Detrimental effects of environmental tobacco smoke in relation to asthma severity

Background

Environmental tobacco smoke (ETS) has adverse effects on the health of asthmatics, however the harmful consequences of ETS in relation to asthma severity are unknown.

Methods

In a multicenter study of severe asthma, we assessed the impact of ETS exposure on morbidity, health care utilization and lung functions; and activity of systemic superoxide dismutase (SOD), a potential oxidative target of ETS that is negatively associated with asthma severity.

Findings

From 2002–2006, 654 asthmatics (non-severe 366, severe 288) were enrolled, among whom 109 non-severe and 67 severe asthmatics were routinely exposed to ETS as ascertained by history and validated by urine cotinine levels. ETS-exposure was associated with lower quality of life scores; greater rescue inhaler use; lower lung function; greater bronchodilator responsiveness; and greater risk for emergency room visits, hospitalization and intensive care unit admission. ETS-exposure was associated with lower levels of serum SOD activity, particularly in asthmatic women of African heritage.

Interpretation

ETS-exposure of asthmatic individuals is associated with worse lung function, higher acuity of exacerbations, more health care utilization, and greater bronchial hyperreactivity. The association of diminished systemic SOD activity to ETS exposure provides for the first time a specific oxidant mechanism by which ETS may adversely affect patients with asthma.     

IL13 gene polymorphisms modify the effect of exposure to tobacco smoke on persistent wheeze and asthma in childhood,a longitudinal study

Background

Tobacco smoke and genetic susceptibility are risk factors for asthma and wheezing. The aim of this study was to investigate whether there is a combined effect of interleukin-13 gene (IL13) polymorphisms and tobacco smoke on persistent childhood wheezing and asthma.

Methods

In the Isle of Wight birth cohort (UK, 1989–1999), five IL13 single nucleotide polymorphisms (SNPs): rs1800925 (-1112C/T), rs2066960, rs1295686, rs20541 (R130Q) and rs1295685 were genotyped. Parents were asked whether their children had wheezed in the last 12 months at ages 1, 2, 4 and 10 years. Children who reported wheeze in the first 4 years of life and also had wheezing at age 10 were classified as early-onset persistent wheeze phenotype; non-wheezers never wheezed up to age 10. Persistent asthma was defined as having a diagnosis of asthma both during the first four years of life and at age 10. Logistic regression methods were used to analyze data on 791 children with complete information. Potential confounders were gender, birth weight, duration of breast feeding, and household cat or dog present during pregnancy.

Results

Maternal smoking during pregnancy was associated with early-onset persistent wheeze (OR 2.93, p < 0.0001); polymorphisms in IL13 were not (OR 1.15, p = 0.60 for the common haplotype pair). However, the effect of maternal smoking during pregnancy was stronger in children with the common IL13 haplotype pair compared to those without it (OR 5.58 and OR 1.29, respectively; p for interaction = 0.014). Single SNP analysis revealed a similar statistical significance for rs20541 (p for interaction = 0.02). Comparable results were observed for persistent childhood asthma (p for interaction = 0.03).

Conclusion

This is the first report that shows a combined effect of in utero exposure to smoking and IL13 on asthma phenotypes in childhood. The results emphasize that genetic studies need to take environmental exposures into account, since they may explain contradictory findings.     

Biomarkers of exposure to environmental tobacco smoke in infants

Non-invasive biomonitoring of exposure to environmental tobacco smoke (ETS) by means of hair is attractive in children, although systematic evaluation is required in infants. The objective was to compare nicotine and cotinine concentrations in hair and plasma and parentally reported exposure to ETS in a birth cohort of 411 infants. Plasma was collected from 356 six-month-old infants and hair samples were collected from 368 one-year-old infants. Concentrations of nicotine and cotinine were measured by an optimized gas chromatography-mass spectrometry (GC/MS)-based method requiring 4 mg hair or 200 µl plasma. Information was obtained on the number of days with ETS exposure during the first year of life, the smoking habits of the parents, and the number of cigarettes smoked per day in the home. All three parentally reported indices of ETS exposure were significantly associated with the biomarkers, with clear dose–response relationships. There was a significant association between days with ETS exposure and nicotine in hair at relatively low exposure levels (10–99 days per year), whereas the other biomarkers only showed significant increases at higher exposure levels. In conclusion, nicotine in hair appears to be the biomarker most strongly associated with parental reports on exposure to ETS in infants.     

