Updated view of tars for psoriasis: what have we learned over the last decade?

Tars are one of the most effective, unknown, and oldest therapies for psoriasis. They include coal tar (CT) and biomass-derived products. These treatments, particularly the CT, have proven to be cost-effective with long remission times compared to other systemic or topical treatments. However, they have hardly evolved in recent years, as they are not well-embraced by clinicians or patients because of concerns regarding cosmesis and safety. This review summarizes current knowledge about the chemical characterization, mechanism of action, toxicity, and clinical studies supporting the use of tars for psoriasis over the last decade. Trends within these above aspects are reviewed, and avenues of research are identified. CT is rich in polycyclic aromatic hydrocarbons, whereas biomass-derived tars are rich in phenols. While the activation of the aryl hydrocarbon receptor is involved in the antipsoriatic effect of CT, the mechanism of action of biomass-derived products remains to be elucidated. No conclusive evidence exists about the risk of cancer in psoriasis patients under CT treatment. Large, randomized, double-blind, controlled clinical trials are necessary to promote the inclusion of tars as part of modern therapies for psoriasis.

Cumulative cigarette tar exposure and lung cancer risk among Japanese smokers.

OBJECTIVE: Tar concentration in cigarette brands is chronologically decreasing in the USA and Japan. However, studies investigating lung cancer risk with cumulative tar exposure in Western and Asian countries are insufficient. To investigate the risk of lung cancer with cumulative cigarette tar exposure, we conducted a case-control study among Japanese current smokers. METHODS: This study used data from the US-Japan lung cancer joint study in 1993-1998. A total of 282 subjects with histologically confirmed lung cancer and 162 hospital and 227 community controls were included in the study, and two control groups were combined. The information regarding tar concentration was obtained from the published documents and additional estimation using the equation of regression. Cumulative tar concentration was calculated by multiplying the annual value of brand-specific tar concentration by years of smoking. The odds ratios and 95% confidence intervals for lung cancer with cumulative tar exposure were estimated using a logistic model. RESULTS: The odds ratios for lung cancer with both lower (1-59.8 × 105 mg) and higher (>59.8 × 105 mg) total cumulative tar exposure were statistically significant (3.81, 2.23-6.50 and 11.64, 6.56-20.67, respectively) with increasing trend (P < 0.001). The stratification analysis showed higher odds ratios in subjects with higher cumulative tar exposure regardless of inhalation, duration of smoking filtered cigarettes and histological type. CONCLUSIONS: This study showed that cumulative tar exposure is a dose-dependent indicator for lung cancer risk, and low-tar exposure was still associated with increased cancer risk.

Tar, nicotine and carbon monoxide yield of UK cigarettes and the risk of non-muscle-invasive and muscle-invasive bladder cancer.

Cigarette smoking is a major risk factor for bladder cancer (BC); however, the impact of cigarette content remains unclear. This study aims to investigate tar, nicotine and carbon monoxide (TNCO) yields of different filtered cigarettes in relation to BC risk. From the Bladder Cancer Prognosis Programme 575 non-muscle-invasive bladder cancer (NMIBC) cases, 139 muscle-invasive bladder cancer (MIBC) cases and 130 BC-free controls with retrospective data on smoking behaviour and cigarette brand were identified. Independently measured TNCO yields of cigarettes sold in the UK were obtained through the UK Department of Health and merged with the Bladder Cancer Prognosis Programme dataset to estimate the daily intake of TNCO. BC risk increased by TNCO intake category for NMIBC cases (P <0.050 in all multivariate models), but only for the daily intake of tar for MIBC cases (P=0.046) in multivariate models. No difference in risk was observed between smokers of low-tar/low-nicotine and high-tar/high-nicotine cigarettes compared with never smokers, either for NMIBC (P=0.544) or MIBC (P=0.449). High daily intake of TNCO additionally increases the risk of both NMIBC and MIBC compared with low daily intake. However, as there is no difference in BC risk between low-tar/low-nicotine and high-tar/high-nicotine cigarette smokers, it remains unclear whether smoking behaviour or TNCO yield of cigarettes explains this association.

