CLEARING THE SMOKE

ASSESSING THE SCIENCE BASE FOR TOBACCO HARM REDUCTION

Kathleen Stratton, Padma Shetty, Robert Wallace, and Stuart Bondurant, Editors

Committee to Assess the Science Base for Tobacco Harm Reduction

Board on Health Promotion and Disease Prevention

INSTITUTE OF MEDICINE

NATIONAL ACADEMY PRESS
Washington, D.C.



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Clearing the Smoke: Assessing the Science Base for Tobacco Harm Reduction CLEARING THE SMOKE ASSESSING THE SCIENCE BASE FOR TOBACCO HARM REDUCTION Kathleen Stratton, Padma Shetty, Robert Wallace, and Stuart Bondurant, Editors Committee to Assess the Science Base for Tobacco Harm Reduction Board on Health Promotion and Disease Prevention INSTITUTE OF MEDICINE NATIONAL ACADEMY PRESS Washington, D.C.

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Clearing the Smoke: Assessing the Science Base for Tobacco Harm Reduction NATIONAL ACADEMY PRESS 2101 Constitution Avenue, NW Washington, D.C. 20418 NOTICE: The project that is the subject of this report was approved by the Governing Board of the National Research Council, whose members are drawn from the councils of the National Academy of Sciences, the National Academy of Engineering, and the Institute of Medicine. The members of the committee responsible for the report were chosen for their special competences and with regard for appropriate balance. Support for this project was provided by the Food and Drug Administration (FDA) prior to the March 2000 decision by the Supreme Court denying FDA comprehensive authority over tobacco products. The views presented in this report are those of the Institute of Medicine Committee to Assess the Science Base for Tobacco Harm Reduction and are not necessarily those of the funding agencies. Library of Congress Cataloging-in-Publication Data Clearing the smoke: assessing the science base for tobacco harm reduction/Kathleen Stratton…[et al.], editors. p.; cm. ISBN 0-309-07282-4 (alk. paper: case) 1. Smoking—Health aspects. 2. Smoking cessation programs. 3. Tobacco habit—Prevention. [DNLM: 1. Tobacco Smoke Pollution—prevention & control. 2. Biological Markers. 3. Environmental Exposure—adverse effects. 4. Neoplasms—etiology. 5. Nicotine—pharmacology. 6. Smoke—adverse effects. QV 137 C6225 2001] I. Title: Assessing the science base for tobacco harm reduction. II. Stratton, Kathleen R. RA645.T62 C56 2001 362.29'66–dc21 2001002837 ISBN 0-309-07282-4 Additional copies of this report are available for sale from the National Academy Press, 2101 Constitution Avenue, N.W., Box 285, Washington, DC 20055. Call (800) 624–6242 or (202) 334–3313 (in the Washington metropolitan area), or visit the NAP’s home page at www.nap.edu. The full text of this report is available at www.nap.edu. For more information about the Institute of Medicine, visit the IOM home page at www.iom.edu. Copyright 2001 by the National Academy of Sciences. All rights reserved. Printed in the United States of America. The serpent has been a symbol of long life, healing, and knowledge among almost all cultures and religions since the beginning of recorded history. The serpent adopted as a logotype by the Institute of Medicine is a relief carving from ancient Greece, now held by the Staatliche Museen in Berlin.

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Clearing the Smoke: Assessing the Science Base for Tobacco Harm Reduction “Knowing is not enough; we must apply. Willing is not enough; we must do.” —Goethe INSTITUTE OF MEDICINE Shaping the Future for Health