Biomarkers of exposure to environmental tobacco smoke in infants

Non-invasive biomonitoring of exposure to environmental tobacco smoke (ETS) by means of hair is attractive in children, although systematic evaluation is required in infants. The objective was to compare nicotine and cotinine concentrations in hair and plasma and parentally reported exposure to ETS in a birth cohort of 411 infants. Plasma was collected from 356 six-month-old infants and hair samples were collected from 368 one-year-old infants. Concentrations of nicotine and cotinine were measured by an optimized gas chromatography-mass spectrometry (GC/MS)-based method requiring 4 mg hair or 200 µl plasma. Information was obtained on the number of days with ETS exposure during the first year of life, the smoking habits of the parents, and the number of cigarettes smoked per day in the home. All three parentally reported indices of ETS exposure were significantly associated with the biomarkers, with clear dose-response relationships. There was a significant association between days with ETS exposure and nicotine in hair at relatively low exposure levels (10-99 days per year), whereas the other biomarkers only showed significant increases at higher exposure levels. In conclusion, nicotine in hair appears to be the biomarker most strongly associated with parental reports on exposure to ETS in infants.     

Genotoxicity of environmental tobacco smoke: a review

Environmental tobacco smoke (ETS), or second-hand smoke, is a widespread contaminant of indoor air in environments where smoking is not prohibited. It is a significant source of exposure to a large number of substances known to be hazardous to human health. Numerous expert panels have concluded that there is sufficient evidence to classify involuntary smoking (or passive smoking) as carcinogenic to humans. According to the recent evaluation by the International Agency for Research on Cancer, involuntary smoking causes lung cancer in never-smokers with an excess risk in the order of 20% for women and 30% for men. The present paper reviews studies on genotoxicity and related endpoints carried out on ETS since the mid-1980s. The evidence from in vitro studies demonstrates induction of DNA strand breaks, formation of DNA adducts, mutagenicity in bacterial assays and cytogenetic effects. In vivo experiments in rodents have shown that exposure to tobacco smoke, whole-body exposure to mainstream smoke (MS), sidestream smoke (SS), or their mixture, causes DNA single strand breaks, aromatic adducts and oxidative damage to DNA, chromosome aberrations and micronuclei. Genotoxicity of transplacental exposure to ETS has also been reported. Review of human biomarker studies conducted among non-smokers with involuntary exposure to tobacco smoke indicates presence of DNA adducts, urinary metabolites of carcinogens, urinary mutagenicity, SCEs and hypoxanthine-guanine phosphoribosyltransferase (HPRT) gene mutations (in newborns exposed through involuntary smoking of the mother). Studies on human lung cancer from smokers and never-smokers involuntarily exposed to tobacco smoke suggest occurrence of similar kinds of genetic alterations in both groups. In conclusion, these overwhelming data are compatible with the current knowledge on the mechanisms of carcinogenesis of tobacco-related cancers, occurring not only in smokers but with a high biological plausibility also in involuntary smokers.     

Epidemiological study of wheeze,doctor diagnosed asthma,and cough in preschool children in Leicestershire.

