish a greater daily number of cigarettes
smoked by users of the lower "tar" products, because gross sales
figures include purchases by smokers not included in this analysis (e.g.,
institutionalized persons including the military forces, adolescent
smokers, occasional smokers, and interviewees whose smoking status is
unknown).

218


Comparison of changes in the "tar" level of chosen brand is possible
for the years 1970 and 1979. The proportion of male smokers choosing
cigarettes yielding less than 10 mg "tar" increased from 1.1 to 11.1
percent and females choosing these brands increased from 2.7 to 15
percent. The use of high "tar" (2 15 mg) declined from 1970 to 1979
from 89.4 to 71.6 percent for males and from 90.5 to 61.4 percent for
females (based on data from the 1979 Smoking Supplement of the
National Health Interview Survey and from U.S. Public Health
Service (37)).

Analysis of cigarette choice by nicotine yield shows the same
patterns by demographic variables, with the proportion of current
regular smokers who use lower nicotine products increasing with
increasing age and the proportion of smokers using products with
higher nicotine yields also increasing with increasing age. Whites use
lower nicotine products in greater proportions than do blacks.

A further measure of consumption suggests that the actual toxic
exposure of smokers by age, race, and sex may, however, differ
significantly from that implied by consideration only of cigarette "tar"
or nicotine yield. Table 2 shows the estimated mean daily "tar" or
nicotine dose derived from combining the reported yield per cigarette
and the number of cigarettes smoked daily by each individual in that
group. There is a consistent trend toward higher dose with increasing
age of smokers for race and sex groups. Although these figures do not
consider possible systematic differences in the style of smoking (e.g.,
butt length unsmoked, frequency and depth of inhalation, etc.), they do
illustrate marked differences in an estimate of mean dose of "tar" or
nicotine by age, sex, and race. It shows that if all smokers smoked in
the same manner, blacks would nonetheless experience a lower daily
dose of "tar" and nicotine than whites. Thus, although blacks smoke
higher "tar" products in higher proportions, the lower numbers of
cigarettes they smoke daily may result in a lower average daily dose of
smoke constituents,

More recent data on cigarette brand choice reveal changes. Table 3
presents data on the percentage distribution of smokers by "tar" and
nicotine yield of cigarettes in the period July through December 1978
versus 1979. These two surveys, each of which represents approximate-
ly 12,060 interviews, showed a shift in the percentage of persons using
lower "tar" (<15 mg) cigarettes from 23.8 percent in 1978 to 33.7
percent only a year later; a similar downward shift was observed at
nicotine yields below the highest category. Such a shift might be
caused by either an actual brand change or an involuntary downward
"creep" due to reduction in the "tar" or nicotine yield of the product by
the manufacturer. As noted previously, however, the cigarette brands
reported were coded in both 1978 and 1979 by the 1978 FTC "tar" and
nicotine yield values. Thus, the downward shift observed over this l-

219


TABLE 2.-Mean daily dose* of "tar" or nicotine for current
     regular smokers by race, sex, and age, U.S., 1979**

Mean daily dose @q/day)

                             -iTic        Nicotine
Males                                  406            26.3
White              All ages >_ 17           417            26.9
                    17-24              809            202
                    2544              416            27.1
                    4564              482            31.3
                    65+              424            25.1

BlZWk

All age3 2 17           308            21.1
  17-24              234            17.4
  2544              294            al.7
  4.564              387            26.5
  65+              239            14.1

Females                                 316            21.0

White              All age3 2 17           824            21.4
                    17-a              286            19.1
                    25-u              826            220
                    45-64              359            23.3
                    6.5+              289            17.8

Black              All agea 2 17           244            16.9
                   17-24              204            14.6
                   2544              24.3            17.0
                   4564              262            17.5
                   65+              392            28.0

`Number of cigarettes consumed multiplied by the level of "tar" or nicotine.
**IA& two calendar qu- only.

SOURCE: Based on data from the 19'79 Smoking Supplement of the National Health Interview Survey.

year interval in cigarette "tar" and nicotine yield represents an actual
change in the brand of cigarettes used by smokers.

Similar patterns have been observed in smoking among adolescents.
In a 1979 national telephone interview survey of 2,699 adolescents, the
percentage of all adolescent smokers who selected brands of lower
"tar" (115 mg) had increased from 6.7 percent observed in 1974 for
both sexes (Table 4) to 33.5 percent in 1979. Direct comparison of the
percentage distribution of "tar" yield among adolescents with that
observed among adults is complicated by different groupings of "tar"
level and by different definitions of "regular" smokers in the two
surveys (after having smoked 100 cigarettes, "regular" smokers were
defined for adolescents as "smoking regularly each week"; for adults,
as any positive response to "when did you start smoking regularly?").
Nonetheless, a similar trend toward increasing use of lower "tar"
products is observed among adolescents and adults.

Table 5 presents data on brand choice by "tar" level among
adolescents of different ages from the largest recent smoking survey
of adolescents. The small numbers of smokers, and the relatively large
numbers of individuals who are unclassifiable, make interpretation of

220


TABLE 3.-Estimated percentage distribution of current regular
     smokers by `Yar" and nicotine yield of primary
     cigarette used, U.S., 19'78* and 1979*

"Tar"yield
15 mg
M nlg
1614 mg
1619 mg
La mg

PWCJZntage           Percentage
in 1978                in 1979

  4.2                  4.0
  1.5                  9.0
  17.1                  20.7
  61.4                  56.8
  9.8                  9.6

Nicotine yield
<0.5 mg
0.80.9 nlg
l&1.2 lug
l.bl.6 mg
21.7 tng

PeKi?ntage           PelWntage
in 19'78                in 1979

  4.3                  4.2
  26.7                  31.7
  41.1                  37.7
  26.7                  25.3
  12                  1.2

SOURCE: Based on data from the 1973 Smoking Supplement of the National Health Interview Survey.

TABLE I.-Estimated percentage distribution of regular smokers
     by Yar" yield, adolescents aged 12-18, U.S., 1974 and
        1979

"Tar" yield
510 w
11-14 mg
1619 mg
220 nlg

Percentage
   boys
1974      1979

0.5       2.5
5.6      29.5
73.7      60.8
20.3       1.4

Percentage
  girls
1974      1979

0.5      123
6.8      Z.6
74.4      59.5
18.2       5.5

PeFcentage
  both gexea
1974      1979

0.5       7.8
6.2      25.7
74.0      60.1
19.3       6.3

SOURCE: National Iastituteof Education(Zf).

product choice among adolescents by age group difficult. Thus, a clear
definition of the relationship of the adolescent smoker's age to choice
of cigarette. smoked is not possible from this series.

In Table 6, the mean age of onset of smoking cigarettes for all
current regular smokers is 18.2 years. Although most of the data in the
National Health Interview Survey Smoking Supplement involves
reca.ll, the mean age at onset is perhaps the most subject to bias,
whether in remembrance or in reporting preference. Nonetheless, the
reported age at onset of smoking is higher among older age groups.
This might reflect (1) a real change in recent years in the age at which
younger cohorts start to smoke, (2) the addition of a few late-starting
smokers during the extra years "at risk," causing a higher reported
age at onset among older cohorts, or (3) an effect of different mortality
rates for early versus late beginning smokers. The demonstration that
the average age at onset of smoking among females has declined from
35 years among women born prior to 1900 to 16 years among women

221


TABLE 5.-Percent distribution of adolescent regular smokers by
     "tar" yield of primary brand, by sex and age, U.S.,
       1979

          115 mg       >15 w      UiWpkfii      Don't know
BwagegroUP 7%      n      w      n      I      n      %      0

B-14      11.1      2     ri5.6     10     27.8     5     5.6      1
1616      29.4     15     62.7     32      1.8     4
17-18      26.4     19     58.3     42     15.3     11
19       23.6     13     63.6     35     x2.27     I

          115 mg       >15 mg      UnSpecified      Don't know
Girls age group    40      n      %      n      46      n      I      O

Kc14      25.0      6     `1'0.8     17     4.2      1
15-16      B.9     11     Ii.5     26     13.0     6     6.5     8
17-18      34.7     34     520     51     l2.2     12     1.0      1
19       30.5     18     W.8     30     16.6     11

SOURCE: N,bional 1natitut.e of EXuc&ioo (17)

born between 1951 and 1960 (26) explains a portion of the observed
differences in age at onset by cohort. Older cohorts may not fit the
assumption that the survivors within that cohort are representative of
all individuals within the original cohort. The amount and direction of
the effects of (l), (2), and (3) remain to be defined. However, there is a
general trend that, for each age cohort, the higher the "tar" level of
the cigarette currently smoked, the younger the reported age of onset
of smoking. The same observation is also found in the relationship
between nicotine yield and age of onset, except that an older age of
onset is indicated for those smoking the highest nicotine yield (>1.7
mg) cigarettes, which value is based on a small sample size.