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Clearing the Smoke: Assessing the Science Base for Tobacco Harm Reduction THE NATIONAL ACADEMIES National Academy of Sciences National Academy of Engineering Institute of Medicine National Research Council The National Academy of Sciences is a private, nonprofit, self-perpetuating society of distinguished scholars engaged in scientific and engineering research, dedicated to the furtherance of science and technology and to their use for the general welfare. Upon the authority of the charter granted to it by the Congress in 1863, the Academy has a mandate that requires it to advise the federal government on scientific and technical matters. Dr. Bruce M.Alberts is president of the National Academy of Sciences. The National Academy of Engineering was established in 1964, under the charter of the National Academy of Sciences, as a parallel organization of outstanding engineers. It is autonomous in its administration and in the selection of its members, sharing with the National Academy of Sciences the responsibility for advising the federal government. The National Academy of Engineering also sponsors engineering programs aimed at meeting national needs, encourages education and research, and recognizes the superior achievements of engineers. Dr. Wm. A. Wulf is president of the National Academy of Engineering. The Institute of Medicine was established in 1970 by the National Academy of Sciences to secure the services of eminent members of appropriate professions in the examination of policy matters pertaining to the health of the public. The Institute acts under the responsibility given to the National Academy of Sciences by its congressional charter to be an adviser to the federal government and, upon its own initiative, to identify issues of medical care, research, and education. Dr. Kenneth I.Shine is president of the Institute of Medicine. The National Research Council was organized by the National Academy of Sciences in 1916 to associate the broad community of science and technology with the Academy’s purposes of furthering knowledge and advising the federal government. Functioning in accordance with general policies determined by the Academy, the Council has become the principal operating agency of both the National Academy of Sciences and the National Academy of Engineering in providing services to the government, the public, and the scientific and engineering communities. The Council is administered jointly by both Academies and the Institute of Medicine. Dr. Bruce M.Alberts and Dr. Wm. A.Wulf are chairman and vice chairman, respectively, of the National Research Council.

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Clearing the Smoke: Assessing the Science Base for Tobacco Harm Reduction COMMITTEE TO ASSESS THE SCIENCE BASE FOR TOBACCO HARM REDUCTION STUART BONDURANT, M.D. (Chair), Professor, Department of Medicine, University of North Carolina, Chapel Hill ROBERT WALLACE, M.D., M.Sc. (Vice-Chair), Professor, Departments of Epidemiology and Internal Medicine, University of Iowa Colleges of Public Health and Medicine J.RICHARD CROUT, M.D., President, Crout Consulting GARRET FITZGERALD, M.D., Professor and Chair, Department of Pharmacology, University of Pennsylvania ADI GAZDAR, M.D., Professor, Department of Pathology, University of Texas Southwestern Medical Center GARY GIOVINO, Ph.D., M.S., Senior Research Scientist, Roswell Park Cancer Institute DOROTHY HATSUKAMI, Ph.D., Professor, Department of Psychiatry and Psychology, University of Minnesota ROGENE F.HENDERSON, Ph.D., Senior Biochemist/Toxicologist, Lovelace Respiratory Research Institute PETER REUTER, Ph.D., Professor, School of Public Affairs and Department of Criminology, University of Maryland DAVID J.RILEY, M.D., Professor of Medicine, Division of Pulmonary and Critical Care Medicine, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School PETER SHIELDS, M.D., Professor and Chief, Cancer Genetics and Epidemiology Program, Lombardi Cancer Center, Georgetown University Medical Center JAMES WILLERSON, M.D., Professor and Chair of Internal Medicine, University of Texas Medical School Health Promotion and Disease Prevention Board Liaison KENNETH E.WARNER, Ph.D., Professor, Department of Health Management and Policy, School of Public Health, University of Michigan Neuroscience and Behavioral Health Board Liaison RICHARD J.BONNIE, L.L.B., John S.Battle Professor of Law, Director, Institute of Law, Psychiatry, and Public Policy, University of Virginia School of Law

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Clearing the Smoke: Assessing the Science Base for Tobacco Harm Reduction Consultants NEAL BENOWITZ, M.D., Professor and Chief of the Division of Clinical Pharmacology, Departments of Medicine, Biopharmaceutical Sciences, and Psychiatry, University of California, San Francisco CHRISTOPHER LOFFREDO, Ph.D., M.S., Assistant Professor, Lombardi Cancer Center, Georgetown University Medical Center Staff KATHLEEN STRATTON, Ph.D., Study Director PADMA SHETTY, M.D., Program Officer ANN W.ST. CLAIRE, Senior Project Assistant ROSE MARIE MARTINEZ, Sc.D., Director, Board on Health Promotion and Disease Prevention TERRY PELLMAR, Ph.D., Director, Board on Neuroscience and Behavioral Health