OBJECTIVE--To determine the cumulative prevalences of wheeze and doctor diagnosed asthma and the point prevalences of recurrent cough and wheeze in children aged 5 years and under. DESIGN--Questionnaire survey of population based random sample of children registered on regional authority''s child health index for immunisation; questionnaire completed by parents. SETTING--Leicestershire. SUBJECTS--1650 white children born in 1985-9 who were surveyed in 1990. MAIN OUTCOME MEASURES--Cumulative prevalences of wheeze and doctor diagnosed asthma and point prevalences of recurrent cough and wheeze by age and sex. RESULTS--There were 1422 replies (86.2%; 726 for boys, 696 for girls). Overall, 11.0% (95% confidence interval 9.4% to 12.6%) of children had formally been diagnosed as having asthma, the cumulative prevalence in boys (12.7%) being somewhat higher than in girls (9.2%) (age adjusted odds ratio 1.47, p = 0.03). As expected, the cumulative prevalence of asthma increased significantly with age (7.5% (13/173) in children under 1 year, 15.9% (61/383) in children of 4 years and over; p < 0.001). The cumulative prevalence of wheeze overall was 15.6% (13.7% to 17.5%), being higher in boys (17.6%) than in girls (13.5%) (odds ratio 1.38, p = 0.03). The overall prevalence of recurrent cough without colds was 21.8% (19.6% to 23.9%), with a non-significant excess in boys (23.1% v 20.4%). The overall prevalence of wheezing attacks during the previous 12 months was 13.0% (11.3% to 14.8%) with a non-significant excess in boys (14.5% v 11.5%). CONCLUSIONS--These findings are baseline results and emphasise the importance of studying the age group of interest rather than relying on the recall of parents of school age children.     

Endotoxin as a determinant of asthma and wheeze among rural dwelling children and adolescents: A case--control study

ABSTRACT: BACKGROUND: The association between endotoxin exposure and asthma is complex and has been associated with rural living. We examined the relationship between domestic endotoxin and asthma or wheeze among rural school-aged children (6--18 years) and assessed the interaction between endotoxin and other characteristics with these outcomes. METHODS: Between 2005 and 2007 we conducted a case--control study of children 6--18 years in the rural region of Humboldt, Canada. Cases (n = 102) reported doctor-diagnosed asthma or wheeze in the past year. Controls (n = 208) were randomly selected from children without asthma or wheeze. Data were collected to ascertain symptoms, asthma history and indoor environmental exposures (questionnaire), endotoxin (dust collection from the play area floor and child's mattress), and tobacco smoke exposure (saliva collection). Statistical testing was completed using multiple logistic regression to account for potential confounders and to assess interaction between risk factors. A stratified analysis was also completed to examine the effect of personal history of allergy. RESULTS: Among children aged 6--12 years, mattress endotoxin concentration (EU/mg) and load (EU/m2) were inversely associated with being a case [odds ratio (OR) = 0.44, 95 % confidence interval (CI) = 0.20-0.98; and OR = 0.38, 95 % CI = 0.20-0.75, respectively]. These associations were not observed in older children or with play area endotoxin. CONCLUSIONS: Our results suggest that endotoxin exposure might be protective for asthma or wheeze. The protective effect is found in younger school-aged, non-allergic children. These results may help explain the inconsistencies in previous studies and suggest that the protective effects of endotoxin in the prevention of atopy and asthma or wheeze are most effective earlier in life.     

NAD(P)H: Quinone oxidoreductase 1, glutathione S-transferase M1, environmental tobacco smoke exposure, and childhood asthma

Environmental tobacco smoke (ETS) exposure might increase the risk for childhood asthma, and we hypothesized the effect may be modified by the phase II genes NAD(P)H: quinone oxidoreductase 1 (NQO1) and glutathione S-transferase (GST) M1. To investigate the genetic and environmental associations with asthma, GSTM1 and NQO1 functional polymorphisms and ETS were analyzed in a two-staged cross-sectional study among elementary schoolchildren in Taiwan. Multiple logistic regression analysis revealed a significant association between the Ser allele of the NQO1 Pro187Ser polymorphism and asthma (OR = 1.6, 95% CI 1.3–1.8). Although GSTM1 genotype itself was not significantly associated with asthma (OR = 1.0, 95% CI 0.8–1.1), the GSTM1 genotype modified the association between the NQO1 polymorphism and asthma in children exposed to ETS (p = 0.0002). The NQO1 gene might be involved in the development of asthma, especially in children carrying the GSTM1 null genotype who are exposed to ETS.     

