Clearing the Smoke: Assessing the Science Base for Tobacco Harm Reduction

by Institute of Medicine, Board on Health Promotion and Disease Prevention, Committee to Assess the Science Base for Tobacco Harm Reduction, Stuart Bondurant (Editor), Robert Wallace (Editor)

Overview

Despite overwhelming evidence of tobacco's harmful effects and pressure from anti-smoking advocates, current surveys show that about one-quarter of all adults in the United States are smokers. This audience is the target for a wave of tobacco products and pharmaceuticals that claim to preserve tobacco pleasure while reducing its toxic effects.

Clearing the Smoke addresses the problems in evaluating whether such products actually do reduce the health risks of tobacco use. Within the context of regulating such products, the committee explores key questions:

• Does the use of such products decrease exposure to harmful substances in tobacco?
• Is decreased exposure associated with decreased harm to health?
• Are there surrogate indicators of harm that could be measured quickly enough for regulation of these products?
• What are the public health implications?

This book looks at the types of products that could reduce harm and reviews the available evidence for their impact on various forms of cancer and other major ailments. It also recommends approaches to governing these products and tracking their public health effects.

With an attitude of healthy skepticism, Clearing the Smoke will be important to health policy makers, public health officials, medical practitioners, manufacturers and marketers of "reduced-harm" tobacco products, and anyone trying to sort through product claims.

Product Details

ISBN-13:	9780309072823
Publisher:	National Academies Press
Publication date:	10/17/2001
Pages:	656
Product dimensions:	6.00(w) x 9.00(h) x (d)

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CLEARING THE SMOKE

Assessing the Science Base for Tobacco Harm Reduction

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NATIONAL ACADEMIES PRESS

Copyright © 2001 National Academy of Sciences
All right reserved.
ISBN: 978-0-309-07282-3

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Chapter One

Executive Summary

BACKGROUND

Tobacco smoke is the cause of the most deadly epidemic of modern times. Smoking causes cancer (e.g., lung, oral cavity, esophagus, larynx, pancreas, bladder, kidney), chronic obstructive pulmonary disease (COPD), myocardial infarction, and stroke. The continuing toll of tobacco use has prompted the search for means of harm reduction for those who cannot or will not stop using tobacco. Numerous products that make implied or explicit claims to reduce the burden of smoking while allowing continued nicotine consumption are now entering the market. This report is concerned with the evaluation of these products.

Nearly one-quarter of adult Americans-an estimated 47 million people-smoke cigarettes (CDC, 2000a). Although this is far lower than the 42% recorded in 1965, the decline in the rates of smoking among adults appears to have leveled off during much of the 1990s (PHS, 2000). In a recent survey, 12.8% of middle school children and 34.8% of high school students reported some form of tobacco use during the month prior to their being interviewed (CDC, 2000b). The vast majority of smokers begin tobacco use during adolescence (IOM, 1994).However, 70% of smokers say they want to quit (CDC, 1994), and 34% of smokers make an attempt to quit each year. Thus, many but not all tobacco users find it very difficult to quit and continually expose themselves to known toxic agents.

DEFINITION OF HARM REDUCTION

For the purposes of this report, a product is harm-reducing if it lowers total tobacco-related mortality and morbidity even though use of that product may involve continued exposure to tobacco-related toxicants. Many different policy strategies may contribute to harm reduction. However, this report focuses on tobacco products that may be less harmful or on pharmaceutical preparations that may be used alone or concomitantly with decreased use of conventional tobacco. The committee does not use the term "safer cigarette," in particular, in order to avoid leaving the impression that any product currently known is "safe." Every known tobacco-containing product exposes the user to toxic agents; every pharmaceutical product can have adverse effects.

HISTORY OF EFFORTS TO REDUCE HARM FROM CIGARETTES

There have been many efforts in the past to develop less harmful cigarettes, none of which has proved to be successful. One of the first innovations with the promise of harm reduction was the development of cigarettes with filters. Filters attempt to reduce the amount of toxicants that go into the smoke inhaled by the smoker. The next major modification of cigarettes with safety implications was "low-yield" cigarettes. These products emit lower tar, carbon monoxide (CO), and nicotine than other products as measured by the Federal Trade Commission (FTC) assay (the "smoking machine"). Many consumers believed, and still do, that these products pose less risk to health than other cigarettes.

However, data on the health impact of low-yield products are conflicting, in part due to a lack of systematic study early in the introduction of the products. Most current assessments of morbidity and mortality suggest that low-yield products are associated with far less health benefit, if any, than would be predicted based on estimates of reduced toxic exposure using FTC yields. In order to maintain the desired intake of nicotine, many smokers who changed to low-yield products also changed the way they smoked (e.g, compensated by inhaling more deeply than when smoking higher-yield products). Thus, their exposure to tobacco toxicants is higher than would have been predicted by standardized assays and people who have continued to use these products have not significantly reduced their disease risk by switching to them. Moreover, widespread use of these products might have increased harm to the population in the aggregate if tobacco users who might otherwise have quit did not, if former tobacco users resumed use, or if some people who would otherwise not have used tobacco did so because of perceptions that the risk with low-yield products was minimal.

