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8 Principal Conclusions he science base for assessing tobacco harm reduction is incomplete. T Nonetheless, the presence of potential reduced-exposure products (PREPs) on the market suggests an urgent need for proactive plans to evaluate the potential risks and benefits. The potential for reduction in morbidity and mortality that could result from the use of less toxic prod- ucts by those who do not stop using tobacco justifies inclusion of harm reduction as a component in a broad program of tobacco control. To date there are two general types of PREPs: pharmaceuticals and modified to- bacco products. The pharmaceuticals include, for example, nicotine re- placement therapy (NRT) and bupropion, while modified tobacco prod- ucts include products with modified tobacco and those with modified delivery systems. Having identified conceptual and operating precepts as stated at the end of Chapter 1, the committee concludes that there can be a successful, scientifically-based harm reduction program that is justifiable and fea- sibleâbut only if implemented carefully and effectively and only if: â¢ 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; â¢ consumers are fully and accurately informed of all of the known, unknown, likely, and potential consequences of using these prod- ucts; 231
232 CLEARING THE SMOKE â¢ promotion, advertising and labeling of these products are firmly regulated to prevent false or misleading claims, explicit or implicit; â¢ health effects of using PREPs are monitored on a continuing basis; â¢ basic, clinical, and epidemiological research is conducted to estab- lish the potential use of PREPs for reducing risks for disease in individuals and for reducing harm to the population as a whole; and â¢ harm reduction is implemented as a component of a comprehen- sive national tobacco control program that emphasizes abstinence- oriented prevention and treatment. The 7 chapters of the committeeâs report that precede this and the extensive reviews found in Section II provide the documentation for the following principal conclusions regarding the four questions posed within the charge, as outlined in Chapter 1. Specific recommendations can be found within the body of the report. Conclusion 1. For many diseases attributable to tobacco use, reducing risk of disease by reducing exposure to tobacco toxicants is feasible. This conclu- sion is based on studies demonstrating that for many diseases, reduc- ing tobacco smoke exposure can result in decreased disease incidence with complete abstinence providing the greatest benefit. Key to this conclusion is the assumption that compensatory increase in exposure does NOT occur with the use of these products. 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 conven- tional tobacco use. (One exception is the use of nicotine replacement therapy for maintenance of cessation in the Lung Health Study. See Chapters 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. Tobacco use causes very serious morbidity and mortality due to several different diseases. Cancer (e.g., of the lung, oral cavity, esophagus, and bladder), cardiovascular disease, chronic obstructive pulmonary disease, and low birthweight are all well-established ef- fects of tobacco use. The conditions can be diagnosed, the natural history of the diseases is reasonably well understood, and scientifi- cally appropriate studies of tobacco users who switch to PREPs could be designed. See Chapters 4 and 11-16 for supporting material. However, such research will be difficult. For example, tobacco us- ers may not use a particular PREP for long enough to see health impact; tobacco PREPs will undoubtedly change substantially over
PRINCIPAL CONCLUSIONS 233 the next decade; many subjects would be required for adequate statis- tical power. For all these and other reasons, conclusive proof of the health effects of PREPs will not be available in the near future, as new PREPs are entering the marketplace. Thus, for purposes of educating the public about PREPs and for purposes of regulating health claims, surrogate measures of health effects must be considered. 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 pre- dict the range of important and common conditions associated with conventional tobacco products in order to be useful for PREP evalua- tion and regulation. PREPs may differentially affect risk of tobacco- related diseases. Furthermore, the efficacy of PREPs will likely de- pend on user population characteristics, e.g., those defined by gender, genetic susceptibility, ethnicity, tobacco history, and medical history. Chapters 12-16 describe clinical studies using surrogate indicators that could be conducted to better understand whether or not PREPs would decrease specific adverse health outcomes. The potential stud- ies vary in terms of the length of time that would be required to document the effect, the number of patients, and the power of the study to predict disease outcome. There is no one panel or group of tests that the committee could recommend at this time that would, as a whole, serve to assure that morbidity and mortality would decrease with use of PREPs. Conclusion 4. Currently available PREPs have been or could be demon- strated to reduce exposure to some of the