Biomedical subjects

M D Hoover

Publications and source records attributed to M D Hoover.

29 records · Page 2Linked to original sources

PubMed1990

Clearance, translocation, and excretion of beryllium following acute inhalation of beryllium oxide by beagle dogs.

Beagle dogs inhaled radiolabeled beryllium oxide (7BeO) particles that were calcined at either 500 or 1000 degrees C, resulting in either high (mean of 50 micrograms/kg body wt) or low (mean of 17 micrograms/kg body wt) initial lung burdens (ILBs) of both preparations of BeO. Levels of beryllium in whole body, tissue, and excreta were measured by external gamma-ray counting. Dogs were euthanized in pairs at 8, 32, 64, and 180 days after exposure to determine beryllium distribution in tissues. Beryllium oxide calcined at 1000 degrees C was retained more tenaciously in the lungs (62% of the ILB retained at 180 days after exposure) than BeO calcined at 500 degrees C (14% of the ILB retained at 180 days after exposure). Most of the beryllium that was cleared from the lungs and not excreted was translocated to the tracheobronchial lymph nodes, skeleton, liver, and blood. More beryllium was translocated to the skeleton and liver at 180 days after inhalation of BeO prepared at 500 degrees C than at 1000 degrees C. The predominant mode of excretion at early times after exposure was through the feces, with urinary excretion assuming predominance at later times. These data are important for interpreting the toxic effects of beryllium in the exposed dogs. Furthermore, because little is known concerning the retention and clearance of inhaled beryllium in man, these results provide information that may be used to understand the disposition of beryllium in accidentally exposed humans.

Administration, Inhalation↗

PubMed1990

The acute toxicity of inhaled beryllium metal in rats.

We exposed rats once by nose only for 50 min to a mean concentration of 800 micrograms/m3 of beryllium metal (initial lung burden, 625 micrograms) to characterize the acute toxic effects within the lung. Histological changes within the lung and enzyme changes within bronchoalveolar lavage (BAL) fluid were evaluated at 3, 7, 10, 14, 31, 59, 115, and 171 days postexposure (dpe). Beryllium metal-exposed rats developed acute, necrotizing, hemorrhagic, exudative pneumonitis and intraalveolar fibrosis that peaked at 14 dpe. By 31 dpe, inflammatory lesions were replaced by minimal interstitial and intraalveolar fibrosis. Necrotizing inflammation was observed again at 59 dpe which progressed to chronic-active inflammation by 115 dpe. This inflammation worsened progressively, as did alveolar macrophage and epithelial hyperplasia, becoming severe at 171 dpe. Low numbers of diffusely distributed lymphocytes were also present but they were not associated with granulomas as is observed in beryllium-induced disease in man. Throughout the experiment, total numbers of cells were elevated within the BAL samples due primarily to increased numbers of neutrophils. Lymphocytes were not elevated in BAL samples collected from beryllium-exposed rats at any time after exposure. Lactate dehydrogenase (LDH), beta-glucuronidase, and protein levels were elevated in BAL fluid from 3 through 14 dpe but returned to near normal levels by 31 dpe. LDH increased once again at 59 dpe and remained elevated at 171 dpe. beta-Glucuronidase and protein levels were slightly, but not significantly, elevated from 31 through 171 dpe. Results indicate that inhalation of beryllium metal by rats results in severe, acute chemical pneumonitis that is followed by a quiescent period of minimal inflammation and mild fibrosis. Progressive, chronic-active, fibrosing pneumonitis is observed later. Chronic beryllium lung disease of man is an immunologically mediated granulomatous lung disease, whereas beryllium-induced lung lesions in rats appear to be due to direct chemical toxicity and foreign-body-type reactions.

Administration, Inhalation↗

PubMed1990

Relative efficacy of long-acting stimulants on children with attention deficit-hyperactivity disorder: a comparison of standard methylphenidate, sustained-release methylphenidate, sustained-release dextroamphetamine, and pemoline.