TYPES OF EXPOSURE REDUCTION PRODUCTS

Tobacco and cigarette-like products have been introduced recently that, under measurement systems such as the FTC smoking machine, result in decreased emission of some toxicants compared to conventional tobacco products. Currently available products include tobacco with reportedly reduced levels of some carcinogens and cigarette-like products that deliver nicotine with less combustion than cigarettes. Two classes of pharmaceutical products approved by the Food and Drug Administration (FDA) for short-term use in smoking cessation might also be used for harm reduction. These include nicotine products, such as in patch, gum, inhaler, and nasal spray preparations, and a nonnicotine product that reduces the craving for tobacco. These cessation drugs could be used long term to maintain cessation or concomitantly with continued but decreased use of conventional tobacco products (see Table 1).

These tobacco and pharmaceutical products could potentially result in reduced exposure to toxicants. The committee uses potentially, because whether exposure to tobacco toxicants is reduced depends on the user's behavior, such as frequency and intensity of use. Reduced exposure, however, does not necessarily assure reduced risk to the user or reduced harm to the population. Therefore, and in order to avoid misinterpretation, the committee uses the generic phrase "potential reduced-exposure products," or PREPs, when discussing the modified tobacco products, cigarette- like products (whether tobacco containing or not), or pharmaceutical products and medical devices (whether nicotine containing or not) used for their tobacco harm reduction potential. More such products are likely to be introduced in the near future, perhaps accompanied by claims that they are less harmful than conventional products.

THE COMMITTEE CHARGE AND ASSUMPTIONS

The Institute of Medicine (IOM) convened a committee of experts to formulate scientific methods and standards by which PREPs (pharmaceutical or tobacco-related) could be assessed. Four questions were imbedded within the charge given to the committee by the Food and Drug Administration in December 1999. Where there are not yet answers, the committee was asked to outline the broad strategy by which the knowledge base might be assembled.

1. Does use of the product decrease exposure to the harmful substances in tobacco?

2. Is this decreased exposure associated with decreased harm to health?

3. Are there surrogate indicators of this effect on health that could be measured in a time frame sufficient for product evaluation?

4. What are the public health implications of tobacco harm reduction products?

The first three questions deal with the adequacy of current scientific methods to determine whether and to what extent these products reduce the risk of morbidity and mortality and the nature of the advice to give to citizens, health professionals, and others. The fourth question is important because it addresses the population impact of these products. That is, although a product might be risk-reducing for an individual's health compared to conventional tobacco products, its use might not be harm-reducing for the population as a whole. The fourth question is also important because the answer lays the groundwork for educational, policy, and regulatory actions.

The committee reviewed the literature and assessed the nature and availability of the data needed to evaluate the feasibility of tobacco harm reduction. Its review encompassed the major disease categories linked by scientific evidence to tobacco consumption, including cancer, cardiovascular disease, respiratory disease, reproductive and developmental disorders, and others. The report is offered to relevant federal and state regulatory and policy bodies, Congress, scientists and health care professionals, tobacco and pharmaceutical industries, and-most importantly-the public, who will have to decide whether or not to use these products.

The committee began with fundamental operating precepts, reiterating and reaffirming overwhelming scientific evidence and the conclusions of many scientific and policy advisory bodies:

Precept 1. Tobacco use causes serious harm to human health.

Precept 2. Nicotine is addictive.

Precept 3. The best means to protect individual and public health from tobacco harms are to achieve abstinence, prevent initiation and relapse, and eliminate environmental tobacco smoke exposure.

Precept 4. A comprehensive and authoritative national tobacco control program, with harm reduction as one component, is necessary to minimize adverse effects of tobacco.

PRINCIPAL CONCLUSIONS

The committee does not evaluate specific PREPs in this report, since the currently available tobacco-related PREPs in particular are most likely prototypes of limited life span. Under present regulatory conditions, tobacco-related PREPs can be changed with little assessment and without disclosure of their contents. Therefore, the committee considered the types of PREPs currently or likely to become available in the foreseeable future. After reviewing a large body of scientific documents and data, hearing presentations from many scientific, regulatory and industrial interests, and publicly soliciting comments on the issues at hand, the committee reaches the following principal conclusions regarding the questions posed by the charge:

Conclusion 1. For many diseases attributable to tobacco use, reducing risk of disease by reducing exposure to tobacco toxicants is feasible. This conclusion is based on studies demonstrating that for many diseases, reducing tobacco smoke exposure can result in decreased disease incidence with complete abstinence providing the greatest benefit.

