Uptake of environmental tobacco smoke

This chapter has reviewed evidence of the uptake of smoke constituents by nonsmokers through exposure to environmental tobacco smoke. Although carbon monoxide absorption reflects an acute exposure, nicotine and its metabolite cotinine are the best markers currently available. Nicotine is found in measurable concentrations in the saliva and urine of most urban nonsmokers, and is present in higher concentrations in those with some recent exposure. But the short half-life of nicotine in the body means that it is best suited to quantifying exposure over a period of a few hours only. Cotinine, which has a half-life of about one day, has been shown to be a valid and sensitive marker of current daily-life exposure to environmental tobacco smoke. Estimating the magnitude of the passive smoking dose is difficult, and it is of doubtful validity to extrapolate from the uptake of one marker to that of another. Over a period when one cigarette-equivalent of carbon monoxide is absorbed, the dose of nicotine appears to be only between one-tenth and one-third of a cigarette-equivalent. Measures of tar deposition are not available, but nicotine is probably a better guide than carbon monoxide to the size of the tar dose. It seems unlikely that nonsmokers could absorb more than one or two mg of nicotine in a day, even if they spend the majority of their waking hours in heavily smoke-polluted atmospheres. Comparison of cotinine concentrations in urban nonsmokers and active smokers suggests that average nonsmokers may receive a dose of about 0.2 mg of nicotine per day. This is a preliminary estimate which depends on a number of assumptions and will be subject to revision as data accumulate on more representative samples. Finally, the confirmation that dose-response relationships exist between cotinine concentrations and self-reported passive smoking validates questionnaire measures of the degree of environmental smoke exposure. Epidemiological studies which suggest that passive smoking carries a risk to health thereby gain increased credibility. But future progress in understanding will be best assured if epidemiological methods and biological monitoring of exposure markers are combined in the same studies.     

Lung carcinogenesis by tobacco smoke

Cigarette smoke is a complex mixture of chemicals including multiple genotoxic lung carcinogens. The classic mechanisms of carcinogen metabolic activation to DNA adducts, leading to miscoding and mutations in critical growth control genes, applies to this mixture but some aspects are difficult to establish because of the complexity of the exposure. This article discusses certain features of this mechanism including the role of nicotine and its receptors; lung carcinogens, co-carcinogens and related substances in cigarette smoke; structurally characterized DNA adducts in the lungs of smokers; the mutational consequences of DNA adduct formation in smokers' lungs; and biomarkers of nicotine and carcinogen uptake as related to lung cancer. While there are still uncertainties which may never be fully resolved, the general mechanisms by which cigarette smoking causes lung cancer are well understood and provide insights relevant to prevention of lung cancer, the number one cancer killer in the world, causing 1.37 million deaths per year.     

Epidemiology of environmental tobacco smoke exposure

The health hazards due to exposure to environmental tobacco smoke (ETS) are increasingly established. ETS contains thousands of chemicals including 43 known carcinogens. One of the most important known health effects of ETS exposure is lung cancer in non-smokers, based on epidemiologic evidence and knowledge of the uptake and metabolism of ETS. Epidemiologic studies need to carefully take into account confounding and potential errors in exposure assessment. More research is needed to understand the genetic factors that influence ETS-induced lung cancer. Studies of the patterns of ETS exposure suggest higher rates of exposure in people employed as blue collar workers, in service occupations, earning lower incomes, and among the less educated. Certain racial/ethnic groups (e.g. Blacks, American Indians) may be at higher risk of ETS exposure. Despite substantial progress in protecting individuals from ETS exposure, additional efforts are needed in improving and enforcing policies to reduce exposure.     