Consumption Patterns

In attempting to define the role of "tar" or nicotine yield on the
daily number of cigarettes smoked, adult regular smokers were divided
into three levels of daily consumption by approximate quintiles of
"tar" and nicotine yield of primary brand (Table 7). This Table shows
that the percentage distribution of smokers by number of cigarettes
per day does not exhibit an association with "tar" or nicotine level of
cigarette used. This Table provides evidence that there is not a
significantly greater proportion of "heavy" smokers among smokers of
the lowest "tar" and nicotine cigarettes than there is among smokers
of the highest "tar" and nicotine cigarettes. It does not, however,
disprove the theory that individual smokers may increase their daily
number of cigarettes smoked when they switch to a cigarette with
lower "tar" or nicotine yield. That is, the absolute number of cigarettes

222


TABLE 6.-Mean age at onset of regular smoking by *`tar" or
      nicotine yield of primary brand, by age at
      interview, current regular smokers, U.S., 1979

Age at interview

"Tar" yield
          Tpkl~~~~W~
<5 w           19.6     16.6     18.3     19.5     20.3     192     23.8
5-9w           18.8     16.3     17.3     18.8     19.6     20.1     24.1
lo-14 mg          X5     162     18.1     18.7     19.3     20.6     224
15-19 mg          18.0     15.6     17.3     18.3     19.0     19.3     25.9
Law          17.0     15.1     17.1     17.0     17.1     181     21.3

TOtd            182     15.8     17.5     18.4     18.8     19.7     232

Nicotine yield

<Oh w          19.7     16.5     la3     19.8     m.5     192     24.1
0.5-0.9 mg         18.7     162     18.1     18.9     19.5     20.7     23.3
1.0-12 mg         16.0     15.7     172     182     19.1     19.7     23.1
1.3-1.6 mg         17.7     152     17.0     17.8     17.6     18.7     226
21.7 mg          19.3     18.0     17.5     17.3     19.4     21.6     20.3

T&d            162     15.8     17.5     18.4     18.8     19.7     292

SOURCE: Bawd on data from the 1979 Smdhg Supplement of the National He&b lnterviera Survey.

smoked by individuals at low "tar" and nicotine yields may, in fact, be
higher than the number of cigarettes the same indizGdu& smoked at
high yield levels, even though there is no cross-sectional difference.

The relationship of "tar" or nicotine yield to the number of
cigarettes smoked daily can also be examined by the average number
of cigarettes smoked in various age groups, as presented in Table 8.
After grouping smokers by age at interview, it is still observed that
neither the level of "tar" nor that of nicotine demonstrates a definite
association with the mean number of cigarettes smoked daily.

The role played by cigarettes of varying "tar" and nicotine yields in
cessation has been widely discussed (25,26). Present survey data have
not sufficed to define the role for varying "tar" and nicotine yields in
cessation, largely because of the lack of longitudinal surveys of
cigarette consumption prior to attempting to quit or after an
unsuccessful attempt. A longitudinal study of smoking patterns by
both cigarette product choice and number smoked daily to determine
their relationship to cessation is being conducted by the NCHS for the
Office on Smoking and Health during 1980 and 1981.

Table 9 examines by cigarette "tar" or nicotine yield the percent of
current smokers who report ever having seriously tried to quit
smoking. Overall, there is a clear inverse relationship between the
"tar" or nicotine yield of the cigarette and the percent of smokers who
have ever tried to quit. The group of lowest yield smokers shows a


TABLE `I.-Estimated percentage distribution of current regular
     smokers by number of cigarettes smoked daily by
     approximate quint&s of "tar" or nicotine yield,
      adults, U.S., 1979

Percent of
total population

Daily number of
cigarettee
<lb
  lM4
2%
        Totah

go       1.1-15       l&17       17-18      2b
w        mg        mg        Igg        mg

19.1

0.5        19.4        19.8

29.9        21.5        312        27.6        m.9
427        45.5        42.4        43s        43.9
21.5        26.9        36.3        292        302
         _-
100.1       99.9     941)       100.1    1oo.o

Percent of
total population

Daily number of
cigarette9
<15
  l&Z4
2%
        Tot&

10.7
w

20.3

O.&l.01
w

`20.3

1.02-1.09
mg

19.7

1.10-1.31
w

21.3

2152
w

la4

392        :29.0        a2        27.5        311)
423        ,46.5        41.4        43.3        43.1
28.5        24.5        39.4        282        x9
1oo.o    Gz    GG       100.0    1oo.o

SOURCE: Band on data from the 1973 Smoking Supplement of UK Ndiond He&h Interview Survey.

higher proportion of persons who have ever tried than those groups
smoking higher yield products. This relationship was found for both
"tar" and nicotine yields for all age groups except those 65 or more
years of age, where the sample size was considerably smaller and the
pattern was less clear.

The finding that greater proportions of current smokers of lower
"tar" or nicotine products report ever attempting to quit than do
smokers of higher "tar" products could result from (1) a higher rate of
attempting to quit (but with a similar failure rate) for more health-
conscious individuals who may also therefore choose lower yield
cigarettes; (2) a difference in the addictive qualities of lower "tar" or
nicotine products, causing a higher probability of relapsing after
attempting to quit; or (3) the choice of a lower "tar" and nicotine
cigarette product after failing to stop smoking. Selection between
these alternatives would require comprehensive data on brand choice
both prior to and following an attempt to quit smoking, as well as
health status measurements that might affect brand switching or quit
attempts. Such information is not available from this data set.

224


TABLE 8.-Mean number of cigarettes smoked daily by "tar" or
     nicotine yield, by age groups, current regular
      smokers, adults, U.S., 1979

rauield
           Tntpl

<5 w           21.5
5-9 mg           al.7
10-14 mg          202
15-19 mg          20.6
1mmg          z?.5

T&d            20.7

liQ4i?iu43!ki4~~~

16.0     195     29.3     26.3     21.8     18.9
17.0     al.7     21.9     23.3     .ZO     18.9
162     al2     23.1     25.7     19.5     16.4
17.5     21.0     P7     a3     Z.1     16.4
152     29.0     34.9     B.9     Zl.6     16.9

17.1     20.8     !a.9     23.4     21.5     172

<o-5 w          21.4     16.9     19.8     229     25.6     21.5     18.7
0.5-0.9 lug         202     162     `al.3     z4     29.7     20.5     184
l&12 mg         21.0     17.7     n.9     23.1     B.5     220     16.9
l.Zhl.6 mg         212     17.6     20.1     23.4     1.7     !a.3     17.3
21.7 tug          18.5      5.5     18.3     21.4     18.8     18.3     17.0

Total            20.7     17.1     al.8     229     33.4     31.5     172

SOURCE: Saed on data from the 1979 Smoking Supplemat of the Natiod He&b Interview Survey.

TABLE 9.-Estimated percent of current regular smokers who
     have tried aeriously at least once to quit, by "tar" or
     nicotine level and age, U.S., 1979

AgegrwP       <5 w     5-Q w    lo-14 mg    l&19 mg    mmg

17-24             629        57.1        57.6        52.3        43.3
2544             729        69.8        63.5        59.8        50.0
4544             71.5        64.0        59.1        53.5        51.0
265             50.8        60.0        61.6        53.4        49.7

NW           69.8        65.3        61.8        53.8        51.5

            <0.5       0.5-0.9      1.0-12      1.3-1.6      21.7
&group          w        w        w        mg        mg

17-24             60.7        58.0        53.6        47.1        50.4
B-44             73.3        65.1        612        55.1        492
454             70.7        60.6        58.4        55.0        48.3
265             53.3        60.8        57.5        54.3        58.6

apges           63.8        621        58.4        53.8        50.0

SOURCE: haed on dab from the 1979 Smoking Suppbmmt of the Nationd He&b Inturr*a Survey.

Table 10 shows a comparison of the frequency distributions of recent
smokers by "tar" or nicotine level of the primary cigarette brand
smoked by those who either did not try to quit, those who tried but
failed to quit, and those who succeeded in quitting smoking within the


12 months prior to interview. In this analysis, "success" in quitting was
arbitrarily defined as persons who had recently been regular smokers
who had attempted to quit within I2 months and who had not smoked
for at least 6 months prior to interview. Persons who smoked regularly
within 1 year prior to the interview and who had attempted to quit
during the last year but had been off cigarettes less than 6 months are
excluded from consideration in this analysis. Unsuccessful quitters
were defined as regular smokers at the time of interview who reported
having attempted seriously to quit at least once within the I2 months
prior to interview date. Interpretation of these data is complicated by
the fact that the primary brand reported for successful quitters
represents the brand smoked prior to a quit attempt, while unsuccess-
ful quitters' brands are those smoked after a quit attempt. Thus, clear
distinction cannot be made between the possible explanations. The
data show that higher proportions of smokers who use the two lowest
"tar" or nicotine cigarette products are found among the unsuccessful
quitters than among successful quitters. The proportion of recent
regular smokers who use cigarettes yielding <5 mg of "tar" is lowest
for persons who did not attempt to quit (3.8 percent), intermediate
among those who succeeded in quitting (4.6 percent), and highest
among those who failed at an attempt to quit (4.9 percent).
Grouping these smokers into larger categories by "tar" level (e.g.,
the percent smoking cigarettes yielding <lO mg or those smoking
cigarettes yielding <15 mg "tar") shows that a lower proportion of
recent smokers who successfully quit used lower "tar" products than
do recent smokers who did not attempt to quit, while smokers who
failed in an attempt to quit reported smoking lower "tar" products in
the highest proportions. Conversely, a lower proportion of unsuccessful
attempters currently smoke higher "tar" products (65.3 percent) than
is found among either nonattempters (69.0 percent) or successful
quitters (72.2 percent). A similar relationship was observed by nicotine
yield: the proportion of persons choosing the lower yield products
(<l.O mg) was highest for unsuccessful quitters, intermediate for
nonattempters, and lowest among successful quitters.
Thus, these data are consistent with the postulated tendency of
smokers to switch to lower "tar" and nicotine cigarettes following an
unsuccessful attempt to quit smoking.
The relationship between number of serious attempts to quit
smoking and the "tar" or nicotine yield of the primary cigarette
smoked is shown in Table 11. Note should be taken that the table
includes only current regular smokers who have tried at least once to
quit. For the lowest categories of "tar" and nicotine yields, there is a
suggestion of a shift in the population toward a greater number of
cessation attempts. No significant difference is observed in the
frequency distributions of smokers of other "tar" and nicotine
products.


