RESUMEN
Humans will again set foot on the moon. The moon is covered by a layer of fine dust, which can pose a respiratory hazard. We investigated the pulmonary toxicity of lunar dust in rats exposed to 0, 2.1, 6.8, 20.8 and 60.6 mg/m(3) of respirable-size lunar dust for 4 weeks (6 h/day, 5 days/week); the aerosols in the nose-only exposure chambers were generated from a jet-mill ground preparation of a lunar soil collected during the Apollo 14 mission. After 4 weeks of exposure to air or lunar dust, groups of five rats were euthanized 1 day, 1 week, 4 weeks or 13 weeks after the last exposure for assessment of pulmonary toxicity. Biomarkers of toxicity assessed in bronchoalveolar fluids showed concentration-dependent changes; biomarkers that showed treatment effects were total cell and neutrophil counts, total protein concentrations and cellular enzymes (lactate dehydrogenase, glutamyl transferase and aspartate transaminase). No statistically significant differences in these biomarkers were detected between rats exposed to air and those exposed to the two low concentrations of lunar dust. Dose-dependent histopathology, including inflammation, septal thickening, fibrosis and granulomas, in the lung was observed at the two higher exposure concentrations. No lesions were detected in rats exposed to ≤6.8 mg/m(3). This 4-week exposure study in rats showed that 6.8 mg/m(3) was the highest no-observable-adverse-effect level (NOAEL). These results will be useful for assessing the health risk to humans of exposure to lunar dust, establishing human exposure limits and guiding the design of dust mitigation systems in lunar landers or habitats.
Asunto(s)
Polvo Cósmico/efectos adversos , Pulmón/efectos de los fármacos , Luna , Administración por Inhalación , Animales , Aspartato Aminotransferasas/metabolismo , Líquido del Lavado Bronquioalveolar/química , Líquido del Lavado Bronquioalveolar/citología , Recuento de Células , L-Lactato Deshidrogenasa/metabolismo , Pulmón/metabolismo , Pulmón/patología , Masculino , Nivel sin Efectos Adversos Observados , Ratas , Ratas Endogámicas F344 , Pruebas de Toxicidad Subaguda , gamma-Glutamiltransferasa/metabolismoRESUMEN
AKR/J mice were exposed to cigarette smoke (CS) and/or lipopolysaccharide (LPS) via inhalation for 3 wk and pulmonary responses were evaluated. The objective was to explore the feasibility of coexposing LPS with cigarette smoke under a subacute exposure, as a surrogate for viral or bacterial insults, that would mimic the pathogenesis of infection-related chronic obstructive pulmonary disease (COPD) exacerbations. The study was the first step in an effort to develop a rodent COPD model in which morphologic lesions of COPD develop in a shorter period of exposure and more closely simulate human COPD. Mice were exposed 6 h/day, 5 days/wk for 3 wk to one of the following: (1) sham control: filtered air; (2) CS: 250 microg/L wet total particulate matter (WTPM) for 5 h/day followed by 1 h/day air; (3) LPS: 0.5 microg/L LPS (055:B5 Escherichia coli; 3,000,000 EU/mg) for the last 1 h/day 2 day/wk (following 5 h/day of filtered air); and (4) CS/LPS: CS 5 h/day followed by air or LPS (2 days/wk) for 1 h/day. After the last exposure, animals were necropsied and subjected to bronchoalveolar lavage (BAL) or histopathology. The BAL neutrophil counts were highest in the LPS group, while macrophage counts were higher in the CS/LPS group than other exposed groups. The LPS group displayed the greatest increases in BAL cytokines, while KC (keratinocyte-derived chemokine) and TARC (thymus and activation-regulated chemokine) were highest in the CS group. The CS/LPS group had generally lower cytokine levels relative to the LPS or CS groups, except for the levels of RANTES and G-CSF (granulocyte-colony stimulating factor) comparable to the LPS group. At microscopic examination of lung sections, cellular inflammatory infiltrates were most notable in the CS/LPS group, which had a diffuse, predominantly macrophage infiltrate with fewer neutrophils. The LPS group had predominantly neutrophils in the pulmonary infiltrate and the CS group had a predominantly macrophage infiltrate in alveolar ducts and adjacent alveoli. Apoptotic labeling of lung cells was highest with the CS/LPS group. In summary, the CS/LPS group displayed greater cellular infiltration and apoptotic responses in the lung with an indication of immunosuppressive effects (lower BAL cytokines) than the CS or LPS group, suggesting that the CS/LPS model shows promise to be further explored as an animal model for studying pathogenesis of COPD exacerbations. A longer term study with interim assessments is needed to confirm that the subacute responses observed in the CS/LPS group will result in greater severity of COPD-related pulmonary lesions following prolonged exposures.
