Scientific Standards for Studies on Modified Risk Tobacco Products (2012) / Chapter Skim
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3 Evidence Base and Methods for Studying Health Effects
3 Evidence Base and Methods for Studying Health Effects
Pages 73-148
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From page 73... ...
. The evaluation of the health effects and mechanisms of modified risk tobacco products (MRTPs)
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The use of chewing tobacco and dry snuff has declined over time. Oral moist snuff is by far the most popular kind of smokeless tobacco in the United States (Federal Trade Commission, 2007)
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. In 2005, total dollar sales for moist snuff accounted for more than 80 percent of total sales for smokeless tobacco (Federal Trade Commission, 2007)
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Commonly Reported Constituents Thousands of compounds have been identified in unburned tobacco (Rodgman and Perfetti, 2009) , but routine analyses of smokeless tobacco have focused on relatively few of these compounds thought to be critical in its biological activities (IARC, 2007; Richter and Spierto, 2003; Richter et al., 2008; Song and Ashley, 1999; Stepanov and Hecht, 2005; Stepanov et al., 2008, 2010)
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From page 77... ...
Unlike cigarette smoke, the most common strong carcinogens in smokeless tobacco products are TSNAs. Extensive data demonstrating their presence in parts per million quantities, greater than nitrosamine concentrations in any other consumer product intended for oral use, are available (IARC, 2007; Richter et al., 2008; Stepanov et al., 2008)
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. Once the combusted material is collected, the methods of analysis of the various constituents of cigarette smoke have some similarities to those used for smokeless tobacco.
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. Furthermore, the same considerations discussed above with respect to smokeless tobacco apply to combusted products.
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In the analysis of smokeless tobacco products, the method of extraction and the method of expressing the results need to be taken into account when comparing data. In the analysis of combusted products, the method of machine smoking is critical when comparisons are to be made.
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It should be emphasized however that the biomarkers discussed here are virtually all biomarkers of exposure to specific tobacco or tobacco smoke constituents. In most cases, they have not been validated as biomarkers of risk.
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. A similar study carried out in smokeless tobacco users demonstrated the reduction of total NNAL after cessation of product use (Hecht, 2002)
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. Biomarkers of the tobacco-specific compounds are similar in smokers and smokeless tobacco users, while those of some of the volatile organic combustion products are considerably lower in smokeless tobacco users (Hecht, 2002; Hecht et al., 2010)
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84 TABLE 3-1 Representative Exposure Biomarkers Related to Tobacco Carcinogens and Toxicants Range of Recent Mean Values or Concentrations Biomarker Source Smokers Nonsmokers References (smokers) References (nonsmokers)
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SPMA Benzene 3.2–32.1 0.17–3.14 (Carmella et al., 2009; Ding et al., (Carmella et al., 2009; nmol/24hr nmol/24hr 2009; Feng et al., 2006a; Mendes Ding et al., 2009; Feng et et al., 2008; Roethig et al., 2007; al., 2006a; Roethig et al., Sarkar et al., 2008; Scherer et al., 2007; Sarkar et al., 2008; 2006, 2007a) Scherer et al., 2006, 2007a; Suwan-ampai et al., 2009)
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86 TABLE 3-1 Continued Range of Recent Mean Values or Concentrations Biomarker Source Smokers Nonsmokers References (smokers) References (nonsmokers)
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. b N/A = Not applicable because these are not detected in the urine of nonsmokers unless they use other tobacco products, nicotine replacement products (for nicotine equivalents, and sometimes NNN [Stepanov et al., 2009]
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. Two molecular epidemiologic studies related total NNAL to lung cancer risk.
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1-HOP is a biomarker of exposure to polycyclic aromatic hydrocarbons, tobacco smoke particulate phase constituents, and products of incomplete combustion. These compounds are also commonly found in polluted air and the diet.
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as well as triglycerides and alkaline phosphatase, all of which were significantly elevated in smokers, including in one recent study that examined the relationship between these biomarkers, machine-measured tar yields, and biomarkers of expo sure to cigarette smoke constituents in more than 3,500 smokers and more than 1,000 nonsmokers (Frost-Pineda et al., 2011; Liu et al., 2011)
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. In a recent study, smokers were randomized to receive the smokeless tobacco products Camel Snus, Taboka, or medicinal nicotine over a 4-week period in which they quit smoking.