TABLE IO.-Estimated percentage distribution of recent smokers
      by status of recent attempt to quit, by "tar" or
      nicotine yield of primary brand, July 1978 through
       December 1979*

status of
recent
attempt to
quit smoking

S-ful     4.6 (13)   5.6 (16)   17.6 (50)   63.4 (1Ea)   8.8 (35)    23  `B4
unaudlll   4.9 (152)   9.2 (286)   20.5 (636)  59.7 (1849)   5.6 (175)   25.6  8098
No attempt    3.8 (355)   8.3 (721)   19.0 (1655)   58.1 (5070)   10.9 (950)   72.1  8731
Total       4.1 (500)   8.4 (1023)   19.3 (2341)  53.6 (7099)   9.5 (1150)   100.0 l21l3

<6.5 w   0.549 mg  l.cL1.2 mg  131.6 mg   21.7 mg
% (n)    % (n)    % ho    % (n)    % (n)

Sueeesaful     4.6  (13)   26.8  (76)   48.0  (122)   25.0  (71)    0.7  (2)    23  284
unaudul    5.0 (155)   32.2  (=v   39.7 (lz29)   223  VW    0.7  (23)    25.6  30%
No attempt     4.0 (351)   29.2 (2553)   33.3 (8340)   27.1 (2368)    1.4 (119)    721  3731
Total        4.3 (519)   30.0 (362s)   38.7 (4691)   25.8 (3131)    1.2 (144)   100.0 12113

o ?*???????? ????

SOURCE: Baaed on data from the l979 Smoking Supplement of the National Health Inter&r Suvey

TABLE Il.-Estimated percentage distribution of current regular
      smokers by number of serious attempts to quit
      smoking, by "tar" or nicotine level, U.S., 1979

Tar I` PI bid    L        2          3         4       25
<5             27.3     KY     Gi     x7     iii
5-9            35.7        289        15.8        4.4        152
w-14           36.9        29.1         14.6        5.5        l3.9
15-19           38.6        26.3        14.7        5.3        l5.0
2m             37.6        23.7        14.9        5.4        18.5

Total            372        27.1        14.6        5.3        15.7

. .
m bl3)
<0.5             26.8        29.4        102        5.7        27.0
0.5-0.9          37.4        28.6        14.9        5.1        14.1
l&12          39.5        26.7        14.1        5.0        147
1.11.6          35.9        252        15.7        62        17.0
21.7            38.6        25.1        21.1        23        129

Total            37.3        27.1         14.6        5.3        15.7

SOURCE: Based on data from the 1979 Smoking Suppkment of the National Health Interview Survey.

The relationship of cigarette choice to the duration of the most
recent unsuccessful quit attempt is shown in Table 12 for current
regular smokers. Although there are large variations in the individual
durations within each "tar" or nicotine grouping, the mean durations


TABLE 12.-Mean duration of most recent attempt to quit, by
      "tar" or nicotine yield of current primary brand,
      current regular smokers, 1979*

                           Inl
<5 w           3.4             (132)
5-g mg           3.1             (20
lo-14 mg           3.8             Gw
l&l9 mg           3.5             (180
mm3           4.1             uw

  Total           3.6             mw

<0.5 mg           3.4              (W
0.5-0.9 mg           3.7              @w
l.@-l.2 mg           3.3             ww
l.sl.6 mg           3.9             (sp)
21.7 mg           6.3              (16)

   Total           3.6             (nss)

SOURCE: Bud on data fmm the 1676 Smoking Supplement of the Ndiod E~~VI Interview Survey.

do not exhibit a relationship to either "tar" or nicotine yield. The
higher mean duration of quit attempt among the smokers of highest
yield products must be interpreted in light of the small numbers of
individuals within those yield groupings.

Summay

1. Public awareness of the dangers of smoking has steadily
increased since 1965. In 1978, more than 90 percent of all
Americans believed cigarette smoking to be hazardous to health.
2. Cigarette product choice has shifted dramatically since the 1950s.
In 1979, 91.7 percent of U.S. smokers used filter-tipped ciga-
rettes, compared with 1.4 percent in the early 1950s.

3. Lower "tar" cigarettes conventionally have been defined as
yielding 15 mg of "tar" or less per cigarette. The proportion of all
cigarettes consumed in the United States that are lower "tar"
has increased from 3.6 percent in 1970 to almost 50 percent in
1979. In 1979,53.5 percent of all cigarette brands marketed in the
United States yielded 15 or fewer mg of "tar."

4. Since 1968, the "tar" content of the "average cigarette" in the
United States has declined by 32.2 percent, and nicotine content
has fallen by 25.6 percent. These declines may be partially
accounted for by lower tobacco weight per cigarette-down 23.8
percent from 1968 to 1978-and by the greater length of the
filter and overwrap of the average cigarette, which could result
in a declining number of machine puffs per cigarette.


5. The prevalence of smoking in the U.S. adult and adolescent
populations has continued to decline. In 1979,32.5 percent of the
adult population smoked cigarettes (36.1 percent of men and 29.4
percent of women). However, evidence suggests that the average
daily number of cigarettes consumed by those adults who
continue to smoke has increased over several decades. The
availability and use of lower "tar" cigarettes have increased over
recent years.
6. In 1979, 33.3 percent of adult regular smokers used cigarettes
yielding 15 mg "tar" or less. Studies show that women smokers
are more likely to use lower yield cigarettes than men are, and
white smokers use lower yield cigarettes in greater proportions
than do blacks. Smokers of higher income and education also
select lower yield cigarettes in a higher percent of cases.
7. A large national survey found that smokers in older aged cohorts
choose both the lowest and highest yield cigarettes in higher
proportions than do younger cohorts.
8. Although black smokers choose cigarettes of higher "tar" and
nicotine in greater proportions than do whites, the lower daily
number of cigarettes smoked by blacks suggests that their
average daily intake of "tar" and nicotine may be lower than that
of white smokers.
9. In 1979, 33.5 percent of adolescent smokers (age 12 to 18) used
lower "tar" cigarettes, compared with 6.7 percent in 1974. Boys
and girls smoke cigarettes of about the same level of "tar"
  content.
10. Adult smokers started smoking regularly at the average age of
18 years. One survey showed that the higher the "tar" level of the
cigarette currently smoked, the younger the reported age of
beginning smoking.
11. Evidence from a large national survey does not support a
correlation between a greater mean number of cigarettes smoked
per day by users of lower "tar" and nicotine cigarettes than by
higher "tar" users.
12. In a national survey, smokers of lower "tar" and nicotine
cigarettes more frequently reported having attempted to quit at
least once, and among these smokers, a higher proportion report
having attempted unsuccessfully to quit multiple times. The
applicability of these data to defining of the role of "tar" or
nicotine yields of cigarettes in quitting behavior is not clear in
the absence of more detailed longitudinal data.
13. Although a greater proportion of unsuccessful quitters reported
smoking the lowest "tar" and nicotine products than did recent
successful quitters in one large survey, interpretation of these
data is made difficult by the noncomparability of brand reported


(i.e., unsuccessful quitters reported the brand smoked after an
attempt, successful quitters reported the brand smoked prior m
the attempt).

14. In a large national suwey, the mean duration of the latest
unsuccessful attempt to quit shows no clear relationship to "tar"
or nicotine yields.

Addendum: Comparison of "Tar" and Nicotine Yields of
Cigarettes in 1978 and 1979

The Federal Trade Commission (FTC) has conducted tests of
commercially available cigarettes in the United States since 1968. The
FTC measures "tar" and nicotine yields of approximately 99.5 percent
of the brands available in the United States and issues annual reports
on these measurements.

This discussion examines the changes in cigarette yields from 1978 to
1979 as published by the FTC. The following should be helpful in
estimating to what extent the coding of NHIS brand data for 1979 by
the "tar" yields measured in 1978 might influence the results presented
above in this section.

Yields of `*Tar" and Nicotine

The cigarettes tested in 1978 (sample collected in 1977) had a mean
"tar" yield of 15.4 mg and in 1979 (sample collected in 1979) the mean
"tar" yield was 13.6. The corresponding mean yields of nicotine were
1.02 and 0.97 mg in the 1978 and 1979 FTC reports (Table 13). These
reductions in yields occurred regardless of the different parameters of
cigarette type (length, menthol/plain, package type, and fil-
ter/nonfilter). If only filter-tipped cigarettes are considered, the mean
nicotine yield declined from 0.95 to 0.90 mg. For all 1979 varieties,
there was a significant difference in "tar" yield between filter and
nonfilter cigarettes, and between menthol and nonmenthol varieties of
cigarettes. Examining filtered cigarettes only, the length of cigarette
was the only parameter that showed a significant difference in mean
"tar" level.

Correlation of Varieties Fteported in 1978 and 1979

There were 144 varieties of cigarettes marketed in both years (1978
and 1979) that were unchanged, as defined by exact variety name,
length, menthol and filter status, and package type. Despite the
identity of all five parameters, the mean "tar" level of varieties
declined over the period mentioned (Table 14). The mean "tar" level
declined from 15.3 mg in 1978 to 14.8 in 1979; for filter-tipped
cigarettes only, the mean "tar" level declined from 13.8 to 13.3 mg.
These decreases, although slight in absolute terms, are statistically
significant. The change in nicotine yields for these same brands of
cigarettes over the same period is negligible.