Asunto(s)
Exposición por Inhalación , Lipopolisacáridos/farmacología , Nicotiana , Sistema Respiratorio/efectos de los fármacos , Humo/efectos adversos , Aerosoles , Animales , Apoptosis/efectos de los fármacos , Biomarcadores/sangre , Peso Corporal/efectos de los fármacos , Líquido del Lavado Bronquioalveolar/química , Líquido del Lavado Bronquioalveolar/citología , Carboxihemoglobina/metabolismo , Cotinina/sangre , Citocinas/biosíntesis , Modelos Animales de Enfermedad , Estudios de Factibilidad , Macrófagos/efectos de los fármacos , Macrófagos/patología , Masculino , Ratones , Ratones Endogámicos AKR , Neutrófilos/efectos de los fármacos , Neutrófilos/patología , Nicotina/sangre , Tamaño de la Partícula , Enfermedad Pulmonar Obstructiva Crónica/sangre , Enfermedad Pulmonar Obstructiva Crónica/inducido químicamente , Enfermedad Pulmonar Obstructiva Crónica/metabolismo , Enfermedad Pulmonar Obstructiva Crónica/patología , Enfermedad Pulmonar Obstructiva Crónica/fisiopatología , Pruebas de Función Respiratoria , Sistema Respiratorio/metabolismo , Sistema Respiratorio/patología , Sistema Respiratorio/fisiopatología , Factores de TiempoRESUMEN
Male C57Bl/6 (C57) and ICR mice were exposed by nose-only inhalation to mainstream cigarette smoke (MS) from 2R4F reference cigarettes, at concentrations of 75, 250, and 600 microg of total particulate matter (TPM) per liter, for up to 6 mo. Respiratory-tract tissue (nose, larynx, and lung), blood, and bronchoalveolar lavage fluid (BALF) samples were collected and analyzed at several time points. Blood samples were analyzed for biomarkers of exposure (COHb and nicotine). BALF was analyzed for biomarkers of cell injury, inflammation, oxidative stress, enzyme activity, and cytokines. Blood COHb and plasma nicotine concentrations increased in a dose-dependent manner, confirming smoke exposure. Mild emphysema was observed following 28 wk of exposure. Macrophage accumulation and inflammatory infiltrates were observed around the alveolar ducts and adjacent vasculature. There was an approximately 13% increase in mean linear intercept (Lm) only in ICR mice exposed to 600 microg/L TPM. There were no significant changes in biomarkers of oxidative stress secondary to smoke exposures; however, 8-isoprostane significantly increased following the 13-wk post-inhalation period. BALF macrophage and neutrophil counts were rapidly and consistently elevated, while lymphocyte counts gradually increased over time. MS-induced inflammatory responses observed in this study are comparable to changes reported in chronic smokers, supporting the role of chronic inflammation in the pathogenesis of emphysema. However, mild emphysema in minimal numbers of mice suggests that MS exposure concentration and/or duration in the current study were not sufficient to induce a definitive emphysema phenotype.