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Smokeless tobacco users had higher levels of several polycyclic aromatic hydrocarbon biomarkers, as well as higher levels of total NNAL, than did nonusers of tobacco. Of 33 biomarkers analyzed, 18 were significantly lower in smokeless tobacco users than in smokers, while 10 of the 33 biomarkers were not different.
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than studies on combusted products because smokeless tobacco products do not deliver significant quantities of these mate rials. Epidemiologic studies demonstrate that the risk for lung cancer is higher in smokers than in smokeless tobacco users.
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, which states that a "tobacco product shall not be marketed in combination with any other article or product regulated under this Act (including a drug, biologic, food, cosmetic, medical device, or a dietary supplement) ."2 2 Family Smoking Prevention and Tobacco Control Act of 2009, Public Law 111-31, 123 Stat.
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For many years, there has been substantial concern about adopting surrogate endpoints as the sole measure of therapeutic efficacy in clinical trials, particularly because there are very important counterexamples in the history of drug regulation where surrogate endpoint control did not lead to disease prevention or amelioration; such intermediate endpoints included blood pressure control, antiarrhythmic treatments, and choles terol-lowering agents. The standards for using biomarkers of risk as surrogate endpoints are even more stringent as "the surrogate endpoints should be a perfect proxy for the effect of an intervention on the recipient's risk of important clinical outcomes" (IOM, 2010)
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Furthermore, some of the outcomes can only be obtained with invasive procedures, and may not be suitable for all research studies. It should be noted that with respect to reflecting true disease outcomes, biomarkers have been controversial.
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Preclinical studies of the effects of smokeless tobacco products and combusted tobacco products are discussed below. Smokeless Tobacco Products Reviews of in vitro assays (Johnson et al., 2009)
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. Number of ST products tested included American moist snuffs, a commercial Swedish moist snuff, and 11 ST products.
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The extract was 1997; Wang et al., 2001; epithelial cells derived from Kentucky loose-leaf ST, dry and moist snuffs, Kentucky Yildiz et al., 1999) • Rodent cell lines reference chewing tobacco, commercial Swedish snuff, or commercial • Chinese hamster khaini.
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epithelial cells which is a calcium-binding protein; activated receptors, TRADD or Fas; • Rodent cell lines cytosol cysteine proteases designated caspases; or nuclear fragmentation by • Golden Syrian denoting nucleosome formation as noted by 180 to 200bp band ladder in hamster oral squamous an electrophoretic gel. Nuclear TUNEL of cleaved ends of DNA is another cell carcinoma routinely used marker.
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ST either by placement, ligation, or with bees wax Dunham, 1962; Hoffmann plugs for up to 2 years produced no tumors. Carcinogens, polycyclic et al., 1981; Homburger, aromatic hydrocarbon, 7,12 DMBA, MCA, or quinone, exemplified by 1971; Jorquera et al., 1992; 4-nitroquinoline-N-oxide or virus (herpes simplex virus)
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-2,5-diphenyltetrazolium bromide; PBS = phosphate buffered saline; ppm = parts per million; ST = smokeless tobacco; STE = smokeless tobacco extract; TRADD = tumor necrosis factor receptor type 1-associated death domain protein; TUNEL = terminal deoxynucleotidyl transferase dUTP nick end labeling.
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A concentration and use pattern consistent with human exposure to smokeless tobacco products should be employed in animal models, but this has not been achieved. Previous studies used smokeless tobacco extracts or derivative concentrations several fold above the single selfadministered exposure by humans (Hoffmann and Adams, 1981; Palladino et al., 1986)
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. Persistent observed formation of tumors or pathologies associated with increased infection, inflammation, or respiratory or cardiovascular harm will be causes for redesign of smokeless tobacco products.
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and glycoprotein (Lin et al., 1989; Wu et secretion in tracheal epithelial cells.
