RESUMEN
Epidemiological studies have established that exposure to tungsten increases the risk of developing cardiovascular diseases. However, no studies have investigated how tungsten affects cardiac function or the development of cardiovascular disease. Inhalation of tungsten particulates is relevant in occupational settings, and inhalation of particulate matter has a known causative role in driving cardiovascular disease. This study examined if acute inhalation to tungsten particulates affects cardiac function and leads to heart tissue alterations. Female BALB/c mice were exposed to Filtered Air or 1.5 ± 0.23 mg/m3 tungsten particles, using a whole-body inhalation chamber, 4 times over the course of two weeks. Inhalation exposure resulted in mild pulmonary inflammation characterized by an increased percentage and number of macrophages and metabolomic changes in the lungs. Cardiac output was significantly decreased in the tungsten-exposed group. Additionally, A', an indicator of the amount of work required by the atria to fill the heart was elevated. Cardiac gene expression analysis revealed, tungsten exposure increased expression of pro-inflammatory cytokines, markers of remodeling and fibrosis, and oxidative stress genes. These data strongly suggest exposure to tungsten results in cardiac injury characterized by early signs of diastolic dysfunction. Functional findings are in parallel, demonstrating cardiac oxidative stress, inflammation, and early fibrotic changes. Tungsten accumulation data would suggest these cardiac changes are driven by systemic consequences of pulmonary damage.
Asunto(s)
Enfermedades Cardiovasculares , Neumonía , Ratones , Animales , Femenino , Tungsteno/toxicidad , Enfermedades Cardiovasculares/metabolismo , Pulmón/metabolismo , Material Particulado/toxicidad , Neumonía/metabolismo , Exposición por Inhalación/efectos adversosRESUMEN
Inhalation of tungsten particulates is a relevant route of exposure in occupational and military settings. Exposure to tungsten alloys is associated with increased incidence of lung pathologies, including interstitial lung disease and cancer. We have demonstrated, oral exposure to soluble tungsten enhances breast cancer metastasis to the lungs through changes in the surrounding microenvironment. However, more research is required to investigate if changes in the lung microenvironment, following tungsten particulate exposure, can drive tumorigenesis or metastasis to the lung niche. This study examined if inhalation to environmentally relevant concentrations of tungsten particulates caused acute damage to the microenvironment in the lungs and/or systemically using a whole-body inhalation system. Twenty-four female BALB/c mice were exposed to Filtered Air, 0.60 mg/m3, or 1.7 mg/m3 tungsten particulates (<1 µm) for 4 h. Tissue samples were collected at days 1 and 7 post-exposure. Tungsten accumulation in the lungs persisted up to 7 days post-exposure and produced acute changes to the lung microenvironment including increased macrophage and neutrophil infiltration, increased levels of proinflammatory cytokines interleukin 1 beta and C-X-C motif chemokine ligand 1, and an increased percentage of activated fibroblasts (alpha-smooth muscle actin+). Exposure to tungsten also resulted in systemic effects on the bone, including tungsten deposition and transient increases in gene expression of proinflammatory cytokines. Taken together, acute whole-body inhalation of tungsten particulates, at levels commonly observed in occupational and military settings, resulted in changes to the lung and bone microenvironments that may promote tumorigenesis or metastasis and be important molecular drivers of other tungsten-associated lung pathologies such as interstitial lung disease.
Asunto(s)
Pulmón , Tungsteno , Administración por Inhalación , Animales , Polvo , Femenino , Exposición por Inhalación/efectos adversos , Pulmón/patología , Ratones , Infiltración Neutrófila , Tungsteno/metabolismo , Tungsteno/toxicidadRESUMEN
Chronic inhalation studies were conducted to compare the toxicity and potential carcinogenicity of evaporative emissions from unleaded gasoline (GVC) and gasoline containing the oxygenate methyl tertiary-butyl ether (MTBE; GMVC). The test materials were manufactured to mimic vapors people would be exposed to during refueling at gas stations. Fifty F344 rats per gender per exposure level per test article were exposed 6 h/d, 5 d/wk for 104 wk in whole body chambers. Target total vapor concentrations were 0, 2, 10, or 20 g/m³ for the control, low-, mid-, and high-level exposures, respectively. Endpoints included survival, body weights, clinical observations, organs weights, and histopathology. GVC and GMVC exerted no marked effects on survival or clinical observations and few effects on organ weights. Terminal body weights were reduced in all mid- and high-level GVC groups and high-level GMVC groups. The major proliferative lesions attributable to gasoline exposure with or without MTBE were renal tubule adenomas and carcinomas in male rats. GMV exposure led to elevated testicular mesothelioma incidence and an increased trend for thyroid carcinomas in males. GVMC inhalation caused an increased trend for testicular tumors with exposure concentration. Mid- and high-level exposures of GVC and GMVC led to elevated incidences of nasal respiratory epithelial degeneration. Overall, in these chronic studies conducted under identical conditions, the health effects in F344 rats following 2 yr of GVC or GMVC exposure were comparable in the production of renal adenomas and carcinomas in male rats and similar in other endpoints.