Analytical Determination of Nicotine and Tar Levels in Various Dokha and Shisha Tobacco Products.

In the Middle East, there is no precise data and literature on tobacco-based products, such as dokha and shisha. The proposed study aims to quantify the levels of nicotine and tar in different kinds of dokha and shisha products that are sold in the local marketplace. The amount of nicotine in dokha and shisha products can be quantitatively determined using a combination of the "kissling" and "silicotungstic acid" method proposed by Robert M. Chapin. The tar residue from the smoke sample was collected on a glass wool placed before the stopcock (tap) of a separatory funnel as the smoke passes through the inlet of an electronically controlled vacuum pump. The nicotine levels in dokha and shisha samples ranged from 23.83 to 52.80 mg/g and 0.80 to 20.52 mg/g, respectively. The nicotine level varies between different tobacco products. It varies from 0.5 to 19.5 mg/g in cigarettes, from 10.3 to 23.1 mg/g in snuff tobacco, from 11 to 18 mg/g in electronic cigarettes and from 2.9 to 16.6 mg/g in chewing tobacco. The tar levels in the dokha and shisha samples ranged from 21.6 to 45.02 mg/g and 1.68 to 11.87 mg/g, respectively. Smokers are at a high risk of getting lung cancer, chronic obstructive pulmonary disease, emphysema and coronary artery disease owing to the high levels of nicotine and tar present in dokha and shisha tobacco products. These findings contradict the widespread belief among teenagers that dokha and shisha tobacco products are safer alternatives to cigarettes.

Mice overexpressing latent matrix metalloproteinase-2 develop lung emphysema after short-term exposure to cigarette smoke extract.

Chronic obstructive pulmonary disease is the major growing cause of mortality and morbidity worldwide, and it is going to become the third most common cause of death by 2020. Chronic obstructive pulmonary disease is pathologically characterized by lung emphysema and small airway inflammation. Animal models are very important to get insights into the disease pathogenesis but current models of chronic obstructive pulmonary disease take a long time to develop. The need of a new model is compelling. In the present study we focus on the role of matrix metalloproteinases in the pathogenesis of chronic obstructive pulmonary disease and hypothesized that lung overexpression of latent matrix metalloproteinases-2 would allow the development of emphysema after short-term exposure to cigarette smoke extract inhalation. Human latent matrix metalloproteinases-2 transgenic mouse expressing high level of the protein in the lungs and wild type mouse were exposed to aerosolized cigarette smoke extract for two weeks. Transgenic mice showed significant lung emphysematous changes, increased infiltration of inflammatory cells and enhanced lung concentrations of inflammatory cytokines in the lungs compared to their wild type counterparts after inhalation of cigarette smoke extract. This novel mouse model will be a very useful tool for evaluating the mechanistic pathways and for development of novel therapies in cigarette smoke-associated lung emphysema.

Investigation into the risk of ultra-low tar cigarettes and lung cancer.

We present analyses relating cigarette type to lung cancer based on a case-control study in five European countries. The analyses involved 3561 cases and 2301 controls with diseases not associated with smoking. Subjects completed a detailed questionnaire, including a lifetime smoking history. Analyses included never smokers, and those who smoked for at least 80% of the "critical period" from 2 to 20 years before diagnosis, ignoring those who ever smoked pipes or cigars, or chewed tobacco. The main analysis compares risk in those who, in the critical period, smoked ultra-low tar (ULT) cigarettes (machine yield ≤3 mg tar/cigarette) for 8 + years, with those who only smoked full flavour (FF) cigarettes (≥10 mg tar/cigarette). After adjustment for sex, age, country, education, age of starting smoking, mean cigarette consumption and mean tar level 21-50 years before interview, the odds ratio (OR) was 0.73 (95% confidence interval (CI) 0.50-1.06). Other analyses showed a modest, not statistically significant, reduction in risk with tar reduction. Risk in ULT smokers for 8 + years was substantially higher than in never smokers (OR 16.27, 95% CI 10.14-26.09). The study was prematurely terminated due to cost overrun, limiting the power to detect an association. More evidence is needed, particularly on lifetime ULT smoking.

Case-control study of cumulative cigarette tar exposure and lung and upper aerodigestive tract cancers.

The development of comprehensive measures for tobacco exposure is crucial to specify effects on disease and inform public health policy. In this population-based case-control study, we evaluated the associations between cumulative lifetime cigarette tar exposure and cancers of the lung and upper aerodigestive tract (UADT). The study included 611 incident cases of lung cancer; 601 cases of UADT cancers (oropharyngeal, laryngeal and esophageal cancers); and 1,040 cancer-free controls. We estimated lifetime exposure to cigarette tar based on tar concentrations abstracted from government cigarette records and self-reported smoking histories derived from a standardized questionnaire. We analyzed the associations for cumulative tar exposure with lung and UADT cancer, overall and according to histological subtype. Cumulative tar exposure was highly correlated with pack-years among ever smoking controls (Pearson coefficient = 0.90). The adjusted odds ratio (95% confidence limits) for the estimated effect of about 1 kg increase in tar exposure (approximately the interquartile range in all controls) was 1.61 (1.50, 1.73) for lung cancer and 1.21 (1.13, 1.29) for UADT cancers. In general, tar exposure was more highly associated with small, squamous and large cell lung cancer than adenocarcinoma. With additional adjustment for pack-years, positive associations between tar and lung cancer were evident, particularly for small cell and large cell subtypes. Therefore, incorporating the composition of tobacco carcinogens in lifetime smoking exposure may improve lung cancer risk estimation. This study does not support the claim of a null or inverse association between "low exposure" to tobacco smoke and risk of these cancer types.

Influence of cigarette circumference on smoke chemistry, biological activity, and smoking behaviour.

Cigarettes with reduced circumference are increasingly popular in some countries, hence it is important to understand the effects of circumference reduction on their burning behaviour, smoke chemistry and bioactivity. Reducing circumference reduces tobacco mass burn rate, puff count and static burn time, and increases draw resistance and rod length burned during puff and smoulder periods. Smoulder temperature increases with decreasing circumference, but with no discernible effect on cigarette ignition propensity during a standard test. At constant packing density, mainstream (MS) and sidestream (SS) tar and nicotine yields decrease approximately linearly with decreasing circumference, as do the majority of smoke toxicants. However, volatile aldehydes, particularly formaldehyde, show a distinctly non-linear relationship with circumference and increases in the ratios of aldehydes to tar and nicotine have been observed as the circumference decreases. Mutagenic, cytotoxic and tumorigenic specific activities of smoke condensates (i.e. per unit weight of condensate) decrease as circumference decreases. Recent studies suggest that there is no statistical difference in mouth-level exposure to tar and nicotine among smokers of cigarettes with different circumferences. Commercially available slim cigarettes usually have changes in other cigarette design features compared with cigarettes with standard circumference, so it is difficult to isolate the effect of circumference on the properties of commercial products. However, available data shows that changes in cigarette circumference offer no discernible change to the harm associated with smoking.

A longitudinal study of smokers' exposure to cigarette smoke and the effects of spontaneous product switching.

A challenge in investigating the effect of public health policies on cigarette consumption and exposure arises from variation in a smoker's exposure from cigarette to cigarette and the considerable differences between smokers. In addition, limited data are available on the effects of spontaneous product switching on a smoker's cigarette consumption and exposure to smoke constituents. Over 1000 adult smokers of the same commercial 10mg International Organization for Standardization (ISO) tar yield cigarette were recruited into the non-residential, longitudinal study across 10 cities in Germany. Cigarette consumption, mouth level exposure to tar and nicotine and biomarkers of exposure to nicotine and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone were measured every 6months over a 3 and a half year period. Cigarette consumption remained stable through the study period and did not vary significantly when smokers spontaneously switched products. Mouth level exposure decreased for smokers (n=111) who switched to cigarettes of 7mg ISO tar yield or lower. In addition, downward trends in mouth level exposure estimates were observed for smokers who did not switch cigarettes. Data from this study illustrate some of the challenges in measuring smokers' long-term exposure to smoke constituents in their everyday environment.

Exposure evaluation of adult male Japanese smokers switched to a heated cigarette in a controlled clinical setting.

The objective of this clinical study was to investigate changes in levels of biomarkers of exposure (BOEs) in healthy Japanese male smokers who switched to a prototype heated cigarette (HC). This was a controlled, semi-randomized, open-label, residential study conducted in Japan. A total of 70 healthy Japanese male smokers were enrolled. Following enrollment, subjects smoked their usual brand of cigarette for 2days and were subsequently randomized either to an HC group or a 10mg tar conventional cigarette (CC10) group for four consecutive weeks. Levels of BOEs for ten selected cigarette smoke constituents (nicotine, carbon monoxide (CO), benzene, 1,3-butadiene, acrolein, hydrogen cyanide, crotonaldehyde, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone [NNK], pyrene, 4-aminobiphenyl), and urine mutagenicity were measured at several time points during the study period. At the end of the study period, except for blood carboxyhemoglobin, levels of BOEs for the other nine constituents and urine mutagenicity were significantly lower in the HC group compared to the CC10 group. These results suggest that exposure to most cigarette smoke constituents, except CO, can be reduced by switching from CC10 to HC.

Estimation of mouth level exposure to smoke constituents of cigarettes with different tar levels using filter analysis.

A nicotine part-filter method can be applied to estimate smokers' mouth level exposure (MLE) to smoke constituents. The objectives of this study were (1) to generate calibration curves for 47 smoke constituents, (2) to estimate MLE to selected smoke constituents using Japanese smokers of commercially available cigarettes covering a wide range of International Organization for Standardization tar yields (1-21mg/cigarette), and (3) to investigate relationships between MLE estimates and various machine-smoking yields. Five cigarette brands were machine-smoked under 7 different smoking regimes and smoke constituents and nicotine content in part-filters were measured. Calibration curves were then generated. Spent cigarette filters were collected from a target of 50 smokers for each of the 15 brands and a total of 780 filters were obtained. Nicotine content in part-filters was then measured and MLE to each smoke constituent was estimated. Strong correlations were identified between nicotine content in part-filters and 41 out of the 47 smoke constituent yields. Estimates of MLE to acetaldehyde, acrolein, 1,3-butadiene, benzene, benzo[a]pyrene, carbon monoxide, and tar showed significant negative correlations with corresponding constituent yields per mg nicotine under the Health Canada Intense smoking regime, whereas significant positive correlations were observed for N-nitrosonornicotine and (4-methylnitrosoamino)-1-(3-pyridyl)-1-butanone.

Occupational skin cancer may be underreported.

INTRODUCTION: Skin cancer may, in some cases, be caused by occupational exposures. The aim of this study was to investigate the prevalence of and exposures leading to occupationally induced skin cancers in Denmark during a ten-year period. MATERIAL AND METHODS: The study is a descriptive, register-based study comprising all patients with recognized occupational malignant and premalignant skin conditions in Denmark in the 01/01 2000-31/12 2009 period. Data were obtained from The National Board of Industrial Injuries and comprise information about diagnosis, occupational and domestic exposure, anatomic localization, occupation, degree of permanent disability, age and sex. RESULTS: A total of 36 patients were recognized as occupational skin cancer cases. The mean age was 61 years (44-75 years), 31 men and five women. The most frequent diagnosis was basal cell carcinoma followed by squamous cell carcinoma. No cases of malignant melanoma were recognized. The primary risk factor for development of occupational skin cancer was ultraviolet (UV) exposure during outdoor working. CONCLUSION: Data based on recognized cases of occupational skin cancer during a ten-year period in Denmark show that non-melanoma skin cancer was the most frequent diagnosis, while the primary risk factor was UV radiation in outdoor occupations. A total of 36 cases were reported over a period of ten years, and underreporting may be suspected. The purpose of the present study was to raise the awareness of occupational skin cancer, and on the basis of existing data to contribute to criteria for the diagnosis of occupational skin cancer. FUNDING: not relevant. TRIAL REGISTRATION: not relevant.