Twenty-two children with attention deficit-hyperactivity disorder underwent a double-blind, placebo-controlled, crossover evaluation of the efficacy of standard methylphenidate twice a day and comparable doses every morning of a sustained-release preparation of methylphenidate (SR-20 Ritalin), a sustained-release form of dextroamphetamine (Dexedrine Spansule), and pemoline. The children were participating in a summer treatment program in which they engaged in recreational and classroom activities. Dependent measures include evaluations of social behavior during group recreational activities, classroom performance, and performance on a continuous performance task. Results revealed generally equivalent and beneficial effects of all four medications. Dexedrine Spansule and pemoline tended to produce the most consistent effects and were recommended for 10 of the 15 children who were responders to medication. The continuous performance task results showed that all four medications had an effect within 2 hours of ingestion, and the effects lasted for 9 hours. The implications of these results for the use of long-acting stimulant medication in children with attention deficit-hyperactivity disorder are discussed.

Adolescent↗

PubMed1989

Determination of the oxide layer thickness on beryllium metal particles.

The hypothesis was tested that beryllium metal particles have a uniformly thick surface coating of beryllium oxide and that smaller particles should have a higher oxide fraction by mass because they have a higher surface to volume ratio. The mass fraction of oxygen, physical density, and specific surface area were determined for size-fractionated samples of respirable beryllium metal particles. The largest particles analyzed (count median diameter 4.6 microns with geometric standard deviation 1.6) contained 7% +/- 1% beryllium oxide by mass; had a physical density of 1.90 +/- 0.02 g/cm3; and had a specific surface area of 4.0 +/- 0.3 m2/g. The smallest particles analyzed (count median diameter 0.4 micron with geometric standard deviation 1.8) contained 31% +/- 3% beryllium oxide by mass; had a physical density of 2.00 +/- 0.17 g/cm3; and had a specific surface area of 20.8 +/- 2.1 m2/g. These shifts in density and oxide content with size and surface area are consistent with a beryllium metal core of density 1.84 +/- 0.02 g/cm3 (1.848 g/cm3 is theoretical); a beryllium oxide layer of density of 2.53 +/- 0.16 g/cm3 (3.025 g/cm3 is the perfect crystalline density); and an oxide layer thickness of 49 +/- 4 A for all particle sizes. These results indicate that the inhalation toxicity of beryllium metal particles may be similar to that of beryllium oxide formed at low temperatures.

Berylliosis↗

PubMed1989

Compartmental modeling of the long-term retention of insoluble particles deposited in the alveolar region of the lung.

The state of the art for modeling the retention of inhaled insoluble particles deposited in the alveolar region of the lung is briefly reviewed, and a new compartmental model of long-term retention is proposed. Wherever possible, this new model favors the replacement of simple first-order kinetics of particle transport processes in the lung by quantified mechanisms derived from or suggested by experimental data of published studies in lung physiology and histopathology. In particular, all macrophage-mediated transport processes, including classical alveolar clearance onto the mucociliary escalator, are modeled as dependent on actual macrophage mobility and are assumed to be influenced by the finite macrophage life time. The mobility is predicted to decrease with increasing particle burden of the macrophage, and there is a limit to the macrophage capacity for accumulating burdens of insoluble particles by phagocytosis. Furthermore, at high particle burdens, macrophages will be progressivity sequestered by irreversible aggregation and immobilization. Using published data on Fischer 344 rats for a quantitative demonstration of the patterns of the new model under chronic exposures, a basic set of model parameters predicts that, at moderate particle deposition rates, retention is limiting itself by establishing a steady state, and the alveolar burden is almost completely eliminated during the postexposure period. However, at high particle deposition rates, the alveolar particle burden increases continuously during the exposure period, and only a small fraction of the deposit is subject to clearance after termination of exposure. In qualitative terms, these are typical features of the "overload" effect which has been observed in a number of recent chronic aerosol inhalation exposure studies with animals.

Kinetics↗

PubMed1989

A canine model of beryllium-induced granulomatous lung disease.

