RESUMEN
The biological effects of inhaled beta-particle-emitting radionuclides are not well known. The non-neoplastic diseases induced by an inhaled, relatively insoluble form of cerium-144 ((144)Ce) were studied in beagle dogs exposed to graded activity levels of (144)Ce in fused aluminosilicate particles by a single, brief inhalation exposure and observed for their life span. The initial lung burdens (ILBs) achieved ranged from 0.000093-7.6 MBq (144)Ce/kg body weight. The (144)Ce was retained in the lung with an effective half-life of about 190 days. Significant (144)Ce was translocated to the tracheobronchial lymph nodes, and the concentration exceeded that of the lung at about 400 days after inhalation exposure. Significant radiation doses were delivered to the lung and tracheobronchial lymph nodes and to the heart adjacent to the tracheobronchial lymph nodes. Radiation pneumonitis was the predominant non-neoplastic disease. The dose response for radiation pneumonitis indicated that an ILB of 1.4 MBq/kg would cause death from radiation pneumonitis in 50% of the exposed dogs. This ILB resulted in a pulmonary dose to death of about 350 Gy. The tracheobronchial lymph nodes developed lesions in dogs with ILBs lower than those causing radiation pneumonitis. The overall results of this study, however, showed that (144)Ce, inhaled in an insoluble form, did not cause any unique or inexplicable biological effects in dogs or cause effects at unusually low doses that might call current radiation protection guidelines into question.
Asunto(s)
Radioisótopos de Cerio/toxicidad , Traumatismos Experimentales por Radiación/etiología , Neumonitis por Radiación/etiología , Administración por Inhalación , Animales , Bentonita/farmacocinética , Bentonita/toxicidad , Partículas beta/efectos adversos , Carga Corporal (Radioterapia) , Radioisótopos de Cerio/farmacocinética , Perros , Femenino , Semivida , Pulmón/metabolismo , Pulmón/patología , Pulmón/efectos de la radiación , Ganglios Linfáticos/metabolismo , Ganglios Linfáticos/efectos de la radiación , Recuento de Linfocitos , Linfocitos/efectos de la radiación , Masculino , Traumatismos Experimentales por Radiación/patología , Neumonitis por Radiación/patología , Solubilidad , Distribución TisularRESUMEN
Doses of internal radiation from inhalation of metal tritide aerosols are potentially a major radiation protection problem encountered by nuclear industry workers. Based on results of experiments with rats intratracheally instilled with titanium tritide particles and on a self-absorption factor of beta particles determined by a numerical method, a biokinetic model was developed for inhaled particles of titanium tritide. Results showed that lung burdens of the tritide are well represented by a two-component exponential equation; biological half-lives derived for the retention of 3H in lung were 0.81 d and 66 d. The tritium clearance rate via urine or feces was described by bi-phase exponential components. At 121 d after instillation, 82% of the initial lung burden of 3H had been eliminated, of which 37% was excreted in urine, 29% via feces, and 16% through exhaled air. Based on simulation results of the biokinetic model, the cumulative absorbed dose and committed effective dose were calculated as well as the annual limit of intake (ALI) and derived air concentration (DAC). The ALI and DAC values for titanium tritide were a factor of 5 lower than values for tritiated water. This information will be useful in developing new guidelines for radiation protection purposes.
Asunto(s)
Pulmón/metabolismo , Titanio/farmacocinética , Tritio/farmacocinética , Administración por Inhalación , Animales , Transporte Biológico , Instilación de Medicamentos , Masculino , Modelos Biológicos , Ratas , Ratas Endogámicas F344 , Titanio/administración & dosificación , Tráquea , Tritio/administración & dosificaciónRESUMEN
This study was conducted in dogs to determine the toxicity of inhaled 91YCl3, which is of interest because 91Y is a fission-product radionuclide that is abundant in a reactor inventory after sustained operation. Yttrium-91 has a short half-life, 59 days, and decays with the emission of beta particles and low-yield gamma rays. The study was conducted in 58 beagle dogs with equal numbers of males and females. Forty-six dogs inhaled the 91YCl3 aerosol, while 12 served as controls. Four exposure levels were used. To determine the long-term retained burden (LTRB) of 91Y, each dog was periodically whole-body counted and its excreta were analyzed radiochemically. Over time, the 91Y transferred from the lung primarily to the skeleton and liver. The dogs were observed over their life spans for biological effects. Fatal hematological dyscrasia occurred from 12 to 33 days after exposure in the dogs with the highest LTRBs. Bone-associated tumors of the nasal and oral mucosae occurred in 5 dogs from 2000 to 5800 days after they inhaled the 91YCl3 aerosols. Five dogs died with malignant lung tumors and 2 dogs with malignant liver tumors. The results of this study were compared to those from similar studies in beagles that inhaled 90SrCl2 or 144CeCl3 or were injected with 137CsCl. The comparison showed that the biological effects in each study were clearly dependent on the cumulative doses to critical organs.
Asunto(s)
Radioisótopos de Itrio/toxicidad , Administración por Inhalación , Animales , Células Sanguíneas/efectos de la radiación , Causas de Muerte , Perros , Femenino , Neoplasias Hepáticas Experimentales/etiología , Neoplasias Pulmonares/etiología , Masculino , Neoplasias Inducidas por Radiación , Dosis de Radiación , Distribución Tisular , Radioisótopos de Itrio/administración & dosificación , Radioisótopos de Itrio/farmacocinéticaRESUMEN
This study evaluated polymorphonuclear leukocyte (PMN) involvement in translocation of dust to bronchial lymph nodes after deposition of dust in the lungs of control and neutropenic F344/N rats. Rats were rendered neutropenic with an intraperitoneal (IP) injection of anti-rat PMN antiserum (APA); control rats were injected IP with 0.9% saline solution. Eighteen hours after IP injections, control and APA-treated rats were instilled intratracheally with 5 x 10(8) microspheres suspended in 0.9% saline solution, which caused an influx of PMNs into the pulmonary airspaces of control rats, but not of APA-treated rats. One day postinstillation (PI), 77.2% of the microspheres recovered in bronchoalveolar lavage fluid (BALF) from control rats were associated with pulmonary alveolar macrophages (PAMs) and 18.8% with PMNs; 4.0% were free. In BALF from the APA-treated rats, 66.3% of the microspheres were associated with PAMs and 0.3% with PMNs; 36.3% were free. Two days PI, about 95% of the microspheres in BALF from control and APA-treated rats were associated with PAMs; by 4 and 7 days PI, essentially 100% were with PAMs. Amounts of microspheres translocated to bronchial lymph nodes of control rats were four fold less than in the APA-treated rats on days 2, 4, and 7 PI (p < .05). The results suggest that PMNs in pulmonary airspaces of F344/N rats phagocytize dust and thereby interfere with the mechanism(s) involved in dust penetration into the pulmonary interstitium.
Asunto(s)
Polvo , Pulmón/metabolismo , Neutropenia/metabolismo , Neutrófilos/metabolismo , Animales , Líquido del Lavado Bronquioalveolar/citología , Recuento de Eritrocitos/efectos de los fármacos , Sueros Inmunes/sangre , Sueros Inmunes/farmacología , Recuento de Leucocitos/efectos de los fármacos , Pulmón/patología , Ganglios Linfáticos/metabolismo , Masculino , Microesferas , Neutropenia/inducido químicamente , Poliestirenos/farmacocinética , Ratas , Ratas Endogámicas F344RESUMEN
The goals of this study were to (1) determine the effects of repeated inhalation of relatively insoluble nickel oxide (NiO) and highly soluble nickel sulfate hexahydrate (NiSO4.6H2O) on lung particle clearance, (2) investigate the effects of repeated inhalation of NiO or NiSO4 on the pulmonary clearance of subsequently inhaled 85Sr-labeled microspheres, (3) correlate the observed effects on clearance with accumulated Ni lung burden and associated pathological changes in the lung, and (4) compare responses in F344 rats and B6C3F1 mice. Male F344/N rats and B6C3F1 mice were exposed whole-body to either NiO or NiSO4.6H2O 6 hr/day, 5 days/week for up to 6 months. NiO exposure concentrations were 0, 0.62, and 2.5 mg NiO/m3 for rats and 0, 1.25, and 5.0 mg NiO/m3 for mice. NiSO4.6H2O exposure concentrations were 0, 0.12, and 0.5 mg NiSO4.6H2O/m3 for rats and 0, 0.25, and 1.0 mg NiSO4.6H2O/m3 for mice. After 2 and 6 months of whole-body exposure, groups of rats and mice were acutely exposed nose-only to 63NiO (NiO-exposed animals only), 63NiSO4.6H2O (NiSO4.6H2O-exposed animals only), or to 85Sr-labeled polystyrene latex (PSL) microspheres (both NiO- and NiSO4.6H2O-exposed animals) to evaluate lung clearance. In addition, groups of rats and mice were euthanized after 2 and 6 months of exposure and at 2 and 4 months after the whole-body exposures were completed to evaluate histopathological changes in the left lung and to quantitate Ni in the right lung. Repeated inhalation of NiO results in accumulation of Ni in lungs of both rats and mice, but to a greater extent in lungs of rats. During the 4 months after the end of the whole-body exposures, some clearance of the accumulated Ni burden occurred from the lungs of rats and mice exposed to the lower, but not the higher NiO exposure concentrations. Clearance of acutely inhaled 63NiO was also impaired in both rats and mice, with the extent of impairment related to both exposure concentration and duration. However, the clearance of acutely inhaled 85Sr PSL microspheres was not impaired. The repeated inhalation of NiO resulted in alveolar macrophage (AM) hyperplasia with accumulation of NiO particles in both rats and mice, chronic alveolitis in rats, and interstitial pneumonia in mice. These lesions persisted throughout the 4-month recovery period after the NiO whole-body exposures were terminated. In contrast, repeated inhalation of NiSO4.6H2O did not result in accumulation of Ni in lungs of either rats or mice and did not affect the clearance of 63NiSO4.6H2O inhaled after either 2 or 6 months of NiSO4.6H2O exposure. Clearance of the 85Sr-labeled microspheres was significantly impaired only in rats exposed to the microspheres after 2 months of exposure to NiSO4.6H2O. Histopathological changes in rats were qualitatively similar to those seen in NiO-exposed rats. Only minimal histopathological changes were observed in NiSO4.6H2O-exposed mice. These results suggest that repeated inhalation of NiO at levels resulting in AM hyperplasia and alveolitis may impair clearance of subsequently inhaled NiO. The potential effects of repeated inhalation of soluble NiSO4.6H2O on the clearance of subsequently inhaled poorly soluble particles are less clear.
Asunto(s)
Pulmón/patología , Níquel/toxicidad , Administración por Inhalación , Animales , Hiperplasia/inducido químicamente , Pulmón/química , Pulmón/fisiopatología , Enfermedades Pulmonares Intersticiales/inducido químicamente , Enfermedades Pulmonares Intersticiales/patología , Macrófagos Alveolares/patología , Masculino , Ratones , Microesferas , Depuración Mucociliar/efectos de los fármacos , Níquel/administración & dosificación , Níquel/análisis , Fibrosis Pulmonar/inducido químicamente , Ratas , Ratas Endogámicas F344 , Proyectos de Investigación , Factores de TiempoRESUMEN
Diesel exhaust (DE) is a known pulmonary carcinogen in rats, and the carcinogenic response is known to require the presence of soot. Many estimates of human lung cancer risk from inhaled DE have been developed from rat bioassay data or from the comparative mutagenic potencies of DE soot extract and known human chemical carcinogens. To explore the importance of the DE soot-associated organic compounds in the lung tumor response of rats, male and female F344 rats were exposed chronically to diluted whole DE or aerosolized carbon black (CB) 16 hr/day, 5 days/week at target particle concentrations of 2.5 mg/m3 (LDE, LCB) or 6.5 mg/m3 (HDE, HCB) or to filtered air. The CB served as a surrogate for the elemental carbon matrix of DE soot. Considering both the mass fraction of solvent-extractable matter and its mutagenicity in the Ames Salmonella assay, the mutagenicity in revertants per unit particle mass of the CB was three orders of magnitude less than that of the DE soot. Both DE soot and CB particles accumulated progressively in the lungs of exposed rats, but the rate of accumulation was higher for DE soot. In general, DE and CB caused similar, dose-related, nonneoplastic lesions. CB and DE caused significant, exposure concentration-related increases, of similar magnitudes, in the incidences and prevalences of the same types of malignant and benign lung neoplasms in female rats. The incidences of neoplasms were much lower in males than females, and the incidences were slightly higher among DE- than CB-exposed males. Survival was shortened in the CB-exposed males, and the shortened survival may have suppressed the expression of carcinogenicity as measured by crude incidence. Logistic regression modeling did not demonstrate significant differences between the carcinogenic potencies of CB and DE in either gender. The results suggest that the organic fraction of DE may not play an important role in the carcinogenicity of DE in rats.
Asunto(s)
Carbono/toxicidad , Enfermedades Pulmonares/inducido químicamente , Neoplasias Pulmonares/inducido químicamente , Pulmón/efectos de los fármacos , Emisiones de Vehículos/toxicidad , Administración por Inhalación , Animales , Cámaras de Exposición Atmosférica , Carga Corporal (Radioterapia) , Peso Corporal/efectos de los fármacos , Carbono/administración & dosificación , Femenino , Pulmón/patología , Masculino , Oportunidad Relativa , Tamaño de los Órganos , Alveolos Pulmonares/efectos de los fármacos , Alveolos Pulmonares/patología , Ratas , Ratas Endogámicas F344 , Organismos Libres de Patógenos Específicos , Pruebas de ToxicidadRESUMEN
Neutropenia can be produced with antimitotic chemicals, but this method lacks specificity. An alternative is to use antibody-dependent cytotoxicity to produce neutropenia; however, this method has not been completely evaluated with respect to efficacy, specificity, and potential collateral damage, especially to constituents of bone marrow. This study used in vitro and in vivo methods to evaluate specific biological effects of a commercially available rabbit anti-rat neutrophil (PMN) antiserum in F344/N rats. The viability of rat pulmonary alveolar macrophages (PAMs), PMNs, and lymphocytes in vitro was quantified using a trypan blue dye exclusion test. Amounts of antiserum in vitro that rendered PMNs 100% nonviable did not decrease the viability or phagocytic ability of the PAMs and did not decrease the viability of the lymphocytes. Intraperitoneal (IP) injection of the antiserum into rats resulted in complete depletion of the PMNs and about a 50% depletion of the lymphocytes in circulating blood within 24 hours. The numbers of both cell types remained lowered for 5 days, but returned to control values by Day 6 after the IP injection. The antiserum had no effect on the numbers of PAMs or lymphocytes in the pulmonary alveolar airspaces, as determined by quantifying the numbers of these cell types in bronchoalveolar lavage fluid (BALF). The numbers of PMNs in BALF, however, decreased on Days 3 and 4 after IP injection of antiserum, but were not different from control values by Day 5. The viability of the PAMs in BALF of treated rats was not different from control values at any time point. There were no morphological indications that the injected antiserum damaged lung tissue or stem cells in bone marrow. Results demonstrate that the anti-rat PMN antiserum administered IP to F344/N rats depletes circulating PMNs and partially depletes lymphocytes for a period of about 6 days without adversely affecting the precursors of red or white blood cells in bone marrow. We concluded that the antiserum is a relatively specific way to temporarily render rats neutropenic without damaging precursor cells in bone marrow.
RESUMEN
This study compared the pulmonary carcinogenicities and selected noncancer effects produced by chronic exposure of rats at high rates to diesel exhaust and carbon black. The comparison was intended to provide insight into the likely importance of the mutagenic organic compounds associated with the soot portion of diesel exhaust in inducing pulmonary carcinogenicity in diesel exhaust-exposed rats. The role of the organic fraction has become important in judging the usefulness of the substantial data base on carcinogenicity in rats for predicting lung cancer risk for humans, and for determining the most appropriate method of extrapolating results across species and exposure concentrations. Rats were exposed chronically to either diesel exhaust or carbon black, which served as a surrogate for diesel exhaust soot with much reduced mutagenic activity associated with its organic fraction. The sequestration of particles in the lung and the induction of pulmonary neoplasia and non-neoplastic changes in the lung were compared in detail. Samples also were provided to collaborators to examine adduct formation in lung DNA and hemoglobin. Approximately 140 female and 140 male F344/N rats were exposed for 16 hours per day, 5 days per week for up to 24 months, beginning at eight weeks of age, to diesel exhaust or carbon black at 2.5 mg or at 6.5 mg particles/m3 of air, or to clean air as controls. The diesel exhaust was generated by light-duty engines burning certification fuel and operating on an urban-duty cycle. The carbon black was selected because it had particle size and surface area characteristics similar to those of diesel exhaust soot, but markedly less mutagenic activity associated with its organic fraction when analyzed using procedures typically used in studies of diesel soot. Rats were killed after 3, 6, 12, 18, or 23 months of exposure to measure lung and lung-associated lymph node burdens of particles, lung weight, bronchoalveolar lavage indicators of inflammation, DNA adducts in whole lung and alveolar type II cells, and chromosome injury in circulating lymphocytes, and to perform histopathologic assessment. In addition, after 3 and 18 months of chronic exposure, one group of rats was acutely exposed to radiolabeled carbon black particles or to fluorescent microspheres. These exposures were conducted to examine the clearance of radiolabeled particles and the sequestration of the fluorescent microspheres in the lungs. These experiments provided information on clearance overload and particle dosimetry. The growth characteristics of lung neoplasms also were examined by transplanting neoplastic cells into athymic mice.(ABSTRACT TRUNCATED AT 400 WORDS)
Asunto(s)
Contaminantes Ocupacionales del Aire/toxicidad , Carbono/toxicidad , Gasolina/toxicidad , Neoplasias Pulmonares/etiología , Emisiones de Vehículos/toxicidad , Animales , Pruebas de Carcinogenicidad , Daño del ADN , Relación Dosis-Respuesta a Droga , Femenino , Pulmón/efectos de los fármacos , Pulmón/patología , Neoplasias Pulmonares/patología , Masculino , Ratas , Ratas Endogámicas F344 , Factores de RiesgoRESUMEN
To develop a better understanding of the influence of cumulative radiation dose and dose rate to the lungs on the biological responses to inhaled radionuclides, several studies are in progress at this institute in which laboratory animals have been exposed once or repeatedly to aerosols of insoluble particles containing 144Ce or 239Pu. In the study reported here, F344 rats were exposed repeatedly to aerosols of 144CeO2 beginning at 94 days of age to reestablish desired lung burdens of 1.9, 9.2, 46, or 230 kBq of 144Ce every 60 days for 1 year (seven exposures). Other 94-day-old rats were exposed once to achieve similar desired initial lung burdens of 144Ce. Older rats were exposed once to achieve desired initial lung burdens of 46 or 230 kBq when 500 days of age, the age of the repeatedly exposed rats when exposed for the last time. Control rats were either unexposed, sham-exposed once or repeatedly, or exposed once or repeatedly to stable CeO2. Approximately equal numbers of male and female rats were used. The cumulative beta-radiation doses to the lungs, liver, and skeleton of rats exposed repeatedly were similar to those of rats with similar total lung burdens of 144Ce from a single inhalation exposure. The average beta-radiation dose rate to the lungs of the rats exposed repeatedly was about one-fifth of that in rats with similar total lung burdens after a single exposure.
Asunto(s)
Huesos/metabolismo , Radioisótopos de Cerio/farmacocinética , Hígado/metabolismo , Pulmón/metabolismo , Aerosoles , Animales , Partículas beta , Cerio/administración & dosificación , Radioisótopos de Cerio/administración & dosificación , Femenino , Masculino , Dosis de Radiación , Ratas , Ratas Endogámicas F344 , Factores de TiempoRESUMEN
The site of uptake of inhaled vapors profoundly influences which respiratory tract tissues receive the highest doses. How the site of uptake depends on the physicochemical properties of inhaled vapors has been the subject of experiment and speculation for decades, but remains undefined. Using techniques that distinguish between vapor uptake in the nose and lung during cyclic breathing by Beagle dogs, we examined uptake of the vapors of 2,4-dimethypentane (DMP), propyl ether, butanone, dioxolane, and ethanol. These compounds have blood/air partition coefficients ranging from 1 to 2000. The effect of altering respiratory rates on vapor uptake was examined for DMP and dioxolane vapors. Deposition of vapors in the nasal cavity during inhalation was highly dependent on the partition coefficient. Vapor deposited in the nasal mucosa during inhalation was desorbed to a substantial extent during exhalation. Lung uptake of total inhaled vapor was limited by the amount available after passage through the nose, but in no case did it exceed 50% of the available amount. The data suggest that the diffusion of vapor molecules through the tissue barrier separating the air/tissue interface from the tissue/blood interface constitutes a significant resistance for both nasal uptake and lung uptake of many inhaled vapors. The data were used to validate a mathematical model describing nasal uptake of vapors. The model is described in the companion paper.
Asunto(s)
Gases/farmacocinética , Pulmón/metabolismo , Cavidad Nasal/metabolismo , Administración por Inhalación , Animales , Perros , Éteres/farmacocinética , Femenino , Masculino , Pentanos/farmacocinética , Sistema Respiratorio/metabolismo , VolatilizaciónRESUMEN
This paper describes apparatus and methods for measuring uptake of inhaled vapors in the nose and lungs of dogs. The system allows sampling of air from the trachea at specific times during inspiration and expiration without surgical manipulation of the animal, thus allowing repeated studies in the same animal. During exposure, the dogs are anesthetized and cyclic respiratory patterns are maintained by means of an external respirator. A pneumotachograph installed in the exposure line is connected to a respiratory monitoring system that both monitors the dog's respiratory pattern and triggers sampling at specific times in the respiratory cycle. Air sampling, both at the nose and within the trachea, can be done during the entire breathing cycle or during specific portions of it. Vapors are sampled at a point just external to the dog's nose and from within the trachea through a modified endotracheal tube. To develop and demonstrate the system, three beagle dogs were exposed to 2,4-dimethylpentane and 1.3-dioxolane at nominal vapor concentrations of 500 ppm; vapor sampling was triggered for the entire inspiratory and expiratory portions of the breathing cycle during 10-min exposures. After correcting data to account for vapor that desorbed from the nasal passages during exhalation (after initially being absorbed in the nose during inhalation), net nasal uptake of 2,4-dimethylpentane was 28.3%; net nasal uptake of 1,3-dioxolane was 66.6%. Lung uptake was 14.0% for 2,4-dimethylpentane and 2.1% for 1,3-dioxolane. The system was developed for use with dogs, but it can be adapted for use with any animal species that can be intubated with endotracheal vapor sampling tubes.
Asunto(s)
Administración por Inhalación , Gases/metabolismo , Pulmón/metabolismo , Mucosa Nasal/metabolismo , Absorción , Animales , Cromatografía de Gases , Dioxolanos/farmacocinética , Dioxolanos/toxicidad , Perros , Femenino , Intubación Intratraqueal , Masculino , Mutágenos/farmacocinética , Pentanos/farmacocinética , Pentanos/toxicidadRESUMEN
The nonstochastic radiobiological effects of combined alpha and beta irradiation of the lungs of rats from inhaled radionuclides were studied. Both respiratory functional morbidity at 18 mo and mortality from radiation pneumonitis within 18 mo after exposure were examined for rats exposed to the beta-emitter 147Pm, the alpha-emitter 238Pu, or both combined. The results were used to validate hazard-function models that were developed (1) for respiratory functional morbidity at 18 mo and (2) for lethality from radiation pneumonitis within 18 mo. Both models were found to adequately predict the experimental observations for chronic alpha plus beta irradiation of the lung. Based on this 18-mo study, a relative biological effectiveness of approximately seven was obtained for 238Pu alpha radiation compared to 147Pm beta radiation for both respiratory functional morbidity and lethality from radiation pneumonitis. However, the relative biological effectiveness for the alpha radiation is likely to increase with longer follow-up.
Asunto(s)
Partículas alfa , Partículas beta , Pulmón/efectos de la radiación , Administración por Inhalación , Aerosoles , Animales , Femenino , Masculino , Morbilidad , Plutonio/administración & dosificación , Neumonía/etiología , Neumonía/mortalidad , Pronóstico , Prometio/administración & dosificación , Ratas , Ratas Endogámicas F344 , Trastornos Respiratorios/etiología , Trastornos Respiratorios/mortalidad , Factores de TiempoRESUMEN
Diesel exhaust (DE) is a pulmonary carcinogen in rats. One potential mechanism for DE-induced carcinogenicity involves the interaction of the organic chemicals associated with DE soot with DNA in target cells. The purpose of this study was to determine whether peripheral lung cells, specifically alveolar type II cells, are at risk from inhaled DE. Rats were exposed 16 hr/day, 5 days/week to filtered air (controls), carbon black (CB) (6.2 mg/m3), or to diluted DE (6.2 mg/m3) for 12 weeks. CB particles were used for comparison with DE soot, because the CB particles are morphologically similar to soot particles, but are virtually devoid of adsorbed organic compounds. Type II alveolar cells were isolated by flow cytometry and DNA in the cells was analyzed for DNA adducts using the 32P-postlabeling assay. There was a significant increase (approximately 4-fold) in the level of total adducts in type II cells of rats exposed to DE and CB, compared with sham-exposed rats. While exposure to CB and DE induced the formation of adducts that were not consistently seen in sham-exposed rats, exposure to these materials also appeared to increase the intensity of adducts present in type II cells from sham-exposed rats. These data underscore the importance of investigating molecular dosimetry at the biological level of the cell. We conclude that the type II alveolar cell may be a risk for damage from inhaled DE.
Asunto(s)
Carbono/farmacología , Carcinógenos , ADN/metabolismo , Gases/toxicidad , Inhalación , Petróleo/toxicidad , Alveolos Pulmonares/metabolismo , Adenosina Trifosfato/metabolismo , Animales , Cámaras de Exposición Atmosférica , ADN/efectos de los fármacos , Femenino , Técnicas In Vitro , Masculino , Alveolos Pulmonares/efectos de los fármacos , Ratas , Ratas Endogámicas F344 , Factores de RiesgoRESUMEN
The fractional deposition of cigarette smoke particles in the respiratory tracts of rats was studied. Male and female rats were conditioned in nose-only exposure tubes 25 min/day for 2 days, exposed to cigarette smoke at mass concentrations of 95 or 341 mg/m3, 25 min/day for 3 days, and then exposed to smoke at mass concentrations of 212 and 657 mg/m3, 25 min/day for 5 days. Mainstream cigarette smoke was generated by a modified Walton smoking machine from two 1R3 research cigarettes burned sequentially for each exposure. Deposition studies were conducted by placing the rats in plethysmograph tubes to allow respiratory minute volume measurements during exposure, then exposing them to [14C]dotriacontane-labeled cigarette smoke at mass concentrations of 202 or 624 mg/m3 for 25 min, using the same smoking machine. Size distribution, real-time concentration, and 14C activity of the smoke particles were determined using a multijet Mercer impactor, a real-time aerosol monitor, and filter samples, respectively. Immediately after the exposure, the rats were terminated to determine the distribution of the 14C. Individual lung lobes, trachea and lobar bronchi, head, larynx, kidneys, liver, gastrointestinal (GI) tract, blood, and depleted carcass of each rat were analyzed for 14C content. Results showed that the GI tract contained 16-31% of the total activity, indicating significant clearance from the large airways and nose to the GI tract during the exposure and during the 10-15 min between the cessation of the exposure and the removal of the organs. Total deposition of the inhaled 14C activity was 20.1 +/- 1.6% for both exposure concentrations. The intrapulmonary deposition fractions (lung lobes plus airways below the lobar bronchi) were 12.4 +/- 0.9 and 15.9 +/- 1.4% for concentrations of 202 and 624 mg/m3, respectively, suggesting a slight enhancement in upper airway deposition for animals exposed to the higher smoke concentration.
Asunto(s)
Sistema Respiratorio/metabolismo , Fumar/metabolismo , Alcanos , Animales , Cámaras de Exposición Atmosférica , Diacetil , Femenino , Pulmón/metabolismo , Masculino , Tamaño de la Partícula , Pletismografía , Ratas , Ratas Endogámicas F344RESUMEN
The relationship between the inhalation exposure concentration of talc and the resulting lung burdens and histologic lesions was studied using groups of 20 F344/Crl rats and 20 B6C3F mice (10 male and 10 female) exposed to one of three concentrations of asbestos-free talc for 6 hr/day, 5 days/week for 4 weeks. Controls were exposed to filtered air using the same schedule. The pulmonary retention of talc and the development of pulmonary pathology were evaluated. The mass median aerodynamic diameter (MMAD) of the talc aerosol was 3.0 microns with a geometric standard deviation (sigma g) of 1.9. The mean exposure concentrations for rats were 0, 2.3, 4.3, and 17 mg talc/m3. Lung burdens in rats averaged 0, 0.07, 0.17, and 0.72 mg talc/g lung after the 20-day inhalation exposure; thus, the amount retained in the lung per unit of exposure concentration increased with increasing concentration. Mean exposure concentrations for the mice were 0, 2.2, 5.7, and 20.4 mg of talc/m3, which resulted in lung burdens of 0, 0.10, 0.29, and 1.0 mg talc/g lung; thus, the relationship between exposure concentration and the amount retained in the lung was approximately constant. Lung burdens from this study were used to project lung burdens that would result from longer exposures of rodents and man. No clinical signs were observed in the rats or mice prior to sacrifice 24 hr after the last exposure day. Histologic alterations in lung tissue consisted of only a modest, diffuse increase of talc-containing, free macrophages within alveolar spaces in both rat and mouse groups exposed to the highest level of talc for 20 days. A model simulating chronic talc inhalation exposure of rats and mice predicted lung burdens of 2-3 mg talc/g lung (wet wt) if animals were exposed to 17 mg talc/m3 for 2 years, and deposition and clearance of talc were unchanged by continued exposure. A potential limitation in this modeling is that if clearance of talc is delayed by continued exposure, the accumulated talc lung burdens would be higher than those projected by the simulation model. Humans exposed to aerosols of respirable talc are projected to accumulate much higher lung burdens than would occur in rodents exposed to the same aerosol, because humans have a higher estimated deposition fraction and slower estimated clearance of the deposited talc dust. Equilibrium lung burdens of greater than or equal to 2 mg talc/g lung were predicted for human exposures at or near the TLV for talc.
Asunto(s)
Pulmón/patología , Talco/farmacocinética , Aerosoles , Animales , Pulmón/efectos de los fármacos , Pulmón/metabolismo , Ratones , Ratones Endogámicos , Ratas , Ratas Endogámicas F344 , Talco/administración & dosificación , Talco/toxicidadRESUMEN
In the absence of adequate data exclusively from studies of inhaled particles in people, the results of inhalation studies using laboratory animals are necessary to estimate particle retention in exposed people. To make accurate projections from animal studies and the limited human data, it is necessary to consider species similarities and differences in lung retention and accumulation patterns for inhaled materials. This paper reviews species similarities and differences in pulmonary retention and clearance for inhaled particles, with emphasis on animal species most commonly used in inhalation toxicology research (rats, guinea pigs, dogs, and nonhuman primates). Simulation models for these four species and for humans were used to compare projected lung burdens which would be accumulated during chronic inhalation exposures. These simulation models project an eightfold difference among these species in the lung concentration of particles per gram of lung after a 2-y chronic inhalation exposure to the same aerosol for 8 h d-1, 5 d wk-1. The largest lung accumulation would occur in guinea pigs, the smallest in rats. To reach the same target lung concentration of particles in the lungs of both animals would therefore require about an eightfold difference in air concentration of the exposure material. These comparisons are useful for selecting appropriate laboratory animal species to study as surrogates for humans, for setting aerosol concentrations to use in inhalation studies, and for making approximations of lung burdens that would result from defined exposure scenarios.
Asunto(s)
Aerosoles , Pulmón/metabolismo , Animales , Simulación por Computador , Perros , Cobayas , Haplorrinos , Humanos , Modelos Biológicos , Ratas , Especificidad de la Especie , Factores de TiempoRESUMEN
Chronic inhalation of insoluble particles of low toxicity that produce substantial lung burdens of particles, or inhalation of particles that are highly toxic to the lung, can impair clearance. This report describes model calculations of accumulations in lung of inhaled low-toxicity diesel exhaust soot and high-toxicity Ga2O3 particles. Lung burdens of diesel soot were measured periodically during a 24-mo exposure to inhaled diesel exhaust at soot concentrations of 0, 0.35, 3.5, and 7 mg m-3, 7 h d-1, 5 d wk-1. Lung burdens of Ga2O3 were measured for 1 y after a 4-wk exposure to 23 mg Ga2O3 m-3, 2 h d-1, 5 d wk-1. Lung burdens of Ga2O3 were measured for 1 y both studies using inhaled radiolabeled tracer particles. Simulation models fit the observed lung burdens of diesel soot in rats exposed to the 3.5- and 7-mg m-3 concentrations of soot only if it was assumed that clearance remained normal for several months, then virtually stopped. Impaired clearance from high-toxicity particles occurred early after accumulations of a low burden, but that from low-toxicity particles was evident only after months of exposure, when high burdens had accumulated in lung. The impairment in clearances of Ga2O3 particles and radiolabeled tracers was similar, but the impairment in clearance of diesel soot and radiolabeled tracers differed in magnitude. This might have been related to differences in particle size and composition between the tracers and diesel soot. Particle clearance impairment should be considered both in the design of chronic exposures of laboratory animals to inhaled particles and in extrapolating the results to people.