A genotoxic assessment of environmental tobacco smoke using bacterial bioassays

Recently, the National Research Council in the U.S.A. stated that laboratory studies of environmental tobacco smoke (ETS) should be important in identifying ETS carcinogens, their concentrations in typical daily environments, and in understanding how these compounds contribute to ETS dose-response relationships. This paper demonstrates that integrated chemical and bacterial mutagenicity information can be used to identify ETS genotoxicants, monitor human exposure, and make comparative assessments. Approximately 1/3 of the ETS constituents for which there is quantitative analytical chemistry information also have associated genotoxicity information. For example, 11 of the quantitated compounds are animal carcinogens. Work presented in this paper demonstrates that both the nonparticle-bound semivolatile and the particulate-bound organic material contain bacterial mutagens. These ETS organics give an equivalent of approximately 86,000 revertants per cigarette. In addition, this article summarized efforts to estimate ETS bacterial mutagenicity, to use bacterial tests for the monitoring of ETS-impacted indoor environments, and to use bacterial assays for the direct monitoring of human exposure.     

Population burden of lung cancer due to environmental tobacco smoke

The population burden of lung cancer due to environmental tobacco smoke is significant because a large fraction of the population is exposed. The risks are, of course, lower than those to smokers themselves; but smoking is self-inflicted, passive smoking is involuntary. Making various assumptions, the proportion of lung cancer cases among non-smokers that could reasonably be attributed to environmental tobacco smoke can be calculated to be about 20–30% in western countries. Thus, non-smokers in the society could benefit considerably from diminishing exposures to other people's smoke.     

Measuring personal exposure to airborne mutagens and nicotine in environmental tobacco smoke

The exposure of individuals to environmental tobacco smoke (ETS) is of increasing public health concern because epidemiological studies have associated passive smoking with increased risk of a variety of adverse health effects among non-smokers including lung cancer. As a way to measure individual exposure to the mutagenic compounds in the complex mixture of ETS, we used a sensitive Salmonella/microsome micro pre-incubation (microsuspension) assay to detect mutagenicity of particulate matter collected on filters from low volume (1.7 1/min flow rate) personal sampling pumps. Airborne nicotine was collected concurrently as a marker for ETS exposure. In pilot-field studies, individual exposure to ETS was measured in two separate indoor environments in which smokers were present: a gambling casino and a bingo parlor. Total suspended particulate matter (TSP) was collected on filters worn near the breathing zone of non-smoking individuals. Sampling times ranged from 40 min to 6 h. All extracts of filters had detectable levels of mutagenic activity (TA98, +S9) resulting in airborne mutagenic activity concentrations of 500-5000 rev/m3. The mutagenic activity of the filters from the casino and bingo parlors was significantly correlated with total particulate matter per filters (n = 12; Rho = 0.85, p less than 0.01) and with airborne nicotine per filter (n = 12; Rho = 0.95, p less than 0.01). The microsuspension assay was sufficiently sensitive to detect the mutagens associated with extracts of particulate matter from low volume samples (0.2-0.6 m3) in these indoor environments over a relatively short sampling time, and could be useful in studies of personal exposure to the mutagens in environmental tobacco smoke. Further, airborne nicotine concentrations were highly correlated with airborne mutagenicity and the mutagenic activity associated with ETS could therefore be estimated by the concentrations of nicotine.     

The accumulated evidence on lung cancer and environmental tobacco smoke.