Asunto(s)
Contaminantes Atmosféricos/toxicidad , Carcinógenos/toxicidad , Gasolina/toxicidad , Éteres Metílicos/toxicidad , Animales , Peso Corporal/efectos de los fármacos , Pruebas de Carcinogenicidad , Relación Dosis-Respuesta a Droga , Femenino , Riñón/efectos de los fármacos , Masculino , Mucosa Nasal/efectos de los fármacos , Tamaño de los Órganos/efectos de los fármacos , Ratas , Ratas Endogámicas F344 , Factores Sexuales , VolatilizaciónRESUMEN
BACKGROUND: Yersinia pestis, the agent of plague, is considered a potential bioweapon due to rapid lethality when delivered as an aerosol. Levofloxacin was tested for primary pneumonic plague treatment in a nonhuman primate model mimicking human disease. METHODS AND RESULTS: Twenty-four African Green monkeys (AGMs, Chlorocebus aethiops) were challenged via head-only aerosol inhalation with 3-145 (mean = 65) 50% lethal (LD(50)) doses of Y. pestis strain CO92. Telemetered body temperature >39 °C initiated intravenous infusions to seven 5% dextrose controls or 17 levofloxacin treated animals. Levofloxacin was administered as a "humanized" dose regimen of alternating 8 mg/kg and 2 mg/kg 30-min infusions every 24-h, continuing until animal death or 20 total infusions, followed by 14 days of observation. Fever appeared at 53-165 h and radiographs found multilobar pneumonia in all exposed animals. All control animals died of severe pneumonic plague within five days of aerosol exposure. All 16 animals infused with levofloxacin for 10 days survived. Levofloxacin treatment abolished bacteremia within 24 h in animals with confirmed pre-infusion bacteremia, and reduced tachypnea and leukocytosis but not fever during the first 2 days of infusions. CONCLUSION: Levofloxacin cures established pneumonic plague when treatment is initiated after the onset of fever in the lethal aerosol-challenged AGM nonhuman primate model, and can be considered for treatment of other forms of plague. Levofloxacin may also be considered for primary presumptive-use, multi-agent antibiotic in bioterrorism events prior to identification of the pathogen.
Asunto(s)
Antibacterianos/administración & dosificación , Levofloxacino , Ofloxacino/administración & dosificación , Peste/tratamiento farmacológico , Enfermedades de los Primates/tratamiento farmacológico , Animales , Bacteriemia/tratamiento farmacológico , Bacteriemia/mortalidad , Bacteriemia/patología , Chlorocebus aethiops , Modelos Animales de Enfermedad , Infusiones Intravenosas , Pulmón/patología , Peste/complicaciones , Peste/mortalidad , Peste/patología , Enfermedades de los Primates/mortalidad , Enfermedades de los Primates/patología , Radiografía Torácica , Análisis de SupervivenciaRESUMEN
Rats were exposed once by inhalation to plutonium-239 dioxide ((239)PuO(2)), resulting in chronic alpha-particle irradiation of the lung, and exposed chronically to cigarette smoke to examine carcinogenic interactions between the two exposures. F344 rats were exposed to (239)PuO(2) to achieve an initial lung burden of 0.5 kBq and then exposed 6 h/day, 5 days/week to cigarette smoke at 100 or 250 mg particulate matter/m(3) for up to 30 months. Exposure to cigarette smoke increased the cumulative radiation dose to lung by slowing the clearance of (239)PuO(2). (239)PuO(2) alone did not affect survival, but the higher cigarette smoke exposure shortened survival in females. Combined exposure to (239)PuO(2) and cigarette smoke acted synergistically to shorten survival in both genders. The combined effects of cigarette smoke and (239)PuO(2) were approximately additive for lung hyperplasia and adenomas but were strongly synergistic for carcinomas. Differences between observed incidences and incidences predicted by survival-adjusted models accounting for increased radiation dose revealed a substantial component of synergy for carcinomas above that attributable to the radiation dose effect. The synergy for malignant lung tumors is consistent with findings from uranium miners and nuclear weapons production workers. These results bolster confidence in the epidemiological findings and have implications for risk assessment.