230


TABLE 13.-M-n yield of "tar" and nicotine of cigarettes, by type of modifier, all and filtertip varieties, U.S.,
       1978 and 1979

Type of modifier
soit
Hard

Filt.t?r
Nonfiltel:

<lo0 mm
>lOO mm

15.4      13.4
15.3      14.0

Menthol          14.0      122.
RegulW          16.1      14.4

"Tar" m

1973     1979
15.9     13.4
15.1      14.7

13.9      l2.4-
25.1      24.7

15.4      13.6

All varieties

Nicotine (mg)
1978     1979
-     -
1.03      096
1.00      1.04

095      0.90**
1.48      1.53

099      093
1.06      1.01

0.97     090
1.05      1.01

1.02      097

No. of varieties       "Tar" (mg)
1978     1979      1978      1979
138   - 149      14.0      122
29      21       13.4      13.3

145      158
22      18

99      100       126      10.9'.
68      76       15.3      14.0

58      lx
109      112

167      176

13.8      122
13.9      125

13.9      124

Filtertip varieties

  Nicotine (mg)
1978     1979
-     -
097      090
0.88     0.91

No. of varieties

1978     1979
- -
119      134

26      24

0.85      O.&F     rl      82
1.06      1.01      68      76

096      0.90      57      61
096     0.W      88      94

0.95      090      145      158

o -P <.ool.
o P <.06.

SOURCE: Federal Trade ?????????* (A, 5).


TABLE 14.-Mean yield of Yar" and nicotine of the varieties of cigarette marketed in both 1978 and 1979, by
      type of modifier, all and filtertip varieties, U.S.

Type of modifier
soft
Hard

Filter         13.8      13.3"     0.95      0.96         126
Nonfilter       25.6      24.7      1.58      1.56          18

<lOO mm       15.3      14.8'      1.01      1.02          83         a.6      121'
>lW mm       152      14.7.     1. 05      1.06          61         l6.2      14.7'

Menth01
Resulw

Total

14.0      13.4.      0.97      0.97         54         13.9      13988
16.0      15.6'      1.06      1.08          90         18.8      l3.4'

isa      14.8"     1.03      1.09         144         l3.8      18a**

  "Tar" m         Nicotine (mg)
1978      1979      1978      1979
152      14.7'.     1.03      1.03
16.5      15.0      1.03      1.05

All varieties                             Filtertip varieties

Nicotine (mg)

No. of varieties

   119
   25

"Tar" (mg)
1973      1979

19.9   ii.&
13.6      13.4

1978      1979      No. of varieties
0.96      097          1@4

O.h9      0.93          a?

0.86      0.86           66
1.06      1.06           61

0.97      0.96          63
0.94      0.96           73

0.96      0.96          126

.`P <.ool.
o P <.06.


TABLE 15.-Comparison of "tar" and nicotine yield on the
      varieties of cigarette marketed in both 1978 and
       1979, U.S.

   "Tar" yield         Mean "tar"        Mean rlimtine         No. of
    in year       difference (mg)     difference (mg)         varieties
   1978 - 1979                        -0.0157             7
   1978 < 1979         -0.6945            am829             55
  1978 > 1979          1.2366            0.0478             82

    Total             0.4958            XL0062            144

Further examination of the changes in the "tar" and nicotine yield
occurring in the same varieties of cigarettes over this period is
presented in Table 15. Of the 144 brands reported on in both periods,
only 7 showed no difference in mean "tar" level. Fifty-five brands
showed a slight increase, with the mean difference being less than 1
mg. Eighty-two brands, however, showed a decline from the 1978
reported yields to the 1979 yield. Once again, however, the mean
decrease was small, only 1.3 mg.

"Tar" and Nicotine Yields of New Brands in 1979

There were 32 varieties of cigarettes defined as new in the 1979 FTC
report (Tables 16 and 17). A "new" variety was defined as a different
name (such as a varietal name change by addition of the word
"lights"), or by a change in one of the other four varietal parameters of
filter, length, package type, or menthol status (e.g., a nonfiltered
cigarette changing to filtered). The average "tar" and nicotine yields
for these 32 new brands in 1979 were 8.5 and 0.67 mg, respectively.
Except for a single new variety, the new varieties yielded less than 15
mg of "tar," with two-thirds of them yielding less than 10 mg "tar." A
similar examination of new 1979 varieties by nicotine yield showed a
similar trend toward lower yields, with 81 percent of them yielding leas
than 0.9 mg of nicotine.

Applications to the Discussion

As noted in the body of this Report, all NHIS variety data on the
Smoking Supplement collected in interviews during 1978 and 1979
were coded to the FTC 1978 "tar" and nicotine yields. Since the
cigarettes reported on in 1978 were collected in 1977, and since the
updated measures of yield for 1979 were not available in time for their
use in coding the 1979 smoking data, the described distribution of
smokers by "tar" and nicotine yields of their cigarettes is conservative
and underestimates to some extent the proportion of smokers who use
lower yield products.

233


TABLE 16.-Mean yield of Yar" and nicotine of the new
      varieties of cigarette marketed in 1979, by type of
      modifier, U.S.

z             6` rr

soft                  8.3              0.66              30
Hard                 117              0.82               2

Fslter                 6.5              0.67              32
Nonfilter

<100 mm              6.5              0.54              17
>lOO mm              10.8              0.82              15

Menthol               7.0              0.57              11
Resul-               9.4              0.72              21

Total                 8.5              0.67              32

SOURCE Federal Trade-n (4.5).

TABLE 17.-Distribution of "tar" and nicotine yield of the new
      varieties of cigarette marketed in 1979, U.S.

            <5        5-9.9       10.0-14.9     15.0-19.9      Total

N        Y-     ic         10         1         32
5%'             21.9        43.8         31.3        3.1        100.0

    <0.49     0.5M3.69     0.7wl.89      0.90-1.09     1.10-123      Total

N   s       4         13          4         2         52
%     26.1       l2.5        40.6         a.5        6s        1lM.o

SOURCE: Fe&d Trade Commiaiia (&9.

234


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237


INDEX

ABORTION, SPONTANEOUS
effect of maternal smoking on risk,
   153
ACIDS

carcinogenicity, 33
cocarcinogenicity, 33
ACROLEIN

cocareinogenicity, 94
ADOLESCENTS
percent distribution of smokers by
  tar yield, 339-232
role of lower tar and nicotine cigar-
  ettes in initiation of smoking ha-
  bit, 133

use of lower tar and nicotine cigar-
  ettes in males vs. females, 133
use of lower tar cigarettes, 33WZ33
ADRENAL CORTEX HORMONES
effect of nicotine on cortisol secre-
  tion, 117-118

ADVERTISING
market trends for lower tar cigar-
  ettes, 202

Age groups See DEMOGRAPIIIC
VARIABLES

AGRICULTURAL PRACTICES
(See also GEIWI'ICS; TOBACCO
  CURING)

effect on cigarette smoke pharma-
cology, research recommendations,
55

effect on smoke composition, 51
ALCOHOL CONSUMPTION
interactive effect with smoking in
  etiology of upper digestive tract
  neoplasma, 42

ALKAmID CONTENT
(see al.so NICOTINE CONTENT)
in cigarette smoke, 97
ALKALOIDS
(See ala NICOTINE)
carcinogenicity, 97
AMINE CONTENT
in gas phase of cigarette smoke, 94

ANGINA PECTQRIS
role of carbon monoxide in exerciee-
  induced angina, 46
ANIMAL MODELS
(See a-h BIOASSAY)
in assessment of health risks of
  lower tar and nicotine cigarettes,
   14

bladder neoplasms, 41
cardiovascular effects of carbon
  monoxide, 46
chronic obstructive lung disease, 43-
   44
effect of maternal smoking on preg-
  nancy, 167
emphysema, 142
esophageal neoplasms, 4%43
laryngeal neoplasms, 41
lung neoplasms, 34-40
nicotine tolerance and physical de-
  pendence, 179
nicotine use, 173-179
oral neoplasms, 43
pancreatic neoplasms, 4249
reduced carcinogenicity of cigarette
  smoke, 94
smoking and cardiovascu1ar diseases,
   124
sudden death due to cardiovascular
  diseaq44,46
tobrelated diseases, research 1p
  commendations, 53
tmmplacental arcinogeneais, 47
ANTmRYPsIN
effect of cigarette smoke on activi-
  ty, 137-133
ANTITRYPSIN DEF'ICIENCY
in emphysema etiology, 137-133
AROMATIC AMIDES
binding to nucleic acids, 91
metabolic activation and carcinogen-
  icity, 91
AROMATIC AMINE CONTENT
in cigarette smoke, 97


INDEX

AROMATIC AMINE CONTENT-Con.
reduction of in cigarette smoke, 95
AROMATIC AMINES
binding to nucleic acids, 91
bladder neoplasms and, 94-95
in bladder neoplasm etiology, 41
metabolic activation and carcinogen-
  icity, 91
AROMATIC BYDROCARBON CON-
TENT
in tobacco smoke, 9596
AROMATIC BYDROCARBONS
"bay" region theory of carcinogene-
  sis, 99
carcinogenicity, -7, 98-95
carcinogenicity of metabolic in-
  temdiatea, 90
cocarcinogenicity, 96
health effects in fetus, research re-
  commendations, 169
ARYL BYDROCARBON BYDROXY-
  LASE
effect of cigarette smoke on activity
  in microsomes, 4748
role in metabolic activation of aro-
  matic hydmcarbons, 99
ATBEROSCLEROSIS
role of cigarette tars, 119