toxicants in most conventional tobacco products. There are many techniques to assess exposure reduc- tion, but the report contains many caveats about the use of all of them, including usually an unknown predictive power for harm. Long-term use of pharmaceutical preparations for maintenance of tobacco cessation will clearly achieve exposure reduction. The safety of these products for long-term use, however, is not well established. For example, it is well known that nicotine affects the autonomic nervous system, with uncertain long-term consequences. However, even if NRT use for maintenance of cessation results in nicotine expo- sure equivalent to that achieved with conventional tobacco products, exposure to the most harmful tobacco toxicants is avoided. See Chap- ters 4, 9, and 11 for supporting material. There is insufficient evidence to decide whether concomitant use of NRT or bupropion with decreased tobacco use will lead to signifi-
234 CLEARING THE SMOKE cantly decreased exposure to tobacco toxicants such as tar and carbon monoxide. Nor is there sufficient evidence to determine how much this PREP strategy will decrease conventional tobacco use or how much compensation will occur. However, there are exposure assess- ment tools to assess this issue, as described in Chapter 7. Tobacco-related PREPs pose different exposure assessment prob- lems. PREPs characterized by the reduction (or, conceivably, elimina- tion) of one class of toxicants, such as the reduced-nitrosamine prepa- rations in varying stages of development and marketing, do result in decreased exposure per cigarette to specific toxicants. Analytic tech- niques exist to demonstrate this. However, the smoking behavior of people who use these PREPs has not been researched well enough to know whether or not compensation occurs (thus increasing net expo- sure to other toxicants and possibly maintaining exposure to the po- tentially reduced chemical). Furthermore, there are insufficient data to allow scientific judgement or prediction of the health effects of removal of one class of chemicals from tobacco products. The cigarette-like PREPs that use heat or reduced burn tempera- ture of tobacco and deliver aerosolized nicotine pose other exposure assessment problems. The prototypes available now have only just begun to be studied by researchers other than the manufacturers. It is clear that the yield of some of these products is different from that of conventional cigarettes. The pattern of yield changes suggests differ- ential reduction in exposure to toxicants. Some preliminary data sug- gest increased yield of specific toxicants concomitant with no change or decreases in others. There does not exist a standard reference product for comparison with tobacco-related PREPs. Assessment of the risk from use of a PREP requires comparison to the risk of the product avoided AND to the risk of the product (including no product, or abstinence) the PREP user would switch to if the PREP were NOT available. Conclusion 5. Regulation of all tobacco products, including conventional ones as recommended in IOM, 1994, as well as all other PREPs is a neces- sary 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 informa- tion 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
PRINCIPAL CONCLUSIONS 235 which it substitutes, regulation is needed to assure that the claim is supported by scientifically sound evidence and that pertinent epide- miological data is collected to verify that claim. The regulation pro- posed by this committee is narrowly focused on assuring that the products reduce risk of disease to the user and accumulating data that would indicate whether or not the products are harm-reducing for the population in the aggregate. Other potential regulatory ap- proaches to tobacco control are not addressed within this report. See Chapter 7 for supporting and explanatory material. 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 biologi- cal harm caused by these products and the individual and commu- nity behaviors with respect to their use. Assessing the public health impact will be difficult and will require classic public health tools of surveillance, research, education, and regulation to assure that the impact is positive. The major concern for public health is that tobacco users who might otherwise quit will use PREPs instead, or others may initiate smoking, feeling that PREPs are safe. That will lead to less harm reduction for a population (as well as less risk reduction for that individual) than would occur without the PREP, and possibly to an adverse effect on the population. PREPs should be a last resort only for people who absolutely can not or will not quit. Population- based research and surveillance can determine whether the intended impact is achieved. However, measurements of health impact at the population level can take years to document, as described in previous sections of this chapter and in the report as a whole. Regulation of PREPs can only assure that a specific PREP could be risk-reducing for a person who uses it compared to the conventional product it replaces. Regulation cannot assure that the availability of risk-reducing PREPs will lead to reduced tobacco-related disease 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 population tobacco product use increases or tobacco- related disease increases, these data would serve as a basis for devel- oping and implementing appropriate public health interventions. See Chapters 3, 6, and 7 for supporting material. Studies using surrogate indictors of population impact could be designed. For example, monitoring the perception that the public, particularly tobacco users and adolescents, has of the risks and ben- efits of PREPs is possible. Research indicating that people perceive PREPs to be more beneficial than scientific judgment indicates would