Conclusion 2. PREPs have not yet been evaluated comprehensively enough (including for a sufficient time) to provide a scientific basis for concluding that they are associated with a reduced risk of disease compared to conventional tobacco use. One narrow exception is the use of nicotine gum in one study for maintenance of cessation, described in Chapters 8, 13, and 14. Carefully and appropriately conducted clinical and epidemiological studies could demonstrate an effect on health. However, the impact of PREPs on the incidence of most tobacco-related diseases will not be directly or conclusively demonstrated for many years. Conclusion 3. Surrogate biological markers that are associated with tobacco-related diseases could be used to offer guidance as to whether or not PREPs are likely to be risk-reducing. However, these markers must be validated as robust predictors of disease occurrence and should be able to predict the range of important and common conditions associated with conventional tobacco products. Furthermore, the efficacy of PREPS will likely depend on user population characteristics (e.g., those defined by gender, genetic susceptibility, ethnicity, tobacco history, and medical history).

Conclusion 4. Currently available PREPs have been or could be demonstrated to reduce exposure to some of the toxicants in most conventional tobacco products. Many techniques exist to assess exposure reduction, but the report contains many caveats about the use of all of them, including usually an unknown predictive power for harm. Conclusion 5. Regulation of all tobacco products, including conventional ones as recommended in IOM, 1994, as well as all other PREPs is a necessary precondition for assuring a scientific basis for judging the effects of using PREPs and for assuring that the health of the public is protected. Regulation is needed to assure that adequate research (on everything from smoke chemistry and toxicology to long-term epidemiology) is conducted and to assure that the public has current, reliable information as to the risks and benefits of PREPs. Careful regulation of claims is needed to reduce misperception and misuse of the products. If a PREP is marketed with a claim that it reduces (or could reduce) the risk of a specific disease(s) compared to the risk of the product for which it substitutes, regulation is needed to assure that the claim is supported by scientifically sound evidence and that pertinent epidemiological data are collected to verify that claim. Conclusion 6. The public health impact of PREPs is unknown. They are potentially beneficial, but the net impact on population health could, in fact, be negative. The effect on public health will depend upon the biological harm caused by these products and the individual and community behaviors with respect to their use. Regulation cannot assure that the availability of risk-reducing PREPs will lead to reduced tobacco-related harm in the population as a whole. However, a regulatory agency can assure that data are gathered that would permit the population effects to be monitored. If tobacco use increases or tobacco-related disease increases, these data would serve as a basis for developing and implementing appropriate public health interventions.

PRINCIPAL RECOMMENDATIONS

The committee believes that harm reduction is a feasible and justifiable public health policy-but only if it is implemented carefully to achieve the following objectives:

Manufacturers have the necessary incentive to develop and market products that reduce exposure to tobacco toxicants and that have a reasonable prospect of reducing the risk of tobacco-related disease;

Consumers are fully and accurately informed of all of the known, likely, and potential consequences of using these products;

Promotion, advertising, and labeling of these products are firmly regulated to prevent false or misleading claims, explicit or implicit;

Health and behavioral effects of using PREPs are monitored on a continuing basis;

Basic, clinical, and epidemiological research is conducted to establish their potential for harm reduction for individuals and populations; and

Harm reduction is implemented as a component of a comprehensive national tobacco control program that emphasizes abstinence-oriented prevention and treatment.

Recommendations about future research needs are based on Principal Conclusions 1-4 and can be found in the following section. They flow primarily from material presented in Section II of the report. Progress in these areas will permit the application of the principles of risk assessment to the evaluation of PREPs in the future. At present, judgement informed by incomplete science will be used to evaluate PREPs. However, immediate actions are required. Therefore, the committee makes recommendations that address Principal Conclusions 5 and 6. These conclusions and recommendations are particularly intertwined, requiring immediate attention and swift action.

The effect of PREPs could be to increase or decrease tobacco-related disease in the population. Assessing a positive public health impact will be difficult and will require extensive surveillance and research to ensure that the impact is positive. Even the strongest surveillance system could not alone provide minimal assurance of safety or protection of the public. Currently there is little public authority over tobacco products of any type. Whatever the current legal or regulatory posture with respect to these products, the committee realized that in order to obtain the best available scientific evaluation of emerging tobacco-related PREPs and to provide the best advice on use of all PREPs to the public, some national authority over these PREPs is needed. Only a comprehensive program of regulation and assessment including extensive premarket testing and surveillance offers a reasonable possibility of net gain in health from use of PREPs instead of conventional tobacco product use.

(Continues...)

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Table of Contents

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
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 andToxicology....................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
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
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
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
A PRESENTATIONS AND SUBMISSIONS....................583
B COMMITTEE BIOGRAPHICAL SKETCHES....................586
C TIME LINE OF TOBACCO EVENTS....................593
INDEX....................607