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2011) NOTE: CS = cigarette smoke; CSE = cigarette smoke extract; H1N1= Influenza A virus; ICAM = inter-cellular adhesion molecule; PAMP = pathogenassociated molecular patterns; poly(I:C)
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Mucus is secreted by airway epithelial cells. A recent advance in culturing airway epithelial cells in vitro is the development of a biphasic culture system in which epithelial cells are maintained in an air-liquid medium interface (Whitcutt et al., 1988)
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, and cancer. Extracts of smokeless tobacco also induce proinflammatory changes in cultured human vascular endothelial cells.
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Cancer Disease Rodent Models for Combusted Tobacco Products Some studies have shown that inhaled tobacco smoke can induce tumors and cancers in animal models, but the data are inconsistent. Studies in hamsters have produced convincing evidence that exposure to cigarette smoke
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The response was due to the gas phase of cigarette smoke, and can be used to investigate the effect of secondhand smoke on lung tumorigenesis (Witschi, 2004)
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TABLE 3-4 Selected Studies of Carcinogenicity in Response to Exposure to Cigarette-Smoke Condensate in Mouse, Rat, and Rabbit No. of Treated Animals/ Exposure Dosage and Strain Sex Group Type of Exposure Duration Tumor Incidence Reference Mouse CAF1 M + F, 44–112 Skin painting CSC/acetone solution (40 mg 36/81 (skin epidermoid (Wynder et 1:1 (dorsal)
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(37%) Other Tobacco Swiss albino M 15 Oral gavage of 1 mg bidi smoke 4 hepatic hemangiomas, (Pakhale et Indian bidi smoke condensate/0.1 mg DMSO, 1 stomach papilloma al., 1988)
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Tobacco smoke and involuntary smoking. Lyon, France: IARC.
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. Summary of Preclinical Studies Although preclinical assays for toxicity and carcinogenicity can pro vide relevant and meaningful data about tobacco products, these assays are limited in their usefulness in this regulatory context.
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These assays should be added to the evaluation process. CLINICAL STUDIES Clinical Trial Methods The use of appropriately designed clinical trials will be important to establish whether use of the MRTP reduces exposure to toxicants or induces positive changes in surrogate markers as claimed by the manu facturer.
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Shortand intermediate-term clinical trials -- where the research participants use the product regularly throughout the day rather than in the confines of a laboratory setting -- are thought to provide a better approximation to real-world use. This is particularly true in regard to the question of an MRTP's ability to be a substitute for cigarettes.
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Although not an exhaustive list, Box 3-2 presents a list of examples of health outcomes that MRTPs might be evaluated for relative to smok ing and smoking cessation. In clinical trial design, the use of at least one control arm is crucial.
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• Short-term residential and nonresidential studies and ntermediate i term clinical studies have different strengths and limitations, and proper evaluation of MRTP effects may require several or even all of these study designs. Use of these different study designs will assist for cross-validation.
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, determining the contrasting potential effects of MRTPs on disease outcomes and population health is a difficult matter. Long, intensive, and robust studies of actual health outcomes would be required to fully evaluate the net effects of MRTPs relative to conventional tobacco products.
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A related issue is that over time, individuals using MRTPs may switch products at irregular intervals, use them at varying rates, use them interchangeably, or even use them simultaneously with conventional tobacco products, making it very difficult to credibly document use patterns that can be related to health outcomes in observational studies. A similar issue arises if many products are not widely used in the general population; in this case, there may be insufficient population exposure to confidently assess particular health outcomes.
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The structure of studies that contrast risk of disease among MRTPs and conventional tobacco products is of paramount interest, and, specu latively, many potential MRTPs with substantial reduction in toxic exposures may show reductions in disease risks. This is likely given the high toxic exposures that occur due to use of conventional cigarettes.
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Some diseases emerge earlier than others after tobacco initiation, or decrease more rapidly when conventional tobacco products are withdrawn, and in these situations it may be possible to acquire earlier answers regarding MRTP health effects. An important example is coronary heart disease, where withdrawal of cigarette smoking is associated with a clear reduction in disease risk within a few years of smoking cessation.
