Mirjana V. Djordjevic

Mandated lowering of toxicants in cigarette smoke: a description of the World Health Organization TobReg proposal

Preventing initiation of tobacco product use, promoting cessation of tobacco use, and protecting the public from exposure to second hand smoke are recognised by the World Health organization (WHO) Framework Convention on Tobacco Control (FCTC) and by the WHO Study Group on Tobacco Product Regulation (TobReg) as the most effective approaches to reducing tobacco related morbidity and mortality. However, the FCTC also recognises the need for tobacco product regulation in articles 9 and 10 of the treaty. In order to inform that process TobReg has developed a series of reports that begin to provide a scientific foundation for tobacco product regulation.1–6 This paper summarises a proposal, and the considerations that led to it, developed by a joint International Agency for Research on Cancer (IARC) and WHO working group, and approved by TobReg, which presents performance standards for cigarettes and a strategy to use them to mandate a reduction in the toxicant yields for cigarette smoke. The most common measurements used historically to categorise cigarette smoke have been machine measured tar, nicotine and carbon monoxide (TNCO) yields per cigarette based on the US Federal Trade Commission (FTC)/International Standards Organization (ISO) testing regimen. There is a current scientific consensus that these per cigarette yields do not provide valid estimates of human exposure or of relative human exposure when smoking different brands of cigarettes.1 7–9 Communication of these measures to smokers as estimates of their exposure or risk creates harm by misleading smokers to believe that differences in exposures and risk are likely to occur with switching to cigarette brands with different machine-measured yields. This ongoing harm precludes continued acceptance of current regulatory strategies based on per cigarette machine measured TNCO levels and necessitates development of new regulatory approaches. Machine smoking regimens other than the FTC/ISO regimen …

Smoking and Lung Cancer Risk in American and Japanese Men: An International Case-Control Study

Rates of lung cancer in American men have greatly exceeded those in Japanese men for several decades despite the higher smoking prevalence in Japanese men. It is not known whether the relative risk of lung cancer associated with cigarette smoking is lower in Japanese men than American men and whether these risks vary by the amount and duration of smoking. To estimate smoking-specific relative risks for lung cancer in men, a multicentric case-control study was carried out in New York City, Washington, DC, and Nagoya, Japan from 1992 to 1998. A total of 371 cases and 373 age-matched controls were interviewed in United States hospitals and 410 cases and 252 hospital controls in Japanese hospitals; 411 Japanese age-matched healthy controls were also randomly selected from electoral rolls. The odds ratio (OR) for lung cancer in current United States smokers relative to nonsmokers was 40.4 [95% confidence interval (CI) = 21.8-79.6], which was >10 times higher than the OR of 3.5 for current smokers in Japanese relative to hospital controls (95% CI = 1.6-7.5) and six times higher than in Japanese relative to community controls (OR = 6.3; 95% CI = 3.7-10.9). There were no substantial differences in the mean number of years of smoking or average daily number of cigarettes smoked between United States and Japanese cases or between United States and Japanese controls, but American cases began smoking on average 2.5 years earlier than Japanese cases. The risk of lung cancer associated with cigarette smoking was substantially higher in United States than in Japanese males, consistent with population-based statistics on smoking prevalence and lung cancer incidence. Possible explanations for this difference in risk include a more toxic cigarette formulation of American manufactured cigarettes as evidenced by higher concentrations of tobacco-specific nitrosamines in both tobacco and mainstream smoke, the much wider use of activated charcoal in the filters of Japanese than in American cigarettes, as well as documented differences in genetic susceptibility and lifestyle factors other than smoking.

