RESUMEN
Alveolar macrophages (AM) harvested by sequential lung lavage procedures are physically, biochemically, and functionally heterogeneous. The present studies were undertaken in order to determine if such AM heterogeneity is a function of their sequential removal from the lung during episodic bronchoalveolar lavage. Our results demonstrate that AM harvested during 'early' lung wash cycles and during 'later' sequential lung wash cycles are essentially identical in terms of their: (1) abilities to exclude a vital dye; (2) volume distributions; (3) plastic substrate adherence characteristics; and (4) Fc gamma receptor-mediated phagocytic activities.
Asunto(s)
Macrófagos/fisiología , Alveolos Pulmonares/citología , Animales , Adhesión Celular , Separación Celular , Macrófagos/citología , Masculino , Fagocitosis , Ratas , Irrigación Terapéutica , Factores de TiempoRESUMEN
Aerosols of 99mTc diethylenetriaminepentaacetic acid ([99mTc]DTPA) used for measuring lung permeability and lung ventilation require a radioaerosol delivery system to produce an aerosol with reproducible size and radiochemical purity. To test how well nebulizers meet this requirement, radiochemical purity of aerosols produced with a jet and an ultrasonic nebulizer was evaluated. The activity median aerodynamic diameter (AMAD) and geometric standard deviation (sigma g) of radioaerosols were 0.46 micron (sigma g = 1.6) for the jet nebulizer and 0.70 micron (sigma g = 1.7) for the ultrasonic nebulizer. Paper and liquid chromatographic assays were obtained on the [99mTc]DTPA aerosol solute produced with each nebulizer. The results of these tests showed major differences in radiochemical purity. Aerosols produced in the jet nebulizer consistently showed greater than 90% of the radioactivity bound to the DTPA ligand whereas aerosols produced in the ultrasonic nebulizer showed less than 10% of the radioactivity bound to DTPA. The results support the need to test radiochemical purity of aerosols before using an aerosol nebulizer for pulmonary imaging and clearance studies.
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Ácido Pentético/metabolismo , Tecnecio/metabolismo , Aerosoles , Animales , Cromatografía Liquida , Cromatografía en Papel , Perros , Estabilidad de Medicamentos , Estudios de Evaluación como Asunto , Femenino , Pulmón/diagnóstico por imagen , Nebulizadores y Vaporizadores , Ácido Pentético/análisis , Radioquímica , Cintigrafía , Tecnecio/análisis , Pentetato de Tecnecio Tc 99mRESUMEN
Designing a therapeutic aerosol on the basis of its physical properties is a very important objective, but experience has also clearly demonstrated the value of controlling the breathing and drug administration patterns. Presently, the state of aerosol technology is well advanced of its use in medicine. The employment of more sophisticated aerosolization methods can undoubtedly be advocated on both intuitive and scientific grounds, but whether the benefit will justify their cost and complexities is far less evident. This report attempts to set the issue in perspective by reviewing the important properties of commonly-prepared heterodisperse aerosols with monodisperse aerosols of the research laboratory in the context of bronchial deposition and retention.
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Aerosoles , Bronquios/metabolismo , Pruebas de Provocación Bronquial , Humanos , Tamaño de la Partícula , Fenómenos Físicos , FísicaRESUMEN
There is potential for human exposure to cyclic siloxanes by the respiratory route. To determine the pharmacokinetics of octamethylcyclotetrasiloxane (D4), a material commonly found in personal care products, the respiratory intake and uptake of D4 were measured in 12 healthy volunteers (25-49 years) on two occasions. Subjects inhaled 10 ppm D4 (122 micrograms/liter) or air (control) during a 1-h exposure via a mouthpiece in a double-blind, randomized fashion. Inspiratory and expiratory D4 concentrations were continuously measured. Exhaled air and plasma D4 levels were measured before, during, and after exposures. Individual D4 uptakes were measured under steady-state conditions during three rest periods (10, 20, and 10 min, respectively) alternating with two 10-min exercise periods. Mean D4 intake was 137 +/- 25 mg (SD) and the mean deposition efficiency was equivalent to 0.74/(1 + 0.45 VE), where VE is the minute ventilation. No changes in lung function were induced by the D4 vapor. Plasma measurements of D4 gave a mean peak value of 79 +/- 5 ng/g (SEM) and indicated a rapid nonlinear blood clearance. Using lung volume and respiratory surface area estimates based on functional residual capacity measurements, we developed a model and determined that the effective mass transfer coefficient for D4 was 5.7 x 10(-5) cm/s from lung air to blood. In an additional eight subjects, we compared D4 deposition with mouthpiece and nasal breathing at resting ventilations. For these individuals, mean deposition was similar for the two exposure protocols, averaging 12% after correction for exposure system losses. These are the first data describing the intake and absorption of D4 and they should contribute to a meaningful safety assessment of the compound.