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Clearing the Smoke: Assessing the Science Base for Tobacco Harm Reduction Preface Tobacco has been used by humans for at least a millennium, and its harmful effects have been suspected for at least 200 years. In the last 50 years, convincing and generally accepted evidence has established the fact that exposure to tobacco products is the major single cause of early human mortality and morbidity in developed nations and in many developing nations as well. Even nonsmokers suffer morbidity and excess mortality from the toxic effects of inhalation of sidestream smoke. Both smokers and their nonsmoking associates are more likely to be injured in fires and automobile accidents. The personal and social price we pay for establishing and sustaining nicotine addiction through exposure to tobacco smoke is our greatest controllable health cost and one of our greatest social burdens. It has been scientifically established that reduced exposure to tobacco smoke by lifelong abstinence and avoidance of smoke eliminates the added risk and harm and that cessation, even after many years of smoking, reduces risk and harm both immediately and in the long term for many tobacco-related conditions. Several smoking cessation programs, some aimed at individuals and some at communities, have been shown to be modestly effective in assisting smokers to quit smoking. These programs have been shown to be more effective with the added use of nicotine replacement by patches for absorption through the skin, by nicotine-containing chewing gum or sprays for absorption through oral or nasal mucous membranes, or by the administration of psychotropic drugs to reduce the desire for nicotine.

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Clearing the Smoke: Assessing the Science Base for Tobacco Harm Reduction However, with the most intensive application of the most effective known programs for prevention and cessation, approximately 10–15% of the adults in the United States are expected to be regular users of tobacco in 2010, and they will continue to suffer the increased incidence of harmful and lethal consequences. Among this group are many who cannot or will not stop using tobacco, and it is to this group that effective programs and products of harm reduction should be directed. New tobacco products and nicotine replacement products are being marketed frequently and, along with products now on the market, often have associated direct or implied health claims. Some of the new products differ from traditional products in ways that appear minor, whereas others involve substantial changes in types of tobacco, in additives, or in curing, blending, or processing of the tobacco. New products may also change the composition of the aerosol the consumer inhales compared to cigarette smoke by changing the burning temperature of the tobacco by new methods of combustion, by limiting the release of smoke into the atmosphere, by dilution of the smoke with air, and/or by adding unnatural carriers for smoke particles. Although many components of tobacco are known to be toxic, little is known of the specific dose-response relations of the individual toxins as they occur in cigarette smoke or of the interactions between the constituents of tobacco smoke. There is little direct evidence that removal of specific substances from tobacco smoke or from tobacco actually reduces risk or harm to human health. In considering the health effects of modified tobacco products it is important to remember that the health consequences of the use of any such product are determined not by the toxic agents removed from the product but by the actual exposure to the toxins that remain. Harm reduction is the net difference in harm between the products as actually used. There is strong evidence that in the range of exposures involved in smoking, there is a quantitative relationship between the magnitude of exposure and the incidence of cancer, coronary vascular disease, pulmonary disease, and several other tobacco-related illnesses. Rarely if ever is there impartial and thorough assessment of the risk associated with new tobacco products relative to the risk of abstinence or the risk of other tobacco products prior to marketing. Unlike new tobacco products, nicotine replacement products are subject to full disclosure of content, rigorous testing, and the regulation of marketing claims by the of the Food and Drug Administration. In addition to cigarette smoke, other forms of tobacco such as cigars, chewing tobacco, and snuff are also vectors of nicotine addiction and often have their own sets of serious toxic consequences.