OBJECTIVE: To estimate the risk of lung cancer in lifelong non-smokers exposed to environmental tobacco smoke. DESIGN: Analysis of 37 published epidemiological studies of the risk of lung cancer (4626 cases) in non-smokers who did and did not live with a smoker. The risk estimate was compared with that from linear extrapolation of the risk in smokers using seven studies of biochemical markers of tobacco smoke intake. MAIN OUTCOME MEASURE: Relative risk of lung cancer in lifelong non-smokers according to whether the spouse currently smoked or had never smoked. RESULTS: The excess risk of lung cancer was 24% (95% confidence interval 13% to 36%) in non-smokers who lived with a smoker (P < 0.001). Adjustment for the effects of bias (positive and negative) and dietary confounding had little overall effect; the adjusted excess risk was 26% (7% to 47%). The dose-response relation of the risk of lung cancer with both the number of cigarettes smoked by the spouse and the duration of exposure was significant. The excess risk derived by linear extrapolation from that in smokers was 19%, similar to the direct estimate of 26%. CONCLUSION: The epidemiological and biochemical evidence on exposure to environmental tobacco smoke, with the supporting evidence of tobacco specific carcinogens in the blood and urine of non-smokers exposed to environmental tobacco smoke, provides compelling confirmation that breathing other people''s tobacco smoke is a cause of lung cancer.     

Genotoxicity and DNA adduct formation of incense smoke condensates: comparison with environmental tobacco smoke condensates

Indoor air pollution has now been recognized as a potentially important problem for public health, since people spend most of their day in closed environments. Incense burning is possibly associated with elevated risks of leukemia and brain tumor in children from the epidemiological studies. Thus, evaluation of the genotoxicity of smoke condensates from incense burning is needed. We examined the genotoxicity of incense smoke condensates (ISC) using the Ames test in S. typhimurium strains with different mutagenic specificity and level of metabolic enzyme, the SOS chromotest in E. coli PQ37, and sister chromatid exchange assay in Chinese hamster ovary cells (SCE/CHO). The genotoxicity of environmental tobacco smoke condensates (TSC) was also evaluated by the three assays to compare with the genotoxicity of ISC, ISC showed a positive response in TA98, but not in TA100. It suggested that ISC only contained frame shift mutagens. The mutagenicity of ISC in both strains of TA98NR with deficient nitroreductase and TA98/1,8-DNP₆ with deficient O-acetyl-transferase was markedly decreased compared to that in TA98 strain. However, the mutagenicity was enhanced in YG1024 with overexpression of O-acetyltransferase activity. Thus, nitroarenes seemed to be responsible in part for the mutagenicity of ISC. Interestingly, all of the four ISC and two TSC samples showed a dose-dependent genotoxic response in the SOS chromotest with E. coli PQ37 but a low SCE induction of those samples were observed in CHO cells. When the genotoxicity was analyzed based on the condensates per one gram of original samples, the genotoxicity of two TSC condensates in prokaryotic cells was higher than that of four ISC samples except for the genotoxicity of TSC-2 in TA98 strain. However, the genotoxicity of certain ISC in eukaryotic cells based on the SCE/CHO assay was higher than that of TSC. To compare the covalent binding of DNA reactive intermediates of ISC and TSC to S. typhimurium TA98, the DNA adducts were evaluated by the ³²P-postlabeling method with butanol extraction version. Similar diagonal radioactive zone (DRZ) was observed between ISC and CSC. However, DNA adduct levels induced by TSC were much greater than that of ISC.     

Cytogenetic effects of tobacco smoke exposure among involuntary smokers

Tobacco smoke is highly genotoxic and produces chromosomal damage in several experimental systems. Active smokers have been shown to have an increased prevalence of somatic chromosome damage in their peripheral blood lymphocytes: this is seen in most cases as an increased sister-chromatid exchange (SCE) frequency and often also as increased structural chromosome aberrations (CAs). Among passive smokers, in association with exposure to environmental tobacco smoke, no such induction of chromosomal damage has been documented. In the present paper we report negative results on induction of chromosomal damage in 2 separate groups of intensive involuntary exposure to tobacco smoke, non-smoking restaurant personnel and newborn children of smoking mothers. While significant exposure in these groups is clearly seen in biochemical intake markers, e.g. cotinine and thiocyanate values in plasma, the conventional cytogenetic parameters, structural chromosome aberrations and sister-chromatid exchanges, are unable to detect the low exposures of involuntary smokers.     

