Varenicline and counseling for vaping cessation: a double-blind, randomized, parallel-group, placebo-controlled trial.

BACKGROUND: Vaping cessation is virtually unexplored. The efficacy and safety of varenicline for vaping cessation has not been studied and rigorous research is required to advance best practice and outcomes for people who use electronic cigarettes (EC) and want to quit. The objective is to evaluate the efficacy and safety of varenicline (1 mg BID, administered for 12 weeks, with follow-up to week 24) combined with vaping cessation counseling in exclusive daily EC users intending to quit vaping. METHODS: Design: Double-blind, randomized, parallel-group, placebo-controlled trial. SETTING: The study took place at a University-run smoking cessation center. PARTICIPANTS: People who exclusively use ECs daily and intend to quit vaping. INTERVENTION: A total of 140 subjects were randomized to either varenicline (1 mg, administered twice daily for 12 weeks) plus counseling or placebo treatment (administered twice daily, for 12 weeks) plus counseling. The trial consisted of a 12-week treatment phase followed by a 12-week follow-up, nontreatment phase. MAIN OUTCOMES AND MEASURES: The primary efficacy endpoint of the study was biochemically validated continuous abstinence rate (CAR) at weeks 4 to 12. Secondary efficacy end points were CAR at weeks 4 to 24 and 7-day point prevalence of vaping abstinence at weeks 12 and 24. RESULTS: CAR was significantly higher for varenicline vs placebo at each interval: weeks 4-12, 40.0% and 20.0%, respectively (OR = 2.67, 95% CI = [1.25-5.68], P = 0.011); weeks 4-24, 34.3% for varenicline with counseling and 17.2% for placebo with counseling (OR = 2.52, 95% CI = [1.14-5.58], P = 0.0224). The 7-day point prevalence of vaping abstinence was also higher for the varenicline than placebo at each time point. Serious adverse events were infrequent in both groups and not treatment-related. CONCLUSIONS: The findings of the present RCT indicate that inclusion of varenicline in a vaping cessation program for people who use electronic cigarettes and intending to quit may result in prolonged abstinence. These positive findings establish a benchmark of intervention effectiveness, may support the use of varenicline combined with counseling in vaping cessation programs, and may also help guiding future recommendations by health authorities and healthcare providers. TRIAL REGISTRATION: The study has been registered in EUDRACT with Trial registration ID: 2016-000339-42.

Patterns of flavored e-cigarette use among adult vapers in the USA: an online cross-sectional survey of 69,233 participants.

BACKGROUND: Flavored e-cigarettes remain a controversial topic with regulators planning or already implementing restrictions worldwide. In this study, we examined patterns of flavor use in e-cigarettes among a convenience sample of US adult vapers. METHODS: Participants aged ≥ 18 years who reported ever using an e-cigarette were included in the study (N = 69,233) and responded to an online questionnaire. Their smoking status was recorded as well as patterns of flavor use at e-cigarette use initiation, at the time of the survey and at the time of smoking cessation (for participants who used to smoke and were using e-cigarettes at the time of quitting). RESULTS: The most popular flavors at e-cigarette use initiation were fruit (82.8%), followed by dessert/pastry/bakery (68.6%) and candy/chocolate/sweet (52.2%). Slightly higher prevalence of using fruit and dessert/pastry/bakery flavors was observed in those who never smoked compared to those who were currently and formerly smoking. Tobacco flavors were used by 20.8% of the participants and was by far the least prevalent among participants who never smoked. Similar patterns were observed with participants' choices at the time of the survey, but tobacco flavor use was substantially reduced (7.7%). Only 2.1% reported tobacco as the single most often used flavor. The most prevalent flavor at the time of quitting smoking was again fruit (83.3%), followed by dessert/pastry/bakery (68.0%) and candy/chocolate/sweet (44.5%). These flavors were considered the most helpful for quitting smoking. Tobacco flavor use at the time of smoking cessation was reported by 15.0%, while 9.3% considered it helpful for quitting smoking. CONCLUSION: Non-tobacco flavors were popular among the US adult vapers who participated in the study, and were popular choices at the time of quitting smoking for those who formerly smoked. Tobacco flavor use prevalence was low and was further reduced over time. Regulators should consider the flavor choice of adult consumers, especially those who quit smoking, when preparing legislation on flavored e-cigarettes.