Asunto(s)
Pulmón/patología , Neumonía/diagnóstico , Neumonía/etiología , Contaminación por Humo de Tabaco/efectos adversos , Administración Intranasal , Animales , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos ICR , Nicotina/análisis , Neumonía/metabolismo , Especificidad de la EspecieRESUMEN
A series of in vitro and in vivo studies evaluated the potential effects of tobacco flavoring and casing ingredients. Study 1 utilized as a reference control cigarette a typical commercial tobacco blend without flavoring ingredients, and a test cigarette containing a mixture of 165 low-use flavoring ingredients. Study 2 utilized the same reference control cigarette as used in study 1 and a test cigarette containing eight high-use ingredients. The in vitro Ames Salmonella typhimurium assay did not show any increase in mutagenicity of smoke condensate from test cigarettes designed for studies 1 and 2 as compared to the reference. Sprague-Dawley rats were exposed by nose-only inhalation for 1 h/day, 5 days/wk for 13 wk to smoke from the test or reference cigarettes already described, or to air only, and necropsied after 13 wk of exposure or following 13 wk of recovery from smoke exposure. Exposure to smoke from reference or test cigarettes in both studies induced increases in blood carboxyhemoglobin ((COHb)) and plasma nicotine, decreases in minute volume, differences in body or organ weights compared to air controls, and a concentration-related hyperplasia, squamous metaplasia, and inflammation in the respiratory tract. All these effects were greatly decreased or absent following the recovery period. Comparison of rats exposed to similar concentrations of test and reference cigarette smoke indicated no difference at any concentration. In summary, the results did not indicate any consistent differences in toxicologic effects between smoke from cigarettes containing the flavoring or casing ingredients and reference cigarettes.
Asunto(s)
Excipientes/toxicidad , Aromatizantes/toxicidad , Exposición por Inhalación/efectos adversos , Sistema Respiratorio/efectos de los fármacos , Fumar/efectos adversos , Administración por Inhalación , Animales , Peso Corporal/efectos de los fármacos , Carboxihemoglobina/análisis , Relación Dosis-Respuesta a Droga , Quimioterapia Combinada , Excipientes/administración & dosificación , Femenino , Aromatizantes/administración & dosificación , Pulmón/efectos de los fármacos , Pulmón/patología , Masculino , Pruebas de Mutagenicidad , Nicotina/sangre , Tamaño de los Órganos/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Pruebas de Función Respiratoria , Mecánica Respiratoria/efectos de los fármacos , Mecánica Respiratoria/fisiología , Sistema Respiratorio/patología , Sistema Respiratorio/fisiopatología , Salmonella/efectos de los fármacos , Salmonella/genéticaRESUMEN
Decalin (decahydronaphthalene) is a widely used industrial solvent known to cause male rat-specific alpha2u-globulin nephropathy. In this project, 13-week and two-year inhalation studies of decalin were conducted consecutively in both sexes of F344/N rats. The key objectives were to (1) characterize the 13-week toxicity of decalin in rats, with an emphasis on nephropathy in males; (2) compare the kidney concentrations of decalin, 2-decalone, and alpha2u-globulin in males over 2 to 13 weeks of decalin exposure; and (3) correlate male rat nephropathy observed in the 13-week study with renal carcinogenicity in the two-year study. F344 rats (M/F) were exposed via whole-body inhalation to 0, 25, 50, 100, 200, or 400 ppm decalin for 13 weeks. Urine was collected at weeks 2 and 6 for creatinine and decalol analyses and at week 12 for clinical urinalysis. Right kidneys were collected from male rats at weeks 2 and 6 and from both sexes at week 13, homogenates were prepared using the whole kidney, and these homogenates were analyzed for alpha2u-globulin, decalin, and 2-decalone. Left kidneys were evaluated for histopathology and cell proliferation utilizing a proliferating cell nuclear antigen technique and counting proximal renal tubular epithelial cells to determine cell labeling indices. Necropsies and histopathologic evaluations were performed at week 13. Decalin exposure caused increases in kidney weight, urinalysis parameters (protein, AST, LDH), kidney alpha2u-globulin concentration, and proximal convoluted renal tubular cell proliferation in males. These changes were accompanied by microscopic lesions (accumulation of hyaline droplets in cortical tubules, regeneration of proximal tubular epithelium, and granular casts in medullary tubules) clearly linked to alpha2u-globulin nephropathy. Both decalin and 2-decalone were related to increased alpha2u-globulin in male kidneys. Kidney concentrations of decalin, 2-decalone, and alpha2u-globulin in exposed females were negligible, while females excreted greater amounts of decalol metabolites in urine than males at weeks 2 and 6. There were no exposure-related microscopic lesions in females. For chronic exposure, F344 rats were exposed via whole-body inhalation to 0, 25, 50 (males only), 100, or 400 ppm decalin for two years. Chronic exposure induced a spectrum of nonneoplastic and neoplastic lesions in the renal cortex of males, ranging from regenerative lesions of chronic nephropathy to tubular carcinomas. Incidences of renal tubular adenoma, tubular carcinoma, combined tubular adenomas and carcinomas, cortical tubular hyperplasia, hyaline droplet accumulation, hyperplasia of pelvic epithelium, and mineralization in renal papilla were increased in exposed males compared to controls. There was a clear increase in the mean severity of chronic nephropathy in decalin-exposed males. It was concluded that the carcinogenic effect on the renal cortical epithelium of male rats exposed to decalin was related to increased turnover of this epithelium, resulting from the cytotoxic effects of alpha2u-globulin accumulation in the renal cortical tubular cell cytoplasm.
Asunto(s)
Adenoma/inducido químicamente , Carcinógenos/toxicidad , Carcinoma/inducido químicamente , Neoplasias Renales/inducido químicamente , Riñón/efectos de los fármacos , Naftalenos/toxicidad , Adenoma/metabolismo , Adenoma/patología , Administración por Inhalación , alfa-Globulinas , Animales , Pruebas de Carcinogenicidad , Carcinógenos/administración & dosificación , Carcinoma/metabolismo , Carcinoma/patología , División Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Femenino , Hialina/metabolismo , Riñón/metabolismo , Riñón/patología , Neoplasias Renales/metabolismo , Neoplasias Renales/patología , Túbulos Renales Proximales/efectos de los fármacos , Túbulos Renales Proximales/patología , Masculino , Naftalenos/administración & dosificación , Tamaño de los Órganos/efectos de los fármacos , Ratas , Ratas Endogámicas F344 , Factores Sexuales , SolventesRESUMEN
Propylene glycol mono-t-butyl ether (PGMBE) is used as a solvent in a variety of commercial applications. Male and female F344/N rats and B6C3F(1) mice were exposed to PGMBE by whole-body inhalation for 2 or 14 weeks (0, 75, 150, 300, 600, or 1200 ppm) or 2 years (0, 75, 300, or 1200 ppm); male NBR rats were exposed for 2 weeks. The kidney and the liver were targets of PGMBE toxicity in rats. Renal lesions suggestive of alpha(2u)-globulin nephropathy were observed in male F344/N, in the 2 and 14-week studies, no kidney lesions were seen in NBR rats. In the 2-year study, male rats displayed exposure-related nonneoplastic lesions in the kidney, and may have shown marginal increases in tubular neoplasms. In the liver, the incidences of hepatocellular adenomas occurred with a positive trend in male rats, and may have been related to PGMBE exposure. In mice of both sexes, the major target of PGMBE toxicity was the liver. In the 2-week study, liver weights and in the 14-week study, liver weights and the incidences of centrilobular hypertrophy were increased. In the 2-year study, the incidences of exposure-related hepatocellular adenoma, adenoma or carcinoma combined, and hepatoblastoma occurred with a positive trend, and were significantly increased in 1200 ppm groups. In summary, exposure to PGMBE resulted in nonneoplastic lesions of the kidney characteristic of alpha(2u)-globulin nephropathy, and may have increased renal tubular neoplasms in male rats. Exposure to PGMBE also produced increases in hepatic tumors in male and female mice.