Comparison of environmental tobacco smoke concentrations and mutagenicity for several indoor environments

Environmental tobacco smoke (ETS) is a major source for indoor air pollution. Although ETS-caused indoor air pollution has been well studied in the developed countries, few studies have examined ETS indoor air pollution in China, which currently has the largest population of tobacco smokers. In this study, respirable-particulate (RP) from ETS-contaminated (RP-ETS) indoor air was collected and measured in 5 different indoor environments during the winter in the northwestern Liaoning Province, China. The extractable portion of RP-ETS (ERP-ETS) was obtained by dichloromethane extraction and used in the Salmonella mutagenicity assay in the presence of S9 using strains TA98, TA100, and TA1538. The percentage of RP-ETS attributable to ETS (ETS-RP) and the percentage of ERP-ETS attributable to ETS (ETS-ERP) were estimated by measuring the concentration of solanesol, an ETS marker. Comparative results in 5 different indoor environments were: (1) the concentration of RP-ETS ranged from 197.3 to 1227.6 microg/m(3) and approximately 64.7 to 92. 0% of the RP-ETS originated from ETS; (2) the concentration of ERP-ETS ranged 88.8 to 601.5 microg/m(3) and approximately 83.1 to 95.4% of the ERP-ETS originated from ETS; (3) the mutagenic potency (revertants/m(3)) of ERP-ETS ranged from 60.4 to 595.5 for TA98, from 33.7 to 312.8 for TA100, and from 49.7 to 475.2 for TA1538. The data indicate that the extent of ETS pollution and the potential health hazards of ETS to humans in the five indoor environments are in the following increasing order: rural bedrooms, urban living rooms, office rooms, restaurants, and passenger cars in that area.     

Genotoxicity of tobacco smoke and tobacco smoke condensate: a review

This report reviews the literature on the genotoxicity of mainstream tobacco smoke and cigarette smoke condensate (CSC) published since 1985. CSC is genotoxic in nearly all systems in which it has been tested, with the base/neutral fractions being the most mutagenic. In rodents, cigarette smoke induces sister chromatid exchanges (SCEs) and micronuclei in bone marrow and lung cells. In humans, newborns of smoking mothers have elevated frequencies of HPRT mutants, translocations, and DNA strand breaks. Sperm of smokers have elevated frequencies of aneuploidy, DNA adducts, strand breaks, and oxidative damage. Smoking also produces mutagenic cervical mucus, micronuclei in cervical epithelial cells, and genotoxic amniotic fluid. These data suggest that tobacco smoke may be a human germ-cell mutagen. Tobacco smoke produces mutagenic urine, and it is a human somatic-cell mutagen, producing HPRT mutations, SCEs, microsatellite instability, and DNA damage in a variety of tissues. Of the 11 organ sites at which smoking causes cancer in humans, smoking-associated genotoxic effects have been found in all eight that have been examined thus far: oral/nasal, esophagus, pharynx/larynx, lung, pancreas, myeoloid organs, bladder/ureter, uterine cervix. Lung tumors of smokers contain a high frequency and unique spectrum of TP53 and KRAS mutations, reflective of the PAH (and possibly other) compounds in the smoke. Further studies are needed to clarify the modulation of the genotoxicity of tobacco smoke by various genetic polymorphisms. These data support a model of tobacco smoke carcinogenesis in which the components of tobacco smoke induce mutations that accumulate in a field of tissue that, through selection, drive the carcinogenic process. Most of the data reviewed here are from studies of human smokers. Thus, their relevance to humans cannot be denied, and their explanatory powers not easily dismissed. Tobacco smoke is now the most extreme example of a systemic human mutagen.