Respiratory health effects of e-cigarette substitution for tobacco cigarettes: a systematic review.

BACKGROUND: E-cigarettes (electronic nicotine delivery system, ENDS) have been presented as a harm reduction strategy for people who smoke tobacco cigarettes but who cannot achieve abstinence, or for those who wish to continue to enjoy nicotine and the habit of smoking. What are the health effects of the substitution of ENDS for tobacco cigarettes? This systematic review evaluates the evidence of human clinical tests on the respiratory effects of ENDS use in participants who smoke tobacco cigarettes. METHODS: A registered and published protocol was developed conforming to PRISMA 2020 and AMSTAR2 standards. The literature search was conducted in PubMed, Scopus, and the CENTRAL Cochrane Library and updated to May 2022. Three supplementary searches and a grey literature search were performed. Studies were evaluated with the JBI quality tools and the Oxford Catalogue of Bias. Due to the heterogeneity (diversity) of the studies, a narrative data synthesis was performed on the test findings plus three sub-group analyses. RESULTS: The review consists of sixteen studies and twenty publications. Spirometry tests comprised the majority of the data. In total, 66 respiratory test measurements were reported, out of which 43 (65%) were not significant. Statistically significant findings were mixed, with 9 tests showing improvements and 14 measuring declines, none of which was clinically relevant. Ten studies were rated at a high risk of bias, and six had some concerns primarily due to inadequate research designs and the conduct of the studies. Reporting bias was documented in thirteen studies. CONCLUSIONS: Most of the studies showed no difference in respiratory parameters. This indicates that ENDS substitution for smoking likely does not result in additional harm to respiratory health. Due to the low quality of the studies, confidence in the conclusions is rated as low. Robust studies with a longer duration and sufficient power are required to validate any potential benefits or possible harms of ENDS substitution. Registration PROSPERO #CRD42021239094, International Registered Report Identifier (IRRID): DERR1-10.2196/29084.

Repeatability of dental plaque quantitation by light induced fluorescence technology in current, former, and never smokers.

BACKGROUND: The effects of smoking on the accumulation of dental plaque have not been studied in depth. We compared dental plaque quantitation obtained with a novel light induced fluorescence technology among current, former, and never smokers and verified measurements' repeatability. METHODS: Dental plaque quantitation was objectively assessed by quantitative light induced fluorescence (QLF) technology on three separate study visits in current, former, and never smokers: baseline (day 0), day 7, day 30. Increase in the fluorescence intensity of at least 30% (ΔR30) and 120% (ΔR120) together with the simple oral hygiene (SOH) scoring were considered for analysis. RESULTS: The QLF parameters were highly repeatable in each study group (p < 0.0001, by regression analyses). All QLF parameters showed a significant difference between never smokers and current smokers (p = 0.041 for ΔR30; p = 0.027 for ΔR120; p = 0.04 for SOH). No significant differences were observed between never and former smokers and between current and former smokers except for ΔR120 (p = 0.033). CONCLUSION: Dental plaque measurements by QLF technology were highly reproducible and showed greater plaque formation among current smokers compared to non-smokers. Objective and reproducible quantitation of dental plaque can be a valuable clinical and regulatory science endpoint to investigate the effect of smoking cessation medications, combustion-free tobacco products, and consumer care products on oral health. CLINICAL RELEVANCE: There is a need to objectively evaluate the relationship between smoking and plaque build-up as well as maturation. Current smokers demonstrated greater and more mature plaque buildup when compared to never and former smokers. Differences in plaque build-up and maturation between current, former and non-smokers may be utilized as an effective tool for patient motivation, identifying therapeutic end-points, translational research as well as prognostication. TRIAL REGISTRATION: The study is a pilot study parts of a larger project with registration ID: NCT04649645. As preliminary study, the pilot study referred into this paper started before the larger study registered in ClinicalTrials.gov.

Repeatability of dental shade by digital spectrophotometry in current, former, and never smokers.

