RESUMEN
There has been a sustained effort in recent years to develop products with the potential to present less risk compared with continued smoking as an alternative for adult smokers who would otherwise continue to smoke cigarettes. During the non-clinical assessment phase of such products, the chemical composition and toxicity of their aerosols are frequently compared to the chemical composition and toxicity of the smoke from a standard research cigarette - the 3R4F reference cigarette. In the present study, it is demonstrated that results of these analytical comparisons are similar when considering commercially available cigarette products worldwide. A market mean reduction of about 90% is observed on average across a broad range of harmful and potentially harmful constituents (HPHC) measured in the aerosol of a candidate modified risk tobacco product, the Tobacco Heating System 2.2 (THS2.2), compared against the levels of HPHC of cigarettes representative of selected markets; this mean reduction is well in line with the reduction observed against 3R4F smoke constituents in previous studies.
Asunto(s)
Sistemas Electrónicos de Liberación de Nicotina , Reducción del Daño , Nicotiana/toxicidad , Fumar/efectos adversos , Productos de Tabaco/efectos adversos , Adulto , Aerosoles , Seguridad de Productos para el Consumidor/normas , Calor , Humanos , Exposición por Inhalación/efectos adversos , Nicotina/toxicidad , Medición de Riesgo , Nicotiana/química , Industria del Tabaco/tendencias , Pruebas de Toxicidad/métodos , Pruebas de Toxicidad/normasRESUMEN
Research conducted during past decades to reduce the level of the tobacco specific nitrosamine N-nitrosonornicotine (NNN) and its precursor nornicotine in tobacco yielded identification of three tobacco genes encoding for cytochrome P450 nicotine demethylases converting nicotine to nornicotine. We carried out trials to investigate the effect of using tobaccos containing three non-functional nicotine demethylase genes on the selective reduction of NNN in cigarette tobacco filler and mainstream smoke. Our results indicate that the presence of non-functional alleles of the three genes reduces the level of nornicotine and NNN in Burley tobacco by 70% compared to the level observed in currently available low converter (LC) Burley tobacco varieties. The new technology, named ZYVERT™, does not require a regular screening process, while a yearly selection process is needed to produce LC Burley tobacco seeds for NNN reduction. The reduction of NNN observed in smoke of blended prototype cigarettes is proportional to the inclusion level of tobacco having ZYVERT™ technology. Inclusion of Burley tobacco possessing the new trait into a typical American blend resulted in a selective reduction of NNN in cigarette smoke, while the levels of other Harmful and Potentially Harmful Constituents (HPHC) currently in the abbreviated list provided by the US Food and Drug Administration are statistically equivalent in comparison with the levels obtained in reference prototype cigarettes containing LC Burley.
Asunto(s)
Sistema Enzimático del Citocromo P-450/genética , Nicotiana/química , Nicotiana/genética , Nicotina/metabolismo , Nitrosaminas/metabolismo , Humo/análisis , Alelos , Nicotina/genética , Semillas/química , Productos de Tabaco/análisisRESUMEN
The evolution of the levels of tobacco-specific N-nitrosamines (TSNA), N-nitrosonornicotine (NNN) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in mainstream (MS) cigarette smoke is investigated based on smoke and tobacco chemistry data of cigarette brands sold by Philip Morris International (PMI) between 2000 and 2014. A total of 315 cigarette samples representing a wide range of product and design characteristics manufactured by PMI between 2008 and 2014 were analyzed and compared to a previously published dataset of PMI brands manufactured in 2000. The data indicate that there is a substantial reduction of NNN and NNK levels in tobacco fillers and MS cigarette smoke per mg of tar and per mg of nicotine using Health Canada Intense (HCI) machine-smoking regime. This observed reduction in NNN and NNK levels in MS cigarette smoke is also supported by the downward trend observed on NNN and NNK levels in USA flue-cured Virginia and Burley tobacco lots from 2000 to 2014 crops, reflecting effectiveness of measures taken on curing and agricultural practices designed to minimize TSNA formation in tobacco.