Asunto(s)
Siloxanos/farmacocinética , Adulto , Método Doble Ciego , Femenino , Humanos , Pulmón/efectos de los fármacos , Pulmón/fisiología , Masculino , Persona de Mediana Edad , Siloxanos/administración & dosificación , Siloxanos/toxicidad , VolatilizaciónRESUMEN
Humans are exposed to silicones in a number of commercial and consumer products. Some of these silicones, including octamethylcyclotetrasiloxane (D4), are volatile. Therefore, there is a potential for respiratory exposure. A pharmacokinetic analysis of respiratory exposure to D4 is presented in the accompanying paper (M. J. Utell et al., 1998, Toxicol. Sci. 44, 206-213). Possible immune effects of respiratory exposure to D4 are investigated in this paper. Normal volunteers were exposed to 10 ppm D4 or air for 1 h via a mouthpiece using a double-blind, crossover study design. Assays were chosen to screen for immunotoxicity or a systemic inflammatory response. Assessment of immunotoxicity included enumeration of peripheral lymphocyte subsets and functional assays using peripheral blood mononuclear cells. Because in humans there is no direct test for adjuvant effect of respiratory exposure, we analyzed proinflammatory cytokines and acute-phase reactants in peripheral blood, markers for a systemic inflammatory response, as surrogate markers for adjuvancy. These tests were repeated when the volunteers were reexposed to D4 approximately 3 months after this initial exposure. Blood was obtained prior to exposure, immediately postexposure, and 6 and 24 h postexposure. In these short-term, controlled human exposures, no immunotoxic or proinflammatory effects of respiratory exposure to D4 were found.
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Inmunidad/efectos de los fármacos , Pulmón/efectos de los fármacos , Siloxanos/toxicidad , Adulto , Citocinas/biosíntesis , Citocinas/sangre , Femenino , Humanos , Pulmón/fisiología , Activación de Linfocitos/efectos de los fármacos , Masculino , Persona de Mediana Edad , Siloxanos/administración & dosificación , Siloxanos/farmacocinéticaRESUMEN
Ultrafine particles (UFP) may contribute to the morbidity and mortality associated with exposure to ambient particles, but few data are available on ultrafine particle numbers in indoor air, where susceptible subjects spend most of their time. We measured particle number, UFP size distribution, and total suspended particulate (JSP) mass in three locations: (I) a medical floor in a large tertiary care hospital, (2) outdoor air above a construction site outside the hospital, and (3) an environmental exposure chamber with purification of intake air. Mass and number concentrations were recorded continuously in each location over 70-110 h. Mean ± SD particle (p) numbers were 3.63 ± 1.l5 } 10(3) p/cm(3) in the hospital, 3.05 ± 6.65 } 10(4) p/cm(3) outside, and 5.86 ± 2.11 } 10(2) p/cm(3) in the environmental chamber. In the hospital, particle number and mass declined during the evening hours when the unit was less active, with the particle number as low as 1.15 } 10(3) p/cm(3). Particle numbers peaked (2.78 } 10(4) p/cm(3)) in the morning hours when activity on the unit was the most intense. "Spikes" in fine particle number were often not accompanied by increases in TSP mass. In the hospital, a distinct population of ultrafine particles (median diameter approximately 23 nm) was observed during the lunch hour, suggesting a change in particle source during this time. Outdoor fine particle numbers above the construction site were highly variable, reaching peaks of greater than 1.7 } 10(6) p/cm(3). These data suggest that, in the indoor environment, particle numbers and size distribution vary with intensity and type of local activity, and significant peaks in particle number are not detected with daily averages. Monitoring of particle mass may be an inaccurate measure of exposure to ultrafine particles indoors.
RESUMEN
This project was undertaken to investigate symptom responses and changes in the pulmonary function of two susceptible groups--people with asthma and people with chronic obstructive pulmonary disease (COPD)--when exposed to 0.3 parts per million (ppm) (560 micrograms/m3) nitrogen dioxide. In these controlled clinical studies, a double-blind crossover design with purified air in a 45-m3 environmental chamber was used. Groups of non-respiratory-impaired (normal) subjects of a comparable age range and of both genders constituted controls for the asthmatic and COPD groups. The exposure protocol required five days: day 1, training and base-line preexposure measurements; day 2, a first exposure to 0.3 ppm nitrogen dioxide or air in a randomized sequence; day 3, 24-hour follow-up measurements of possible delayed effects; day 4, a second exposure; and day 5, a second 24-hour postexposure follow-up. All four-hour exposures included several predetermined periods of exercise and pulmonary function measurements. To examine changes in bronchial responsiveness and to aid in subject selection, bronchial challenges with carbachol and isoproterenol aerosol were used. The project was undertaken in four phases, each lasting approximately one year. In the first year, 20 normal non-smoking volunteers (10 women and 10 men) with an average age of 31.0 years were assessed. The second year, 20 non-smoking subjects with mild to moderate asthma were evaluated. This group was comparable in gender and age to the control group of normal volunteers. The third year, 20 subjects with COPD were studied. This group had a mean age of 60.0 years and consisted of 13 men and seven women. All subjects had a history of smoking. During the fourth and final year of the study, a group of 20 elderly normal volunteers similar in age and gender to the COPD group were evaluated. The main findings of the study were as follows. No significant symptomatic or physiologic responses to nitrogen dioxide could be detected in either the young or the elderly control group. Prior studies of asthmatic subjects had led us to hypothesize that 0.3 ppm nitrogen dioxide is close to the minimum level needed to produce significant functional deficits during moderate activity in this susceptible group. However, in this study the asthmatic group as a whole did not manifest significant reductions in lung function after exposure to 0.3 ppm nitrogen dioxide compared to their preexposure base-line data or to their responses after a comparable four-hour exposure to air.(ABSTRACT TRUNCATED AT 400 WORDS)
Asunto(s)
Asma/fisiopatología , Enfermedades Pulmonares Obstructivas/fisiopatología , Pulmón/efectos de los fármacos , Dióxido de Nitrógeno/toxicidad , Adulto , Anciano , Asma/etiología , Ensayos Clínicos como Asunto , Método Doble Ciego , Prueba de Esfuerzo , Femenino , Humanos , Enfermedades Pulmonares Obstructivas/etiología , Masculino , Persona de Mediana Edad , Pruebas de Función Respiratoria , Factores de RiesgoRESUMEN
We hypothesized that exposure of healthy humans to ozone at concentrations found in ambient air causes both ozonation and peroxidation of lipids in lung epithelial lining fluid. Smokers (12) and nonsmokers (15) were exposed once to air and twice to 0.22 ppm ozone for four hours with exercise in an environmental chamber; each exposure was separated by at least three weeks. Bronchoalveolar lavage (BAL) was performed immediately after one ozone exposure and 18 hours after the other ozone exposure. Lavage fluid was analyzed for two aldehyde products of ozonation and lipid peroxidation, nonanal and hexanal, as well as for total protein, albumin, and immunoglobulin M (IgM) as markers of changes in epithelial permeability. Ozone exposure resulted in a significant early increase in nonanal (p < 0.0001), with no statistically significant relationship between increases in nonanal and lung function changes, airway inflammation, or changes in epithelial permeability. Increases in hexanal levels were not statistically significant (p = 0.16). Both nonanal and hexanal levels returned to baseline by 18 hours after exposure. These studies confirm that exposure to ozone with exercise at concentrations relevant to urban outdoor air results in ozonation of lipids in the airway epithelial lining fluid of humans.