Cigarette smoking contributes to poor oral health and dental discoloration. Therefore, stopping smoking may translate into measurable amelioration of dental shade indices. We compared dental shade parameters by digital spectrophotometry among current, former, and never smokers and verified their repeatability at 7 and 30 days. Dental shade parameters (CIE L*a*b* and corresponding whiteness index for dentistry-WID) were measured in current, former, and never smokers with a digital spectrophotometer (Vita Easyshade V) on three separate study visits: at baseline (day 0), at day 7, and day 30. Dental shade parameters were analyzed in 18 current, 18 former, and 20 never smokers. The repeatability of shade parameters was consistent in current, former, and never smokers. L*, a*, b*, and WID show significant short and long-term repeatability (p < 0.0001, by regression analyses). The mean (± SD) WID score of 13.42 (± 4.9) in current smokers was significantly lower compared to the WID score of 20.38 (± 5.3) in never smokers (p = 0.001). No significant differences were observed between current and former smokers and between former smokers and former smokers. Dental shade measurements by digital spectrophotometry were highly reproducible and showed that teeth whiteness of current smokers is substantially inferior compared to never smokers. Objective discrimination of dental shade can be a valuable regulatory science endpoint for investigating oral hygiene and dental aesthetics of consumer care products, smoking cessation medications, and tar-free tobacco products (e-cigarettes, heated tobacco products, oral nicotine products) for cigarette substitution.Clinical trial registration: the study was not registered in ClinicalTrials.gov considering that it is a pilot study, parts of a larger project with ID: NCT04649645.

A Single-Arm, Open-Label, Pilot, and Feasibility Study of a High Nicotine Strength E-Cigarette Intervention for Smoking Cessation or Reduction for People With Schizophrenia Spectrum Disorders Who Smoke Cigarettes.

INTRODUCTION: An estimated 60%-90% of people with schizophrenia smoke, compared with 15%-24% of the general population, exacerbating the already high morbidity and mortality rates observed in this population. AIMS AND METHODS: This study aimed to assess the feasibility of using a new-generation high strength nicotine e-cigarette to modify smoking behavior in individuals with schizophrenia spectrum disorders who smoke cigarettes. A single-arm pilot study was conducted with 40 adults with schizophrenia spectrum disorders who smoked and did not intend to reduce or quit smoking. Participants were given a 12-week supply of a JUUL e-cigarette loaded with a 5% nicotine pod. The primary outcome was smoking cessation at week 12. Additional outcomes included: smoking reduction, continuous abstinence at week 24, adoption rate, adherence to the e-cigarette, feasibility, acceptability, and subjective effects. RESULTS: Sixteen (40%) participants quit by the end of 12 weeks. For the whole sample, we observed an overall, sustained 50% reduction in smoking or smoking abstinence in 37/40 (92.5%) of participants and an overall 75% reduction in median cigarettes per day from 25 to six was observed by the end of the 12 weeks (p < .001). CONCLUSIONS: A high strength nicotine e-cigarette has the potential to help people with schizophrenia spectrum disorders to quit or reduce smoking. Further research with a larger sample and a comparator group is needed. The results provide useful information and direction to augment the existing body of knowledge on smoking cessation for people with schizophrenia spectrum disorders. IMPLICATIONS: Considering that most people with schizophrenia spectrum disorders continue smoking, alternative and efficient interventions to reduce or prevent morbidity and mortality are urgently needed. This study showed that adults who smoke and were not motivated to quit, when provided a new-generation e-cigarette with high nicotine content, demonstrated substantially decreased cigarette consumption without causing significant side effects. Although not specifically measured in this study, nicotine absorption in new-generation devices has been shown to be consistently superior compared with the first generation of e-cigarette devices, and this may help explain the lower quit rates in studies using earlier generation devices.

Nicotine dosimetry and stability in cambridge filter PADs (CFPs) following different smoking regime protocols and storage conditions.

Despite the growing numbers of studies on cigarettes and electronic nicotine delivery products (ENDs), no standard assessment of nicotine stability in various matrix post exposure is currently available. The aim of the present study was to evaluate the optimal standard condition to store Cambridge Filter Pads (CFPs) before chemical analysis in order to guarantee the titer of nicotine.We further performed data normalization according to different smoking or vaping runs. Smoke and vapor generated respectively by a reference tobacco cigarette (1R6F) and ENDs under different exposure regimes (ISO, HCI and CRM81) were collected on CFPs as total particulate matter (TPM) and subsequently analyzed for nicotine content. For each exposure, some CFPs were analyzed at time zero, whereas the others were stored under different conditions for nicotine assessment after 30 days. Principal Component Analysis (PCA) showed the best correlation between nicotine on CFPs and TPM for normalization. This study suggests that different exposure regimes and products can affect the preservation of nicotine titer on CFPs while samples storage at -80 °C may prevent the loss of nicotine. Finally, normalization of nicotine with TPM is strongly recommended for regulatory purpose.

Screening of different cytotoxicity methods for the assessment of ENDS toxicity relative to tobacco cigarettes.

Electronic Nicotine Delivery Systems (ENDS), i.e., electronic-cigarettes (e-cigs) and Tobacco Heating Products (THPs), are rapidly growing in popularity. Nonetheless, comprehensive quality and safety requirements for regulatory purposes are still under development. Cytotoxicity studies are important initial steps in appraising the potential ENDS toxicity. The aim of the present study was to screen different in vitro cytotoxicity methods for the assessment of ENDS toxicity. We evaluated NRU, MTT, Annexin V apoptosis (AN-V), High-Content Screening (HCS) assays and Real-Time Cell Analysis (RTCA), to compare two e-cigs and two THPs with the 1R6F reference tobacco cigarette. Human adenocarcinoma lung epithelial cells (H292) were exposed to tobacco smoke and ENDS vapor at air-liquid interface. All tests showed reduced cell viability following 1R6F smoke exposure and slight or no reduction with ENDS at 24 h. AN-V and RTCA exhibited a further significant reduction in cell viability following 1R6F exposure. AN-V allowed to discriminate viable cells from those in early/late apoptosis. RTCA and HCS being time-resolved analyses elucidate the kinetic dependency parameter for toxicity of smoke/vapor chemicals on cell viability. In conclusion, NRU assay may be considered a suitable test, especially when combined with a time-resolved analysis, for assessing the kinetic of cytotoxicity induced by these products.

Critical appraisal of the European Union Scientific Committee on Health, Environmental and Emerging Risks (SCHEER) Preliminary Opinion on electronic cigarettes.

BACKGROUND: In preparation for the 2021 revision of the European Union Tobacco Products Directive, the Scientific Committee on Health, Environmental and Emerging Risks (SCHEER) has posted its Preliminary Opinion on Electronic Cigarettes. They concluded that e-cigarettes only achieve a sub-optimal level of protection of human health. In this paper, we provide evidence that the Opinion's conclusions are not adequately backed up by scientific evidence and did not discuss the potential health benefits of using alternative combustion-free nicotine-containing products as substitute for tobacco cigarettes. METHODS: Searches for articles were conducted in PubMed and by citation chasing in Google Scholar. Articles were also retrieved with a review of references in major publications. Primary data from World Health Organization surveys, the conclusions of reviews, and peer-reviewed non-industry studies were cited to address errors and omissions identified in the Opinion. RESULTS: The Opinion omitted reporting on the individual and population health benefits of the substitution of e-cigarettes (ENDS) for cigarette smoking. Alternative hypotheses to the gateway theory were not evaluated. Its assessment of cardiovascular risk is contradicted by numerous reviews. It cites ever-use data that do not represent current patterns of use. It did not report non-nicotine use. It presented erroneous statements on trends in ENDS prevalence. It over-emphasized the role of flavours in youth ENDS initiation. It did not discuss cessation in sufficient length. CONCLUSIONS: For the delivery of a robust and comprehensive final report, the members of the Working Group of the Scientific Committee on Health, Environmental and Emerging Risks will need to consider (1) the potential health benefits of ENDS substitution for cigarette smoking, (2) alternative hypotheses and contradictory studies on the gateway effect, (3) its assessment of cardiovascular risk, (4) the measurements of frequency of use, (5) non-nicotine use, (6) the role of flavours, and (7) a fulsome discussion of cessation.

Carbon monoxide levels after inhalation from new generation heated tobacco products.

Heated tobacco products (HTPs) are new tech devices that release nicotine and other volatile compounds into an inhalable aerosol by heating the tobacco. At their operating temperatures, tobacco combustion is unlikely.The aim of this randomized cross-over study was to measure the exposure levels of the combustion marker, carbon monoxide in the exhaled breath (eCO) of subjects after use of two HTPs and to compare these levels with participants' own brand of cigarettes.A total of 12 healthy smokers who reported smoking ≥10 conventional cigarettes per day for at least 5 years took part in the study. Product administration consisted of a first round of 10 puffs, which was followed by an identical second round after a 5 min pause in between rounds. After obtaining a baseline eCO value, this measure was recorded at 5, 10, 15, 30, and 45 min after the first puff of the first round. In contrast to combustible cigarettes, no eCO elevations were observed in the exhaled breath after use of the HTPs under investigation in any of the study participants.