BRBAV'IOR
effect of maternal smoking on chil-
  dren, 159
BEHAVIOR, ANIMAL
self-administration of nicotine, 179
BENZ(a)AN?DRACENES
carcinogenicity, 95
in tobacco smoke, 95
BENZOPLUORANTB&BS
carcinogenicity, 95
in tobacco smoke, 95
BENZO(~$,J~PERYLBNB
cocarcinogenicity, 96
in tobacco smoke, 96
BENZO(c)PBBNANTBBENE
carcinogenicity, 95
in tobacco smoke, 95
BENZO(a)PYRENE
carcinogenicity, 86-87, 95
health effects in fetus, research re-
  commendations, 159
metabolic activation, 90
BENZO(a)PYRBNE CONTENT
in cigarettes (1955-1980), 8586

BENZO(a)PYRBNE CONTENT-Con.
in tobacco smoke, 95
BENZO(eWYRBNB
carcinogenicity, 95
cocareinogenicity, 98
in tobacco smoke, 95-96
BIOASSAY
(See a-k ANIMAL MODELS)
in assessment of health risks of
  lower tar and nicotine cigarettes,
   14
cigarette smoke components, re-
  search recommendations, 58
mouse skin assay for lung neo-
  Ph+sms, 84-85
BIRTB WEIGBT
effect of lower tar and nicotine cig-
  arettes, 159
effect of maternal smoking, 158
BLADDER NEOPLASMS
animal models, 41
aromatic amines and, 41, 94-95
carcinogens and mutagens in cigar-
  ette smoke, 41, 97
BLOOD CBBMICAL ANALYSIS
recommendations for cliical testing
  facilities, 184
BLOOD PLATELETS
effect of nicotine, 118
BLOOD PRESSURE
effect of nicotine, 117
BLOOD Y
effect of nicotine, 117
effect of tobacco antigens on en-
  dothelium, 119
BREAST PBEDING
(.% alao LACTATION)
recommended reseamh on maternal
  smoking and, 168
Bronchial epithelium &c TBACBEO-
  BRONCHLAL BPITBBLWM
BRONCBITIS
(see ah CRRONIC 0BsTRum
  LUNG DISBASB)
effect of filtered cigarettes on mor-
   tality risk, 140-141
smoking and, 185186

CADMIUM
hypertension and, 119
CADMIUM CONTENT
in cigarette smoke, 97


INDEX

Cancer See NEOPUSMS
CARBON MONOXIDE
(See aleo CARBOXYHEMOGLOBIN)
animal models of cardiovascular ef-
  fects, 46

in cardiovascular disease etiology,
118

in coronary heart disease etiology,
10

effect on heart function, 118
effect on myocardium, 118
effect on pregnancy, 46-47
exercise-induced angina and, 48
health effects, research recommenda-
tions, 57

health effects in fetus, research re-
  commendations, 163169
CARBON MONOXIDE CONTENT
(See aleo CARBOXYHEMWLOBIN
  -W

in alveoli, effect of lower tar and
nicotine cigarettes, 181
correlation with tar yield, 299, 211
factors influencing yield in main-
stream smoke, 10
in filtered vs. nonfiltered cigarettes,
9M7, 119-120

reduction of in cigarettes, Public
  Health Service recommendations,
   201
CARBOXYIIBMOGLOBIN
(See a&o CARBON MONOXIDE)
in cardiovascular disease etiology,
   118
CARBOXYHBMOGLOBIN LEVEIS
(See ulao CARBON MONOXIDE
  CONTENT)
effect of lower tar and nicotine cig-
  arettes, 181-182
CARCINOGENBSIS
(See ah MUTAGENESIS)
"bay" region theory, 96
induced by lower tar and nicotine
  cigarettes, 8889
recommendations for research on
  lower tar and nicotine cigarettes,
   99-101
role of nicotine, 91-93
role of smok&nduced microsomal
  oxidase activity, 48
transplacental carcinogenesis, 9899
value of mutagenesis assays in pre-
  diction of, 4243

CA.RCINOGENBSIS-Con.
value of sebaceous gland suppression
  assay in prediction of, 43
CARCINOGENS
(see u-!ao cocARcmoGENs; Mu-
  TAGENS)

benzo(a)pyrene, 36-37
binding to proteins, 9&91
formation and activation in vivo,
89-93

in gas phase of cigarette smoke, 9%
94

lung carcinogens in cigarette smoke,
3541

maternal-fetal exchange of cigarette
smoke components, 98-99
metabolic activation by mixed func-
tion oxidase systems, 89
nicotine, 39, 91-93
nitrosamines, 37, 49
organ-specific agents in particulate
phase, 94, 9'7

in particulate phase of tobacco
smoke, 94-95

polonium-210, 46
polycyclic aromatic hydrocarbons,
36-37,93-94

prediction of activity by mutagene-
sis assay systems, 42-43
prediction of activity by sebaceous
gland suppression test, 43
t.obacco flavor additives, 99
weak acids, 38

CARDIOVASCULAR DISEASES
(See dao CORONARY DISEASE)
animal models of sudden death, 44,
   46

carbon monoxide in etiology of, 118
effect of lower tar and nicotine ci-
  garettes on risk, summary of
  findings, 19-20, l!25-126
effect of smoking on risk, 115117
research recommendations, 120-125
CARDIOVASCULAR SYSTEM
(See alao BBART FUNCTION;
  BEART RATE)

effect of carbon monoxide, 46
effect of lower nicotine cigarettes
on function, 118
effect of nicotine on function, 117-
118

CATECHOL CONTENT
in tobacco smoke, 96

241


INDEX

CATECHOLS

carcinogenicity, 98
cocarcinogenicity, 68, 96
CATECHOLAMINE LEVELS
effect of nicotine, 117-118
CEREBROVASCULAR DISORDERS
(See a&w CARDIOVASCULAR DI-
  SEASES)

effect of filtered cigarettes on mor-
tality, 119

CESSATION OF SMOKING
(See ah EX-SMOKERS; REDUC-
  TION OF SMOKING)
effect on coronary heart disease
  risk, 115-116

effect on neoplasm risk, 89
males vs. females, 214
recommended programs for pregnant
women, 162-162
recommended research on pregnancy
and, 162166

relationship of tar and nicotine yield
  to cessation attempts, 223-226
role of lower tar and nicotine cigar-
  ettes, 186,~226
role of lower tar and nicotine cigar-
  ettes, summary of findings, 24,
   22%230
CHILDREN

(See also NEONATE)
effect of maternal smoking on
  health, 156159
effect of maternal smoking on phy-
  sical, intellectual, and emotional
  development, 159
effect of maternal smoking, sum-
  mary of findings, 21-22, 170
effect of parental smoking on
  health, E&L159
CHROMOSOMES
(See also MUTAGENESIS)
aberrations in smokers vs. nonsmok-
  ers, 48

CHRONIC OBSTRUCTIVE LUNG DI-
SEASE

(See also BRONCHITIS; EM-
PHYSEMA)

animal models, 43-44
effect of lower tar cigarettes on
risk, 11-12

effect of lower tar and nicotine cig-
arettes on risk, summary of find-
ings, 29-21, 146149

242

CHRONIC OBSTRUCTIVE LUNG
DISEASE-Con.

lower tar and nicotine cigarettes in
etiology of, research recommenda-
tions, 142-148

smoking characteristics and, 129
smoking in etiology of, 11-12, 135-
136

smoking in etiology of, summary of
  findings, 20-21, 146149
CHRYSENE

carcinogenicity, 95
CBRYSENE CONTENT
in tobacco smoke, 95
CIGARETI'E PAPER
effect of porosity on smoke composi-
  tion, 50

Cigarette smoke See SMOKE, CIGAR

Cigarette smoke+ gas phree See GAS
PHASE, CIGARETTE SMOKE
Ciearette rpaoLe, partidate phe See
PARTICULATE PHASE, CIGA&
ETI'E SMOKE

Cigarette smoking See SMOKING
Cigamttetus&eTARS,CIGARElTE
CIGARETI'E VENTILATION
effect on smoke composition, 50
CIGABEllW3

benzo(u)pyrene content (1955-1980),

consumption trends, 80
correlation between carbon monox-
ide yield and tar yield, 209, 211
correlation between nicotine yield
and tobacco weight, 299-210
correlation between tar yield and
nicotine yield, 206, 206-210
correlation between tar yield and
tobacco weight, XW-210, 212
development of optimum tar to ni-
cotine ratios, 184185
effect of butt and overwrap lengths
on tar and nicotine yields, 211
effect of product design on smoke
composition, 49-50
federal regulation of, 6, 201
monitoring smoke components in
new products, 52

nicotine yields of U.S. brands (1978-
1979), 23ce34

recommendations for research cigar-
ettes, 164-185


INDEX

CIGAREITES-Con.
tar yields of U.S. brands (1973
  1979), 230-234

trends in daily consumption, 213-214
trends in per capita consumption,
213-216

CIGAREWES, FILTRRED
(se5 ah FILTERS)
carbon monoxide content, 9697
effect on bronchitis mortality risk,
   140-141

effect on cardiovascular disease risk,
summary of findings, 20, 126
effect on cerebrovascular disorder
mortality, 119

effect on coronary heart disease
morbidity and mortality, 119l26
effect on cough prevalence, 140
effect on laryngeal neoplasm risk,

effect on lung neoplasm risk, 8285
nicotine yields of U.S. brands (1973
1979), 230-234