236 CLEARING THE SMOKE provide early evidence of the risk for an adverse public health impact. Action of various sorts (e.g., regulatory review of claims, public health education campaigns) could then be taken. Chapters 1 and 5 include discussions of the utility of a risk assessment framework for organizing the scientific basis for evaluation of PREPs. It is useful to return to that framework to put the committeeâs conclusions and recommendations into the proper light. Although the committee did not perform a risk assessment for any existing PREP, the committeeâs conclu- sions and recommendations provide a means to assure that a risk assess- ment can be done in the future. As Table 8-1 illustrates, the committeeâs principal conclusions (discussed in a preceding section of this chapter) assume use of the conventional risk assessment framework, and the con- clusions and recommendations for surveillance and regulation point a way to develop the necessary data for such an evaluation. Hazard identification is inherent in the first question of the commit- teeâs charge, Does the product decrease exposure to the harmful substances in tobacco? The principal conclusions that harm reduction is feasible and that exposure reduction can be demonstrated require identification of the toxicants within or produced by use of the PREP. The element of the proposed surveillance system related to specific tobacco constituents and several of the regulatory principles (#1, #3, #7, #8, #9) will assure that the necessary toxicology data are gathered, validated, and made available to scientists, public health officials, and regulators. Dose-response assessment is inherent in the second question of the charge, Is decreased exposure associated with decreased harm to health? An important issue when considering this question in the context of PREP assessment is that while some data are available when assessing a dose- response relationship, there are virtually no data describing the change in response due to dose reduction after a period of higher exposure. This data would reflect the extent of disease reversibility or halting of disease progression possible from exposure reduction. Dose-response assessment is also inherent in the third question of the charge, Are there useful surro- gate indicators of disease that could be used? The principal conclusion that surrogate measures could be used to predict harm reduction requires the development of surrogate disease indicators (response) so that a dose- response assessment (and therefore a risk characterization) could be made in some reasonable timeframe, without waiting decades to assess cancer morbidity and mortality. The surveillance system component addressing disease outcomes will help provide some of these necessary data and the regulatory principle #6 requiring postmarketing surveillance and epide- miologic studies for PREPs with claims will assure that the data are col- lected.
TABLE 8-1 Relationship of Conclusions and Recommendations for PREP Risk Assessment Hazard Identification Dose Response Exposure Assessment Risk Characterization Risk Management Committee 1. Does product 2. Is decreased 1. Does product 4. What are the public 4. What are the public charge decrease exposure exposure associated decrease exposure? health implications? health implications? to the harmful with decreased substances in or harm to health? produced during 3. Are there useful use of tobacco? surrogate indicators of disease that could be used? Principal 1. Risk reduction is 3. Surrogate measures 4. Exposure reduction 1. Risk reduction is 5. Regulation is a conclu- feasible could be used to can be feasible necessary sions 4. Exposure reduction predict risk demonstrated 2. Risk reduction not precondition for can be reduction yet demonstrated assuring a science demonstrated 6. Public health base and for impact is unknown assuring protection of the health of the public Elements of Specific tobacco Disease outcomes Consumption of Disease outcomes Tobacco product surveillance constituents of both tobacco products marketing, system the products and and of PREPs including PREPs the smoke they Biomarkers of generate exposure to tobacco products Personal tobacco product use and related behavioral 237 patterns