Treatment of Allergic Rhinitis as a Strategy for Preventing Asthma.

PURPOSE OF REVIEW: To evaluate the impact of allergic rhinitis (AR) on the development of asthma and to update readers on recent literature suggesting that early treatment of allergic subjects with immunotherapy may prevent asthma onset. RECENT FINDINGS: AR is frequently associated with asthma, leading to the concept that these two conditions are different aspects of the same disease. There is increasing evidence that AR precedes the onset of asthmatic symptoms and current treatment strategies are beneficial in symptom control with no impact prevention. There is limited knowledge about the risk factors responsible for the progression of AR to asthma, though recent data supports the notion that it is possible to prevent asthma onset by allergen immunotherapy. Despite significant advances in specific immunotherapy (SIT) therapy strengthening its efficacy in AR and possible prevention of progression to asthma, the adoption of this therapeutic strategy is still restricted in comparison to therapies directed towards treatment of AR symptoms. Unlike corticosteroids and other symptomatic therapies, the benefit of SIT treatment in allergic individuals has been shown to prevent the development of allergic conditions. Hence, large well-conducted randomized clinical trials with long-term efficacy of SIT are required to confirm or refute the concept that SIT may abrogate the progression of AR to asthma in patients.

A critique of the US Surgeon General's conclusions regarding e-cigarette use among youth and young adults in the United States of America.

BACKGROUND: In December 2016, the Surgeon General published a report that concluded e-cigarette use among youth and young adults is becoming a major public health concern in the United States of America. METHODS: Re-analysis of key data sources on nicotine toxicity and prevalence of youth use of e-cigarettes cited in the Surgeon General report as the basis for its conclusions. RESULTS: Multiple years of nationally representative surveys indicate the majority of e-cigarette use among US youth is either infrequent or experimental, and negligible among never-smoking youth. The majority of the very small proportion of US youth who use e-cigarettes on a regular basis, consume nicotine-free products. The sharpest declines in US youth smoking rates have occurred as e-cigarettes have become increasingly available. Most of the evidence presented in the Surgeon General's discussion of nicotine harm is not applicable to e-cigarette use, because it relies almost exclusively on exposure to nicotine in the cigarette smoke and not to nicotine present in e-cigarette aerosol emissions. Moreover, the referenced literature describes effects in adults, not youth, and in animal models that have little relevance to real-world e-cigarette use by youth. The Surgeon General's report is an excellent reference document for the adverse outcomes due to nicotine in combination with several other toxicants present in tobacco smoke, but fails to address the risks of nicotine decoupled from tobacco smoke constituents. The report exaggerates the toxicity of propylene glycol (PG) and vegetable glycerin (VG) by focusing on experimental conditions that do not reflect use in the real-world and provides little discussion of emerging evidence that e-cigarettes may significantly reduce harm to smokers who have completely switched. CONCLUSIONS: The U.S. Surgeon General's claim that e-cigarette use among U.S. youth and young adults is an emerging public health concern does not appear to be supported by the best available evidence on the health risks of nicotine use and population survey data on prevalence of frequent e-cigarette use. Nonetheless, patterns of e-cigarettes use in youth must be constantly monitored for early detection of significant changes. The next US Surgeon General should consider the possibility that future generations of young Americans will be less likely to start smoking tobacco because of, not in spite of, the availability of e-cigarettes.

Changes in breathomics from a 1-year randomized smoking cessation trial of electronic cigarettes.