Lung Cancer Risk in White and Black Americans

PURPOSE To test whether differences in smoking-related lung cancer risks in blacks and whites can explain why lung cancer incidence is greater in black males than in white males but about equal in black and white females, given that a greater proportion of blacks are smokers, but smoke far fewer cigarettes per day than do whites. METHODS A hospital-based case-control study was conducted between 1984 and 1998 that included interviews with 1,710 white male and 1,321 white female cases of histologically confirmed lung cancer, 254 black male and 163 black female cases, and 8,151 controls. Relative risks were estimated via odds ratios using logistic regression, adjusted for age, education, and body mass index. RESULTS We confirmed prior reports that smoking prevalence is higher but overall dosage is lower among blacks. Overall ORs were similar for blacks and whites, except among the heaviest smoking males (21+ cigarettes per day or 37.5 pack-years), in whom ORs for blacks were considerably greater than for whites. Long-term benefits of cessation were similar for white and black ex-smokers. Smokers of menthol flavored cigarettes were at no greater risk for lung cancer than were smokers of unflavored brands. CONCLUSIONS Lung cancer risks were similar for whites and blacks with similar smoking habits, except possibly for blacks who were very heavy smokers; this sub-group is unusual in the general population of African American smokers. Explanations of racial disparities in lung cancer risk may need to account for modifying factors including type of cigarette (yield, mentholation), diet, occupation, and host factors such as ability to metabolize mainstream smoke carcinogens.

Does smoking reduction result in reduction of biomarkers associated with harm? A pilot study using a nicotine inhaler

The aim of the study was to determine if smoking reduction using a nicotine inhaler in heavy cigarette smokers who wanted to reduce but not stop smoking results in decreased levels of known biomarkers of harm. The study design was a one-sample within-subject comparative open-label study of 23 (10 male and 13 female) subjects using a nicotine inhaler to reduce smoking, with follow-up at 24 weeks. A structured protocol was used with a smoking-reduction schedule from 40 or more cigarettes per day to 10 cigarettes per day by week 9. Behavioral counseling was provided by a research assistant and ad lib use of the nicotine inhaler for 12 weeks was permitted. Blood thiocyanate, cotinine, 4-aminobiphenyl hemoglobin adducts; urine NNAL and NNAL-glucuronide; and expired air carbon monoxide were measured. On average, the subjects were able to reduce their smoking by over 50% at week 12, but only two were able to reduce to 10 cigarettes per day. The reported reduction in smoking was not associated with a consistent reduction in the biomarkers. There was no reduction in the NNAL, 4-aminobiphenyl hemoglobin adducts nor carbon monoxide levels of expired air. There was a significant reduction of NNAL-glucuronide and the sum of NNAL and NNAL-glucuronide but only at week 24. Thiocyanate levels increased. Before widely promoting harm reduction as a treatment strategy for heavy smokers, more research needs to be performed to prove conclusively that such smokers who want to reduce but not stop can actually reduce and maintain their smoking rate at a level which is likely to reduce harm. It also needs to be determined whether a reduction in the smoking rate translates into reduction of harm. At the present, for heavy smokers, an abstinence approach seems to be more scientifically sound.

Formation and analysis of tobacco-specific N-nitrosamines

Chemical-analytical studies during the past 4 years led to several new observations on the formation of tobacco-specific N-nitrosamines (TSNA) and their occurrence in smokeless tobacco, mainstream smoke (MS), and sidestream smoke (SS) of American and foreign cigarettes. When snuff was extracted by means of supercritical fluid extraction with carbon dioxide containing 10% methanol, analysis of this material confirmed that the extraction with organic solvents had been partially incomplete. Epidemiological studies in the northern Sudan showed a high risk for oral cancer for users of toombak, a home-made oral snuff. Toombak contains 100-fold higher levels of TSNA than commercial snuff in the U.S. and Sweden. The TSNA content in the saliva of toombak dippers is at least ten times higher than that reported in the saliva of dippers of commercial snuff. Biomarker studies have shown corresponding high levels of hemoglobin adducts with metabolites of NNN and NNK as well as for urinary metabolites of NNK. These data supported the epidemiological findings. The analyses of MS of U.S. and foreign cigarettes smoked under FTC conditions revealed comparable data for the smoke of nonfilter cigarettes and filter cigarettes except in the case of low- and ultralow-yield cigarettes, which showed reduced TSNA yields. The MS of cigarettes made from Burley or dark tobacco is exceptionally high in TSNA, primarily because of the high nitrate content of those tobacco types. Taking puffs of larger volume and drawing puffs more frequently, practices observed among most smokers of cigarettes with low nicotine yield, results in high TSNA values in the MS. The formation of the lung carcinogen NNK is favored during the smoldering of cigarettes, between puffs, when SS is generated. Consequently, in most samples from indoor air polluted with environmental tobacco smoke (ETS), the highest concentration of an individual TSNA is that of NNK. When nonsmokers had remained for up to 2 h in a test laboratory with high ETS pollution, they excreted measurable amounts of NNK metabolites in the urine, indicative of the uptake of TSNA.