nitrogen oxide content, 97
recommendations for research cigar-
ettes, 184

tar yields of U.S. brands (1973
1979) 23&2&I

use trends, 201
CIGAREITES, HIGH-NICOTINE
demographic characteristics of users,
   219

effect on pancreatic elsstase levels
in dogs, 4445

CIGARElTES. HIGH-TAR
demographic characteristics of users,
   217-218

use trends in males vs. females,
217-219

CIGARETES, LOWER TAR AND
NICOTINE

sssessment of relative health risks,
8-15

behavioral and economic factors af-
fecting use, 182
carcinogenicity, 83-89
carcinogenicity, summary of find-
ings, 18-19, 101-102
in chronic obstructive lung disease
etiology, research recommenda-
tions, 142-148

compensatory smoking behavior, 73,
52, 57, 86, 97-98, 119, 177, HO-
182

CIGARElTES, LOWER TAR AND
NXCOTINJLCon.
determination of physical and chem-
  ical properties of smoke, research
  recommendations, 55-56
development of research cigarettes,
  58-59,134-185

effect on antitrypsin activity, 137-
133

effect on biihweight, 158
effect on cardiovascular disease risk,
research recommendations, l2O-
125

effect on cardiovascular disease risk,
summary of findings, N-20, l25
126

effect on chronic obstructive lung
disease risk, 11-12
effect on chronic obstructive lung
disease risk, summary of findings,
20-21, 148-149

effect on coronary heart disease
mortality, 119-120
effect on coronary heart disease
risk, 9-11, 1X-117
effect on elastase activity, 137-138
effect on lung function, research re-
commendations, 144-146
effect on lung neoplasm morbidity
and mortality rates, 79
effect on lung neoplasm mortality
risk, 8135

effect on mortality rate, E-13
effect on pregnancy, 12, 159
effect on pregnancy and infant
health, research recommendations,
160-162, X9-170
effect on pregnancy and infant
health, summary of findings, 21-
2z& 170

effect on tracheobronchial epitheli-
urn, 87-88, `142

market trends, 80, 199-212
product choice and use, summary of
findings, Z-24, 223-236
recommendations for carcinogenesis
research, 99-101

research recommendations from the
Working Meeting on Low-Yield
Cigarettes (June 1980), 24-26
role in cessation of smoking, sum-
mary of findings, 24, -230
role in cessation or reduction of
smoking, 183

243


INDEX

CIGARRITES, LGWER TAR AND
NICOTINE

role in initiation, maintenance, and
cessation of smoking, summary of
findings, 22, 186
role in initiation of smoking habit,
182183

role in maintenance of smoking ha-
bit, 183

use in male vs. female adolescents,
183

use trends, 199-223
CIGARRITES, LOW-NICOTINE
compensatory smoking behavior, 177,
   18&182

demographic characteristics of users,
219

effect on cardiovascular function,
118

compensatory smoking behavior, re-
search recommendations, 57
role in cessation of smoking, Z%
228

trends in sales-weighted average,
2oiRo8

use trends, 177, 219221
CIGARRITES. LOW-TAR
compensatory smoking behavior, 7-8,
  177, 189-182
definition, 295
demographic characteristics of users,
   217-218

effect of compensatory smoking on
chronic obstructive lung disease
risk, 149

effect on chronic obstructive lung
disease risk, 11-12
effect on coronary heart disease
risk, 9-11

effect on lung function, 139-149
effect on lung neoplasm risk, 9
effect on neoplasm risk, 89
effect on sputum production, 139
149

health effects of side&ream smoke,
research recommendations, 56
market trends, 29-292, 295-206
role in cessation of smoking, 22%
228

trends in sales-weighted average,
206208

use trends in adolescents, 226-222
use trends in males vs. females,
217-221

244

CIGARRITE& LOW-TAR-Con.
yield of non-tar constituenta, 7-8
CIGARETTES MRDIUM-N'ICOTINE
recommendations for use, 98, 186
research recommendations, 53
CIGARRITE& NON-NICOTINE
attitudes of smokers, 177
CIGARETTRS NONTORACCO
effect of nicotine content on pr+
  duct use, 177

CJLL4RY ACTIVITY
(See &so PULMONARY CLEAR
  ANCE)

determination of ciliatoxic smoke
  components, 57
effect of cigarette smoke, 47
cocARcINoGENs
@c-e do CARCINOGENS: MUTA-
  GENS)
catechol, 38
nicotine, 39-49. 94
in particulate phase of tobacco
  smoke, 94, 96
phenols, 33
weak acids, 38

Compensatory tanking See SMOKING
cHAB.A-cs
CORONARY DISEASE
(See c&o CARDIOVASCUIAR DE
  !3EAsEs)

carbon monoxide in etiology of, 10
effect of filtered cigarettes on mor-
bidity and mortality, 11%I29
effect of lower tar and nicotine cig-
arettes on mortality, 119l29
effect of lower tar and nicotine cig-
arettes on risk, 9-11, 116117
effect of lower tar and nicotine cig-
arettes on risk, summary of find-
ings, 19-29, 125-l.%
effect of lower tar cigarettes on
risk, 9-11

effect of smoking on risk, 910,
115-117

Multiple Risk Factor Intervention
  Trial (MRFIT), I22
risk in ex-smokem, 115-116
Coronary heat disease See CORO-
NARY DISEASE
COUGH

(See d-so RESPIRATORY SYMP-
TOMS)

effect of filtered cigarettea on pre-
valence, 140


CYANIDE CONTENT
in cigarette smoke, 94

DEMOGIUPBIC VARIABLES
(See u&m SEX RATIO)
high- vs. low-nicotine cigarette
  users, 219

high- vs. low-tar cigarette users,
217-218

mean daily dose of tar and nicotine
in smokers by race, sex, and age,
219-226

use of high- vs. low-tar cigarettes
in smokers by educational level,
218

use of high- vs. low-tar cigarettes
  in smokers by income level, 218
DIBENZACRIDINES
carcinogenicity, 95
in tobacco smoke, 95
DIBENZ(a,Jr)ANTBRACENE
carcinogenicity, 95
in tobacco smoke, 95
DIBENZO(c,g)CARBAZOLE
carcinogenicity, 95
in tobacco smoke, 95
DIBENZOPYRENES
carcinogenicity, 95
in tobacco smoke, 95

Educational level See DEMOGRAPBIC
VARIABLES
ELASTASE

effect of cigarette smoke on levels,
137-138

effect of high-nicotine cigarette
smoke on levels in dogs, 4445
role in emphysema etiology, 4344,
137-138

EMPHYSEMA
(see ah0 CHRONIC OBSTRUCTIVE
  LUNG DISEASE)
animal models, 142
biochemical markers in early detec-
  tion of, 139

cigarette smoke in etiology of, 4344
etiology, 43-44, 137-138
induced by smoke inhalation in ani-
mals, 43, 142

nitrogen oxides in etiology of, 138-
139

smoking and, 135-136
smoking in etiology of, 137-139

Endothetinm S'ce BLOOD VESSELS
ENVIRONMENTAL POLLUTION
(See also OCCUPATIONAL EXPO-
  s=)

interaction with smoking, research
  recommendations, 56-57
ENZYME ACTIVITY
(Se &o ARYL HYDROCARBON
  BYDROXYLASE; ELASTASE;
  OXIDASE ACTMTY)
effect of cigarette smoke on elas-
  tase, 137-138

effect of cigarette smoke on micro-
somal oxidases, 47-48
effect of high-nicotine cigarette
smoke on elastase levels in dogs,
4445

role in metabolic activation of carci-
nogens, 89

role of elsstase in emphysema etiol-
  ogy, 4&u, 137-138
ESOPHAGEAL NEOPLASMS
animal models, 42-43
carcinogens in particulate matter of
  cigarette smoke, 97
induced by nitrosonornicotine in
  rata, 41-42

smoking and alcohol consumption in
  etiology of, 42
EX-SMOKERS
(See &so CESSATION OF SMOK-
  ING)

coronary heart disease risk, 115-116

FATN ACIDS
effect of nicotine on levels in blood,
   117

FETAL MORTALITY
(See &UI PERINATAL MORTALI-
  J-V

effect of maternal smoking, 158
FETUS

effect of lower tar and nicotine cig-
arettes, 159

effect of maternal smoking, 157-159
effect of maternal smoking, research
  recommendations, 159-170
Filtmed cigarettes See CIGARETTES,
  FILTERED
FILTERS

(See also CIGARETTES,
FILTERED)
effect on carbon monoxide delivery,
119120

INDEX


INDEX

FILTERS-Con.
effect on smoke composition, 59
perforated type, 97
Forced expiratmy volume See LUNG
FUNCTION; RESPIRATORY
FUNCTION TESTS
Forced vital capacity See LUNG
FUNCTION; RESPIRATORY
FUNCTION TESTS
GAS PHASE, CIGARKITE SMOKE
(See deo SMOKE, CIGAREITE)
carcinogens, 98-94
toxic components, 88
GENETICS

effect on cigarette smoke pharma-
cology, research recommendations,
55

use in modification of cigarette
smoke composition, 50

BEALTB EDUCATION
public awareness of health hazards
  of smoking, 200-202
BEART FUNCTION
effect of carbon monoxide, 118
effect of nicotine, 117
BEART RATE
effect of nicotine, 117
BETEROCYCLIC NITROGEN COM-
POUNDS
carcinogenicity, 97
in cigarette smoke, 94, 97
BUMECTANTS
(See also TOBACCO ADDITIVES;
  TOBACCO FLAVOR)
in cigarettes, 51-52
HYPERTENSION
cadmium and, 119

IMMUNE SYSTEM
effect of smoking, 48
INDOLES
cocarcinogenicity, 96
in tobacco smoke, 96
INFANT MORTALITY
(See cdao PERINATAL MORTALI-
  W
effect of maternal smoking on sud-
  den infant death syndrome risk,
   158-159

246

Infant, newborn (%I month) See NEO
NATE

Inhalation See SMOKING CBARAC-
TERIsTIcs

-AL DEVJ3LOPMENT
effect of maternal smoking on chil-
  dren, 159

KIDNEY NEOPLASMS
carcinogens in particulate phase of
  cigarette smoke, 97

LACTATION

(&e also BREAST FEEDING)
recommended research on maternal
  smoking and, 156
LARYNGEAL NEOPLASMS
animal models, 41
effect of filtered cigarettes on risk,

induced by cigarette smoke inhala-
  tion in hamsters, 41
induced by nitrosamines in ham-
  sters, 41
LEGISLATION

federal regulation of tobacco indus-
try, 2Jx

bwer nicotine cigarettes See CIGAR
ElTES, LOWER TAR AND NICO-
TINE: CIGARETTES, LOW-NICO-

Lower tar cigarettea See CIGAR-
J!XTES. LOWER TAR AND NICO
TINE: CIGAREITES LOW-TAR
LUNG FUNCTION
(See also PULMONARY CLEAR-
  ANCE; RESPIRATORY FUNC-
  TION TESTS)
effect of lower tar and nicotine cig-
  arettes, research recommenda-
  tions, 144-148

effect of smoke inhalation in rats,
43

effect of smoking, 188
effect of tar yield, X39-140
smokers vs. nonsmokers, 141
LUNG NEOPLASMS
animal models, 8449
carcinogens in cigarette smoke, 85-

41, 97

cigarette tar in etiology of, 79
effect of filtered cigarettes on risk,


INDEX

LUNG NEOPLASMS-Con.
effect of lower tar and nicotine cig-
  arettes on morbidity and mortali-
  ty rates, 79

effect of lower tar and nicotine cig-
arettes on risk, summary of find-
ings, 18-19, 101-192
effect of lower tar cigarettes on
risk, 9

effect of smoking on risk, 9
effect of tar and nicotine content
  on mortality risk, 81-85
LUNGS

small airway pathology in smokers,
138

MATERNALFETAL EXCDANGE
animal models of transplacental car-
  cinogen&s, 47

cigarette smoke carcinogens, 9399
Maternal smoking See SMOKING,
MATERNAL

Maximum midexpiratory flow mea-
surements See LUNG FUNCTION;
RESPIRATORY FUNCTION
TESTS

Mixed fmction oxidasea See OXIDASE
ACTIVITY
MORBIDITY

dose-response relationship between
  smoking and disease, 63
MORTALITY

(See dso FETAL MORTALPrY; IN-
FANT MORTALITY; PERINA-
TAL MORTALITY)
cardiovascular diseases, effect of fil-
tered cigarettes on risk, 119-120
effect of lo! er tar and nicotine cig-
arettes, U-13

MUTAGENESIS
(see uzso cARCINOGENES1s;
  CHROMOsoMES)
sister chromatid exchange in smok-
  ers vs. nonsmokers, 48
value of assays in prediction of car-
  cinogenic potential, 4243
MUTAGENS

(See also CARCINOGENS; COCAR-
CINOGENS)
in cigarette smoke, 3733
tobacco flavor additives, 99
in urine in smokers vs. nonsmokers,
41

MYOCARDIIJM
effect of carbon monoxide, 118

NAP-
in bladder neoplasm etiology, 41
NEONATE

effect of maternal smoking, 153-159
effect of maternal smoking, research
  recommendations, 159-170
effect of maternal smoking, sum-
  mary of findings, 21-22, 170
NEOPIASMS

effect of cessation of smoking on
risk, 80

effect of lower tar and nicotine cig-
arettes on risk, summary of find-
ings, 1319, 101-102
effect of lower tar cigarettes on
risk, 80

smoking in etiology of, 79311
NICREL CONTRNT
carcinogenicity, 97
in cigarette smoke, 97
NICOTINE

animal models of tolerance and phy-
sical dependence, 179
animal models of nicotine use, 173
179

cocarcinogenicity, 39-40, 94
effect on blood platelets, 118
effect on cardiovsscular function,
117-118

effect on catecholamine levels, 117
effect on cortisol secretion, 117-118
effect on fatty acid levels in blood,
117

effect on pregnancy, 4ti7
evaluation of health effects, re-
  search recommendations, 54
health effects in fetus and child, re-
  search recommendations, 163
intravenous and oral exposure in
  smokers, 177-178
role in carcinogenesis, 39, 91-93
role in maintenance of smoking ha-
  bit, 177-180, 183
self-administration in animals, 179
NICOTINR CONTENT
in blood, effect of lower tar and
  nicotine cigarettes, 181-182
cessation of smoking attempts and,
   22sB3

in cigarettes, development and vali-
dation of analytical methods, 53

247


NICOTINE CONTENT-Con.
cigarettes in the United States
  (19x%-1979), 239-234
correlation with tar yield, 206, 2@-
   210

NUCLEIC ACIDS
binding of aromatic amides and
  amines, 91

correlation with tobacco weight per
cigarette, 299-210
effect of puffing profile on yield,
210-211

effect of smoking characteristics on
yield, 216211

effect on daily cigarette consump
tion, Z2-225

INDEX

effect on lung neoplasm mortality
risk, 81-85

mean daily dose in smokers by race,
  sex, and age, 219-229
percentage distribution of smokers
  by nicotine yield, 219, 221
relationship to nitrosamine content
  in tobacco smoke, 39
NICOTINE REDUCTION
Public Health Service recommenda-
  tions, 2cHL201

NITRATE CONTENT
Znitropropane in cigarette smoke,
   94

NITROGEN OXIDE CONTENT
in cigarettes with perforated filter
  tips, 97

NITROGEN OXIDES
in emphysema etiology, 133139
NlTRosAMINE CONTENT
in cigarette smoke, 3'7, 94-95, 97
in tobacco, 37
reduction of in cigarette smoke, 40,
   95-96

relationship to nicotine content in
  tobacco smoke, 39
NITROSAMINES
carcinogenicity, 37, 49, 91-92, 97
carcinogenicity in animals, 95-93
in esophageal neoplasm induction in
  rata, 4142

formation in cigarette smoke, 40
formation in tobacco and tobacco
smoke, 95

formation in vivo, 40, 92-93, 95-96
in laryngeal neoplasm induction in
hamsters, 41

in pancreatic neoplasm induction in
hamsters, 42

NITROSOMETBYLUREA
in neoplasm induction in animals, 92

Oha&uctive airway flimafm See
BRONCBITIS; CHRONIC OB
STRUCTIVE LUNG DISEASE;
RMPIIYSEMA
OCCUPATIONAL EXPOSURE
(see ah0 ENVIRONMENTAL POL
  LUTION)
interaction with smoking, research
  recommendations, 56-57
ORAL NEOPLASM!3
animal models, 42
smoking and alcohol consumption in
  etiology of, 42
OXIDASE ACllVlTY
effect of cigarette smoke on micro-
  somal oxidases, 47-43
role in carcinogenesis, 43, 39
PANCREATIC NEOPLASMS
animal models, 42-43
carcinogens in particulate phase of
  cigarette smoke, 97
induced by diisopropylnitrosamine in
  rata, 42
hrental amking See SMOKING, PA-
  RENTAL
PARTICULATE PHASR, CIGARElTE
  SMOKE
(See aleo SMOKE, CIGARKITE;
  SMOKE, TOBACCO; TARS, CIG
  mm)
carcinogens, 94-95, 97
cocarcinogens, 94. 96
toxic components, 33-34
PASSIVE SMOKING
(See ah SMOKE STREAMS)
h&&h effects of lower tar and nit+
  tine cigarettes, research recom-
  mendations, 56, 53
public attitudes toward health ef-
  fects, 204
Peak expiratory fbw meammmnta
See LUNG FUNCl'ION; RRSPIRA-
  TORY FUNCTION TESTS
PERINATAL MORTALITY
(See also INFANT MORTALITY)
effect of lower tar and nicotine cig-
   arettes on risk, 159
effect of maternal smoking, 153
risk factors. 153

248


INDEX

PRENOIS

carcinogenicity, 96
cocarcinogenicity, 96
PLACENTA

effect of maternal smoking, 157-156
effect of maternal smoking, research
  recommendations, X4-165
PoL4mruM-210
carcinogenicity, 40, 97
formation in cigarette smoke, 49
formation in tobacco, 40
PoLoNnJM-210 CONTENT
in cigarette smoke, 97
reduction of in tobacco, 46
Polycyclic aromatic hydroaarbona See
AROMATIC HYDROCARBONS
PRKGNANCY

(See also FETUS; NEONATE)
animal models of maternal smoking
and, 167

effect of lower tar and nicotine cig-
arettes, rz, 159

effect of lower tar and nicotine cig-
arettes, research recommenda-
tions, 169-162, W-170
effect of maternal smoking, 46-47,
157-159

effect of maternal smoking, sum-
  mary of findings, 21-22, 170
effect of maternal smoking, research
  recommendations, 159-170
perinatal projects, 161
recommended research on smoking
  cessation and, 162-169
PREMATURITY
effect of maternal smoking on risk,
   158
PRGTRINS

binding of carcinogens, 9691
Puffing pan-am&era See SMOKING
cHARAcTERIsTIcs
PULMONARYCLEARANCE
(See abo CILIARY ACllVlTY;
  LUNG FUNCIION)
effect of cigarette smoke, 47
Pulmonary function See LUNG FUNC-
TION

