RESUMEN
Male strain A/J mice were exposed for 6 h per day, 5 days per week to a mixture of 89% cigarette sidestream smoke and 11% mainstream smoke. Total suspended particulate concentrations were 137 mg/m(3). In experiment 1, animals were exposed for 5 months to tobacco smoke and given a 4 month recovery period in air. Lung tumor multiplicity was 2.4 and incidence 89%. Animals exposed to filtered air had 1.0 tumor per lung (65% incidence). In animals kept for 5 months in smoke, removed into air and then fed a diet containing a mixture of myoinositol and dexamethasone, tumor multiplicity was 1.0 and incidence was 62%. These values were significantly (P < 0.01) lower than in animals exposed to smoke and identical to values seen in controls. In animals fed a diet containing 250 mg/kg each of phenethyl isothiocyanate and benzyl isothiocyanate during the entire 9 months, lung tumor multiplicity was 2.1 and incidence 96%, not significantly different from animals exposed to smoke and fed control diet. In experiment 2, animals were exposed for 5 months to smoke, followed by a 4 month recovery period in air and were fed during the entire period a diet containing either D-limonene or 1, 4-phenylenebis(methylene)selenoisocyanate (p-XSC). In animals exposed to tobacco smoke and fed control diet, lung tumor multiplicity was 2.8, whereas in the animals fed D-limonene it was 2. 6 and in the animals fed p-XSC it was 2.4. The differences to the controls were statistically not significant. It was concluded that myoinositol-dexamethasone successfully prevents the development of tobacco smoke-induced lung tumors even if administered when the animals have 'quit' smoking. On the other hand, agents otherwise shown to prevent lung tumor formation following administration of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone or benzo[a]pyrene were ineffective against tobacco smoke.
Asunto(s)
Anticarcinógenos/administración & dosificación , Neoplasias Pulmonares/prevención & control , Humo/efectos adversos , Animales , Peso Corporal , Dieta , Masculino , Ratones , Plantas Tóxicas , Cese del Hábito de Fumar , NicotianaRESUMEN
Male A/J strain mice were fed AIN-76A diet supplemented with myo-inositol/dexamethasone (10 g and 0.5 mg/kg diet) or acetylsalicylic acid (300 mg/kg) and exposed for 5 months to a mixture of sidestream and mainstream cigarette smoke at a concentration of 132 mg total suspended particulates/m3. After tobacco smoke exposure, they were allowed to recover for another 4 months in filtered air. In the animals fed AIN-75A diet alone or acetylsalicylic acid, the average number of tumors/lung was 2.1, whereas in the animals given the myo-inositol/dexamethasone diet, the average lung tumor multiplicity was 1.0 (P < 0.05). In animals exposed to filtered air, lung tumor multiplicities were 0.6 for animals fed AIN-76A or myo-inositol/dexamethasone and 1.2 for animals fed acetylsalicylic acid. It was concluded that the combination of myo-inositol and dexamethasone constitutes an effective chemopreventive regimen against tobacco smoke-induced lung tumorigenesis.
Asunto(s)
Antiinflamatorios/uso terapéutico , Quimioprevención , Dexametasona/uso terapéutico , Inositol/uso terapéutico , Neoplasias Pulmonares/prevención & control , Nicotiana/efectos adversos , Plantas Tóxicas , Humo/efectos adversos , Animales , Antiinflamatorios/administración & dosificación , Aspirina/administración & dosificación , Aspirina/uso terapéutico , Cámaras de Exposición Atmosférica , Peso Corporal/efectos de los fármacos , Dexametasona/administración & dosificación , Suplementos Dietéticos , Inositol/administración & dosificación , Neoplasias Pulmonares/inducido químicamente , Masculino , Ratones , Factores de TiempoRESUMEN
The question was asked whether ozone would act as a lung carcinogen in mice. To test the hypothesis, female strain A/J mice were exposed for 6 h/day, 5 days/week to 0.12 ppm, 0.5 ppm, or 1.0 ppm of ozone; control animals were kept in filtered air. No ozone-related deaths were observed at any time during the experiment. After 5 months, one-third of the animals were killed. The remaining animals were split into two groups: exposure to ozone continued for one group, whereas the other group was transferred into filtered air. Four months later, these animals were killed. No significant increase in lung tumor multiplicity (average number of tumors per lung) or lung tumor incidence (percentage of tumor-bearing animals) was found in the animals exposed to ozone when compared to animals kept in filtered air, regardless of ozone concentration. Morphometric analysis of lungs of animals exposed to the highest ozone concentration (1.0 ppm) showed a small, statistically not significant increase in centriacinar lesions. It was concluded that ozone is not a lung carcinogen in strain A/J mice at those exposure levels. Moreover, this mouse strain appears to be particularly resistant towards chronic ozone toxicity.
