5
The Scientific Basis for PREP Assessment

Assessing health risks from conventional tobacco products is similar to that for many environmental and occupational exposures. Tobacco risks, however, are among the more complicated to assess for several reasons. The general components of risk assessment (hazard identification, dose-response assessment, exposure assessment, and risk characterization) described in Chapter 1 are still useful to consider (see Table 5–1).

Hazard identification is challenging because tobacco and the smoke generated upon its combustion are complex mixtures. Some of the hundreds (or thousands) of known or suspected toxicants are fairly well understood; however, the relative contribution to overall toxicity of most of the individual compounds is not. In addition, tobacco products contain added constituents or ingredients, but the identity and concentration of these compounds within a specific tobacco product is unknown, due to proprietary concerns. Animal models of tobacco toxicity are limited, posing additional barriers to complete hazard identification.

Dose-response assessment is complicated. Because the exposure is a complex mixture, the diseases associated with tobacco exposure are many and the dose-response relationships vary significantly. Assessing the dose in epidemiological studies is complicated in part by the factors described for hazard identification. In addition, the dose a tobacco user is exposed to can change often over a long and variable smoking history. Finally, the responses are most often diseases with long periods of disease progression until diagnosis and from time point of dose estimation.



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Clearing the Smoke: Assessing the Science Base for Tobacco Harm Reduction 5 The Scientific Basis for PREP Assessment Assessing health risks from conventional tobacco products is similar to that for many environmental and occupational exposures. Tobacco risks, however, are among the more complicated to assess for several reasons. The general components of risk assessment (hazard identification, dose-response assessment, exposure assessment, and risk characterization) described in Chapter 1 are still useful to consider (see Table 5–1). Hazard identification is challenging because tobacco and the smoke generated upon its combustion are complex mixtures. Some of the hundreds (or thousands) of known or suspected toxicants are fairly well understood; however, the relative contribution to overall toxicity of most of the individual compounds is not. In addition, tobacco products contain added constituents or ingredients, but the identity and concentration of these compounds within a specific tobacco product is unknown, due to proprietary concerns. Animal models of tobacco toxicity are limited, posing additional barriers to complete hazard identification. Dose-response assessment is complicated. Because the exposure is a complex mixture, the diseases associated with tobacco exposure are many and the dose-response relationships vary significantly. Assessing the dose in epidemiological studies is complicated in part by the factors described for hazard identification. In addition, the dose a tobacco user is exposed to can change often over a long and variable smoking history. Finally, the responses are most often diseases with long periods of disease progression until diagnosis and from time point of dose estimation.

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Clearing the Smoke: Assessing the Science Base for Tobacco Harm Reduction TABLE 5–1 Tobacco and PREP Risk Assessment   Hazard Identification Dose Response Exposure Assessment Risk Characterization Risk Management 1983 “Red Book” Epidemiology Animal bioassay Short-term Studies Comparisons of molecular structure Epidemiology Low-dose extrapolation Animal to human extrapolation Dose to which humans are exposed Dose of special populations Estimation of size of population potentially exposed Estimate of the magnitude of the public health problem A risk-assessment (qualitative or quantitative) may be one of the bases of risk management Challenges in risk assessment of tobacco Complex mixture Animal models are limited Constituents and additives are proprietary information Dose changes for an individual over time Dose of individual toxicants varies over time Exposure at time of disease progression Changes in smoking topography Complex mixture For which disease? At which point in smoking history? FTC regarding advertising Additional challenges of PREP risk assessment Products will change rapidly with time Assessing effect of moving backwards on a dose-exposure curve, assuming long-time previous higher exposure Changing exposure after long-term higher dose exposure Some toxicants could increase Need models to consider effects on initiation, cessation, and relapse FDA authority currently exerted only over pharmaceutical PREPs

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Clearing the Smoke: Assessing the Science Base for Tobacco Harm Reduction   Hazard Identification Dose Response Exposure Assessment Risk Characterization Risk Management Committee charge 1. Does product decrease exposure to the harmful substances in or produced during use of tobacco? 2. Is decreased exposure associated with decreased harm to health? 3. Are there useful surrogate indicators of disease that could be used? 1. Does product decrease exposure? 4. What are the public health implications? 4. What are the public health implications? Disease-specific summary data (Chapter 5; Section II) 3. Utility of preclinical research to judge feasibility 1. Dose-response data for conventional tobacco products 2. Validation and development of biomarkers 4. Short-term clinical and epidemiological studies 2. Validation and development of biomarkers 4. Short-term clinical and epidemiological studies 5. Long-term epidemiological studies and surveillance   NOTE: Numbers correspond to research recommendations listed in the Executive Summary.