Groups of beagle dogs were exposed by inhalation to attain either low or high initial lung burdens (ILB) of BeO calcined at 500 degrees or 1000 degrees C. Dogs were killed at 8, 32, 64, 180, and 365 days after exposure for evaluation of beryllium tissue burdens and histopathologic examination. Histologic lesions were characterized by perivascular and peribronchiolar infiltrates of lymphocytes and macrophages 8 days after exposure. These lesions progressed to distinct microgranulomas accompanied by patchy granulomatous pneumonia. Lesions were more severe in dogs exposed to 500 degrees C BeO. Additional dogs were sampled by bronchoalveolar lavage at 3, 6, 7, 11, 15, 18, and 22 months after exposure for characterization of lung cytology and lung immune responses. Lymphocyte percentages and numbers were increased in lavage samples 3 months after exposure in dogs with both the high and low ILB of 500 degrees C. Values for both parameters decreased rapidly thereafter. Dogs with either low or high ILB of 1000 degrees C-treated BeO displayed negligible to low and variable changes in both lymphocyte percentages and numbers. In vitro lymphocyte stimulation by beryllium was increased 180 and 210 days after exposure in dogs with the high ILB 500 degrees C BeO only. A marked degree of individual variation in both histologic lesions and lymphocyte responses among dogs was noted. Less soluble 1000 degrees C-treated BeO was retained in the lung longer than the more soluble 500 degrees C-treated material that was cleared almost entirely by 1 year after exposure. Because these changes are similar to those reported in humans with chronic beryllium disease, these data suggest that the beagle represents a good model to study histologic and immunologic aspects of this disease syndrome.

Aerosols↗

PubMed1988

The effect of beryllium compound solubility on in vitro canine alveolar macrophage cytotoxicity.

Pulmonary alveolar macrophage cells (PAM), obtained by bronchopulmonary lavage of Beagle dogs, were exposed in vitro to beryllium oxide (BeO) particles calcined at either 500 or 1000 degrees C or to beryllium sulfate (BeSO4). Cell viability was determined by trypan blue dye exclusion after 20 h in culture. The most toxic material tested was BeSO4, followed by BeO calcined at 500 degrees C, then BeO calcined at 1000 degrees C. An in vitro dissolution technique was used to measure the relative solubility of the BeO particles. The BeO prepared at 500 degrees C exhibited greater solubility compared with BeO prepared at 1000 degrees C. This study extends previous work by examining the effects of beryllium compounds on canine PAM, and by relating PAM cytotoxicity with measured values of beryllium compound solubility.

Animals↗

PubMed1987

Collection and characterization of aerosols from metal cutting techniques typically used in decommissioning nuclear facilities.

This study was designed to collect and characterize aerosols released during metal cutting activities typically used in decommissioning radioactively contaminated facilities. Such information can guide in the selection of appropriate control technologies for these airborne materials. Mechanical cutting tools evaluated included a multi-wheel pipe cutter, reciprocating saw, band saw, chop saw, and large and small grinding wheels. Melting-vaporization cutting techniques included an oxy-acetylene torch, electric arc cut rod and plasma torch. With the exception of the multi-wheel pipe cutter, all devices created aerosols in the respirable size range (less than 10 micron aerodynamic diameter). Time required to cut 2-in. (5-cm) Schedule 40, Type 304L, stainless steel ranged from about 0.6 min for the plasma torch to about 3.0 min for the reciprocating saw. Aerosol production rate ranged from less than 10 mg/min for the reciprocating saw to more than 3000 mg/min for the electric arc cut rod. Particles from mechanical tools were irregular in shape, whereas particles from vaporization tools were spheres and ultrafine branched-chain aggregates.

Aerosols↗

PubMed1986

Generation of Li combustion aerosols for animal inhalation studies.

A system was developed for generating Li aerosols to determine the potential health hazards of postulated accidents associated with the use of Li as a fusion reactor blanket or coolant. The aerosol was generated by sweeping Ar through a stainless steel chamber filled with Li metal that was heated inductively to temperatures up to 1300 degrees C. Argon carried the Li vapor into a burning chamber where it was mixed with air. The reaction of Li vapor with air formed an intense white flame that produced typical branched-chain condensation aerosol particles. This system generated well-controlled concentrations up to 2500 mg/m3 for periods of 4 h. The mass median aeordynamic diameter of the aerosol was approximately 0.66 micron with a geometric standard deviation of 1.5. Aerosols could be generated that were greater than 96% Li2O and LiOH, LiOH.H2O, or Li2CO3 by controlling the CO2 and H2O concentrations in the supply air. The system is currently being used to investigate the acute toxicity of Li combustion aerosols in laboratory animals.

Accidents↗

PubMedDate not supplied

Chronic granulomatous pneumonia and lymphocytic responses induced by inhaled beryllium metal in A/J and C3H/HeJ mice.