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The issue has been perhaps best evaluated with respect to varying causes of death, where smoking leads to any number of important illnesses, most precluding the occurrence of the others, a phenomenon called "competing mortality." Because it is an important goal for MRTPs to prevent and alleviate suffering from a variety of diseases, composite outcomes may more accurately reflect general health outcomes, in the same way that selfreported health status and disability-adjusted life years summarize health status across individual disease states. It might even be worthwhile to weight disease outcomes in terms of clinical importance or likely relation to product use (e.g., with lung cancer receiving a higher weighting than chronic bronchitis)
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Other situations exist where confounding factors may be important when considering studies that contrast disease outcomes of MRTPs versus conventional tobacco products: a. Cigarette smokers often try to stop smoking, as documented in this report, but it may be important to understand some of the motivations.
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; that is, those with lower educational attainment, those with lower personal and family income, and "blue-collar" workers are more likely to encumber higher rates of adverse occupational or environmental exposures. Epidemiologic studies that compare conventional cigarette smokers with nonsmokers or MRTP users thus need to scrupulously adjust for socioeconomic differences among these groups in order to avoid confounding by this potent factor, which is related to both rates of tobacco use and adverse health outcomes.
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Benchmarking the Health Effects of MRTPs A generally useful but sometimes tacit presumption in evaluation studies of MRTPs is that conventional tobacco product use is the health benchmark against which MRTPs are evaluated. However, this could be difficult to execute in the common situation where a credible lifetime history of cigarette smoking is difficult to obtain.
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However, there are also prominent or at least potential limitations to this design: • Important and severe chronic illnesses may be uncommon and take many years to occur, even in a population of cigarette smokers, and thus
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. It is possible to contrast product exposures among those with vary ing levels of biomarkers or disease outcomes -- intermediate or clinically
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Crossover designs could be used to evaluate participants who switch from one MRTP to another, or who switch from an MRTP back to conventional cigarettes or other tobacco products. Applying the Methodology of Comparative Effectiveness Research (CER)
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There are substantial ethical limitations on the application of MRTPs or contrasting conventional tobacco products in planned intervention studies, although some situations do allow for such interventions. A discussion on the ethical considerations of tobacco research is found in Chapter 2.
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These data play an increasingly important role in the evaluation of population exposure to various MRTPs or conventional tobacco products, and they help set boundaries to better understand potential rates of potential adverse events.
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An integrated mathematical model for tobacco harm reduction should consider dose-response relationships for multiple disease outcomes. That is, a model with a dose-response relationship for only a single disease outcome will limit the relevance of the data, as tobacco product use leads to multiple health outcomes.
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1999. Smokeless tobacco, oxidative stress, apoptosis, and antioxidants in human oral keratinocytes.
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2010. Temporal stability of urinary and plasma biomarkers of tobacco smoke exposure among cigarette smokers.
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2007. Determination of 10 carcinogenic polycyclic aromatic hydrocarbons in mainstream cigarette smoke.
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2011c. Draft initial list of harmful/potentially harmful constituents in tobacco smoke or smokeless tobacco products.
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2007a. Changing smokeless tobacco products: New tobacco delivery systems.
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1992. Carcinogenesis of smokeless tobacco.
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2007. Smokeless tobacco and tobacco-specific nitrosamines.
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2009. Evaluation of in vitro assays for assessing the toxicity of cigarette smoke and smokeless tobacco.
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2011. Relationship between biomarkers of cigarette smoke exposure and biomarkers of inflammation, oxidative stress, and platelet activation in adult cigarette smokers.
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2011. Differential exposure biomarker levels among cigarette smokers and smokeless tobacco consumers in the National Health and Nutrition Examination Survey 1999-2008.
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2003. Surveillance of smokeless tobacco nicotine, pH, moisture, and unprotonated nicotine content.
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2010. Brand specific responses to smokeless tobacco in a rat lip canal model.
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2010. Analysis of 23 polycyclic aromatic hydrocarbons in smokeless tobacco by gas chromatography-mass spectrometry.
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2009. Involuntary tobacco smoke exposure and urinary levels of polycyclic aromatic hydrocarbons in the United States, 1999 to 2002.
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2009. Urinary levels of tobacco-specific nitrosa mine metabolites in relation to lung cancer development in two prospective cohorts of cigarette smokers.
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