Asunto(s)
Nicotiana/química , Nitrosaminas/análisis , Humo/análisis , Productos de Tabaco/análisis , Contaminación por Humo de Tabaco/análisis , Agricultura , Comercio , Seguridad de Productos para el Consumidor , Humanos , Nitrosaminas/efectos adversos , Medición de Riesgo , Humo/efectos adversos , Fumar/efectos adversos , Factores de Tiempo , Nicotiana/efectos adversos , Nicotiana/crecimiento & desarrollo , Productos de Tabaco/efectos adversos , Contaminación por Humo de Tabaco/efectos adversosRESUMEN
Cigarette smoke is a complex mixture of more than 8000 smoke constituents. The quantification of selected mainstream smoke constituent yields is one of the methods to evaluating and comparing the performance of different products. Numerous regulatory and scientific advisory bodies have used cigarette smoke constituent yield data for reporting and product comparison purposes. For more than a decade limitations of the indiscriminate application of traditional statistical methods such as the t-test for differences in comparative smoke constituent yield assessments lacking a specific study design, have been highlighted. In the present study, the variability of smoke constituent yields is demonstrated with data obtained under the ISO smoking regime for the Kentucky reference cigarette 3R4F and one commercial brand, analyzed on several occasions between 2007 and 2014. Specifically it is shown that statistically significant differences in the yields of selected smoke constituents do not readily translate to differences between products, and that tolerances need to be defined. To this end, two approaches have been proposed in the literature--minimal detectable differences, and the statistical equivalence. It is illustrated how both approaches provide more meaningful comparison outcomes than the statistical t-test for differences. The present study provides considerations relevant for comparative tobacco product assessments both in the scientific and regulatory contexts.
Asunto(s)
Nicotiana/anatomía & histología , Humo/análisis , Fumar/efectos adversos , Productos de Tabaco/análisis , HumanosRESUMEN
The prognostic value of tumor-associated angiogenesis is still a subject of debate. As microvascular density and the expression of different growth factors were not demonstrated to be good predictors of the response to antiangiogenic and antivascular therapy, there is a strong need to search for more sensitive markers. In the present study we evaluated by double immunohistochemical staining the profile of tumor-associated blood vessels and the rate of endothelial cell proliferation in patients with thymoma (n=38). Results were compared with specimens of normal thymus and from patients with myasthenia gravis. We found a significant increase in the number of immature and intermediate blood vessels in the tumor area of thymoma, regardless the histological type of the tumor. Proliferating endothelial cells were found in 15 cases, and co-expression of Ki67 and CD34 had the highest value in immature vessels. Both blood vessel type and endothelial cell proliferation significantly correlated with invasive thymoma. Based on these findings, it can be assumed that the type of tumor-associated vessel together with endothelial cell proliferation are useful predictors of invasion, immature and intermediate vessels can be targeted with antivascular drugs and endothelial cell proliferation could be used as a good predictor of the response to antiangiogenic therapy.
Asunto(s)
Timoma/irrigación sanguínea , Neoplasias del Timo/irrigación sanguínea , Antígenos CD34/metabolismo , Estudios de Casos y Controles , Proliferación Celular , Células Endoteliales/patología , Humanos , Antígeno Ki-67/metabolismo , Microvasos/patología , Neovascularización Patológica , Pronóstico , Timoma/inmunología , Timoma/patología , Neoplasias del Timo/inmunología , Neoplasias del Timo/patologíaRESUMEN
Human thymus development and thymoma behavior remain elusive, in spite of many acquisitions in the field in last decades. In the present paper, we analyzed the immunohistochemical expression of D2-40 in the normal human thymus and thymoma. In both fetal and postnatal normal thymus, we found a strong expression of D2-40 in the subcapsular and cortico-medullary epithelial cells, and lack of expression in the thymus of involution. These findings support a role for podoplanin in the proliferation of some subtypes of epithelial cells of the normal thymus stroma. In thymoma, the expression of D2-40 was detected in neoplastic cells in 18 from 26 cases (69.23%). No correlation was found between D2-40 expression and histological types of thymoma, but strong correlation was noticed with tumor stage. Based on these results, it is suggested that D2-40 expression is a good predictor of invasion and can be considered as a potential target for therapy in selected cases.