Asunto(s)
Cocarcinogénesis , Neoplasias Pulmonares/etiología , Nicotiana , Plutonio/toxicidad , Humo , Aerosoles , Animales , Femenino , Exposición por Inhalación , Pulmón/patología , Pulmón/efectos de la radiación , Masculino , Dosis de Radiación , Ratas , Ratas Endogámicas F344RESUMEN
Exposure atmospheres for a rodent inhalation toxicology study were generated from the exhaust of a 4.3-L gasoline engine coupled to a dynamometer and operated on an adapted California Unified Driving Cycle. Exposure levels were maintained at three different dilution rates. One chamber at the lowest dilution had particles removed by filtration. Each exposure atmosphere was characterized for particle mass, particle number, particle size distribution, and detailed chemical speciation. The majority of the mass in the exposure atmospheres was gaseous carbon monoxide, nitrogen oxides, and volatile organics, with small amounts of particle-bound carbon/ions and metals. The atmospheres varied according to the cycle, with the largest spikes in volatile organic and inorganic species shown during the "cold start" portion of the cycle. Ammonia present from the exhaust and rodents interacted with the gasoline exhaust to form secondary inorganic particles, and an increase in exhaust resulted in higher proportions of secondary inorganics as a portion of the total particle mass. Particle size had a median of 10-20 nm by number and approximately 150 nm by mass. Volatile organics matched the composition of the fuel, with large proportions of aliphatic and aromatic hydrocarbons coupled to low amounts of oxygenated organics. A new measurement technique revealed organics reacting with nitrogen oxides have likely resulted in measurement bias in previous studies of combustion emissions. Identified and measured particle organic species accounted for about 10% of total organic particle mass and were mostly aliphatic acids and polycyclic aromatic hydrocarbons.
Asunto(s)
Cámaras de Exposición Atmosférica , Gasolina , Exposición por Inhalación , Emisiones de Vehículos , Cámaras de Exposición Atmosférica/efectos adversos , Gasolina/efectos adversos , Exposición por Inhalación/efectos adversos , Material Particulado/administración & dosificación , Material Particulado/efectos adversosRESUMEN
INTRODUCTION: The term 'select agent' (SA) refers to a list of microorganisms and toxins and are defined as those that have the potential to pose a severe threat to public health and safety (42 C.F.R. Part 73). In order to carry out a research with SAs, an Animal Biosafety Level 3 (ABSL3) containment facility is required. Our newly completed ABSL3 facility is developing protocols for implementing safety and efficacy studies of therapeutics for SAs. METHODS: The primary purpose of this study was to develop methods for exposing non-human primates (NHP) to aerosolized SAs in the ABSL3 and systematically measure specific ventilatory endpoints (frequency, tidal volume, minute volume, and accumulated volume) using a head-out plethysmograph to more precisely control dosimetry. This report details the equipment and protocols used to conduct such studies within a containment facility. RESULTS: After validating the performance of the plethysmography system, we successfully exposed NHPs to an agent using the integrated plethysmography system. The system enabled an acquisition and analysis of ventilatory characteristics, facilitating accurate estimations of the inhaled dose. DISCUSSION: This system will have clear uses in the development of novel therapeutics and vaccines for the treatment of SAs in NHPs.
Asunto(s)
Contención de Riesgos Biológicos/instrumentación , Pletismografía/instrumentación , Pruebas de Función Respiratoria/instrumentación , Administración por Inhalación , Aerosoles/administración & dosificación , Animales , Cámaras de Exposición Atmosférica , Macaca fascicularis , Macaca mulattaRESUMEN
Small increases in concentrations of ambient particulate matter (PM*) have been linked to adverse health effects, especially in older people and people with preexisting respiratory disease. Some epidemiologic studies have shown the association to be stronger with PM less than 2.5 microm in aerodynamic diameter (PM2.5) than with PM less than 10 microm in aerodynamic diameter (PM10). Some scientists and regulators suggest that 2.5 microm might be an arbitrary cutoff and that the effects might be more pronounced for PM less than 0.1 microm in aerodynamic diameter (ultrafine PM). Our first aim was to determine the relation between size of respirable particles and particle toxicity, as well as the health effects of short-term increases (spikes) in particle concentration against backgrounds of relatively low or high baseline exposures. Our second aim was to determine the effect of spikes in concentration of fine particles (0.7 microm in mass median aerodynamic diameter [MMAD]) and ultrafine particles (35 nm in count median diameter [CMD]) of disparate composition: vanadium pentoxide (V2O5) and carbon black. The relative toxicity of these particles was determined in aged rats with mild pulmonary inflammation induced by instilled endotoxin. Our third aim was to determine the influence of age (aged vs young adult) on particle-induced toxicity in these rats.
Asunto(s)
Carbono/efectos adversos , Exposición por Inhalación/análisis , Compuestos de Vanadio/efectos adversos , Factores de Edad , Animales , Carbono/administración & dosificación , Masculino , New Mexico , Tamaño de la Partícula , Neumonía/fisiopatología , Ratas , Ratas Endogámicas F344 , Ratas Sprague-Dawley , Compuestos de Vanadio/administración & dosificaciónRESUMEN
Although cigarette smoke has been epidemiologically associated with lung cancer in humans for many years, animal models of cigarette smoke-induced lung cancer have been lacking. This study demonstrated that life time whole body exposures of female B6C3F1 mice to mainstream cigarette smoke at 250 mg total particulate matter/m(3) for 6 h per day, 5 days a week induces marked increases in the incidence of focal alveolar hyperplasias, pulmonary adenomas, papillomas and adenocarcinomas. Cigarette smoke-exposed mice (n = 330) had a 10-fold increase in the incidence of hyperplastic lesions, and a 4.6-fold (adenomas and papillomas), 7.25-fold (adenocarcinomas) and 5-fold (metastatic pulmonary adenocarcinomas) increase in primary lung neoplasms compared with sham-exposed mice (n = 326). Activating point mutations in codon 12 of the K-ras gene were identified at a similar rate in tumors from sham-exposed mice (47%) and cigarette smoke-exposed mice (60%). The percentages of transversion and transition mutations were similar in both the groups. Hypermethylation of the death associated protein (DAP)-kinase and retinoic acid receptor (RAR)-beta gene promoters was detected in tumors from both sham- and cigarette smoke-exposed mice, with a tendency towards increased frequency of RAR-beta methylation in the tumors from the cigarette smoke-exposed mice. These results emphasize the importance of the activation of K-ras and silencing of DAP-kinase and RAR-beta in lung cancer development, and confirm the relevance of this mouse model for studying lung tumorigenesis.
Asunto(s)
Metilación de ADN , Silenciador del Gen/efectos de los fármacos , Neoplasias Pulmonares/inducido químicamente , Neoplasias Pulmonares/genética , Pulmón/efectos de los fármacos , Fumar/efectos adversos , Adenocarcinoma/inducido químicamente , Adenocarcinoma/genética , Adenocarcinoma/secundario , Adenoma/inducido químicamente , Adenoma/genética , Adenoma/patología , Administración por Inhalación , Animales , Proteínas Reguladoras de la Apoptosis , Peso Corporal , Proteínas Quinasas Dependientes de Calcio-Calmodulina/genética , Proliferación Celular/efectos de los fármacos , Proteínas Quinasas Asociadas a Muerte Celular , Femenino , Genes ras/efectos de los fármacos , Hiperplasia/inducido químicamente , Hiperplasia/genética , Hiperplasia/patología , Incidencia , Pulmón/metabolismo , Pulmón/patología , Neoplasias Pulmonares/patología , Ratones , Ratones Endogámicos , Tamaño de los Órganos , Papiloma/inducido químicamente , Papiloma/genética , Papiloma/patología , Mutación Puntual , Regiones Promotoras Genéticas , Alveolos Pulmonares/efectos de los fármacos , Alveolos Pulmonares/metabolismo , Alveolos Pulmonares/patología , Receptores de Ácido Retinoico/genética , Tasa de SupervivenciaRESUMEN
Microcystins, a family of cyclic heptapeptides produced by the cyanobacteria, Microcystis aeruginosa, have documented hepatotoxic and tumor promoting activities. The purpose of this study was to evaluate the toxicity of inhaled microcystin LR (microcystin). Male BALB/c mice were exposed by nose-only inhalation to 260-265 microg microcystin/m(3) for 7 days. The low-, mid- and high-dose groups were exposed for 0.5, 1, and 2h, respectively. Control animals were sham exposed to aerosolized vehicle. Treatment-related microscopic lesions were observed only in the nasal cavity of the mid- and high-dose groups. These lesions consisted of minimal to moderate multifocal degeneration and necrosis of the respiratory epithelium, with variable neutrophilic inflammation and minimal to marked degeneration, necrosis, and atrophy of the olfactory epithelium. The no-adverse-effect dose for the nasal lesions was approximately 3 microg/kg body weight, or 20 ng/cm(2) of nasal epithelium. In serum, only two protein peaks, occurring at m/zs of 11,688 and 11,829 Da, exhibited decreases in intensity that were microcystin dose-dependent. While these proteins have not been positively identified, they may be useful in the future as biomarkers of microcystin exposure in humans.
Asunto(s)
Mucosa Olfatoria/efectos de los fármacos , Péptidos Cíclicos/toxicidad , Mucosa Respiratoria/efectos de los fármacos , Administración por Inhalación , Análisis de Varianza , Animales , Proteínas Sanguíneas , Relación Dosis-Respuesta a Droga , Técnicas Histológicas , Masculino , Toxinas Marinas , Ratones , Ratones Endogámicos BALB C , Microcistinas , Necrosis , Nivel sin Efectos Adversos Observados , Mucosa Olfatoria/patología , Péptidos Cíclicos/administración & dosificación , Mucosa Respiratoria/patología , Factores de TiempoRESUMEN
Exposure atmospheres for a rodent inhalation toxicology study were generated from the exhaust of a 2000 Cummins ISB 5.9L diesel engine coupled to a dynamometer and operated on a slightly modified heavy-duty Federal Test Procedure cycle. Exposures were conducted to one clean air control and four diesel exhaust levels maintained at four different dilution rates (300:1, 100:1, 30:1, 10:1) that yielded particulate mass concentrations of 30, 100, 300, and 1000 microg/m3. Exposures at the four dilutions were characterized for particle mass, particle size distribution (reported elsewhere), detailed chemical speciation of gaseous, semivolatile, and particle-phase inorganic and organic compounds. Target analytes included metals, inorganic ions and gases, organic and elemental carbon, alkanes, alkenes, aromatic and aliphatic acids, aromatic hydrocarbons, polycyclic aromatic hydrocarbons (PAH), oxygenated PAH, nitrogenated PAH, isoprenoids, carbonyls, methoxyphenols, sugar derivatives, and sterols. The majority of the mass of material in the exposure atmospheres was gaseous nitrogen oxides and carbon monoxide, with lesser amounts of volatile organics and particle mass (PM) composed of carbon (approximately 90% of PM) and ions (approximately 10% of PM). Measured particle organic species accounted for about 10% of total organic particle mass and were mostly alkanes and aliphatic acids. Several of the components in the exposure atmosphere scaled in concentration with dilution but did not scale precisely with the dilution rate because of background from the rodents and scrubbed dilution air, interaction of animal derived emissions with diesel exhaust components, and day-to-day variability in the output of the engine. Rodent-derived ammonia reacted with exhaust to form secondary inorganic particles (at different rates dependent on dilution), and rodent respiration accounted for volatile organics (especially carbonyls and acids) in the same range as the diesel exhaust at the lowest exhaust exposure concentrations. Day-to-day variability in the engine output was implicated partially for differences of several components, including some of the particle bound organics. Though these observations have likely occurred in nearly all inhalation exposure atmospheres that contain complex mixtures of material, the speciations conducted here illustrate many of them for the first time.
Asunto(s)
Exposición por Inhalación , Metales Pesados/toxicidad , Hidrocarburos Policíclicos Aromáticos/toxicidad , Emisiones de Vehículos/efectos adversos , Emisiones de Vehículos/análisis , Animales , Recolección de Datos , Relación Dosis-Respuesta a Droga , Metales Pesados/análisis , Tamaño de la Partícula , Hidrocarburos Policíclicos Aromáticos/análisis , Valores de Referencia , Reproducibilidad de los Resultados , Roedores , Pruebas de Toxicidad/métodosRESUMEN
An animal model of lung carcinogenicity induced by chronic inhalation of mainstream cigarette smoke would be useful for research on carcinogenic mechanisms, smoke composition-response relationships, co-carcinogenicity, and chemoprevention. A study was conducted to determine if chronic whole-body exposures of rats would significantly increase lung tumor incidence. Male and female F344 rats (n = 81 to 178/gender) were exposed whole-body 6 h/day, 5 days/week for up to 30 months to smoke from 1R3 research cigarettes diluted to 100 (LS) or 250 (HS) mg total particulate matter/m(3), or sham-exposed to clean air (C). Gross respiratory tract lesions and standard lung and nasal sections were evaluated by light microscopy. A slight reduction of survival suggested that the HS level was at the maximum tolerated dose as commonly defined. Cigarette smoke exposure significantly increased the incidences of non-neoplastic and neoplastic proliferative lung lesions in females, while nonsignificant increases were observed in males. The combined incidence of bronchioloalveolar adenomas and carcinomas in females were: HS = 14%; LS = 6%; and C = 0%. These incidences represented minima because only standard lung sections and gross lesions were evaluated. Mutations in codon 12 of the K-ras gene occurred in 4 of 23 (17%) tumors. Three mutations were G to A transitions and one was a G to T transversion. The incidence of neoplasia of the nasal cavity was significantly increased at the HS, but not the LS level in both males and females (HS = 6%, LS = 0.3%, C = 0.4% for combined genders). These results demonstrate that chronic whole-body exposure of rats to cigarette smoke can induce lung cancer.