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Clearing the Smoke: Assessing the Science Base for Tobacco Harm Reduction The latent period between beginning exposure to tobacco and the development of most of the major adverse consequences is so long that empirical, direct evidence (assessment of immediate and long-term toxicity of individual tobacco products in humans) that one tobacco product is less harmful than another will rarely be available in time to be a basis for informing users. In the absence of direct evidence, conflicting claims of the degree of harm reduction are likely and informed usage decisions by smokers and nonsmokers will be difficult. No one knows the dose-response relations, the specific toxins, the pathogenic mechanisms, or the interrelationship between the many components of tobacco smoke with enough precision to make scientifically reliable quantitative judgments about the risk or actual harm reduction associated with use of any tobacco product. Since we do not know which of many toxins may be the cause of specific harmful effects, we can only infer but we cannot know the health effects of the elimination of any one or several tobacco components. Further, we are just beginning to identify and understand the genetic basis and other causes of the differences in susceptibility to toxic effects among groups or individuals that largely determine the response of an individual to a toxin. Nonetheless, it is reasonable to expect that some of the new products will reduce exposure to tobacco toxins and possibly reduce harm to some users and to others who are exposed to them. It is, therefore, urgent and important that the assessment of exposure to tobacco toxins resulting from the use of modified tobacco products or drugs be based on the best available evidence, made by the most qualified judges, and communicated to policy makers and the public completely and honestly. There is little direct evidence available to serve as a basis for judgment as to the potential for harm reduction of specific new tobacco and pharmaceutical products. Therefore, any conclusions as to the relative harm of these products must necessarily be inferred from a base of indirect knowledge. The continuing introduction of new tobacco products with implicit or explicit claims of risk or harm reduction makes it important and urgent that the capacity for the best possible scientific assessment of these claims be put in place. Since even the availability of harm reduction products may deter some from following the healthier course of abstinence or cessation, assessment of health claims should be based on an estimate of the effect of the product on the prevalence of smoking in the population, as well as the effect on the health risk to the individual smoker. The most reliable scientific interpretation of necessarily incomplete indirect evidence comes when individuals who are experts in the related fields are not biased and are free of conflict of interest form a consensual

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Clearing the Smoke: Assessing the Science Base for Tobacco Harm Reduction judgment. Such a judgment based on evidence of high quality should be a requirement for a conclusion that the use of a product is in fact associated with decreased exposure to toxins and that the decreased exposure is likely to be associated with less harmful outcomes. Further, since these judgments of risk will necessarily be inferential because they are based on indirect and inconclusive evidence, some form of postmarketing surveillance of each product is important. The charge to the committee is to address the science base for harm reduction from tobacco. The committee concluded early in its deliberations that the science base for harm reduction will evolve over time. There will inevitably be important interactions between the types of products that are developed and the science base. There will also be interactions between any regulatory process and the science base (the science base will influence regulation, and regulation will focus pertinent science) and, obviously, between regulations and products. For these reasons, the committee realized that the science base for harm reduction can be usefully considered only in the context of some sense of the types of specific products and of the consequences of regulation. Accordingly, portions of this report address both general categories of potential harm reduction products and regulatory considerations. It is the strong sense of the committee that claims of less harm or risk associated with the use of tobacco products or drugs should be available—but only if four conditions are met: (1) There should be strong and widely available programs designed to avoid initiation and to achieve abstinence; (2) There should be premarketing evidence satisfactory to a group of disinterested experts that—as the product will actually be used by consumers—there is less exposure to toxic agents without coincidental increase in harm to the individual from other smoke components or to the population from encouraging initiation or continuation of smoking, the burden of proof of assertions of harm reduction should rest entirely with those making the assertion; (3) The public should be fully informed of the strength of the claims as assessed by an independent panel of experts; and (4) There should be an effective surveillance system in place to determine short-term behavioral and the long-term health consequences of the use of the new products. The committee wishes to express its great appreciation to the many individuals, listed in Appendix B, who contributed generously and substantially to its deliberations. Representatives of many health agencies as well as tobacco interests responded thoughtfully and extensively to the committee’s questions. Dr. Kathleen Stratton contributed perspective, insight, meticulous attention to detail, and essential oversight to the work and report. This

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Clearing the Smoke: Assessing the Science Base for Tobacco Harm Reduction report would not be possible without her substantial and important contributions. Dr. Padma Shetty assumed responsibility for blocks of the report, and both the full report and many specific parts are testimony to her analytic, organizational, and expressive proficiency. Ann St. Claire organized the arrangements for the work of the committee with great finesse and also made useful contributions to the analytical work of the committee. Every member of the committee is deeply appreciative of the work of Dr. Stratton, Dr. Shetty, and Ms. St. Claire. Stuart Bondurant Chair