Racial groups See DRMOGRAPIIIC
VARLWLES

RRDUCTION OF SMOKING
(See duo CESSATION OF SMOK-
  ING)

REDUCTION OF SMOKING-Con.
role of lower tar and nicotine cigar-
  ettes, 166

RRSPIRATGRY FUNCTION TESTS
(See also LUNG FUNCTION)
in early detection of lung disease,
  43, 141

RESPIRATORY SYMPTOMS
(See ala COUGH)
effect of tar yield, 139-146

SEX RATIO

(See also DEMOGRAPHIC VARIA-
BJ.JW

cessation of smoking, 214
smoking habit in the United States,
211-214

use trends for high- and low-tar
  cigarettea, 217-219
use trends for lower tar cigarettes
  among adoleacenta, Z?
SMOKE, CIGARFTIE
(See also GAS PHASE, CIGAR-
  ElTE SMOKE; PARTICULATR
  PHASE, CIGAREITR SMOKE;
  SMOKE SW; SMOKE,
  TOBACCO)

analysis of components, research re-
commendations, 52-59
animal models of reduced carcino-
genicity, 94

bioasaays of selected components, re-
search recommendations, 59
in chronic obetructive lung dii
etiology, 149-144
determination of toxicity, research
recommendations, 52-59
development of analytical methods,
56 l24

effect of agricultural practices on
composition, 51
effect of cigarette design on compo-
sition, 49-50

effect of filters on composition, 56
effect of tobacco additives on com-
pceition and activity, 51-52
effect of tobacco curing on compasi-
tion, 51

effect of tobacco process' ing on com-
position, 51

effect of tobacco varieties on com-
position, 56
effect of ventilation on composition,
50

249


INDEX

SMOKR, CIGARETl'B-Con.
effect on ciliary activity, 47
effect on pulmonary clearance, 47
in emphysema etiology, 4344
formation of components, 33
lung carcinogens, 3541
metabolism of carcinogenic compo-
  nents, 89-93

monitoring components in new pro
ducts, 53

monitoring relative vs. absolute
yields of components, 54-55
mutagenic vs. carcinogenic compo-
nents, 37-38

pharmacology and toxicology, sum-
mary of findings, 1618, 59-61
yield of constituents in lower tar
products, 7-8

SMOKE INHALATION
in emphysema induction in rats, 43
in laryngeal neoplasm induction in
  hamsters, 41

SMORE STREAMS
(See al-m SMOKE, CIGARElTE;
  SMOKE, TOBACCO)
health effects of sidestream smoke
  from lower tar and nicotine cig-
  arettes, 56, 58

SMORR, TOBACCO
pharmacology and toxicology, sum-
  mary of findings, 1618, 5961
SMOKERS VS. EXSMOKERS
attitudes toward health hazards of
  smoking, 263

SMOKERS VS. NONSMOKERS
attitudes toward health effects of
  passive smoking, 294
chromosomal aberrations, 48
coronary heart disease risk, 115
lung function, 141
mutagens in urine, 41
sister chromatid exchange, 48
small airway pathology, 138
tracheobronchial epithelium, 8788
SMOKING

(See also SMOKE. CIGAREPI'E;
SMORB INIIALATION; SMORE,
TOBACCO; SMOKING, MATER-
NAL; SMORING, PARENTAL)
in chronic obstructive lung disease
etiology, 135136
effect on cardiovascular disease risk,
115117

250

SMOKING-Con.
effect on coronary heart disease
  risk, 115-117

SMOKING ANB BEALTII
dose-response relationship between
  smoking and morbidity, 6-8
public attitudes toward health ef-
  fects of smoking, 202-264
public awareness of health effects
  of smoking, 266-262
recommendations for clinical testing
  facilities for smokers, 184
Smoking behavior See SMOKING
CHARACTERISTICS
SMOKING CHARA-CS
accuracy of smoking machines in rc+
  production of, 49, 186, 185
compensatory smoking behavior with
  lower tar and nicotine cigarettea,
  7-8, 52, 57, 86, w-98, 119, 177,
   186-182

compensatory smoking behavior,
summary of findings, 22, 186
effect of compensatory smoking be-
havior on obstructive airway di-
sease risk, 146

effect on acute airway reaponse to
smoke inhalation, 139
effect on tar and nicotine yields,
216-211

effect on yield of cigarette smoke
constituents, 49

research recommendations, 53-54
SMOKING IIABIT
age at onset by tar and nicotine
  yield, 221-223

behavioral aspecta, summary of find-
ings, 22, 186

effect of alternative modes of nico-
tine exposure, 177-178
effect of tar and nicotine yield on
daily cigarette consumption, 222-
225

males vs. females in the United
Statea, 211-214

role of lower tar and nicotine cigar-
ettes in initiation of, 182183
role of lower tar and nicotine cigar-
ettes in maintenance of, 183
role of nicotine in maintenance of,
177-186, 183

trends in daily cigarette consumg
tion, 86, 213-214


INDEX

SMOKING HABIT-Con.
trends in per capita cigarette and
  tobacco consumption, 219-216
trends in use of lower tar and nico-
  tine products, 199
trends in use of lower tar and nico-
  tine cigarettes, summary of find-
  ings, 22-24, 228-296
SMOKING MACHINES
accuracy in reproducing smoking be-
  havior, 49, 186, 185
design parameters, 49-49, 59
monitoring relative vs. absolute
  yields of smoke components, 54
   55

recommendations for improvement,
185

recommendations for maximum yield
=wh 185

SMOKING, MATERNAL
behavioral studies of pregnant wom-
  en, research recommendations,
   162-163

effect on birthweight, 158
effect on fetal mortality, 158
effect on health of offspring, 158
159

effect on perinatal mortality, 158
effect on physical, intellectual, and
emotional development in chil-
dren, 159

effect on placenta, 157-158
effect on pregnancy, 4647, 157-159
effect on pregnancy and infant
health, research recommendations,
159-170

effect on pregnancy and infant
health, summary of findings, 21-
22, 170

effect on prematurity risk, 158
effect on spontaneous abortion risk,
158

effect on sudden infant death syn-
  drome risk, 158-159
SMOKING, PARENTAL
effect on health of offspring, l!%-
   159

SMOKING SURVEYS
attitudes toward health effects of
  smoking in smokers vs. ex-smok-
  ers, 203

National Clearinghouse on Smoking
and Health surveys, 269

SMOKING SURVEYS-Cm.
National Health Interview Study
  (NHIS), 199-201
public attitudes toward health ef-
  fects of smoking, 202-204
public awareness of health effects
  of smoking, 209-202
Roper Survey on smoking and
  health, 264

use of filtered cigarettes, 201
spirometric meamuementa See LUNG
FUNCI'ION

SPUTUM PRODUCTION
effect of tar yield, 199146

TAR CONTENT
cessation of smoking attempts and,
   2?3-228

cigarettes in the United States
(1978-1979), 230-234
correlation with carbon monoxide
yield. 299, 211
correlation with nicotine yield, 206,
-210

correlation with tobacco weight per
cigarette, 209-210, 212
development of analytical methods,
56, 124

effect of puffing profile on yield,
210-211

effect of smoking characteristica on
yield, 219-211

effect on daily cigarette consump
tion, BY225

effect on lung function, 199-149
effect on lung neoplasm mortality
risk, 81-85

effect on respiratory symptoms,
199-146

effect on sputum production, 19%
146

mean daily dose in smokers by race,
  sex, and age, 21%226
percent distribution of smokers by
  tar yield, 219-222
TAR REDUCTION
effect on coronary heart disease
  risk, CL11

Public Health Service recommenda-
  tions, 299-Xl1
TARS, CIGAREXTR
(see QLSO PARTKXJLATE PHASE,
  CIGARETTE SMORE)
atherosclemis and, 119

251


INDEX

TARS, CIGABBPIT-Con.
in lung neoplasm etiology, 79
TOBACCO ADDITIVES
(.%z also IIUMECTANTS; TOBAC-
  CO FLAVOR)

assessment of health risks, 6, 8
carcinogenicity and mutagenicity of
  flavoring agents, 99
effect on smoke composition, 51-52
flavoring agents, 5152
humectants, 51-52
TOBACCO ANTIGENS
effect on endothelium, 119
TOBACCO CURING
(See aleo AGRICULTURAL PRAC-
  TICES)

effect on cigarette smoke pharma-
  cology, research recommendations,
   55
effect on smoke composition, 51
TOBACCO FLAVOR

TOBACCO FLAVOR-Con.
flavoring agents in cigarettes, 51-52
TOBACCO INDUSTRY
federal regulation of, 6, 291
TOBACCO PROCESSING
effect on smoke composition, 51
TOBACCO VARIBTIW
smoke composition, 50
TRACIIEOBRONCIIIAL EPITBELI-
UM

effect of lower tar and nicotine cig-
  arettes, 87438,142
effect of smoking, 87-88
Tumor initiating agentJJ &see CARCE
NOGENS

TumorpmmotingagentaseecocAR
CINOGENS

URETHANES
content in cigarette smoke, 94

(See ah HUMECTANTS; TOBAC-    VINYL CHLORIDE
CO ADDITIVES)           content in cigarette smoke, 94
carcinogenicity and mutagenicity of    metabolic activation, 98
additives, 99            Vital apacity Sex LUNG PUNCTION

252