Asunto(s)
Neoplasias Pulmonares/inducido químicamente , Neoplasias Pulmonares/patología , Neoplasias Nasales/inducido químicamente , Neoplasias Nasales/patología , Humo/análisis , Fumar/patología , Administración por Inhalación , Animales , Peso Corporal/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Enfermedad Crónica , Codón/genética , Relación Dosis-Respuesta a Droga , Femenino , Genes ras/efectos de los fármacos , Pulmón/efectos de los fármacos , Pulmón/enzimología , Pulmón/patología , Neoplasias Pulmonares/epidemiología , Masculino , Moco/metabolismo , Mucosa Nasal/efectos de los fármacos , Mucosa Nasal/enzimología , Mucosa Nasal/patología , Neoplasias Nasales/epidemiología , Tamaño de los Órganos/efectos de los fármacos , Ratas , Ratas Endogámicas F344 , Análisis de SupervivenciaRESUMEN
B6C3F1 female mice were exposed to cigarette smoke (CS) (250 mg/m3 total particulate material) or filtered air (FA), 6 hours/day, 5 days/week, for 6, 7, or 10 weeks, or to CS for 6 weeks, then FA for 1 or 4 additional weeks. Exposure to CS increased macrophages, neutrophils, lymphocytes, and matrix metalloproteinase (MMP)-2 and MMP-9 content in bronchoalveolar lavage fluid. Partial recovery of most lavage parameters (except lymphocytes) was observed 1 week after cessation of CS exposure with further reductions after 4 weeks, but interstitial inflammation persisted longer. These results support a role for MMPs in CS-induced emphysema and indicate that smoking cessation allows restoration toward normal homeostasis.
Asunto(s)
Pulmón/inmunología , Metaloproteinasa 2 de la Matriz/metabolismo , Metaloproteinasa 9 de la Matriz/metabolismo , Cese del Hábito de Fumar , Fumar/efectos adversos , Fumar/inmunología , Animales , Líquido del Lavado Bronquioalveolar/citología , Líquido del Lavado Bronquioalveolar/inmunología , Enfisema/inmunología , Enfisema/metabolismo , Femenino , Pulmón/enzimología , Pulmón/patología , Linfocitos/inmunología , Macrófagos Alveolares/inmunología , Ratones , Ratones Endogámicos , Neutrófilos/inmunologíaRESUMEN
Inhalation of crystalline silica may lead to acute or chronic silicosis. Although chronic silicosis is associated with increased incidence/exacerbation of autoimmune disorders, the immunologic effects of chronic silicosis are not completely understood. In an animal model of chronic silicosis, Lewis rats were exposed to filtered air or silica (1.75 microm average particle size) at an exposure concentration of 6.2 mg/m(3), 6 h/d, 5 d/wk for 6 wk, and observed up to 27 wk after the exposure. Based on silica burden, lung histopathology, and immunologic changes, two distinct stages were identified in the development of chronic silicosis. Stage 1 (4-28 d after exposure) was characterized by silica deposition in various tissues, and augmented antibody and cellular immunity. Although bronchoalveolar lavage contained an increased number of activated macrophages, protein and lactate dehydrogenase levels were comparable to controls. In Stage 2 (>/= 10 wk), silica was localized in epithelioid macrophages, and T cell immunity had returned to normal, but the lavage fluids contained increased protein concentration and lactate dehydrogenase activity. Moreover, lungs from silica-treated animals contained neutrophils and lymphocytes, and exhibited granulomatous changes around the silica-containing epithelioid macrophages. Thus, in the early stages of silicosis, silica activates the immune system; however, the progression of lung granulomas does not depend on a continually activated adaptive immune system.