Asunto(s)
Carcinógenos/toxicidad , Glicoles de Propileno/toxicidad , Solventes/toxicidad , Adenoma de Células Hepáticas/inducido químicamente , Adenoma de Células Hepáticas/patología , Administración por Inhalación , alfa-Globulinas/metabolismo , Animales , Pruebas de Carcinogenicidad , Carcinógenos/administración & dosificación , Carcinoma Hepatocelular/inducido químicamente , Carcinoma Hepatocelular/patología , Relación Dosis-Respuesta a Droga , Femenino , Hepatoblastoma/inducido químicamente , Hepatoblastoma/patología , Neoplasias Renales/inducido químicamente , Neoplasias Renales/patología , Túbulos Renales/efectos de los fármacos , Túbulos Renales/metabolismo , Túbulos Renales/patología , Neoplasias Hepáticas/inducido químicamente , Neoplasias Hepáticas/patología , Masculino , Ratones , Ratones Endogámicos , Mutágenos/toxicidad , Glicoles de Propileno/administración & dosificación , Ratas , Ratas Endogámicas F344 , Salmonella typhimurium/efectos de los fármacos , Salmonella typhimurium/genética , Solventes/administración & dosificaciónRESUMEN
This paper describes some important differences in normal histology of the upper respiratory tract of laboratory animals. It also provides examples of lesions observed or reported in the upper respiratory tract of laboratory animals, predominantly rodents, exposed via inhalation. The anatomy and physiology of upper respiratory tract tissues play a major role in the response to an insult, given that different epithelial types vary in susceptibility to injury and toxicant exposure concentrations throughout the airway vary due to airflow dynamics. Although dogs and nonhuman primates are utilized for inhalation toxicology studies, less information is available regarding sites of upper respiratory injury and types of responses in these species. Awareness of interspecies differences in normal histology and zones of transition from squamous to respiratory to olfactory epithelium in different areas of the upper respiratory tract is critical to detection and description of lesions. Repeated inhalation of chemicals, drugs, or environmental contaminants induces a wide range of responses, depending on the physical properties of the toxicant and concentration and duration of exposure. Accurate and consistent fixation, trimming, and microtomy of tissue sections using anatomic landmarks are critical steps in providing the pathologist the tools needed to compare the morphology of upper respiratory tract tissues from exposed and control animals and detect and interpret subtle differences.
Asunto(s)
Contaminantes Atmosféricos/toxicidad , Laringe/efectos de los fármacos , Cavidad Nasal/efectos de los fármacos , Xenobióticos/toxicidad , Administración por Inhalación , Animales , Modelos Animales de Enfermedad , Perros , Ratones , RatasRESUMEN
The laryngeal mucosa responds to insult similarly to other epithelial tissues but the response depends on location within the larynx since important anatomic differences exist, even within rodent species. Although dogs and nonhuman primates are also utilized for inhalation toxicology studies, little published information is available regarding sites of injury from inhaled toxicants in these species. Accurate and consistent fixation, trimming, and microtomy of laryngeal sections allow the pathologist to compare the morphology of laryngeal mucosa from exposed and control animals and detect and interpret subtle differences resulting from inhalation exposure. There are anatomic landmarks that are keys to providing consistent sections through important areas of the laryngeal mucosa. Repeated inhalation of toxic concentrations of chemicals, drugs, or environmental contaminants induces a wide range of responses, depending on the physical properties and concentration of the toxic substance and duration of exposure. Responses include edema, acute to chronic inflammation, fibrosis, mucosal ulceration, degeneration, and necrosis. Attempts at repair include regeneration, hyperplasia, squamous metaplasia, hyperkeratosis, and neoplasia. Awareness of normal histology and zones of transition from squamous to respiratory epithelium in different areas of the larynx in different species is critical to avoid confusing normal epithelium with metaplasia or hyperplasia. Microscopic examination of laryngeal mucosa from animals exposed via inhalation and necropsied following a recovery period provides the opportunity to determine the degree of regression or progression of exposure-induced laryngeal lesions.