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Clearing the Smoke: Assessing the Science Base for Tobacco Harm Reduction REVIEWERS The report was reviewed by individuals chosen for their diverse perspectives and technical expertise in accordance with procedures approved by the National Research Council’s Report Review Committee. The purpose of this independent review is to provide candid and critical comments to assist the authors and the Institute of Medicine in making the published report as sound as possible and to ensure that the report meets institutional standards for objectivity, evidence, and responsiveness to the study charge. The content of the review comments and the draft manuscript remain confidential to protect the integrity of the deliberative process. The committee wishes to thank the following individuals for their participation in the report review process: Daniel Azarnoff, D.L.Azarnoff Associates Alfred Fishman, University of Pennsylvania Margaret Gilhooley, Seton Hall University Jack Henningfield, Pinney Associates Peter Barton Hutt, Covington and Burling Roger McClellan, Chemical Industry Institute of Toxicology, President Emeritus Patricia Dolan Mullen, University of Texas Peter Nowell, University of Pennsylvania William Parmley, University of California, San Francisco Thomas Pearson, University of Rochester Frederica Perera, Columbia University John Pierce, University of California, San Diego Stephen Rennard, University of Nebraska Joseph Rodricks, The Life Sciences Consultancy Jonathan Samet, Johns Hopkins University Thomas Schelling, University of Maryland John Slade, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School Judith Wilkenfeld, Campaign for Tobacco Free Kids Gerald Wogan, Massachusetts Institute of Technology Raymond Woosley, Georgetown University Although the reviewers listed above have provided many constructive comments and suggestions, they were not asked to endorse the conclusions or recommendations nor did they see the final draft of the report before its release. The review of this report was overseen by David Challoner, (review monitor) University of Florida and Hugh Tilson, (review coordinator) University of North Carolina. Appointed by the

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Clearing the Smoke: Assessing the Science Base for Tobacco Harm Reduction National Research Council and Institute of Medicine, they were responsible for making certain that an independent examination of this report was carried out in accordance with institutional procedures and that all review comments were carefully considered. Responsibility for the final content of this report rests entirely with the authoring committee and the institution.

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Clearing the Smoke: Assessing the Science Base for Tobacco Harm Reduction Contents     EXECUTIVE SUMMARY   1 SECTION I:   INTRODUCTION, BACKGROUND, AND CONCLUSIONS         1 INTRODUCTION   21     History of Harm Reduction,   26     Definitions,   27     Nicotine,   28     Pharmaceutical Products,   29     Regulatory Issues and Authorities,   30     Committee Charge and Process,   31     Application of Risk Assessment to Tobacco Harm Reduction,   33     Operating Precepts,   35     2 PRINCIPLES OF HARM REDUCTION   38     Conceptual Framework for Harm Reduction,   39     Applications,   41     Comparing Other Harm Reduction Interventions to Those for Smoking,   50     Conclusions,   53     3 HISTORICAL PERSPECTIVE AND LESSONS LEARNED   60     Tobacco Marketing: Early Health Claims,   60

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Clearing the Smoke: Assessing the Science Base for Tobacco Harm Reduction     Health Impact of Low-Yield Products,   66     Risk Perception,   67     Potential Influence of PREPs on Tobacco Use Behaviors,   73     Summary and Relevance to PREPs,   76     4 PRODUCTS FOR TOBACCO EXPOSURE REDUCTION   82     Tobacco and Tobacco Products,   82     Pharmaceutical Products,   95     Other Potential Harm Reduction Methods: Behavioral Strategies and Tobacco Control Policies,   116     Regulation of Exposure Reduction Products,   122     5 THE SCIENTIFIC BASIS FOR PREP ASSESSMENT   140     Tobacco Smoke and Toxicology,   147     Exposure and Biomarker Assessment in Humans,   150     Nicotine Pharmacology,   161     Cancer,   163     Cardiovascular Disease,   167     Nonneoplastic Respiratory Disease,   170     Reproductive and Developmental Effects,   172     Other Health Effects,   174     6 SURVEILLANCE FOR THE HEALTH AND BEHAVIORAL CONSEQUENCES OF EXPOSURE REDUCTION   180     Existing Tobacco Surveillance Systems,   183     Proposed Surveillance System Enhancements,   188     Issues and Limitations Regarding Surveillance Systems for Assessing Tobacco-Related Health Outcomes,   195     Summary and Recommendations,   197     7 IMPLEMENTATION OF A SCIENCE-BASED POLICY OF HARM REDUCTION   201     Next Steps: An Overview,   203     Principles for Regulating Potential Reduced-Exposure Products,   206     Summary,   228     8 PRINCIPAL CONCLUSIONS   231