The carcinogenicity of environmental tobacco smoke

Male strain A/J mice were exposed for 6 h a day, 5 days a week to environmental tobacco smoke (ETS) generated from Kentucky 1R4F reference cigarettes. Chamber concentrations were 87 mg/m3 of total suspended particulate matter (TSP), 246 p.p.m. of CO and 16 mg/m3 of nicotine. After 5 months, 33% of the ETS exposed and 11% of the control animals had one or several lung tumors; the difference was statistically not significant. A second group of animals exposed for 5 months to ETS was allowed to recover for another 4 months in filtered air. When they were killed, 85% of the ETS animals had lung tumors (average number per lung: 1.4 +/- 0.2), whereas in the control group 38% had lung tumors (average number of lung tumors in all animals 0.5 +/- 0.2). The differences in tumor incidence and multiplicity were statistically significant. More than 80% of all tumors were adenomas, the rest adenocarcinomas. When animals were pretreated with a carcinogen, lung tumor multiplicity was lower in the ETS exposed animals after 5 months compared with controls injected with a carcinogen and kept in air. However, after an additional 4 month recovery period in air, lung tumor multiplicities were the same in ETS plus carcinogen exposed mice as in carcinogen-treated air-exposed controls. Histopathologic and morphometric analysis of the lung tissue failed to reveal any differences between ETS exposed and control animals. However, immediately after ETS exposure, immunohistochemistry revealed increased staining for CYP1A1 in airway epithelia and lung parenchyma; following recovery in air, the staining disappeared again. Analysis of cell kinetics showed an initial burst of increased DNA synthesis in the epithelial cells of the airways and a smaller early positive response in the parenchyma. Feeding of butylated hydroxytoluene during ETS exposure did not modulate lung tumor development. It was concluded that ETS is a pulmonary carcinogen in strain A/J mice.      

Assessment of the carcinogenic N-nitrosodiethanolamine in tobacco products and tobacco smoke

A simple, reproducible gas chromatography-thermal energy analyzer(g.c.-TEA) method has been developed for the analysis of N-nitrosodiethanolainlne(NDELA) in tobacco and tobacco smoke. The extract of tobaccoor the trapped particulates of tobacco smoke are chromatographedon silica gel. The NDELA containing fractions are concentrated,silylated and analyzed with a modified g.c.-TEA system. [¹⁴C]NDELAserves as internal standard for the quantitative analysis. Experimentalcigarettes made from tobaccos which were treated with the suckergrowth inhibitor maleic hydrazide-diethanolamlne (MH-DELA) contained115–420 p.p.b. of NDELA and their smoke contained 20–290ng/cigarette, whereas hand-suckered tobacco and its smoke werefree of NDELA. The tobacco of US smoking products contained115–420 p.p.b. of NDELA and the mainstream smoke fromsuch products yielded 10–68 ng/cigar or cigarette. NDELAlevels in chewing tobacco ranged from 220–280 p.p.b. andin two commercial snuff products were 3,200 and 6,800 p.p.b.Although the five analyzed MH-DELA preparations contained between0.6–1.9 p.p.m. NDELA it is evident that the major portionof NDELA in tobacco is formed from the DELA residue during thetobacco processing. Based on bioassay data from various laboratorieswhich have shown that NDELA is a relatively strong car cinogenand based on the results of this study the use of MH-DELA forthe cultivation of tobacco is questioned.     

Chemical constituents and bioactivity of tobacco smoke

Tobacco smoke contains more than 3900 constituents. In this presentation we have summarized our present knowledge as to the physicochemical nature of tobacco smoke and specific agents therein. Emphasis has been placed on the discussion of formation and identification of toxic and, especially, of tumorigenic agents in tobacco smoke. In the concluding Table 13 we have listed those smoke constituents in the mainstream smoke of cigarettes that we regard as important contributors to the toxic and carcinogenic potential of tobacco smoke. This judgement is based on extensive laboratory studies. Finally, data are presented in support of the concept that product modification can reduce the carcinogenic potential of cigarettes. However, it must be emphasized that the only safe way to avoid the cancer risks associated with smoking is to refrain from smoking.     