Toxicological assessment of cigarette ingredients.

Ingredients have been used in industrial manufacture of tobacco products since the early part of the 20th century. However, unlike other consumer goods, until now no regulatory authority has determined how tobacco ingredients should be assessed. Although there is currently no consensus on how added cigarette ingredients should be evaluated, this paper reviews some of the institutional guidance alongside published literature with a view to determining if there is a generally accepted approach in the absence of any strict regulation. Our aim was to review the recommendations, to compare them to the working practices as demonstrated from published studies, and to draw conclusions on currently used methodologies for testing ingredients added to cigarettes. The extent of testing is discussed in the light of practical and theoretical constraints and an example of an industry testing program is presented.

Association of daily tar and nicotine intake with incident myocardial infarction: results from the population-based MONICA/KORA Augsburg Cohort Study 1984-2002.

BACKGROUND: Cigarette smoking has been shown to be one of the most important risk factors for cardiovascular diseases. However, little is known about cumulative effects of daily tar and nicotine intake on the risk of incident myocardial infarction (MI) so far. To bridge this gap, we conducted an analysis in a large prospective study from Southern Germany investigating associations of daily tar and nicotine intake with an incident MI event. METHODS: The study was based on 4,099 men and 4,197 women participating in two population-based MONICA Augsburg surveys between 1984 and 1990 and followed up within the KORA framework until 2002. During a mean follow-up of 13.3 years, a number of 307 men and 80 women developed an incident MI event. Relative risks were calculated as hazard ratios (HRs) estimated by Cox proportional hazards models adjusted for cardiovascular risk factors. RESULTS: In the present study, male regular smokers consumed on average more cigarettes per day than female regular smokers (20 versus 15) and had a higher tar and nicotine intake per day. In men, the MI risk compared to never-smokers increased with higher tar intake: HRs were 2.24 (95% CI 1.40-3.56) for 1-129 mg/day, 2.12 (95% CI 1.37-3.29) for 130-259 mg/day and 3.01 (95% CI 2.08-4.36) for ≥ 260 mg/day. In women, the corresponding associations were comparable but more pronounced for high tar intake (HR 4.67, 95% CI 1.76-12.40). Similar associations were observed for nicotine intake. CONCLUSIONS: The present study based on a large population-based sample adds important evidence of cumulative effects of tar and nicotine intake on the risk of incident MI. Even low or medium tar and nicotine intake revealed substantial risk increases as compared to never-smokers. Therefore, reduction of tar and nicotine contents in cigarettes cannot be seen as a suitable public health policy in preventing myocardial infarction.

The effects of cigarette smoke condensate on vocal fold transepithelial resistance and inflammatory signaling in vocal fold fibroblasts.

OBJECTIVES/HYPOTHESIS: In response to chronic cigarette smoke exposure, a subset of patients present with edematous vocal folds, characteristically referred to as Reinke's edema. This phenotype differs from the tissue changes associated with prolonged smoke exposure in the lower airway, and the mechanism underlying Reinke's edema remains poorly described. We hypothesize that the effects of smoke are diffuse and involve both the epithelium and mucosa. STUDY DESIGN: In vitro, ex vivo experiment. METHODS: Transepithelial resistance (R(T) ) was quantified in an ex vivo, viable, porcine vocal fold model. Excised tissue was exposed to cigarette smoke condensate (CSC) and R(T) was computed at baseline and 1 and 4 hours after exposure. In vitro, human vocal fold fibroblasts were exposed to CSC. Cyclooxygenase 2 (COX-2), microsomal prostaglandin E synthase-1, and 15-hydroxyprostaglandin dehydrogenase mRNA expression were assessed at 4 hours. Prostaglandin E2 (PGE2) synthesis was quantified via immunoassay following 24 hours of CSC exposure. RESULTS: CSC had no effect on R(T) . CSC did, however, induce COX-2 mRNA expression as well as its downstream lipid mediator PGE2. PGE2 metabolism appears to be regulated via both synthetic and degradative enzymes in response to cigarette smoke. CONCLUSIONS: In vitro, CSC initiates an inflammatory response in vocal fold fibroblasts. However, in isolation, the epithelial resistance is not altered by CSC, at least acutely. These data may suggest a role for the interaction between the inflammatory response in the mucosa and compromised epithelial barrier function, as has been shown in other tissues.