Asunto(s)
Dióxido de Silicio/inmunología , Dióxido de Silicio/metabolismo , Silicosis/inmunología , Animales , Química Encefálica , Líquido del Lavado Bronquioalveolar/química , Modelos Animales de Enfermedad , Sistema Inmunológico/fisiología , Pulmón/citología , Pulmón/metabolismo , Pulmón/patología , Masculino , Tamaño de la Partícula , Ratas , Receptores de Antígenos de Linfocitos T/inmunología , Receptores de Antígenos de Linfocitos T/metabolismo , Dióxido de Silicio/química , Silicosis/metabolismo , Silicosis/patología , Bazo/química , Bazo/citología , Bazo/metabolismoRESUMEN
The purpose of these studies was to evaluate the tissue uptake, distribution, metabolism, and excretion of methyl tertiary-butyl ether (MTBE) in rats and to determine the effects of coinhalation of the volatile fraction of unleaded gasoline on these parameters. Male F344 rats were exposed nose-only once for 4 h to 4, 40, or 400 ppm 14C-MTBE and to 20 and 200 ppm of the light fraction of unleaded gasoline (LFG) containing 4 and 40 ppm 14C-MTBE, respectively. To evaluate the effects of repeated inhalation of LFG on the fate of inhaled MTBE, rats were exposed for 7 consecutive days to 20 and 200 ppm LFG followed on d 8 by exposure to LFG containing 14C-MTBE. Three subgroups of rats were included for evaluation of respiratory parameters, rates and routes of excretion, and tissue distribution and elimination. MTBE and its chief metabolite, tertiary-butyl alcohol, were quantitated in blood and kidney (immediately after exposure), and the major urinary metabolites, 2-hydroxyisobutyric acid and 2-methyl-1,2- propanediol, were identified and quantified in urine. Inhalation of MTBE alone or as a component of LFG had no concentration-dependent effect on respiratory minute volume. The initial body burdens (IBBs) of MTBE equivalents achieved after 4 h of exposure to MTBE did not increase linearly with exposure concentration. MTBE equivalents rapidly distributed to all tissues examined, with the largest percentages distributed to liver. Between 40 and 400 ppm, there was a significant reduction in percentage of the IBB present in the major organs examined, both immediately and 72 h after exposure. At 400 ppm, the elimination rates of MTBE equivalents from tissues changed significantly. Furthermore, at 400 ppm there was a significant decrease in the elimination half-time of volatile organic compounds (VOCs) in breath and a significant increase in the percentage of the IBB of MTBE equivalents eliminated as VOCs in breath. LFG coexposure significantly decreased the percentage of the MTBE equivalent IBBs in tissues and increased rates of elimination of MTBE equivalents. The study results indicate that the uptake and fate of inhaled MTBE are altered upon increasing exposure levels from 4 to 400 ppm, suggesting that toxic effects observed previously upon repeated inhalation of concentrations of 400 ppm or greater may not necessarily be linearly extrapolated to effects that might occur at lower concentrations. Furthermore, coexposure to LFG, whether acute or repeated, decreases tissue burdens of MTBE equivalents and enhances the elimination rate of MTBE and its metabolites, thereby potentially reducing the toxic effects of the MTBE compared to when it is inhaled alone.
Asunto(s)
Contaminantes Atmosféricos/farmacocinética , Gasolina , Éteres Metílicos/farmacocinética , Contaminantes Atmosféricos/sangre , Contaminantes Atmosféricos/orina , Análisis de Varianza , Animales , Exposición por Inhalación , Riñón/metabolismo , Masculino , Éteres Metílicos/sangre , Éteres Metílicos/orina , Ratas , Ratas Endogámicas F344 , Distribución Tisular , VolatilizaciónRESUMEN
Coexposure to subclinical levels of nerve gas and to heat stress may have induced some of the clinical symptoms of the Gulf War Syndrome. We tested the hypothesis that single or repeated subclinical exposure to sarin, particularly under conditions of heat stress, would impair regulation of body temperature and locomotor activity. Male F344 rats were housed at 25 degrees C or under mild heat stress at 32 degrees C and were exposed 1 h/day for 1, 5, or 10 days to 0, 0.2, or 0.4 mg/m(3) of sarin in a nose-only exposure system. Body temperature and activity were monitored continuously by telemetry during exposure and 1 month postexposure. Exposed rats showed no clinical symptoms of toxicity such as tremors, despite evidence of reduced red blood cell cholinesterase activity. Heat stress consistently elevated body temperature in unexposed animals, particularly during the dark period when animals are most active. Inhalation of sarin gas at the two subclinical levels did not affect body temperature acutely in a biologically meaningful manner after the first exposure nor after 5 or 10 repeated exposures, either at thermoneutral ambient temperature or during chronic heat stress. There were no consistent effects of sarin or housing temperature on activity. The data suggest that subclinical levels of sarin have minimal effects on temperature regulation and locomotor activity under these observation conditions.