Significance of exposure to sidestream tobacco smoke

The presence of toxins and carcinogens in ambient air polluted with tobacco smoke is largely due to the sidestream smoke emissions from the smouldering tobacco products. Levels of these toxins and carcinogens in sidestream smoke often exceed their concentrations in mainstream smoke. Dosimetry of tobacco-specific markers of exposure in physiologic fluids suggests that in regard to nicotine--which is the major tobacco alkaloid--exposure of humans to environmental tobacco smoke causes but a few percent of the nicotine levels reached as a result of active inhalation of cigarette mainstream smoke. Yet, this measurement of exposure is not universally applicable to all of the tobacco smoke pollutants in this complex matrix. Existing knowledge of the chemical composition of sidestream smoke and evidence of biological activity of sidestream smoke components suggests that this environmental pollutant has carcinogenic potential. Significance of exposure to environmental tobacco smoke must be evaluated on the basis of the severity of the pollution, the duration of exposure and personal variations in uptake.     

Non-Hodgkin's lymphoma and type of tobacco smoke.

BACKGROUND: In recent decades, the incidence of non-Hodgkin's lymphoma (NHL) has increased in all industrialized countries. Tobacco smoke contains several recognized or putative carcinogenic compounds that differ in concentration depending on which of the two main types, blond or black, is consumed. This investigation sought to evaluate the association between NHL and type of tobacco smoked (blond, black, or mixed), focusing on the Working Formulation (WF) subgroups. METHODS: Reanalysis of Italian data from a recent multicenter population-based case-control study. The 1450 cases of NHL and 1779 healthy controls from 11 Italian areas with different demographic and productive characteristics were included in the study, corresponding to approximately 7 million residents. Odds ratios (ORs) adjusted for age, gender, residence area, educational level, and type of interview were estimated by unconditional logistic regression model. RESULTS: A statistically significant association [OR = 1.4, 95% confidence interval (CI) 1.1-1.7] was found for blond tobacco exposure and NHL risk. A dose-response relationship was limited to men younger than 52 years (chi(2) for trend = 9.95, P < 0.001). Subjects starting smoking at an early age showed a higher risk in men younger than 65 years, whereas no clear trend was evident for the other age and gender subgroups. The analysis by WF categories showed the highest risks for follicular lymphoma in blond (OR = 2.1, 95% CI 1.4-3.2) and mixed (OR = 1.8, 95% CI 1.1-3.0) tobacco smokers and for large cell within the other WF group (OR = 1.6, 95% CI 1.1-2.4) only for blond tobacco. CONCLUSIONS: Smoking blond tobacco could be a risk factor for NHL, especially follicular lymphoma.     

N-nitroso compounds in cigarette tobacco and their occurrence in mainstream tobacco smoke

The tobacco and mainstream smoke of 20 commercial brands of filter and non-filter cigarettes were analysed for N-nitroso compounds. The concentrations of N-nitrosodimethylamine (NDMA), N-nitrosoethylmethylamine (NEMA) and N-nitrosopyrrolidine (NPYR) in cigarette tobacco were very much lower than in mainstream smoke, where the levels were 6.3-76.4 ng/cig NDMA, less than 1.0-7.1 ng/cig NEMA and 3.9-41.2 ng/cig NPYR. N-Nitrosodiethylamine was not detected in mainstream smoke and N-nitrosopiperidine (less than 1.0 ng/cig) was detected in the smoke of four unfiltered cigarette brands. The five major non-volatile nitrosamines present in cigarette tobacco were 4-(N-nitroso-N-methylamino)butyric acid (not detected to 200 ng/cig), N-nitrosopipecolic acid (not detected to 670 ng/cig), N-nitrososarcosine (22-460 ng/cig), 3-(N-nitroso-N-methylamino)propionic acid (110-4990 ng/cig) and N-nitrosoproline (580-15000 ng/cig). The tobacco-specific nitrosamines N-nitrosoanabasine and N-nitrosoanatabine were found at levels of 270-2330 ng/cig and 18-205 ng/cig in cigarette tobacco and mainstream smoke respectively. N-Nitrosonornicotine was present at 400-5340 ng/cig and 19-855 ng/cig in cigarette tobacco and mainstream smoke respectively. 4-(N-Nitrosomethyl-amino)-1-(3-pyridyl)-1-butanone concentrations of 100-960 ng/cig and 21-470 ng/cig in cigarette tobacco and mainstream smoke were determined. 4-(N-Nitrosomethyl-amino)-4-(3-pyridyl)-1-butanol (iso-NNAL) was detected in four dark (French) tobacco unfiltered cigarettes at a concentration range of 140-240 ng/cig and 5-11 ng/cig in the corresponding mainstream smoke. For non-filter cigarettes, a transfer rate of 3.4-4.6% for iso-NNAL was calculated.     