Inhalation of beryllium (Be) has been associated with 2 syndromes: an acute chemical pneumonitis and a granulomatous lung disease known as chronic beryllium disease (CBD). Key to the pathogenesis of CBD is a delayed-type hypersensitivity reaction, in which Be most likely functions as a hapten and acts as a Class II-restricted antigen, stimulating local proliferation and accumulation in the lung of Be-specific CD4+ T cells. The purpose of this study was to establish a mouse model of CBD using the inhalation route of exposure. A/J (H-2a haplotype) and C3H/HeJ (H-2a) mice were exposed once for 90 min in nose-only exposure tubes to aerosols of Be metal. Six mo later, lung histopathologic responses were assessed. Further analyses defined the phenotypic profile of lymphocytes in pulmonary lesions and evaluated proliferation of lymphocytes in situ and in response to Be in vitro. Responses were similar in both strains of mice. The lungs of all Be-exposed mice had interstitial compact aggregates of lymphocytes, and granulomatous pneumonia characterized by vacuolated macrophages and giant cells in alveoli, neutrophils in alveoli and alveolar septa, multifocal interstitial granulomas, and interstitial infiltrates of lymphocytes, plasma cells, monocytes, and macrophages. Most Be-exposed mice had minimal to mild interstitial fibrosis. The majority of lymphocytes in interstitial infiltrates and in microgranulomas were CD4+ T cells. Interstitial compact aggregates of lymphocytes contained B cells centrally and CD4+ cells peripherally. Lymphocyte labeling indices, used to assess proliferation in situ, were significantly greater within microgranulomas compared to compact lymphocytic aggregates. Lymphocyte stimulation indices in response to BeSO4 in vitro were not positive in blood, spleen, or tracheobronchial lymph node samples. Be-specific immune responses and nonspecific inflammatory responses to toxic and foreign-body properties of Be may have contributed to the histopathology in both strains of mice. The interstitial mononuclear cell infiltrates, presence of microgranulomas, multinucleated foreign-body and Langhans' giant cells, interstitial fibrosis, and CD4+ T-cell predominance with local proliferation are features similar to CBD in humans. The chronic lung disease induced in these mice by inhaled Be can be used to investigate the importance of variables such as dose, exposure pattern, and physicochemical form of Be in producing this disease.

Administration, Inhalation↗

PubMedDate not supplied

Carcinogenic responses of transgenic heterozygous p53 knockout mice to inhaled 239PuO2 or metallic beryllium.

The transgenic heterozygous p53+/- knockout mouse has been a model for assessing the tumorigenicity of selected carcinogens administered by noninhalation routes of exposure. The sensitivity of the model for predicting cancer by inhaled chemicals has not been examined. This study addresses this issue by acutely exposing p53+/- mice of both sexes by nose-only inhalation to either air (controls), or to 1 of 2 levels of 239PuO2 (500 or 100 Bq 239Pu) or beryllium (Be) metal (60 or 15 micrograms). Additional wild-type p53+/+ mice were exposed by inhalation to either 500 Bq of 239PuO2 or 60 micrograms of Be metal. These carcinogens were selected because they operate by differing mechanisms and because of their use in other pulmonary carcinogenesis studies in our laboratory. Four or 5 of the 15 mice per sex from each group were sacrificed 6 mo after exposure, and only 2 pulmonary neoplasms were observed. The remainder of the mice were held for life-span observation and euthanasia as they became moribund. Survival of the p53+/- knockout mice was reduced compared to the p53+/+ wild-type mice. No lung neoplasms were observed in p53+/- mice exposed to air alone. Eleven of the p53+/- mice inhaling 239PuO2 developed pulmonary neoplasms. Seven p53+/+ mice exposed to 239PuO2 also developed pulmonary neoplasms, but the latency period for pulmonary neoplasia was significantly shorter in the p53+/ mice. Four pulmonary neoplasms were observed in p53+/- mice exposed to the higher dose of Be, whereas none were observed in the wild-type mice or in the heterozygous mice exposed to the lower dose of Be. Thus, both p53+/- and p53+/+ mice were susceptible to 239Pu-induced carcinogenesis, whereas the p53+/- but not the p53+/+ mice were susceptible to Be-induced carcinogenesis. However, only 2 pulmonary neoplasms (1 in each of the 239PuO2 exposure groups) were observed in the 59 p53+/ mice that were sacrificed or euthanatized within 9 mo after exposure, indicating that the p53+/- knockout mouse might not be appropriate for a 6-mo model of carcinogenesis for these inhaled carcinogens.

Adenocarcinoma↗