BACKGROUND: Electronic cigarette (EC) use is an emerging behaviour that has been shown to help smokers to reduce cigarette consumption. The aim of this study was to illustrate long-term changes in exhaled breath measurements and respiratory symptoms in smokers invited to quit or reduce their cigarette consumption by switching to ECs. MATERIALS AND METHODS: Prospective evaluation of cigarette consumption, fractional nitric oxide concentration in exhaled breath (FeNO), exhaled carbon monoxide (eCO) and symptom scores was performed in a 1-year randomized, controlled trial of 'healthy' smokers receiving 2·4% nicotine, 1·8% nicotine or no nicotine ECs. FeNO and eCO data are presented on the basis of participants' pooled continuous smoking phenotype classification (failures, reducers and quitters). RESULTS: A significant effect of quitting classification was found on FeNo and eCO at all time points (P < 0·0001). Among quitters, FeNO (medians and interquartile range) rose from 5·5 (4·5-6·9) ppb to 17·7 (13·3-18·9) ppb by week 52. Baseline eCO (medians and interquartile range) decreased from 17 (12-20) ppm to 3 (1-4) ppm by week 52. No significant changes in FeNO and eCO levels were observed in failures and reducers. Improvements in FeNO and eCO levels were correlated with attenuations in symptom scores. CONCLUSIONS: Smokers invited to switch to electronic cigarettes who completely abstained from smoking showed steady progressive improvements in their exhaled breath measurements and symptom scores. FeNo and eCO normalization is highly supportive of improved respiratory health outcomes and adds to the notion that quitting from tobacco smoking can reverse harm in the lung.

Evidence for harm reduction in COPD smokers who switch to electronic cigarettes.

BACKGROUND: Electronic cigarettes (ECs) are battery-operated devices designed to vaporise nicotine, which may help smokers quitting or reducing their tobacco consumption. There is a lack of data on the health effects of EC use among smokers with COPD and whether regular use results in improvement in subjective and objective COPD outcomes. We investigated long-term changes in objective and subjective respiratory outcomes in smokers with a diagnosis of COPD who quit or reduced substantially their tobacco consumption by supplementing with or converting only to ECs use. METHODS: We conducted a retrospective chart review of patients with COPD to identify those reporting regular daily use of ECs on at least two follow-up visits at 12- (F/up1) and 24-months (F/up2). Regularly smoking COPD patients were included as a reference group. RESULTS: A marked reduction in cigarette consumption was observed in ECs users. A significant reduction in COPD exacerbations was reported in the COPD EC user group, their mean (±SD) decreasing from 2.3 (±1) at baseline to 1.8 (±1; p = 0.002) and 1.4 (±0.9; p < 0.001) at F/up1 and F/up2 respectively. A significant reduction in COPD exacerbations was also observed in ECs users who also smoked conventional cigarettes (i.e. 'dual users'). COPD symptoms and ability to perform physical activities improved statistically in the EC group at both visits, with no change in the control group. CONCLUSIONS: These findings suggest that ECs use may aid smokers with COPD reduce their cigarette consumption or remain abstinent, which results in marked improvements in annual exacerbation rate as well as subjective and objective COPD outcomes.

Lung function and respiratory symptoms in a randomized smoking cessation trial of electronic cigarettes.

Quitting smoking is the most important step smokers can take to improve their health. Nonetheless, there is little information on long-term improvements in lung function and/or respiratory symptoms after smoking cessation. Here we illustrate long-term changes in spirometric indices as well as in respiratory symptoms in smokers invited to quit or reduce their cigarette consumption by switching to electronic cigarettes (ECs). Prospective evaluation of cigarette consumption, spirometry and symptoms was performed in a 1-year randomized controlled trial of smokers receiving EC containing 2.4%, 1.8% or 0% nicotine. Spirometric data are presented on the basis of participants' pooled continuous smoking phenotype classification (Quitters, Reducers, Failures), whereas respiratory symptoms on the basis of their point prevalence-smoking phenotype. Smoking phenotype classification (Quitters, Reducers, Failures) had no significant effect on spirometric indices (FEV1, FVC and FEV1/FVC) with the exception of FEF25-75%, which significantly (P =0.034) increased over the time among Quitters; their FEF25-75% (% predicted) improving from (means±S.D.) 85.7±15.6% at baseline (BL) to 100.8±14.6%. High prevalence of cough/phlegm (43.1%) and shortness of breath (SoB; 34.8%) was reported at BL with substantial reduction in their frequency at subsequent follow-up visits. These symptoms virtually disappeared very quickly in both quitters and reducers. Smokers invited to switch to ECs who completely abstained from smoking showed steady progressive improvements in their FEF25-75% Normalization of peripheral airways function was associated with improvement in respiratory symptoms, adding to the notion that abstaining from smoking can reverse tobacco harm in the lung.