Tobacco-specific nitrosamines, an important group of carcinogens in tobacco and tobacco smoke

Tobacco-specific nitrosamines are a group of carcinogens that are present in tobacco and tobacco smoke. They are formed from nicotine and related tobacco alkaloids. Two of the nicotine-derived nitrosamines, NNK and NNN, are strong carcinogens in laboratory animals. They can induce tumors both locally and systemically. The induction of oral cavity tumors by a mixture of NNK and NNN, and the organospecificity of NNK for the lung are particularly noteworthy. The amounts of NNK and NNN in tobacco and tobacco smoke are high enough that their total estimated doses to long-term snuff-dippers or smokers are similar in magnitude to the total doses required to produce cancer in laboratory animals. These exposures thus represent an unacceptable risk to tobacco consumers, and possibly to non-smokers exposed for years to environmental tobacco smoke. The permission of such high levels of carcinogens in consumer products used by millions of people represents a major legislative failure. Indeed, the levels of tobacco-specific nitrosamines in tobacco are thousands of times higher than the amounts of other nitrosamines in consumer products that are regulated by government authorities. Although the role of tobacco-specific nitrosamines as causative factors in tobacco-related human cancers cannot be assessed with certainty because of the complexity of tobacco and tobacco smoke, several lines of evidence strongly indicate that they have a major role, especially in the causation of oral cancer in snuff-dippers. Epidemiologic studies have demonstrated that snuff-dipping causes oral cancer. NNK and NNN are quantitatively the most prevalent known carcinogens in snuff, and they induce oral tumors when applied to the rat oral cavity. A role for NNK in the induction of lung cancer by tobacco smoke is likely because of its organospecificity for the lung. Tobacco-specific nitrosamines may also be involved in the etiology of tobacco-related cancers of the esophagus, nasal cavity, and pancreas. Because they are derived from nicotine, and therefore should be associated only with tobacco, tobacco smoke and other nicotine-containing products, tobacco-specific nitrosamines as well as their metabolites and macromolecular adducts should be ideal markers for assessing human exposure to, and metabolic activation of, tobacco smoke carcinogens. Ongoing research has demonstrated the formation of globin and DNA adducts of NNK and NNN in experimental animals. Sensitive methods for the detection and quantitation of these adducts in humans would provide an approach to assessing individual risk for tobacco-related cancers.(ABSTRACT TRUNCATED AT 400 WORDS)     

Analysis and pyrolysis of some N-nitrosamino acids in tobacco and tobacco smoke.

A new tobacco-specific nitrosamine, 4-(N-nitrosomethylamino)-4-(3-pyridyl)butyric acid (iso-NNAC), has been identified in tobacco, and its structure was confirmed by gas chromatography-mass spectrometry following enrichment of a tobacco extract. The levels of iso-NNAC ranged from 0.01 to 0.95 ppm. It does not induce DNA repair in primary rat hepatocytes and is inactive as a tumorigenic agent in strain A mice. In order to study the fate of nitrosamino acids during smoking, we spiked cigarettes with the following N-nitrosamino acids: iso-NNAC, 3-(nitrosomethylamino)propionic acid (NMPA), 4-(nitrosomethylamino)butyric acid (NMBA), N-nitrososarcosine (NSAR) and N-nitrosoproline (NPRO). NMPA and NMBA were partially transferred, unchanged, during smoking and partially formed the corresponding methyl esters, while pyrolysis of NSAR and NPRO resulted mainly in their decarboxylating products. This is the first time that the pyrosynthesis of methyl esters has been observed during smoking.