TABLE 8-1 Continued 238 Hazard Identification Dose Response Exposure Assessment Risk Characterization Risk Management Regulatory 1. Ingredient 6. Products with 2. Yield assessment 5. Labeling for 10. Enforcement principles disclosure claims would 4. With specific products with power (all refer to 3. Preclinical testing require post- claims, no increased claims cannot be tobacco- required to support marketing exposure to false or misleading related health-related surveillance and unclaimed PREPS, claims epidemiological compounds except for 7. Evidence for no studies 9. Performance 11) increased risk standards 8. Added ingredient 11. Exposure review reduction claims 9. Performance for pharmaceutical Standards PREPs Research 3. Develop 1. Sufficient data to 4. Clinical and Comprehensive Regulation is and other appropriate animal allow estimation of epidemiological surveillance is recommended recommen- models and in vitro dose-response studies in human recommended dations assays of 2. Develop validated are required pathogenesis biomarkers of disease
PRINCIPAL CONCLUSIONS 239 Exposure assessment is inherent also in the first question of the committeeâs charge. The principal conclusion that exposure reduction can be demonstrated is fairly straightforward. Several components of the pro- posed surveillance system will provide important exposure information and at least four regulatory principles (#2, #4, #9, #11) would assure that relevant data are collected. Risk characterization is the central question of the report and, indeed, of harm reduction writ large. The fourth question of the committeeâs charge regarding the public health impact of the products is perhaps the most important asked of the committee. The principal conclusions that harm reduction is feasible but not yet convincingly demonstrated and that a beneficial public health impact is not assured are two that are most easily misunderstood as contradictory if not carefully considered. They drive important considerations of the reportâharm reduction should be pur- sued and encouraged but every aspect of it should be watched and studied vigilantly. Appropriate tools of public health must be available and must be powerful. Surveillance of personal tobacco product use and related behavioral patterns and of disease outcomes will provide some of the data necessary to assure a positive population impact. The regulatory principle that labeling for PREPs with claims cannot be false or misleading is an- other necessary safeguard against a negative public health impact. Risk management, the culmination of the risk assessment process, is directly related to the committeeâs principal conclusion that regulation is a necessary precondition for advancing knowledge and for ensuring a public health benefit. Two of the most important tools for a risk manager, are knowledge, which will be developed if the research and surveillance recommendations are followed and if the regulatory principles #1-9 are adhered to, and enforcement power, which is called for in regulatory principle #10. A properly conducted risk assessment outlines gaps in the knowledge required by the risk manager and the assumptions used for the risk characterization in the absence of complete data. Explicit descrip- tion of these assumptions can help identify the research that will most significantly improve understanding of risk and, thereby, affect public policy. Questions asked by a risk manager help to integrate the scientific data and assumptions provided by the formal risk assessment into the desired public policy. The questions also assure that regulation, a risk-manage- ment tool for tobacco harm reduction proposed by this committee, is based on and informed by the risk assessment process. Questions might include: â¢ Which of the thousand known tobacco-related toxicants are most important to consider in the assessment of risk? Is the scientific data available for adequate hazard identification?
240 CLEARING THE SMOKE â¢ Are the data presented by the manufacturer based on assays re- flecting the manner in which the product is actually used by the consumer? â¢ Are the claims by the manufacturer adequately supported by the scientific data? Is the risk characterization accurately conveyed in a manner understandable to the consumer? â¢ What constitutes a substantial degree of overall risk reduction? â¢ Who has the burden of proof for each type of claim? Is the burden of proof sufficient to assure the products will provide a benefit to the user? Is the burden of proof so high that innovation will be stifled and the possible benefit never realized? â¢ What can be done immediately to manage the possible risks of these products, given that the science base is currently inadequate? â¢ Are there parties responsible for assessing and assuring harm re- duction outside this regulatory agency? And if so, are the bound- aries of risk-management responsibility and authority clear to all parties? The data presented and scientific limitations identified in Chapter 5, the surveillance system outlined in Chapter 6, and the regulatory frame- work described in Chapter 7 provide a sound basis for the risk manage- ment for tobacco harm reduction. In summary, tobacco harm reduction could lead to reduced risk of disease for those who cannot give up tobacco. Unfortunately, without the appropriate public health tools of research, surveillance, education, and regulation, tobacco harm reduction could result in a personal and public health disappointment. REFERENCES IOM (Institute of Medicine). 1994. Growing Up Tobacco Free. Washington, DC: National Academy Press. NRC (National Research Council). 1983. Risk Assessment in the Federal Government. Managing the Process. Washington, DC: National Academy Press.
Section II Evidence for the Science Base