Asunto(s)
Aerosoles , Pulmón/metabolismo , Modelos Biológicos , Administración por Inhalación , Animales , Carbono/metabolismo , Femenino , Galio/administración & dosificación , Galio/metabolismo , Masculino , Ratas , Factores de Tiempo , Emisiones de VehículosAsunto(s)
Polvo , Modelos Biológicos , Sistema Respiratorio/metabolismo , Administración por Inhalación , Animales , Humanos , Sistema Linfático/anatomía & histología , Sistema Respiratorio/anatomía & histología , Transporte Respiratorio , Solubilidad , Especificidad de la Especie , Factores de TiempoRESUMEN
This study was designed to determine the deposition patterns and fate of large particles inhaled by two species of small laboratory animals during nose breathing. Rats and guinea pigs inhaled 3-, 9-, or 15 micron polystyrene latex microspheres labeled with 46Sc. Approximately 1.4% and 0.55% of the initial internally deposited body burden of 3-micron microspheres was in the alveolar region of the respiratory tract of rats and guinea pigs, respectively. None of the 9- or 15-micron microspheres were detected in the alveolar regions of the rats or guinea pigs. Ninety-five to 99% of the deposited microspheres cleared from these animals with biological half-times of 0.5-1.0 day. Most of the cleared radioactivity was in the feces. Approximations for long-term biological half-times for alveolar retention of the 3-micron microspheres were 63 days for rats and 83 days for guinea pigs. About 1% of the initial lung burden of 3-micron microspheres was translocated from lung to lung-associated lymph nodes in both species; none of the 9- or 15-micron microspheres were detected in those lymph nodes. Small fractions of the microspheres initially deposited in the airways of the head were retained with biological clearance half-times ranging from 9 to 350 days. Results from this study do not allow projections for deposition and retention patterns for similar particles inhaled by humans. Such projections must come from studies with humans, or from studies with animal species having deposition patterns for inhaled materials more comparable to those of humans.
Asunto(s)
Contaminantes Radiactivos del Aire/análisis , Contaminantes Atmosféricos/análisis , Animales , Pruebas de Provocación Bronquial , Modelos Animales de Enfermedad , Cobayas , Pulmón/diagnóstico por imagen , Microesferas , Tamaño de la Partícula , Radioisótopos , Cintigrafía , Ratas , EscandioRESUMEN
F344 rats were chronically exposed to diesel exhaust at target soot concentrations of 0 (control, C), 0.35 (low, L), 3.5 (medium, M), and 7.0 (high, H) mg/m3. Accumulated lung burdens of diesel soot were measured after 6, 12, 18, and 24 months of exposure. Parallel measurements of particle deposition and clearance were made to provide insight into the mechanisms of particle accumulation in lungs. The fractional deposition of inhaled 67Ga2O3 particles after 6, 12, 18, and 24 months of exposure and of inhaled 134Cs-fused aluminosilicate particles after 24 months were similar for all groups. Progressive increases in lung burdens of soot particles were observed in M and H exposed rats, reaching levels of 11.5 +/- 0.5 and 20.5 +/- 0.8 mg/lung (mean +/- SE), respectively, after 24 months. Rats in the L group had smaller relative increases in lung burden, reaching levels of 0.60 +/- 0.02 mg/lung after 24 months. Tracheal mucociliary clearance measurements, using 99mTc-macroaggregated albumin deposited in the trachea, showed no changes at anytime. There were statistically significant increases in clearance half-times of inhaled radiolabeled particles of 67Ga2O3 as early as 6 months at the H level and 18 months at the M level; no significant changes were seen at the L level. Rats inhaled fused aluminosilicate particles labeled with 134Cs after 24 months of diesel exhaust exposure to measure long-term components of pulmonary clearance. The long-term clearance half-times were 79 +/- 5, 81 +/- 5, 264 +/- 50, and 240 +/- 50 days (mean +/- SE) for the C, L, M, and H groups, respectively. Differences were significant between the C and both the M and H exposure groups (p less than 0.01). Lung burdens of diesel soot were more than expected at the H and M levels and were also associated with impaired particle clearance while smaller responses were observed in both burdens and clearance at the L level.