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Clearing the Smoke: Assessing the Science Base for Tobacco Harm Reduction SECTION II:   EVIDENCE FOR THE SCIENCE BASE         9 NICOTINE PHARMACOLOGY   243     Basic and Human Pharmacology,   243     Pharmacokinetics,   246     Pharmacodynamics,   252     Research Agenda,   269     10 TOBACCO SMOKE AND TOXICOLOGY   283     Physical and Chemical Characteristics of Tobacco Smoke,   283     Toxicity of Tobacco Smoke,   287     Assessment of Potential Exposure Reduction Products,   293     Synergistic Effects with Other Pollutants,   298     Molecular Biology Testing Tools,   298     Smokeless Tobacco Toxicity,   299     General Research Agenda and Recommendations,   302     11 EXPOSURE AND BIOMARKER ASSESSMENT IN HUMANS   309     External Exposure Assessment: The FTC Method and Questionnaire Data,   317     Biomarkers of Exposure,   323     Biomarkers Estimating the Biologically Effective Dose,   326     Biomarkers of Potential Harm,   333     Host Susceptibility,   344     Genetic Predispositions to Smoking Addiction,   347     Biomarker Assessment for Environmental Tobacco Smoke Exposure,   348     Development and Validation of Biomarker Assays, Including Quality Control,   348     Conclusions,   349     Research Agenda,   352     12 CANCER   367     Mutagenesis and DNA Damage,   368     Carcinogenesis,   370     Tobacco Mutagens and Carcinogens,   373     Scientific Methods for Assessing Harm Reduction Strategies,   379     Lung Cancer,   392     Oropharyngeal Cancers,   415     Bladder Cancer,   418     Endometrial Cancer,   421     Environmental Tobacco Smoke,   422     Cigar Smoking,   425

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Clearing the Smoke: Assessing the Science Base for Tobacco Harm Reduction     Smokeless Tobacco Products,   426     Studies of Nicotine Mutagenicity and Carcinogenicity,   429     Conclusions,   430     Research Agenda,   434     Special Issues in Study Designs,   438     13 CARDIOVASCULAR DISEASE   470     Coronary Heart Disease,   471     Extracardiac Vascular Disease,   481     Other Variables Influenced by Smoking,   482     Surrogate Markers,   483     Conclusions,   486     Research Agenda,   491     14 NONNEOPLASTIC RESPIRATORY DISEASES   500     Biomarkers of Respiratory Diseases,   501     Chronic Obstructive Pulmonary Disease,   503     Asthma,   518     Respiratory Infections,   525     Summary and Conclusions,   530     Research Agenda,   532     15 REPRODUCTIVE AND DEVELOPMENTAL EFFECTS   543     Fertility Impairment,   544     Spontaneous Abortions,   545     Placental Complications,   545     Preterm Delivery,   546     Low Birthweight,   547     Sudden Infant Death Syndrome (SIDS),   549     Congenital Malformations,   549     Cognitive and Behavioral Deficits in Childhood,   550     Fetal Lung Development,   551     Smokeless Tobacco,   551     Conclusions,   552     Recommendations,   553     16 OTHER HEALTH EFFECTS   560     Peptic Ulcers,   560     Surgical Wound Healing,   561     Inflammatory Bowel Disease,   561     Rheumatoid Arthritis,   562     Oral Disease,   563     Dementia,   564

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Clearing the Smoke: Assessing the Science Base for Tobacco Harm Reduction     Orthopedic Consequences,   565     Ocular Disease,   565     Dermatologic Conditions,   566     Diabetes,   567     Renal Disease,   567     Schizophrenia,   568     Depression,   568     Weight Change,   569     Drug Interactions,   570     Fire Safety,   570     Parkinson’s Disease,   571     Preeclampsia,   572     Summary,   572     Recommendations,   573     APPENDIXES         A PRESENTATIONS AND SUBMISSIONS   583     B COMMITTEE BIOGRAPHICAL SKETCHES   586     C TIME LINE OF TOBACCO EVENTS   593     INDEX   607

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