Asunto(s)
Temperatura Corporal/efectos de los fármacos , Sustancias para la Guerra Química/toxicidad , Inhibidores de la Colinesterasa/toxicidad , Modelos Animales de Enfermedad , Actividad Motora/efectos de los fármacos , Síndrome del Golfo Pérsico/etiología , Sarín/toxicidad , Animales , Masculino , Ratas , Ratas Endogámicas F344RESUMEN
The purpose of this study was to determine whether exposure to levels of sarin causing no overt clinical signs would cause more subtle, adverse health effects that persisted after the exposure ended. Inhalation exposures of male Fischer 344 rats to 0, 0.2, or 0.4 mg/m(3) of sarin for 1 h/day for 1, 5, or 10 days under normal (25 degrees C) and heat-stressed (32 degrees C) conditions were completed and observations were made at 1 day and 1 month after the exposures. The sarin exposures had no observed effects on body weight, respiration rate, and minute volume during exposure nor in body temperature and activity during the 30-day recovery period. There was no evidence of cellular changes in brain determined by routine histopathology nor of any increase in apoptosis. Brain mRNA for interleukin (IL)-1beta, tumor necrosis factor-alpha, and IL-6 was increased in a dose-dependent manner. Autoradiographic studies demonstrated that M1 cholinergic receptor site densities were unchanged at 1 day after repeated exposures with or without heat stress. At 30 days, there was a decrease in M1 receptors in the olfactory tubercle (with and without heat), and, with heat stress, M1 sites also decreased in a dose-dependent manner in the frontal cortex, anterior olfactory nucleus, and hippocampus. M3 receptor sites were not affected by sarin exposure alone. In the presence of heat stress, there was an upregulation in binding site densities in the frontal cortex, olfactory tubercle, anterior nucleus, and striatum immediately after exposure, and these effects persisted at 30 days. Although red blood cell acetylcholinesterase (AChE) was not greatly inhibited by the 1-day exposure, there were 30 and 60% inhibitions after repeated exposures at the low and high doses, respectively. Histochemical staining for AChE demonstrated that sarin exposure alone reduced AChE in the cerebral cortex, striatum, and olfactory bulb. Sarin exposure under heat stress reduced AChE staining in the hippocampus, an area important for memory function. Thus, repeated exposures under heat-stress conditions, to levels of sarin that would not be noticed clinically, resulted in delayed development of brain alterations in cholinergic receptor subtypes that may be associated with memory loss and cognitive dysfunction.
Asunto(s)
Sustancias para la Guerra Química/toxicidad , Inhibidores de la Colinesterasa/toxicidad , Sarín/toxicidad , Acetilcolinesterasa/metabolismo , Animales , Apoptosis/efectos de los fármacos , Temperatura Corporal/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Encéfalo/efectos de los fármacos , Encéfalo/enzimología , Encéfalo/patología , Citocinas/biosíntesis , Pulmón/efectos de los fármacos , Pulmón/fisiología , Masculino , Ratas , Ratas Endogámicas F344 , Receptores Muscarínicos/análisis , Receptores Muscarínicos/efectos de los fármacosRESUMEN
Wood smoke is a significant source of air pollution in many parts of the United States, and epidemiological data suggest a causal relationship between elevated wood smoke levels and health effects. The present study was designed to provide information on the potential respiratory health responses to subchronic wood smoke exposures in a Native American community in New Mexico. Therefore, this study used the same type of wood under similar burning conditions and wood smoke particle concentrations to mimic the conditions observed in this community. Brown Norway rats were exposed 3 h/day, 5 days/week for 4 or 12 weeks to air as control, or to 1 or 10 mg/m3 concentrations of wood smoke particles from pinus edulis. The wood smoke consisted of fine particles (< 1 microm) that formed larger chains and aggregates having a size distribution of 63-74% in the < 1-microm fraction and 26-37% in the > 1-microm fraction. The particle-bound material was primarily composed of carbon, and the majority of identified organic compounds consisted of sugar and lignin derivatives. Pulmonary function, specifically carbon monoxide-diffusing capacity and pulmonary resistance, was somewhat affected in the high-exposure group. Mild chronic inflammation and squamous metaplasia were observed in the larynx of the exposed groups. The severity of alveolar macrophage hyperplasia and pigmentation increased with smoke concentration and length of exposure, and the alveolar septae were slightly thickened. The content of mucous cells lining the airways changed from Periodic Acid Schiff- to Alcian Blue-positive material in the low-exposure group after 90 days. Together, these observations suggest that exposure to wood smoke caused minor but significant changes in Brown Norway rats. Further studies are needed to establish whether exposure to wood smoke exacerbates asthmalike symptoms that resemble those described for children living in homes using wood stoves for heating and cooking.