Clearing the Smoke Assessing the Science Base for Tobacco Harm Reduction (2001) / Chapter Skim
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5 The Scientific Basis for Pres Assessment
5 The Scientific Basis for Pres Assessment
Pages 140-179
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From page 140... ...
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.
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From page 143... ...
· 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?
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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)
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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)
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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.
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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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The evaluation of conventional tobacco products and tobacco-related PREPs is complicated by a lack of adequate in viva models of tobacco-related morbidities in man. Toxicology studies, both in vitro and in viva, provide the opportunity to evaluate the potential harm reduction offered by potential reducedexposure products.
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From page 149... ...
, 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)
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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.
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Thus, different types of biomarkers along the pathway from internal exposure, biologically effective dose, and potential harm are needed, and additional research is necessary to identify the best combination of markers to be used. Experimental toxicity testing (in vitro and animal models)
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152 TABLE 5-4 Biomarkers of Potential Harmful Effectsa b CLEARING THE SMOKE Associated Target Dose- with Tissue Specific Variables Used Response Cessation Assay Chemical to Category in Literature Data or Half-life Available Specificity Tobacco Enzymatic Aryl hydrocarbon No >30 d Yes Yes No induction hydroxylase CYP1A2 No NDA Yes Yes DNA repair NDA Yes Yes NA enzymes No No Microarray assays NDA NDA Yes NA No for mRNA expression and proteomics Chromosomal Chromosomal Yes Yes Yes No No alterations aberrations Micronuclei Yes Yes Yes No No Sister chromatic Yes Yes No No No exchanges Loss of Yes Yes Yes No No heterozygosity
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Association with cancer in case-control studies may have case bias. Significant lack of specificity and wide overlap between smokers and nonsmokers Technically complex; relationship to cancer risk unknown continues
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154 TABLE 5-4 Continued CLEARING THE SMOKE Associated Target Dose- with Tissue Specific Variables Used Response Cessation Assay Chemical to Category in Literature Data or Half-life Available Specificity Tobacco Mutations in Yes Yes No No No reporter genes (HPRT, GPA) Mutational load NA NDA Yes No No in target genes (p53, K-ras)
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THE SCIENTIFIC BASIS FOR PREP ASSESSMENT 155 Chemical specificity Related Specific to a to Disease Tobacco Risks Strengths Limitations Jo No NDA Facile assay in blood Relationship to target tissue or blood unknown Jo No NDA Target gene specificity Very difficult to do in normal tissues Jo No NDA Provides corroborative marker Relationship to disease not established Jo No No Facile assay Relationship to disease unknown Jo No No Similar lesions observed in Technically difficult; cancers relationship to risk unknown (es No Yes May be directly related to disease risk Levels among heavy smokers cannot be distinguished. Wide interindividual variation.
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156 TABLE 5-4 Continued CLEARING THE SMOKE Associated Target Dose- with Tissue Specific Variables Used Response Cessation Assay Chemical to Category in Literature Data or Half-life Available Specificity Tobacco Urinary Yes No No Yes No thromboxane and prostacyclins Platelet activation Yes NDA Yes No No and survival Blood cell White blood cell Yes Yes Yes Yes No parameters counts (i.e., lymphocytes, neutrophils, total counts) Hematocrit, Yes Yes Yes No No hemoglobin, red blood cell mass Bronchio- Inflammatory Yes Yes Yes No No alveolar cells, protein, ravage cytokines response Neutrophil Yes Yes Yes No No elastase al antiprotease complex ocl-antitrypsin No No Yes Yes Yes Inflammatory Leukotrienes Yes NDA No Yes No mediators of response Pulmonary FEV1, FVC Yes Yes Yes No No function tests Periodontal Periodontal Yes Yes Yes No No disease height Gum bleeding Yes Yes Yes No No
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Wide interindividual and intraindividual variation and large number of confounders Jo No No Can reflect both cardiac and Insensitive; wide interindividual respiratory disease risk differences Jo No NDA Provides different types of data Bronchoscopy is too invasive for with single procedure large epidemiological studies Jo No NDA Provides different types of data Bronchoscopy is too invasive for with single procedure large epidemiological studies (es Yes NDA May be specific to tobacco Requires invasive test; short smoke half-life (es No NDA May be measured in urine, Substantial number of bronchioalveolar ravage, and confounders serum Jo No Yes Widely available Low sensitivity for mild disease. Decrease in function with aging.
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Previously, the most common way to infer exposure reduction (e.g., through use of low-tar cigarettes) has been via methods that simulate human smoking behavior, such as the Federal Trade Commission (FTC)
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Biomarkers may be shown to reveal differences in individual susceptibilities and differences in response depending on dose. Thus, biomarkers that measure both complex exposures and single tobacco product constituents are needed and should be assessed for the range of possible human exposures, and those that assess complex exposures should carry a greater weight.
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The assessment of harm and harm reduction should be made through direct human experience, as these products are used by the general population. Most of what is known about harmful tobacco products has resulted from epidemiology and supported by in vitro studies, laboratory animal studies, and human experiments.
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NICOTINE PHARMACOLOGY (SEE SECTION II, CHAPTER 9) Nicotine is the addictive component of tobacco products, and the strength of this addiction affects the individual's ability to stop smoking (U.S.
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of cigarette smoking, latency until the practice becomes habitual (Starlings et al., 1999) , and the quantity that is then smoked (Koopmans et al., 1999)
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Nonetheless, reduction in exposure to tobacco smoke and tobacco products to the lowest possible levels may provide some benefit to individual users and to the general population. However, there are insufficient data from which to conclude how much reduction in exposure would yield a measurable benefit and which individuals would benefit.
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This conclusion is consistent with the fact that there are many carcinogens in tobacco smoke, and the aggregate might increase risk at any level. Modeling for low-dose exposures indicates that there is an increased risk with less than one cigarette per day.
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Although there are many reasonable models with which to assess individual tobacco smoke products, better models are needed for assessing exposures to complex mixtures. Such studies are not alone sufficient to support claims of potential harm reduction.
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These studies, through the use of biomarkers and surrogate indicators of cancer risk, can evaluate the manipulation of carcinogens and nicotine to reduce exposures and how these changes might affect smoking behavior, metabolic activation, enzymatic induction, conjugation, excretion, biologically effective doses (or their validated surrogates) , and biomarkers of potential harm.
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The consideration of nicotine as a carcinogenic agent, if at all, is trivial compared to the risk of other tobacco constituents. Some smokeless tobacco products increase the risk of oral cavity cancers, and a dose-response relationship exists.
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In summary, the data from quitters encourage the prospect that a graded reduction in cardiovascular risk and in biomarkers of this risk may accompany a reduction in the number of cigarettes smoked in pursuit of a harm reduction strategy. It is possible, indeed likely, that individuals and perhaps populations, differ in their susceptibility to tobaccoinduced cardiovascular risk and, indeed, in their potential benefit from a harm reduction strategy.
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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.
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, 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.
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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.
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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~.
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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.
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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.
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From page 175... ...
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.
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From page 176... ...
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.
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1999. Acceleration of atherosclerotic plaque formation in ApoEmice by exposure to tobacco smoke.
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2000. A systematic review and meta-analysis of prospective studies on the association between maternal cigarette smoking and preterm delivery.
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1997a. The carcinogenic potential of the gas phase of environmental tobacco smoke.
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