Asunto(s)
Contaminantes Atmosféricos/efectos adversos , Aldehídos/metabolismo , Líquido del Lavado Bronquioalveolar/química , Exposición a Riesgos Ambientales/efectos adversos , Ozono/efectos adversos , Adulto , Análisis de Varianza , Animales , Biomarcadores , Líquido del Lavado Bronquioalveolar/inmunología , Relación Dosis-Respuesta a Droga , Ejercicio Físico , Femenino , Humanos , Masculino , Proyectos Piloto , Ratas , Ratas Sprague-Dawley , Mecánica Respiratoria/efectos de los fármacos , FumarRESUMEN
These studies were undertaken to evaluate pulmonary responses of humans sequentially exposed to acidic aerosols and ozone at levels that could reasonably be encountered in actual environmental exposures. Subjects first were exposed to sulfuric acid (H2SO4) aerosol to sensitize the airways to ozone. The exposure protocols were designed to provide more quantitative information about the threshold levels of ozone that produce adverse biological effects and to provide exposure-response data on ozone. Two groups of 30 nonsmoking volunteers of both sexes, between the ages of 18 and 45 years, were recruited. The healthy study population comprised 16 men and 14 women with an average age of 28 years and no airway hyperreactivity. The second group comprised 10 men and 20 women comparable in age to the control group, but with allergic asthma and positive skin tests. The study examined an exposure-response relationship using three levels of ozone ranging from below the current standard to one and one-half times the ambient air quality standard (0.08, 0.12, and 0.18 ppm* [parts per million]) with preexposure 24 hours earlier to H2SO4 (100 micrograms/m3) or sodium chloride (NaCl) (control) aerosol in a 45-m3 environmental chamber. The study used an incomplete block design in which each subject was exposed to four of the six paired experimental atmospheres. Both the selection of paired exposures and the order in which they were presented were randomized. The exposure protocol required nine days: Day 1, training and baseline preexposure measurements; Day 2, the first of the three-hour particle (H2SO4 or NaCl) exposures; Day 3 (24 hours after Day 2), ozone exposure at 0.08, 0.12, or 0.18 ppm for three hours; Day 4 (two to four weeks later), exposure to the same ozone concentration as on Day 4. After at least another two weeks, Days 6, 7, 8, and 9 repeated Days 2, 3, 4, and 5 using a second ozone concentration. All three-hour exposures included several predetermined periods of exercise and pulmonary function measurements. To examine for delayed effects, pulmonary function tests were measured two and four hours after exposure on the ozone days. Data were analyzed over the time course of exposure and by exposure level of ozone at each time point to reveal dose-response relationships more closely. The main findings of the study are as follows. No significant symptomatic or physiologic effects of exposure to either aerosol or ozone on lung function were found for the healthy group.(ABSTRACT TRUNCATED AT 400 WORDS)
Asunto(s)
Contaminantes Atmosféricos/efectos adversos , Asma/fisiopatología , Pulmón/efectos de los fármacos , Pulmón/fisiopatología , Oxidantes/efectos adversos , Ozono/efectos adversos , Ácidos Sulfúricos/efectos adversos , Adolescente , Adulto , Aerosoles , Hiperreactividad Bronquial/fisiopatología , Espasmo Bronquial/fisiopatología , Relación Dosis-Respuesta a Droga , Femenino , Volumen Espiratorio Forzado/efectos de los fármacos , Humanos , Hipersensibilidad/fisiopatología , Masculino , Persona de Mediana Edad , Oxidantes/administración & dosificación , Ozono/administración & dosificación , Esfuerzo Físico/fisiología , Ácidos Sulfúricos/administración & dosificación , Capacidad Vital/efectos de los fármacosRESUMEN
These studies were undertaken to evaluate short-term respiratory effects and identify markers of nitrogen dioxide toxicity during exposures designed to approximate realistic conditions. With the development of bronchoalveolar lavage as a clinical investigative technique, the evaluation focused on the assessment of effects induced at the alveolar level. The exposure protocols were designed to assess the duration of nitrogen dioxide-induced effects and determine exposure-response relationships. Groups of normal, nonsmoking volunteers of both sexes between the ages of 18 and 40 years, without airway hyperreactivity, constituted the study population. The exposure protocols required a total of three to five days for each subject, depending on the timing of bronchoalveolar lavage. Subjects were exposed to nitrogen dioxide or air for three hours in a double-blind, randomized fashion in a 45-m3 environmental chamber, with intermittent exercise sufficient to quadruple minute ventilation. Pulmonary function was measured during and after exposure, and airway reactivity to carbachol was assessed before and after exposure. Lavaged cells were examined for their capacity to inactivate influenza virus and secrete IL-1 in vitro. Cell-free lavage fluid was analyzed for total protein, albumin, alpha 2-macroglobulin, arylsulfatase, and alpha 1-protease inhibitor. The studies were undertaken in three phases, each of approximately one year's duration. In Phase 1, 15 subjects were exposed to a background concentration of 0.05 parts per million2 (ppm) nitrogen dioxide and to three 15-minute peaks of 2.0 ppm, and underwent bronchoalveolar lavage 3.5 hours after nitrogen dioxide exposure. During Phase 2, 8 subjects were exposed to continuous 0.60 ppm nitrogen dioxide and underwent bronchoalveolar lavage 18 hours later. Finally, in Phase 3, 15 subjects were exposed to continuous 1.5 ppm nitrogen dioxide and underwent bronchoalveolar lavage 3.5 hours after exposure. No significant symptomatic or pulmonary function changes could be detected in response to any of the nitrogen dioxide exposures. However, a small but significant increase in airway reactivity was observed in normal subjects after exposure to 1.5 ppm nitrogen dioxide. Following the highest dose of carbachol (10 mg/mL), the forced expiratory volume in one second decreased 7.5 +/- 1.1 percent after nitrogen dioxide exposure compared to 4.8 +/- 1.1 percent after exposure to air (p less than 0.05). No symptoms were induced in any of the groups by the carbachol exposures. Analyses of cells recovered by bronchoalveolar lavage during all three phases revealed no differences in total cell recovery, cell viability, or differential cell counts.(ABSTRACT TRUNCATED AT 400 WORDS)
Asunto(s)
Contaminantes Atmosféricos/toxicidad , Enfermedades Pulmonares Obstructivas/inducido químicamente , Dióxido de Nitrógeno/toxicidad , Adolescente , Adulto , Resistencia de las Vías Respiratorias , Líquido del Lavado Bronquioalveolar/citología , Método Doble Ciego , Femenino , Humanos , Enfermedades Pulmonares Obstructivas/diagnóstico , Enfermedades Pulmonares Obstructivas/patología , Mediciones del Volumen Pulmonar , Macrófagos Alveolares/fisiología , Masculino , Orthomyxoviridae/efectos de los fármacosRESUMEN
Exposure to ozone at levels near the National Ambient Air Quality Standard causes respiratory symptoms, changes in lung function, and airway inflammation. Although ozone-induced changes in lung function have been well characterized in healthy individuals, the relationship between airway inflammation and changes in pulmonary function have not been prospectively examined. The purpose of this study was to determine whether individuals who differ in, lung function responsiveness to ozone also differ in susceptibility to airway inflammation and injury. A secondary goal was to determine whether ozone exposure induces airway inflammation in smokers, a population known to have airway inflammation and an increased burden of toxic oxygen species. Healthy nonsmokers (n = 56) and smokers (n = 34) were exposed to 0.22 parts per million (ppm)* ozone for 4 hours, with intermittent exercise, for the purpose of selecting ozone "responders" (decrement in forced expiratory volume in 1 second [FEV1] > 15%) and "nonresponders" (decrement in FEV1 < 5%). Selected subjects then were exposed twice to ozone (0.22 ppm for 4 hours with exercise) and once to air (with the same exposure protocol), each pair of exposures separated by at least 3 weeks, in a randomized, double-blind fashion. Nasal lavage (NL) and bronchoalveolar lavage (BAL) were performed immediately after one ozone exposure and 18 hours after the other, and either immediately or 18 hours after the air exposure. Indicators of airway effects in lavage fluid included changes in inflammatory cells, proinflammatory cytokines, protein markers of epithelial injury and repair, and generation of toxic oxygen species. In the classification exposure, fewer smokers than nonsmokers were responsive to ozone (11.8% vs. 28.6%, respectively); an insufficient number of smoker-responders were identified to study as a separate group. In the BAL study, all groups developed a similar degree of airway inflammation, consisting of increases in interleukins 6 and 8 (maximal immediately after exposure), and increases in polymorphonuclear leukocytes (PMNs), lymphocytes, and mast cells (maximal 18 hours after exposure). The increase in PMNs was inversely correlated with age (p = 0.013), but gender, nonspecific airway responsiveness, and allergy history were not predictive of inflammation. Alveolar macrophage production of toxic oxygen species decreased after ozone exposure in nonsmokers; however, not in smokers. Findings from nasal lavage did not mirror lower airway inflammatory responses in these studies. We conclude that, in response to ozone exposure, smokers experienced smaller decrements in lung function and fewer symptoms than nonsmokers; however, the intensity of the airway inflammatory response was independent of smoking status or airway responsiveness to ozone. Furthermore, the burden of toxic oxygen species following ozone exposure was greater for smokers than for nonsmokers. Subjects were young, healthy, and able to sustain exercise; the results may not be representative of nonsmokers or smokers in general. Nevertheless, the findings indicate that measuring symptoms and spirometric changes is not sufficient to assess the potential risks associated with ozone exposure.
Asunto(s)
Hiperreactividad Bronquial/inducido químicamente , Pulmón/efectos de los fármacos , Ozono/efectos adversos , Mecánica Respiratoria/efectos de los fármacos , Fumar , Adolescente , Adulto , Líquido del Lavado Bronquioalveolar/química , Líquido del Lavado Bronquioalveolar/citología , Interpretación Estadística de Datos , Método Doble Ciego , Femenino , Citometría de Flujo , Volumen Espiratorio Forzado , Humanos , Inflamación , Interleucina-6/análisis , Interleucina-8/análisis , Pulmón/patología , Pulmón/fisiología , Macrófagos Alveolares , Masculino , Mastocitos , Cloruro de Metacolina , Esfuerzo Físico , Especies Reactivas de Oxígeno , Fumar/fisiopatología , Espirometría , Irrigación Terapéutica , Factores de Tiempo , Capacidad VitalRESUMEN
PURPOSE: The purpose of this research was to examine the effects of inhalation of toluene on respiratory function and neuropsychological performance of humans. METHODS: We exposed six healthy adults to 100 ppm toluene or air (control) for 6 h, in a double-blind, randomized fashion, with exposures separated by at least 14 d and including 30 min of exercise at a level that quadrupled minute ventilation. Blood and exhaled air toluene levels were measured before, during, immediately, and 1 and 2 h post-exposure. Lung function was measured before and immediately after exposure. Three repetitions of two computerized neuropsychological tests were performed, including a brief standard neuropsychological battery (ANAM) and a 1-h complex performance test (SYNWORK). Statistical analysis of the psychological data was conducted as a repeated measures ANOVA. FINDINGS: Following exercise, the mean blood and exhaled air toluene levels averaged 1.5 micrograms and 28 ppm, respectively. Lung function was unchanged post-exposure. On the SYNWORK test, the Composite score obtained over time during toluene exposure was lower than that during room air (F = 29.20, p = 0.005), with the score from the final hour reduced by 10%. On standard neuropsychological tests, latency but not accuracy proved the sensitive measure for five of the seven subtests presented. CONCLUSIONS: Performance of complex tests and response time to simple brief tests can be disrupted by toluene inhalation at 100 ppm. Differences in performance between air and toluene conditions were greatest after exercise, indicating that physical activity may enhance the response to volatile organic solvents.
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Contaminación del Aire Interior/efectos adversos , Procesos Mentales/efectos de los fármacos , Exposición Profesional/efectos adversos , Tolueno/efectos adversos , Adulto , Medicina Aeroespacial , Análisis de Varianza , Estudios Cruzados , Femenino , Humanos , Masculino , Memoria/efectos de los fármacos , Exposición Profesional/análisis , Tiempo de Reacción , Tolueno/metabolismoRESUMEN
Coal dust aerosols with cesium-134 and scandium-46 labels were studied in dogs and rats following brief inhalation exposures by external measurement of gamma photons in the 0.6 to 0.8 and 0.9 to 1.1 MeV regions, respectively. Ancillary in vitro studies of the leaching characteristics of the two radionuclides from coal were made and control studies utilizing the "free" radionuclides were undertaken for each of the investigations with radioactive coal dust. The biological data strongly infer that coal dust retention in canine lungs is extremely protracted with a biological half-life no shorter than approximately 4.3 yr and probably much longer. The biological model which was formulated and analyzed to obtain this finding is discussed along with its limitations.