NIH electronic cigarette workshop: Developing a research agenda

BACKGROUND Electronic cigarettes (e-cigarettes) represent an emerging public health issue. These devices deliver nicotine along with other constituents, including flavorants, via an inhalable aerosol. Their uptake is rapidly increasing in both adults and youths, primarily among current smokers. Public debate is increasing on how these devices should be regulated and used, yet only limited peer-reviewed research exists. To develop a informed policy for e-cigarettes, their effects on human behavior, physiology, and health need to be understood. PURPOSE This paper describes proceedings from a National Institutes of Health-sponsored workshop, which was held in November 2013, to identify research needs related to the effects of e-cigarettes. Discussion topics included e-cigarette risks and abuse potential; the potential role for e-cigarettes in harm reduction and smoking cessation; unintended consequences of e-cigarette use, such as becoming a gateway to conventional cigarettes; and dual use of both e-cigarettes and conventional cigarettes. RESULTS AND CONCLUSIONS The research needs identified by the workshop participants included the following: standards to measure the contents and emissions of e-cigarettes; biomarkers of exposure; physiological effects of e-cigarettes on tissues and organ systems, including pulmonary and cardiovascular; information on e-cigarette users, how the devices are used, and identification of the best tools to assess these measures; factors that drive use and influence patterns of use; and appropriate methods for evaluating a potential role for e-cigarettes in smoking or nicotine cessation. To understand fully the challenges and the opportunities that e-cigarettes represent, expertise will be needed in basic, behavioral, translational, and clinical sciences.

Gender Differences Relative to Smoking Behavior and Emissions of Toxins from Mainstream Cigarette Smoke

This study examined whether gender differences exist in the exposure to select mainstream cigarette smoke toxins as a result of differences in smoking behavior or type of cigarettes smoked among 129 female and 128 male smokers. Smoking topography data indicated that, compared with men, women took smaller puffs (37.6 ml/puff vs. 45.8 ml/puff; p = .0001) of shorter duration (1.33 s/puff vs. 1.48 s/puff; p = .002) but drew more puffs per cigarette (13.5 vs. 12.0; p = .001) and left longer butts (36.3 mm or 40.2% of cigarette length vs. 34.3 mm or 39.2% of cigarette length; p = .01). These trends were similar in both African Americans and European Americans. The emissions of select toxins per cigarette, as determined by mimicking human smoking behaviors were greater among the male smokers than the female smokers and correlated significantly with delivered smoke volume per cigarette. The geometric means of emissions of nicotine from cigarettes were 1.92 mg/cigarette (95% CI = 1.80-2.05) for women versus 2.20 (95% CI = 2.04-2.37) for men (p = .005). Cigarettes smoked by women yielded 139.5 ng/cigarette of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK; 95% CI = 128.8-151.0), compared with 170.3 ng/cigarette (95% CI = 156.3-185.6) for men (p = .0007); benzo(a)pyrene (BaP) emissions were 18.0 ng/cigarette (95% CI = 17.0-19.0) for women and 20.5 ng/cigarette (95% CI = 18.8-22.3) for men (p = .01). The gender differences with regard to cigarette smoke yields of toxins were more profound in European Americans than in African Americans. On average, African American mens smoking habits produced the highest emissions of select toxins from cigarettes, and European American female smokers had the lowest exposure to carcinogens and toxins. Several studies have suggested that women may be more susceptible than men to the ill effects of carcinogens in tobacco and tobacco smoke, whereas other studies have not found differences in lung cancer risk between men and women. The present study suggests that gender differences in exposure to tobacco smoke cannot account for a higher rate of lung cancer in female smokers compared with male smokers.