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Clearing the Smoke: Assessing the Science Base for Tobacco Harm Reduction Exposure assessment is difficult for some of the same reasons. There is a multiplicity of tobacco products on the market. The specific exposures associated with any one “branded” product could change throughout time because the product can change. Changes in exposure throughout time are not documented. In addition, smokers of “low-yield” products often compensate (change smoking behavior to increase nicotine exposure), so their exposures to nicotine and tobacco/smoke toxicants are often higher than predicted by a common form of exposure assessment, self-report. The objective of a potential reduced-exposure product (PREP) risk assessment is to determine if the risk of harm from the use of the PREP is less than the risk of harm in the absence of the PREP (see Table 5–1). The risk management objective considered by the committee is not to ban or control the exposure per se, as is the case for environmental and occupational exposures. The risk management objective, as will be made clear in Chapter 7, is primarily to verify whether or not a product is associated with either exposure reduction or harm reduction. A PREP risk assessment involves lowering the dose of a complex mixture in a person (or population) with varying degrees of pre-existing pathology or cellular damage caused by a complex mixture exposure (that of conventional products) and trying to reverse early damage or to stop disease progression. This is problematic at this point, as there are no adequate human or animal studies that replicate this scenario. While some studies report risks in persons who switch from nonfiltered cigarettes to filtered cigarettes, or from high- to low-tar cigarettes, this “switching” did not reduce exposure (due to compensation) significantly in many people. The reduction in risk, if any, would occur only in persons who do not compensate for lower nicotine levels by smoking more or smoking differently. The basic elements of risk assessment can, however, be still considered. The questions become slightly different, and the data required or the study designs might be different from that required for a tobacco risk assessment. For hazard identification, the questions include: Does the PREP contain (or produce during use) toxicants known to cause adverse health effects? To what extent are the compounds targeted for reduced exposure causally linked to a tobacco-related disease? How does its content compare with the toxicants in the conventional tobacco product to which it is compared? Are there unique toxicants in a PREP compared to conventional tobacco products? For hazard identification, it is essential to know the composition of the material to which people will be exposed from the PREP compared to

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Clearing the Smoke: Assessing the Science Base for Tobacco Harm Reduction the standard product. Any new material, such as flavors, added to standard products must be included in the analyses. It is important to analyze the product that actually enters the body (for example, the combustion products that are inhaled) rather than the composition of the product as sold. The approach to testing the toxicity of the material to which people are exposed in the tobacco-related PREP compared to standard tobacco products is discussed in Chapter 10. The objectives of the toxicity tests are to determine what toxic effects can be induced by the test materials (the tobacco-related PREP compared to the standard product) and how much of the test materials is required to cause the adverse effect, i.e., the dose-response characteristics in animals of the test materials. Data from animal studies can be used to eliminate new products that are much more toxic than existing ones. A series of comparative potency tests is appropriate. In vitro studies in cultured cells from both animals and humans can be used to determine the ability of the test materials (from the tobacco-related PREP and the standard product) to induce cellular damage, an inflammatory response, or cell death. Assays of the mutagenic or clastogenic activity of the test materials can be done in bacterial or mammalian cell systems. In animal studies, tests for tobacco-related toxicity should include evaluation of the ability to induce adverse health effects or cancer in the respiratory tract, the nervous system, the cardiovascular system, the reproductive and developmental systems, and other organs. Toxicokinetic studies should be used to determine dosimetry to different organs and to suggest biomarkers of internal dose that can be used in humans. Short-term clinical tests in humans should be done to compare the potencies of the test materials to induce acute adverse health effects (such as reduced pulmonary function) and to determine the toxicokinetics of the tobacco-related PREP compared to the standard product. For dose-response assessment, the questions include: What are the dose-response characteristics of the PREP compared to the conventional tobacco product? Do smokers use PREPs at a time in their individual smoking history (and therefore of disease progression) that induce different dose-response effects? Are the patterns of adverse health effects different from PREPs compared to conventional tobacco products? What is the evidence that reduction in exposure to the targeted compounds in the complex mixture or other hazardous material in the PREP will decrease or reverse the development of disease? What is the dose-response relationship between the targeted compounds and the disease outcome?

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Clearing the Smoke: Assessing the Science Base for Tobacco Harm Reduction What quantitatively happens to disease induction if exposures are reduced? How much exposure needs to be reduced to result in a measurable benefit? Are there individual susceptibilities (age, gender, genetic makeup, and prior use of tobacco products) that change this dose-response relationship? Some dose-response information can be obtained from standard preclinical animal studies. However, there will be uncertainties in extrapolating from animal data to humans. Additionally, it will be difficult, even in animals, to determine the response to a reduction in dose after a period of higher exposure. For exposure assessment, the questions include: Do PREP users compensate differently than users of more conventional “low-yield” products? Do PREP users exclusively use PREPs or do they switch back and forth between PREPs and conventional products? How does the PREP change the exposure pattern for the population? Does the introduction of the PREPs increase the number of people initiating use of tobacco products or decrease cessation attempts? What is the overall balance in exposures (directly and as environmental tobacco smoke) with or without the PREP? Past experiences with “low-yield” cigarettes containing less tar and nicotine than other products underscore the need to determine internal dosimetry of toxic material entering the body during use of tobacco-related PREPs. The internal dosimetry of the new products can be compared to that of standard products in short term toxicokinetic studies in humans. Biological markers of internal dosimetry of key ingredients can be used when available. The risk assessment process will need to rely on the use of animal preclinical and human clinical studies, in which biomarkers of exposure and potential harm can be measured. Biomarkers of exposure to tobacco products have been validated and are in current use. Unfortunately, few specific early indicators of biomarkers have been validated as predictive of later disease development. It is recognized that today, biomarkers of exposure are better validated compared to biomarkers of potential harm, and that it is more feasible to consider exposure reduction in contrast to risk reduction. However, while an assessment of risk reduction through biomarkers will have more uncertainty, these will need to be included in the PREP risk assessment process in order to enhance confidence that there is no worsening risk, in the least.

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Clearing the Smoke: Assessing the Science Base for Tobacco Harm Reduction For risk characterization, the questions include: Can the exposure levels of the PREP, given its dose-response characteristics, be expected to result in reduced risk of one or more tobacco-related diseases than the standard tobacco product to which it is compared? What is the magnitude of any reduction in risk? What are the limits in understanding of the risk reduction? Do fewer tobacco users quit and use PREPs instead? Do former tobacco users relapse to PREPs? Do nonusers initiate tobacco use through PREPs? In order to achieve a level of confidence that a PREP will provide meaningful reductions in risk, especially compared to the real possibility of others using this product to initiate or resume smoking, prospective epidemiological studies are required. This could be done in a timely manner for some disease endpoints, such as birth outcomes or recurrence of myocardial infarction. For many other diseases associated with tobacco use, however, definitive demonstration of reduced harm will require studies of a long duration. Moreover, it is reasonable to anticipate that the design of PREPs would change rapidly in the coming years so that assessing PREP use will be difficult. The claim that a PREP will result in a reduction of the risk for harm requires scientific evidence for the validity of that claim. A discussion of the information relevant to hazard identification and dose-response information (the first two elements of risk assessment) is given in Chapter 10. Information on the best means of evaluating exposures is given in Chapter 11. In the case of tobacco products, animal models of adverse health effects have been problematic in the past, but new animal models show promise for being useful (see Chapter 10). There currently are no population risk assessment models that mimic the types of predictions hoped for tobacco users who switch to PREPS and how the public health will be effected by the initiation of PREP use by never and former smokers. The committee has evaluated the science base regarding the toxic effects of tobacco on the major diseases known to be caused by tobacco exposure (i.e., cancer and diseases of the cardiovascular, pulmonary, reproductive systems). The committee has done so to arrive at summary conclusions regarding the evidence base that would directly feed into a risk assessment paradigm, such as that described above (see Table 5–1). Specifically, the committee has elaborated in each of the major disease-oriented chapters of Section II and summarized later in this chapter the evidence regarding:

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Clearing the Smoke: Assessing the Science Base for Tobacco Harm Reduction the dose-response relationship between tobacco smoke and/or constituent exposure and health outcomes, identification and development of surrogate markers for disease, the utility of preclinical research in understanding the potential of PREPs to be harm reducing for the disease under review, utility of short-term clinical and epidemiological studies, and the role of long-term epidemiological studies and surveillance. The review of preclinical research and the material in Chapter 10 (Toxicology) provide information on hazard identification and, in part, dose-response assessment. The material on surrogate markers for disease is informative for both dose-response assessment and exposure assessment. The review of the short-term clinical studies, epidemiology, and surveillance data provide the proof of reduced harm. In conclusion, the PREP risk assessment process will be challenging because no single definitive study, either human or experimental animal study, would stand up to rigorous scientific scrutiny to be used in such a process. Therefore, today, several types of data will be needed that includes both experimental animal studies and human clinical data, with a definitive plan to conduct epidemiological and surveillance studies. The clinical data is needed because animal studies cannot predict interindividual differences in human behavior that would affect how the PREP is used or cause damage, and because there are too many uncertainties about the use of animal data. During this interim time, and with more research, the regulatory process might be able to identify key types of data needed for the risk assessment process. At this point in time, however, it can only be concluded that both experimental animal and clinical human studies would be needed, and that this would include both the consideration of exposure to individual PREP constituents and as a complex mixture. It is conceivable that the PREP risk assessment process can be simplified, for example by comparing only experimental data for one PREP to another, but this will require substantial experience and characterizing the data for existing PREPs. Sufficient data for streamlining this process in not available today. The remainder of this chapter provides a summary of the major conclusions and recommendations, arranged by chapter, reached by the committee in Section II of this report. TOBACCO SMOKE AND TOXICOLOGY (SEE SECTION II, CHAPTER 10) Mainstream tobacco smoke and environmental tobacco smoke each is a complex mixture of toxicants composed of carcinogens and other chemi-

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Clearing the Smoke: Assessing the Science Base for Tobacco Harm Reduction cals with health effects that alone or in combination are only partially known (see Table 5–2) (Davis and Nielson, 1999). The evaluation of conventional tobacco products and tobacco-related PREPs is complicated by a lack of adequate in vivo models of tobacco-related morbidities in man. Toxicology studies, both in vitro and in vivo, provide the opportunity to evaluate the potential harm reduction offered by potential reduced-exposure products. The comparative potency of the PREP can be determined in a series of preclinical studies that include both the PREP and the standard tobacco product that can be replaced by the PREP. The preclinical tests should include in vitro tests in both animal and human cells TABLE 5–2 List of Selected Tobacco Mutagens and Carcinogensa Constituent Class Phase IARC Evaluationb Examples N-Nitrosamines Particulate Sufficient in animals Tobacco-specific nitrosamines (NNK, NNN), dimethylnitrosamine, diethylnitrosamine Polycyclic aromatic hydrocarbons Particulate Probable in humans Benzo[a]pyrene, benzo[a]anthracene, benzo[b]fluoranthene, 5-methylchrysene Aryl aromatic amines Particulate Sufficient in humans 4-Aminobiphenyl, 2-toluidine, 2-naphthylamine Heterocyclic amines Particulate Probable in humans 2-Amino-3-methylimidazo[4,5-b]quinolone (IQ) Organic solvents Vapor Sufficient in humans Benzene, methanol, toluene, styrene Aldehydes Vapor Limited in humans Acetaldehyde, formaldehyde Volatile organic compounds Vapor Probable 1,3-Butadiene, isoprene Inorganic compounds Particulate Sufficient in humans Arsenic, nickel, chromium, polonium-210 NOTE: NNK=nicotine-derived nitroketone; NNN=N-nitrosonornicotine. aThis list is intended to provide a conceptual overview of the complexity of tobacco product exposures. It is not all-inclusive but is presented to allow the reader to understand the number of considerations that must be made in assessing harm reduction strategies. bInternational Agency for Research on Cancer: The classifications here refer to evaluations of the compound from any exposure, not just tobacco. Not all chemicals within the class are considered carcinogenic in humans. There is no consideration in this table to delivered dose or route of exposure (IARC, 1986).

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Clearing the Smoke: Assessing the Science Base for Tobacco Harm Reduction to determine the cytotoxicity and the genotoxicity of the tobacco product to which humans will be exposed. Such tests have recently been reported for a new tobacco-related PREP (Eclipse Expert Panel, 2000). Such a test must include dose-response studies to determine the amount of the exposure material required to cause toxicity. Next, studies should be conducted in vivo in the best animal models available to determine the comparative potency of the PREP versus the standard product in producing: (1) pulmonary inflammation, (2) COPD, (3) cardiovascular disease, (4) reproductive toxicology, and (5) pulmonary neoplasms. In vitro studies and in vivo animal studies are useful but limited tools in evaluating the toxicity of products that claim to reduce exposure to tobacco toxicants and potentially reduce tobacco-related harm. In vitro studies may allow rapid, low-cost screening for the toxic properties of conventional tobacco products and tobacco-related PREPs, although the relationship between in vitro toxicity and in vivo human response has not been established for most compounds. These assays include cytotoxicity and genotoxicity assays, which are possible screens for the carcinogenic or inflammatory potential of products. In vivo toxicity testing can be developed to supplement in vitro and clinical studies. Such animal models, if developed, may be useful as a screening assessment of the efficacy of PREPs for reduction of various tobacco-attributable diseases (see Chapters 12–16). The committee concludes that animal models should be used to test for the potential adverse health effects of tobacco smoke or any proposed additives. The A/J mouse model, which is sensitive to induction of lung adenomas, shows promise as an animal model for screening the potential of tobacco products to induce lung tumors (Witschi et al., 2000; Witschi et al., 1999; Witschi et al., 1997a,b). Future studies should validate the model. These studies (Witschi et al., 2000) indicated that removal of single classes of carcinogens, such as nitrosamine or polycyclic aromatic hydrocarbons (PAHs) may not be protective against induction of lung tumors by smoke. Studies also indicate that some animal models show promise for use in studying the development of symptoms similar to those of chronic obstructive pulmonary disease (COPD), the development of cardiovascular disease, adverse effects on the immune system, intrauterine growth retardation, and poor fetal lung maturation from the inhalation of new or existing tobacco products (see Chapter 10). Testing the general toxicity of smokeless tobacco and evaluating of the potential harm reduction properties of smokeless tobacco (e.g., Swedish snus) use in smokers may greatly benefit from assays for genotoxic and cytotoxic potential and the animal models discussed above. Details to be considered in determining the specific set of toxicity tests include species and strain of test animal, duration of test, end points of interest, dose-response considerations, biomarkers of dosimetry and

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Clearing the Smoke: Assessing the Science Base for Tobacco Harm Reduction response, and standard comparison products to be tested as positive and negative controls. EXPOSURE AND BIOMARKER ASSESSMENT IN HUMANS (SEE SECTION II, CHAPTER 11) Accurate measures of exposure and the development of biomarkers of adequate specificity and sensitivity are needed to evaluate the toxicity and harm reduction potential of PREPs. Biomarkers can be defined as measurements of tobacco constituents, tobacco smoke constituents, or changes in body fluids (including exhaled air) and organs. The assessment of a PREP will have to include markers of external exposure and biomarkers indicative of internal exposure, biologically effective dose (Perera, 1987), and potential harm. The definitions of each are provided in Table 5–3. There have been different definitions of types of exposure assessments used previously, but more recent understandings of biomarker uses and limitations, as well as different approaches needed for PREP evaluation lead to a need for clarification and redefinition. The latter three measurements in Table 5–3 improve upon the first by quantifying exposure at the cellular level to characterize low-dose exposures or low-risk populations, provide a relative contribution of individual TABLE 5–3 Exposure and Biomarker Assessment Definitions Exposure or Biomarker Assessmenta Definition External exposure marker A tobacco constituent or product that may reach or is at the portal of entry to the body Biomarker of exposure A tobacco constituent or metabolite that is measured in a biological fluid or tissue that has the potential to interact with a biological macromolecule; sometimes considered a measure of internal dose Biologically effective dose (BED) The amount that a tobacco constituent or metabolite binds to or alters a macromolecule; estimates of the BED might be performed in surrogate tissues Biomarker of potential harm A measurement of an effect due to exposure; these include early biological effects, alterations in morphology, structure, or function, and clinical symptoms consistent with harm; also includes “preclinical changes” aCategories and definitions reflect concept that the critical exposure is at the level of a biological macromolecule, so that exposure for this discussion is not limited to a measurement at the portal of entry to the body.

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Clearing the Smoke: Assessing the Science Base for Tobacco Harm Reduction Utility in a Preclinical Setting Studies in cell culture and model systems can afford much needed information on tobacco-related cardiovascular risk. These might include a profiling of gene expression and translation in cardiovascular tissues in response to cigarette smoke, constituents of smoke, and potential harm reduction substituents. These might identify proteins of potential functional relevance to the transduction of cardiovascular risk. Such studies might be coupled with gene inactivation and overexpression studies to address the role of these proteins in vivo. Similarly, studies of exposure to cigarette smoke or to discrete constituents of smoke might be deployed to investigate effects on atherosclerosis progression, susceptibility to vascular injury, thrombotic stimuli, graft rejection, cardiovascular development, or endothelial dysfunction in model systems such as mice. Studies of cardiovascular genomics and ultimately proteomics can also be extended to model systems to investigate gene expression and translation in response to exposure to tobacco-related products in vivo. These observations may, in turn, be related to the pattern of gene expression and translation in cardiovascular tissues obtained from cigarette smokers. Biomarkers of Tobacco-Related Disease The predominant mechanisms by which cigarette smoking induces cardiovascular injury is unknown. However, small studies in smokers of potentially relevant biomarkers of platelet and vascular activation, lipid peroxidation, and inflammation afford evidence of a dose-response relationship and a decline on quitting. There is even evidence of a signal in individuals exposed to ETS in the case of some of these markers. More mechanism-based clinical studies are required to confirm and expand these findings. Where possible, these should be related to surrogate measurements of cardiovascular function, such as hemodynamics, flow-mediated endothelial function and estimates of plaque progression by ultrasound or electron-beam computerized tomography (EBCT). Furthermore, biomarker studies can usefully be integrated into many studies in model systems as well as studies of clinical outcome to afford their ultimate validation. Clinical Assessment of Tobacco-Related Disease The time course of offset of myocardial infarction and stroke in people who stop smoking suggests that cardiovascular disease represents a tractable scenario in which one might evaluate harm reduction strategies. Clearly, the health effects experienced by the individual and the assessment

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Clearing the Smoke: Assessing the Science Base for Tobacco Harm Reduction of the impact of such events can occur in a more reasonable time frame than from cancer in which declines in risk from tobacco exposure reduction may only be apparent after years or decades. NONNEOPLASTIC RESPIRATORY DISEASE (SEE SECTION II, CHAPTER 14) In evaluating harm reduction strategies for tobacco-related lung disease, three major nonneoplastic respiratory diseases linked to cigarette smoking are considered: COPD, asthma, and respiratory infections. Respiratory diseases are major tobacco-related illnesses, and there is a clear need to mitigate the harmful effects of exposure to both mainstream and secondary tobacco smoke. It is generally accepted that cessation of smoking slows or stops the progression of the lung diseases related to smoking and it is plausible that decreasing smoking will reduce the severity of chronic lung diseases and the incidence of respiratory infections. However, there is no adequate scientific evidence to support this because the effects of reduced smoking on harm reduction have not been extensively studied in man. Dose-Response Relationship There is a need to determine dose-response relationships more precisely and to develop biomarkers of respiratory disease. Rational design of studies to assess harm reduction requires knowledge of the dose-response relationship. At present, such data for respiratory diseases are limited and of uncertain quality. Study design would also incorporate biomarkers of disease, and the testing of current and new biomarkers might be done concurrently in the models and populations studied for dose-effects. The Cancer Prevention Studies I and II, large-scale prospective studies, however, do suggest a direct dose-response relationship between cigarettes smoked per day and mortality rates from COPD (NIH, 1996, 1997), indicating that decreasing the number of cigarettes smoked may lead to fewer deaths from COPD. Biomarkers of Tobacco-Related Disease There are currently no specific molecular biomarkers of the nonneoplastic respiratory diseases due to smoking tobacco products. No unique molecular or genetic defect specific for tobacco-related respiratory disease has been identified. The processes involved, such as inflammation and increased levels of oxidants, are not unique to tobacco-related respiratory

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Clearing the Smoke: Assessing the Science Base for Tobacco Harm Reduction diseases. Identifying unique biomarkers is further confounded by the heterogeneous nature of these diseases, the complex mixture of tobacco smoke, and the range of individual susceptibilities to the harmful effects of tobacco smoke. The most widely used markers of tobacco-related respiratory diseases in population studies are symptom questionnaires and pulmonary function testing. These have well-known limitations of specificity and sensitivity, particularly for detecting the early effects of tobacco smoke on lungs (U.S. DHHS, 1989). Subtle effects of tobacco smoke exposure on the lung can be detected by sampling fluid in the lower respiratory tract via a bronchoscope inserted into the airways, but the significance of these changes for clinically important pulmonary disease has not been established. Newer approaches such as sampling the subjects’ urine (Pratico et al., 1998) or exhaled gas (Ichinose et al., 2000) for metabolic products due to tissue injury have the advantage of noninvasive sampling but must be validated. Clearly, the greatest obstacle for rational development of a specific biomarker is the lack of fundamental information on mechanisms of how tobacco smoke exposure causes specific respiratory diseases. The availability of dose-response data and validated biomarkers may improve the design of contemplated intervention studies and allow greater confidence in the results. However, the time frame for generating dose-response data and testing biomarkers is uncertain. The inclusion of dose-response considerations and biomarkers in the design of clinical trials on reduction of harm from respiratory diseases must also be validated. Clinical Assessment of Tobacco-Related Disease An alternative is to proceed with interventional trials based on current knowledge if there are uncertainties about the added value of dose-response data or untested biomarkers to study design. As an example, an intervention study of the effect of smoking reduction on COPD could be considered, similar in design to the Lung Health Study (Anthonisen et al., 1994), a large prospective trial of the effects of smoking cessation on rate of decline of FEV1 (forced expiratory volume at 1 second) in middle-aged smokers with mild COPD. Another approach is to conduct a trial using a low-tar and moderate-nicotine product made available from a noncommercial source to avoid product endorsement issues. Design of population studies for harm reduction of major respiratory diseases is challenging because of uncertainties about effectiveness and long-term compliance with harm reduction interventions. Reduction in the burden of tobacco-related respiratory diseases through harm reduction strategies should be a major priority for the nation’s public health.

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Clearing the Smoke: Assessing the Science Base for Tobacco Harm Reduction REPRODUCTIVE AND DEVELOPMENTAL EFFECTS (SEE SECTION II, CHAPTER 15) Feasibility of Harm Reduction in Therapy Cigarette smoking is a major cause of fetal and infant morbidity and mortality (U.S. DHHS, 1988, 1990; Kleinman et al., 1988). This is particularly true for the associations with low-birthweight and its consequences, as well as preterm delivery and SIDS (CDC, 2000; Leach et al., 1999; Shah and Bracken, 2000; U.S. DHHS, 1983). For several important adverse reproductive effects of maternal smoking, a decrease in smoking has been found to be associated with a decrease in risks to the fetus and infant (Li et al., 1993; Hebel et al., 1988). The greatest benefit, of course, comes from smoking cessation. However, the smoking cessation rate for women smokers who become pregnant is very low and remain comparable to those in the general population, despite knowledge of the harmful effects of smoking and personal experience with adverse fetal and infant conditions. Moreover, as current rates of smoking increase slowly among adolescent women, these adverse effects associated with tobacco smoke exposure while pregnant are likely to worsen. Dose-Response Relationship On average, infants exposed to maternal smoking in utero are 200 grams lighter and 1.4 cm shorter than those unexposed (Wang et al., 1997). A strong dose-response relationship has been supported in numerous studies (Li et al., 1993), and a decrease in dose (number of cigarettes) in controlled studies has led to increased birthweights in a predictable pattern (Wang et al., 1997). What is known about the mechanism of effect of cigarette smoke on the fetus suggests that several agents in tobacco smoke contribute to the adverse effects. There is evidence that CO plays a major role in growth retardation through increased tissue hypoxia (Benowitz et al., 2000). Nicotine has also been thought to play a role through increasing vasoconstriction and decreasing perfusion through the placenta. Although nicotine replacement products and buproprion are currently not approved by the Food and Drug Administration for use by pregnant women, the Agency for Healthcare Research and Quality’s (AHCRQ) Clinical Practice Guidelines for Treating Tobacco Use and Dependence (Fiore et al., 2000) recommend that “Pharmacotherapy should be considered when a pregnant woman is otherwise unable to quit, and when the likelihood of quitting, with its potential benefits, outweighs the risks of the pharmacotherapy and potential continued smoking”. It is generally thought that NRT can reasonably be used with pregnant patients

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Clearing the Smoke: Assessing the Science Base for Tobacco Harm Reduction if prior behavioral modifications have failed and the patient continues to smoke at least 10–15 cigarettes per day (ACOG, 1997). There are no data regarding the efficacy of potential reduced-exposure products (PREPs) during pregnancy, but there is the presumption that the tobacco-related PREPs are likely to have adverse effects at some level and that until further evidence is produced, existing guidelines concerning pharmacologic PREPs still pertain. Clinical Assessment of Tobacco-Related Disease and Utility in a Preclinical Setting To practically assess the health effects of PREPs, reliable measures of health outcomes that can be utilized in a relatively short time are desired. Among the reproductive outcomes of maternal smoking, intrauterine growth retardation resulting in low-birthweight babies has been studied extensively, and a large body of evidence has supported a causal link with cigarette smoke exposure. The committee recommends, based on currently available scientific knowledge, that fetal birthweight be used as a reliable outcome measure for evaluating the harm reduction potential of specific PREPs. Study designs should include repeated cohort or case-control studies of pregnant women, with an appropriate distribution of exposures to both PREPs and conventional products, and suitable contrast groups. Concomitant, coordinated toxicological studies should be undertaken to provide biological correlations with clinical outcomes. Such outcomes as fetal birth weight and the incidence of other reproductive and developmental health outcomes (e.g., fertility outcomes, placental complications, gestational age at birth, incidence of sudden infant death syndrome [SIDS], spontaneous abortions) should be considered primary objects of study in order to assess the harm reduction potential of specific PREPs. Findings in pregnant women exposed to PREPs may have value beyond maternal or fetal outcomes. The nature of adverse effects derived from PREP exposure will likely be determined much sooner in this case than findings on chronic disease outcomes in humans, such as various cancers and cardiovascular disease. Should adverse findings become apparent, there may be substantial implications for chronic illnesses among older adults, and coordinated pathogenic studies might allow conclusions on new tobacco product outcomes in advance of studies exploring longer “incubation periods.” The committee recommends that further basic research be undertaken to elucidate the components of cigarette smoke that are primarily responsible for adverse health outcomes. In order to evaluate the safety of many PREPs, it is important to understand the toxicity of specific smoke

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Clearing the Smoke: Assessing the Science Base for Tobacco Harm Reduction components, especially nicotine and CO, on the pathogenesis of intrauterine growth retardation, spontaneous abortion, and other health outcomes. In addition, a better understanding of the risks of bupropion SR use by pregnant women (i.e., seizure risk) and the teratogenic effects of nicotine on the central nervous system (CNS) is needed for adequate risk-benefit analysis of the harm reduction potential of these products. Surveillance of Tobacco Use Patterns Among Pregnant Women Central to understanding exposure to tobacco products is continuous population information on usage patterns among pregnant women. This may not be attainable by general population survey methods because of inadequate sample sizes and insufficient representation of various geographic or demographic groups or of the earliest stages of pregnancy. There is a need for surveys devoted specifically to pregnant women in all stages of gestation, irrespective of the receipt of medical care. Survey content should include other known or putative causes of adverse maternal or fetal outcomes, as well as detailed product types and usage patterns. Recommendations for general population surveillance can be found in Chapter 6 of this report. Biochemical and toxicological exposure measures should be a routine part of surveillance for exposure to conventional products as well as PREPs. These will be necessary to conduct more precise, coordinated toxicological studies and also to assess actual exposure rates more accurately. For example, dose may be measured by maternal serum and urine cotinine levels, which have shown reliable correlations with maternal, and consequently fetal, tobacco smoke exposure. Self-reported data have been found unreliable, since pregnant women tend to underreport tobacco use because of the stigma attached to smoking. Also, self-reports do not adequately account for differences in depth and frequency of puffs among smokers. OTHER HEALTH EFFECTS (SEE SECTION II, CHAPTER 16) Feasibility of Harm Reduction in Therapy Several important diseases and conditions of adults, in addition to cardiovascular diseases, chronic obstructive lung disease and various cancers, have been associated with tobacco use, including—but not limited to—peptic ulcer disease, poor wound healing, inflammatory bowel disease, rheumatoid arthritis, oral disease, dementia, osteoporosis, ocular disease, diabetes, dermatological disease, schizophrenia, and depression (see Chapter 16). Some of these associations are supported by substantial

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Clearing the Smoke: Assessing the Science Base for Tobacco Harm Reduction scientific evidence, and a causal linkage is likely. These illnesses must ultimately be subjected to the same evaluation of changing risks and outcomes associated with PREPs, because these are common and clinically important conditions, even if they are not as often fatal as cancer, cardiovascular disease or pulmonary disease. Further, each of the conditions for which the association with tobacco use is substantial also offers the opportunity to address pathogenic mechanisms related to the varying constituents of PREPs, as well as the impact on disease incidence of concomitant behaviors and exposures such as alcohol use, various dietary elements, and certain medications. Utility of Preclinical Studies and Short-term Indicators of Clinical Harm Reduction Some of the conditions reviewed in this chapter may be applied as indicators of the general biological effects of new tobacco products. For example, cigarette smoking has been consistently found to be an independent risk factor for an adverse clinical course of both peptic ulcer disease and wound healing. The effects of smoking on ulcer formation and healing have been clearly described clinically and in animal models (Ma et al., 1999). Peptic ulcers have been found to be larger, slower to heal, and more likely to recur among smokers and to exhibit clinically improved healing upon cessation (Tatsuta et al., 1987). Surgical and traumatic wounds heal more slowly among cigarette smokers (Kwaitkowski et al., 1996; Mosely et al., 1978). The committee recommends that rigorous clinical studies be designed and executed to determine whether variations in ulcer and wound-healing rates are related to various categories of tobacco products, including those with claims of harm reduction. This may offer the opportunity to define some clinical outcomes that have clinical relevance in their own right and to identify potential indicators of harm alteration much sooner after the introduction of PREPs than would be possible when evaluating heart disease and cancer. Other candidate diseases for such evaluation might include periodontal disease (Bergstrom, 2000; Haber, 1994), Crohn’s disease (Rhodes and Thomas; 1994), and rheumatoid arthritis (Uhlig et al., 1999). Here the outcomes to assess would be the effect of various conventional tobacco products and PREPs on the natural history of these conditions, including intermittancy, progression or regression, and longitudinally collected biomarkers of disease severity. As noted above, PREPs that alter the history and outcomes of these conditions could be further evaluated for specific constituent exposures associated with this altered history. This may lead to a more refined understanding of pathogenic mechanisms as well.

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Clearing the Smoke: Assessing the Science Base for Tobacco Harm Reduction Clinical and basic research on intermediate clinical outcomes is also needed. For example, as noted in this chapter, the risk of osteoporosis has also been strongly linked to cigarette smoking. In controlled observational studies, bone mineral density has been found to be significantly lower among cigarette smokers, which contributes to a greater risk of osteoporotic fractures among older populations. While the effects of smoking on fracture rates may take a few decades or longer to detect, it is possible that surveillance of bone mineral density among those using PREPs and conventional products may be informative in a shorter time period and, thus, serve to detect important outcomes over an interval in which tobacco policy and clinical preventive interventions may have their greatest effects. Surveillance The committee recommends that selected conditions, as reviewed in this chapter, be part of a comprehensive, population-based surveillance program, outlined in Chapter 6. This will allow determination of the relationship between the use of PREPs and of trends in occurrence for these tobacco-related conditions and assessment on a national basis of whether changes in tobacco product use have an effect on these important health problems. Based on these surveillance findings, more specific population, clinical, and basic research studies can be directed to evaluate PREPs to pursue causal mechanisms and to suggest more effective interventions. REFERENCES ACOG (American College of Obstetricians and Gynecologists). 1997. Educational Bulletin: Smoking and women’s health. International Journal of Gynecology & Obstetrics 60:71–82. Anthonisen NR, Connett JE, Kiley JP, Altose MD, Bailey WC, Buist AS, Conway WA Jr, Enright PL, Kanner RE, O’Hara P, et al. 1994. Effects of smoking intervention and the use of an inhaled anticholinergic bronchodilator on the rate of decline of FEV1. The Lung Health Study. JAMA 272(19):1497–1505. Benowitz NL, Dempsey DA, Goldenberg RL, Hughes JR, Dolan-Mullen P, Ogburn PL, Oncken C, Orleans CT, Slotkin TA, Whiteside HP Jr, Yaffe S. 2000. The use of pharmacotherapies for smoking cessation during pregnancy. Tob Control 9 Suppl 3(2):III91–94. Benowitz NL, Fitzgerald GA, Wilson M, Zhang Q. 1993. Nicotine effects on eicosanoid formation and hemostatic function: comparison of transdermal nicotine and cigarette smoking. J Am Coll Cardiol 22(4):1159–1167. Benowitz NL, Zevin S, Jacob P 3rd. 1998. Suppression of nicotine intake during ad libitum cigarette smoking by high-dose transdermal nicotine. J Pharmacol Exp Ther 287(3):958– 962. Bergstrom J, Eliasson S, Dock J. 2000. Exposure to tobacco smoking and periodontal health. J Clin Periodontol 27(1):61–68. CDC (Centers for Disease Control and Prevention). 2000. Tobacco use during pregnancy. National Vital Statistics Report 48(3):10–11.

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