Mononuclear leukocyte DNA damage and oxidative stress: the association with smoking of hand-rolled and filter-cigarettes.

Cigarette smoking is a major cause of human cancer at various sites, although its carcinogenic mechanisms still remain unestablished. Based on the use of a filter, cigarette smoke can be divided into a gas phase and a tar phase. Both contain different concentrations of oxidants, free radicals and tobacco-specific carcinogens. To explore the effects of both filtered and non-filtered cigarette smoke on DNA damage and oxidative status, we measured the level of mononuclear leukocyte DNA damage by use of the single-cell gel electrophoresis (Comet) assay. We also determined malondialdehyde (MDA), protein carbonyl content (PC) and total antioxidative capacity (TAC) levels in blood plasma of smokers of manufactured filter-cigarettes and of hand-rolled cigarettes. Cotinine levels were also measured in plasma to estimate the degree of smoking. Mononuclear leukocyte DNA damage, plasma MDA, plasma PC and plasma cotinine levels were found significantly higher, while plasma TAC levels were found significantly lower in smokers of filter-cigarettes and smokers of hand-rolled cigarettes, compared with control subjects. TAC levels in hand-rolled and manufactured filter-cigarette smokers were not significantly different from each other. However, the levels of DNA damage, plasma MDA, plasma cotinine, and plasma protein oxidation were significantly higher in hand-rolled cigarette smokers than in filter-cigarette smokers. There was a significant positive correlation between MDA and DNA damage in both hand-rolled cigarette smokers and manufactured filter-cigarette smokers. This study indicates that smoking of hand-rolled cigarettes has stronger genotoxic and oxidative effects on the metabolism than smoking of manufactured filter-cigarettes. We propose that these harmful effects could be attributed to the higher level of oxidants.

The acute effects of water-pipe smoking on the cardiorespiratory system.

OBJECTIVE: There are limited data on the acute effects of water-pipe tobacco smoking, commonly known as water-pipe smoking (WPS), on cardiopulmonary parameters. This study evaluated the acute effects of a single 30-min session of WPS on carboxyhemoglobin (COHb) levels, pulmonary function test results, vital signs, fractional exhaled nitric oxide (Feno) levels, and exhaled breath condensate (EBC) cytokine levels in volunteers in a domestic, open-air, group smoking setting. METHODS: This prospective study evaluated the above-noted outcome parameters before and after 30 min of WPS. The primary outcome parameter was the change in COHb levels. RESULTS: Forty-five volunteers (30 men, 15 women), aged 32.35 ± 15.33 years, were recruited. After one session of WPS, the COHb levels rose significantly, from 1.47% ± 0.57% (median 1.4) to 9.47% ± 5.52% (median 7.4), P < .001. Systolic and diastolic BP levels significantly increased after smoking (systolic, 119.52 ± 12.07 mm Hg vs 131.98 ± 17.8 mm Hg; diastolic, 74.84 ± 7.89 mm Hg vs 82.98 ± 12.52 mm Hg, respectively; P < .001). Heart rates increased from 80.39 ± 9.92 beats/min to 95.59 ± 17.41 beats/min, P < .001; and respiratory rates increased from 14.36 ± 1.63 breaths/min to 16.68 ± 2.24 breaths/min, P < .001. There were decreases in forced expiratory flow between 25% and 75% of FVC, peak expiratory flow rate, Feno levels, percentage of eosinophils in peripheral blood, and 8-isoprostane levels in EBC. CONCLUSIONS: This study shows that one session of WPS causes acute biologic changes that might result in marked health problems. It adds to the limited evidence that WPS is harmful and supports interventions to control the continuing global spread of WPS, especially among youth. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT01157832; URL: www.clinicaltrials.gov.