Asunto(s)
Carcinógenos/toxicidad , Neoplasias Pulmonares/inducido químicamente , Oxidantes Fotoquímicos/toxicidad , Ozono/toxicidad , Administración por Inhalación , Animales , Peso Corporal/efectos de los fármacos , Femenino , Neoplasias Pulmonares/patología , Ratones , Ratones Endogámicos A , Tamaño de los Órganos/efectos de los fármacos , Alveolos Pulmonares/patologíaRESUMEN
Male and female strain A/J mice were exposed to a mixture of cigarette sidestream and mainstream smoke at a chamber concentration of total suspended particulates of 82.5 mg/m3. Exposure time was 6 h/day, 5 days/week for 5 months. The animals were allowed to recover for another 4 months in filtered air before sacrifice and lung tumor count. Male animals were fed either 0.2% N-acetylcysteine (NAC) or 0.05% phenethyl isothiocyanate (PEITC) in diet AIN-76A with 5% corn oil added. Female animals received normal laboratory chow and were given a 1.25% extract of green tea in the drinking water. Corresponding control groups were fed diets without NAC or PEITC or given plain tap water. Exposure to tobacco smoke increased lung tumor multiplicity to 1.1-1.6 tumors/lung, significantly higher than control values (0.5-1.0 tumors/lung). None of the putative chemopreventive agents (NAC, PEITC or green tea extract) had a protective effect. In positive control experiments, PEITC significantly reduced both lung tumor multiplicity and incidence in mice treated with the tobacco smoke-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). In mice treated with three different doses of urethan and fed NAC in the diet, a significant reduction in lung tumor multiplicity was found only at one dose level. Green tea extract did not reduce lung tumor multiplicity in animals treated with a single dose of NNK. It was concluded that successful chemoprevention of tobacco smoke-induced lung tumorigenesis might require administration of several chemopreventive agents rather than just a single one.
Asunto(s)
Acetilcisteína/farmacología , Anticarcinógenos/farmacología , Isotiocianatos/farmacología , Neoplasias Pulmonares/prevención & control , Humo/efectos adversos , Té , Animales , Femenino , Neoplasias Pulmonares/etiología , Masculino , Ratones , Plantas Tóxicas , NicotianaRESUMEN
Female strain A/J mice were exposed to unfiltered or HEPA-filtered environmental tobacco smoke (ETS). Total suspended particulates (TSP) in the full smoke exposure chamber was 78.5 mg/m3 and in the filtered smoke chamber 0.1 mg/m3; nicotine concentrations in the full and filtered smoke chamber were 13.4 and 3.1 mg/m3, respectively. Animals exposed to filtered ETS (6 h a day, 5 days a week) and killed after 5 months had a higher lung tumor incidence and multiplicity than controls maintained in filtered air, although the differences were not statistically significant. Animals exposed to filtered and full ETS and allowed to recover in air for 4 months had an average of 1.2 +/- 0.3 tumors per lung and 1.3 +/- 0.3 tumors per lung, respectively. Air exposed control animals had an average tumor multiplicity 0.5 +/- 0.1 tumors per lung. Increased immunostaining for CYP 1A1 was not evident in the lung of animals exposed to filtered smoke. Based on the chamber concentrations of selected nitrosamines and polycyclic aromatic hydrocarbons, the possible maximum uptakes by the mice of NNK, NNN and benzo[a]pyrene during the 5 months exposure period were three to six orders of magnitude below doses reported in the literature to produce 1 lung tumor in strain A/J mice. It was concluded that the gas phase of ETS is as carcinogenic as is full ETS. The carcinogenicity of the gas phase may be due to some as yet unidentified, yet highly potent carcinogens or by placing a substantial, possibly free radical-mediated oxidative stress on the lung.