Nicotine Content and Delivery Across Tobacco Products

Nicotine is the principal alkaloid in both commercial and homemade products (e.g., cigarettes, smokeless tobacco, bidis, waterpipes) followed by nornicotine, anabasine, anatabine, and many other basic substances that contain a cyclic nitrogenous nucleus. Tobacco types, leaf position on the plant, agricultural practices, fertilizer treatment, and degree of ripening are among some prominent factors that determine the levels of alkaloids in tobacco leaf. From a random examination of 152 cultivated varieties of Nicotiana tabacum, a range of alkaloid variation between 0.17 and 4.93% was determined. In fact, every step in tobacco production that affects plant metabolism will influence the level of alkaloid content to a certain degree. Depending on blending recipe, type and amount of additives, and product design, all types of tobacco products contain a very wide range of nicotine concentration. However, the ultimate emission of nicotine to the user, exposure, and psychophar-macological effects depend not only on the content and emission, but also on the relationship between the product and the user.

Effect of Delivered Dosage of Cigarette Smoke Toxins on the Levels of Urinary Biomarkers of Exposure

Urinary metabolites of tobacco smoke toxins are often used as biomarkers for the evaluation of active and passive exposure to cigarette smoke toxins. In a study of healthy smokers, we investigated concentrations of urinary biomarkers in relation to concentrations of selected toxins in mainstream cigarette smoke as determined by machine smoking of cigarettes in a manner that mimics an individuals smoking behavior (topography). Concentrations of nicotine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, and benzo(a)pyrene, in mainstream smoke determined under human smoking conditions, and their urinary metabolites cotinine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol, and 1-hydroxypyrene were established for 257 individuals who smoked low-yield (0.1-0.8 mg Federal Trade Commission nicotine/cigarette; mean, 0.66; n = 87), medium-yield (0.9-1.2 mg nicotine/cigarette; mean, 1.1; n = 109), and high-yield cigarettes (nicotine, >1.3 mg nicotine/cigarette; mean, 1.41; n = 61). Levels of urinary metabolites expressed per unit of delivered parent compounds decreased with increased smoke emissions. In smokers of low-, medium-, and high-yield cigarettes, the respective cotinine (ng/mg creatinine)-to-nicotine (mg/d) ratios were 89.4, 77.8, and 57.1 (low versus high; P = 0.06); the 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (pmol/mg creatinine)-to-4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (ng/d) ratios were 0.81, 0.55, and 0.57 (low versus high; P = 0.05); and the 1-hydroxypyrene (pg/mg creatinine)-to-benzo(a)pyrene (ng/d) ratios were 1.55, 1.13, and 0.97 (low versus high; P = 0.008). Similarly, means of cotinine per unit of delivered nicotine in smokers who consumed <20 cigarettes per day was 3.5-fold higher than in those who smoked >20 cigarettes per day. Likewise, a negative correlation was observed between cotinine-to-nicotine ratios and delivered doses of nicotine in subgroups of smokers who used the identical brand of cigarette, namely a filter tip-vented Marlboro (r = −0.59), which is a popular brand among Euro-Americans, and Newport (r = −0.37), a menthol-flavored cigarette without filter tip vents that is preferred by African-Americans. Thus, the intensity of the exposures significantly affects the levels of urinary biomarkers of exposure and should be taken into account in the evaluation of human exposure to cigarette smoke toxins. (Cancer Epidemiol Biomarkers Prev 2007;16(7):1408–15)

Menthol Cigarettes: Setting the Research Agenda

The First Conference on Menthol Cigarettes wasconvened in Atlanta, Georgia, on March 21–22, 2002.The purpose of the conference was to evaluate thepresent state of the science concerning the potentialincreased harm caused by adding menthol to cigar-ettes, and to set the priorities for further studies ofmenthol cigarettes. More than 80 researchers andtobacco control experts participated in the conference.This supplement to Nicotine & Tobacco Researchprovides a summary of the state of our knowledge ofthe history, sociology, epidemiology, and toxicologyof menthol cigarettes as well as the proposed futureresearch agenda.IntroductionMenthol is unique in that it is the only cigaretteadditive actively marketed to consumers. It is the onlyaspect of cigarette design that is marketed explicitlybased on its physiological effects, as an anti-irritantand a cooling agent. It is the only cigarette additiveabout which consumers make conscious buyingchoices.Although the tobacco industry has activelyinvestigated menthol as an additive (Best, 1993;Borgerding, 1993; Borschke, 1993; Hopp, 1993;Reid, 1993; Wilson, 1993), relatively few studieshave been published in the public health literatureabout the following topics: