RESUMEN
Chemical analysis of up to 49 harmful and potentially harmful constituents (HPHC) in mainstream smoke, in vitro cytotoxicity of the particulate and gas/vapor phase of mainstream smoke determined in the Neutral Red Uptake assay, and in vitro bacterial mutagenicity of the particulate phase determined in the Salmonella typhimurium Reverse Mutation (Ames) assay are reported for three Electrically Heated Cigarette Smoking System (EHCSS) series-K cigarettes, the University of Kentucky Reference Cigarette 2R4F, and a number of comparator commercial conventional lit-end cigarettes (CC) under ISO machine-smoking conditions and a total of 25 additional smoking regimens reflecting 'human puffing behavior' (HPB). The smoking machines were set to deliver nicotine yields for the EHCSS and comparator CC derived from the 10th percentile to the 90th percentile of nicotine uptake distributions in smokers determined in two clinical studies. Duplication of the smoking intensity 'per cigarette' on a smoking machine may provide an insight into product performance that is directly relevant to obtaining scientific evidence for reduced exposure substantiation based on mainstream cigarette smoke HPHC-to-nicotine regressions. The reported data support an overall evaluation of reduced exposure to HPHC and biological activity.
Asunto(s)
Exposición por Inhalación/prevención & control , Nicotiana , Fumar/efectos adversos , Productos de Tabaco/análisis , Contaminación por Humo de Tabaco/prevención & control , Animales , Células 3T3 BALB , Conducta , Biomarcadores/análisis , Biomarcadores/orina , Monóxido de Carbono/química , Monóxido de Carbono/toxicidad , Supervivencia Celular/efectos de los fármacos , Interpretación Estadística de Datos , Electricidad , Calor , Humanos , Exposición por Inhalación/efectos adversos , Exposición por Inhalación/análisis , Ratones , Modelos Psicológicos , Pruebas de Mutagenicidad , Nicotina/química , Nicotina/toxicidad , Salmonella typhimurium/efectos de los fármacos , Salmonella typhimurium/genética , Fumar/psicología , Breas/química , Breas/toxicidad , Nicotiana/química , Nicotiana/toxicidad , Productos de Tabaco/toxicidad , Contaminación por Humo de Tabaco/efectos adversos , Contaminación por Humo de Tabaco/análisisRESUMEN
The Electrically Heated Cigarette Smoking System Series K (EHCSS) produces smoke through the controlled electrical heating of tobacco. Evaluation of the EHCSS was accomplished by comparison with commercial and reference cigarettes, using International Organization for Standardization (ISO) and alternative puffing regimens based on nicotine exposures measured in a short-term clinical study. Using the alternative puffing regimen and compared with conventional cigarettes on a per cigarette basis, the EHCSS had 50-60% reductions in tar and nicotine; at least 90% reductions in carbon monoxide, nitrogen oxides, 1,3-butadiene, isoprene, acrylonitrile, polyaromatic hydrocarbons, hydrogen cyanide, aromatic amines, tobacco specific nitrosamines, and phenol; and least a 40% reduction in 2-nitropropane. Other important smoke constituents in EHCSS smoke were reduced as well. The in vitro studies showed similar large reductions in biological activity. Ames mutagenicity of total particulate matter (TPM) from the EHCSS was reduced by 70-90%; cytotoxicity of the TPM was reduced by approximately 82% and 65% for the gas-vapor phase. In vivo testing under ISO smoking conditions in the mouse skin painting assay demonstrated later dermal tumor onset, lower dermal tumor incidence, reduced dermal tumor multiplicity, and a lower proportion of malignant dermal tumors in EHCSS smoke condensate-exposed mice. Thirty-five day and 90-day nose-only inhalation studies in rats showed reductions in pulmonary inflammation and other biological activity, including histopathological endpoints. We conclude that under the conditions of these in vitro and in vivo studies, the EHCSS demonstrated significantly lower biological activity compared to conventional cigarettes, and may suggest the potential for reductions in human smokers.
Asunto(s)
Material Particulado/toxicidad , Fumar/metabolismo , Contaminación por Humo de Tabaco/análisis , Administración por Inhalación , Animales , Pruebas de Carcinogenicidad , Electricidad , Femenino , Calor , Agencias Internacionales , Masculino , Ratones , Ratones Endogámicos SENCAR , Pruebas de Mutagenicidad/métodos , Nicotina/química , Material Particulado/química , Ratas , Ratas Sprague-Dawley , Neoplasias Cutáneas/inducido químicamente , Fumar/efectos adversos , Breas/química , Contaminación por Humo de Tabaco/efectos adversosRESUMEN
Toxicological comparisons were made of three commercial cigarettes, namely Marlboro full flavor, Marlboro Lights, and Marlboro Ultra Lights, with the 1R4F reference cigarette. The main comparison was a 90-d inhalation study with mainstream smoke at 150 mg total particulate matter per cubic meter, in Sprague-Dawley rats using 6 h/d and 7 d/w exposures. The principal endpoint was histopathology of the respiratory tract, along with examinations of free lung cell counts after broncho-alveolar lavage. Additional studies on mainstream smoke included Salmonella mutagenicity, cytotoxicity of particulate and gas/vapor phases, and analytical chemistry. The exposures produced effectively the same responses in each of the four groups, and the histopathology results in the commercial cigarette groups were also effectively the same. The 1R4F was also tested at 75 and 200 mg/m(3), and most of the histopathology results obtained here showed dose-response relationships. The free lung cell responses were similar in the 1R4F/commercial cigarette comparison, and there were dose-related changes in the 1R4F groups, most notably for neutrophils. Most of the changes produced in the 90-d of exposure were resolved in a 42-d post-inhalation period. Responses in the in vitro and analytical assays for the four cigarettes were in general similar, when data were expressed either per mg TPM or per mg tar yield. There were judged to be no toxicologically meaningful differences between the profiles evaluated at similar smoke concentrations for the three commercial cigarettes and for the 1R4F using these assays.
Asunto(s)
Nicotiana/toxicidad , Sistema Respiratorio/efectos de los fármacos , Salmonella/efectos de los fármacos , Humo/efectos adversos , Animales , Células 3T3 BALB , Líquido del Lavado Bronquioalveolar/citología , Carboxihemoglobina/análisis , Supervivencia Celular/efectos de los fármacos , Femenino , Masculino , Ratones , Mutágenos/toxicidad , Material Particulado/análisis , Material Particulado/toxicidad , Ratas , Ratas Sprague-Dawley , Pruebas de Función Respiratoria , Sistema Respiratorio/patología , Salmonella/genética , Humo/análisisRESUMEN
Vanillin is a flavoring agent used in cigarettes. Previous toxicological examinations of the effects on the addition of vanillin to tobacco used mixtures with several other flavoring agents. In the present work, toxicological comparisons were made of experimental cigarettes containing no added vanillin against otherwise similar cigarettes with three different amounts of vanillin added to the tobacco. The main toxicological comparison was a subchronic inhalation study with mainstream smoke in Sprague-Dawley rats (exposures of 150 mg/m3 of total particulate matter, 6 h exposure per day, for 90 consecutive days). Vanillin concentrations in the tobacco of the 4 cigarette types at the end of the study were 0, 67, 1233, and 3109 ppm. Additional studies with mainstream smoke were Salmonella mutagenicity (5 bacterial strains, both with and without metabolic activation, particulate phase only), cytotoxicity of both particulate and gas/vapor phases (using the neutral red uptake assay), and analytical chemistry (49 analytes, including 5 metals). Similar responses were seen across the four cigarette types, and the responses were similar to those previously described in the scientific literature. At the same smoke concentration, the inhalation exposures produced effectively the same responses, in each of the four groups. Most of the changes produced in the 90 days of exposure were resolved in a 42-day postinhalation period. The addition of vanillin to tobacco at inclusion rates up to 3109 ppm did not influence a broad range of toxicological endpoints.