Asunto(s)
Carcinógenos Ambientales/toxicidad , Neoplasias Pulmonares/etiología , Nicotiana , Plantas Tóxicas , Humo/efectos adversos , Animales , Benzo(a)pireno/toxicidad , Femenino , Pulmón/patología , Ratones , Nitrosaminas/toxicidadRESUMEN
Male Sprague-Dawley rats were exposed to increasing concentrations of ozone as follows: 0.12, 0.24, 0.36, 0.6, or 0.8 ppm. Controls were kept in chambers ventilated with filtered air. One-half of the animals in ozone was exposed for 12 h a day during daytime hours, and the other one-half of the animals was exposed for 12 h during nighttime. Cumulative labeling indexes were measured after 4 and 7 days in the terminal bronchioles, large intrapulmonary airways, trachea, and nasal epithelia. The penetration of the lesions from the bronchiole-alveolar junction into the alveolar zone was measured with quantitative morphometry. After 4 days of exposure, the extent of injury was dose dependent. Labeling indexes in the terminal bronchioles were 15-20% higher in animals exposed during nighttime compared with the animals exposed during daylight hours. On the other hand, depth of penetration of ozone lesions into the centriacinar region was not significantly different in animals exposed during the night compared with animals exposed during daytime. Labeling indexes in the large airways, trachea, or nasal cavity were not influenced by time of exposure. Between days 4 and 7, the lesions in the terminal bronchioles progressed only to a minimal degree (10%). It was concluded that the pattern of centriacinar tissue remodeling 1) followed a gradient based on ozone concentration and 2) was essentially complete after only 4 days of ozone exposure. Although a difference between daytime and nighttime exposure was observed, it was not considered to be large enough to invalidate conclusions drawn from studies in which animals are exposed to ozone during daylight hours.
Asunto(s)
Ritmo Circadiano , Pulmón/efectos de los fármacos , Ozono/toxicidad , Animales , Bronquios/efectos de los fármacos , Ciclo Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Cinética , Pulmón/citología , Pulmón/patología , Masculino , Índice Mitótico/efectos de los fármacos , Alveolos Pulmonares/efectos de los fármacos , Ratas , Ratas Sprague-DawleyRESUMEN
Male strain A/J mice were exposed for 6 h a day, 5 days a week to environmental tobacco smoke (ETS) generated from Kentucky 1R4F reference cigarettes. Chamber concentrations were 87 mg/m3 of total suspended particulate matter (TSP), 246 p.p.m. of CO and 16 mg/m3 of nicotine. After 5 months, 33% of the ETS exposed and 11% of the control animals had one or several lung tumors; the difference was statistically not significant. A second group of animals exposed for 5 months to ETS was allowed to recover for another 4 months in filtered air. When they were killed, 85% of the ETS animals had lung tumors (average number per lung: 1.4 +/- 0.2), whereas in the control group 38% had lung tumors (average number of lung tumors in all animals 0.5 +/- 0.2). The differences in tumor incidence and multiplicity were statistically significant. More than 80% of all tumors were adenomas, the rest adenocarcinomas. When animals were pretreated with a carcinogen, lung tumor multiplicity was lower in the ETS exposed animals after 5 months compared with controls injected with a carcinogen and kept in air. However, after an additional 4 month recovery period in air, lung tumor multiplicities were the same in ETS plus carcinogen exposed mice as in carcinogen-treated air-exposed controls. Histopathologic and morphometric analysis of the lung tissue failed to reveal any differences between ETS exposed and control animals. However, immediately after ETS exposure, immunohistochemistry revealed increased staining for CYP1A1 in airway epithelia and lung parenchyma; following recovery in air, the staining disappeared again. Analysis of cell kinetics showed an initial burst of increased DNA synthesis in the epithelial cells of the airways and a smaller early positive response in the parenchyma. Feeding of butylated hydroxytoluene during ETS exposure did not modulate lung tumor development. It was concluded that ETS is a pulmonary carcinogen in strain A/J mice.