Biomedical subjects

M D Hoover

Publications and source records attributed to M D Hoover.

At least 19 recordsLinked to original sources

PubMed2005

Characterization of phagolysosomal simulant fluid for study of beryllium aerosol particle dissolution.

A simulant of phagolysosomal fluid is needed for beryllium particle dissolution research because intraphagolysosomal dissolution is believed to be a necessary step in the cellular immune response associated with development of chronic beryllium disease. Thus, we refined and characterized a potassium hydrogen phthalate (KHP) buffered solution with pH 4.55, termed phagolysosomal simulant fluid (PSF), for use in a static dissolution technique. To characterize the simulant, beryllium dissolution in PSF was compared to dissolution in the J774A.1 murine cell line. The effects of ionic composition, buffer strength, and the presence of the antifungal agent alkylbenzyldimethylammonium chloride (ABDC) on beryllium dissolution in PSF were evaluated. Beryllium dissolution in PSF was not different from dissolution in the J774A.1 murine cell line (p = 0.78) or from dissolution in another simulant having the same pH but different ionic composition (p = 0.73). A buffer concentration of 0.01-M KHP did not appear adequate to maintain pH under all conditions. There was no difference between dissolution in PSF with 0.01-M KHP and 0.02-M KHP (p = 0.12). At 0.04-M KHP, beryllium dissolution was increased relative to 0.02-M KHP (p = 0.02). Use of a 0.02-M KHP buffer concentration in the standard formulation for PSF provided stability in pH without alteration of the dissolution rate. The presence of ABDC did not influence beryllium dissolution in PSF (p = 0.35). PSF appears to be a useful and appropriate model of in vitro beryllium dissolution when using a static dissolution technique. In addition, the critical approach used to evaluate and adjust the composition of PSF may serve as a framework for characterizing PSF to study dissolution of other metal and oxide particles.

Aerosols↗

PubMed2000

Assessing risk communication effectiveness: perspectives of agency practitioners.

A study conducted by the Agency for Toxic Substances and Disease Registry (ATSDR), a US public health agency, evaluated ATSDR's risk communication process, specifically the roles and responsibilities, planning, implementation, and coordination of activities in response to illegal indoor spraying of methyl parathion, a hazardous pesticide, in Pascagoula, MS. Interviews of staff members involved in the intervention were conducted and an analysis revealed strengths and areas in need of improvement in the design and implementation of risk communication strategies. Key recommendations included developing a clear strategy for planning and conducting communication activities; determining staff roles and responsibilities for coordination; and developing clear and consistent health messages, a dissemination strategy, and training in the delivery and evaluation of messages, effects, and outcomes.

Air Pollutants↗

PubMed2000

Aerosols generated during beryllium machining.

Some beryllium processes, especially machining, are associated with an increased risk of beryllium sensitization and disease. Little is known about exposure characteristics contributing to risk, such as particle size. This study examined the characteristics of beryllium machining exposures under actual working conditions. Stationary samples, using eight-stage Lovelace Multijet Cascade Impactors, were taken at the process point of operation and at the closest point that the worker would routinely approach. Paired samples were collected at the operator's breathing zone by using a Marple Personal Cascade Impactor and a 35-mm closed-faced cassette. More than 50% of the beryllium machining particles in the breathing zone were less than 10 microns in aerodynamic diameter. This small particle size may result in beryllium deposition into the deepest portion of the lung and may explain elevated rates of sensitization among beryllium machinists.

Aerosols↗

PubMed1999

Modular glovebox connector and associated good practices for control of radioactive and chemically toxic materials.

Design and associated good practices are described for a modular glovebox connector to improve control of radioactive and chemically toxic materials. The connector consists of an anodized aluminum circular port with a mating spacer, gaskets, and retaining rings for joining two parallel ends of commercially available or custom-manufactured glovebox enclosures. Use of the connector allows multiple gloveboxes to be quickly assembled or reconfigured in functional units. Connector dimensions can be scaled to meet operational requirements for access between gloveboxes. Options for construction materials are discussed, along with recommendations for installation of the connector in new or retrofitted systems. Associated good practices include application of surface coatings and caulking, use of disposable glovebags, and proper selection and protection of gasket and glove materials. Use of the connector at an inhalation toxicology research facility has reduced the time and expense required to reconfigure equipment for changing operational requirements, the dispersion of contamination during reconfigurations, and the need for decommissioning and disposal of contaminated enclosures.

Aluminum↗

PubMed1998

Dose-response relationships between inhaled beryllium metal and lung toxicity in C3H mice.

Inhaled beryllium (Be) can induce a range of adverse pulmonary responses in animals and humans including acute pneumonitis, chronic granulomatous lung disease, and cancer. To facilitate comparisons with our previous data describing Be toxicity in rats, we evaluated the toxic effects of inhaled Be metal in mice. Groups of 34 strain C3H/HeJ mice were acutely exposed by the nose-only route to aerosolized Be metal to achieve measured initial lung burdens of 0, 1.7, 2.6, 12, or 34 microg. All mice received aerosolized 85 Sr-labeled fused aluminosilicate particles (85 Sr-FAPs) immediately before their Be exposure so that the influence of Be on lung retention of these poorly soluble tracer particles could be externally quantitated. Groups of mice were euthanized at 8, 15, 40, 90, 210, and 350 days after exposure for evaluation of histopathological changes and for cytologic and biochemical indicators of lung damage measured in bronchoalveolar lavage fluid. Clearance of 85 Sr-FAP tracer particles through 196 days after exposure was delayed in mice receiving the 12 and 34 microg Be lung burdens, but not the 1.7 or 2.6 microg lung burdens. Increased total cell numbers, increased percentage of neutrophils, and elevated levels of total protein and the activities of beta-glucuronidase and lactate dehydrogenase in bronchoalveolar lavage fluid were observed in the two highest Be lung burden groups compared with controls. Lung lesions included particle-containing macrophages, granulomatous pneumonia, lymphocytic interstitial aggregates, and mononuclear interstitial infiltrates. These lesions were occasionally seen in mice receiving the 2.6 microg lung burden, were present in most of the mice receiving 12 or 34 microg lung burdens, and were generally increased in severity with time and lung burden. Thus, we have demonstrated that a single, acute inhalation exposure to Be metal can chronically retard particle clearance and induce lung damage in mice. The initial lung burdens used caused responses ranging from no apparent effects to significant Be-induced responses. A comparison of these data with our previous data from rats indicates that the mass of Be metal required to induce lung damage in mice is similar to that needed for rats. When expressed on a lung weight-normalized basis, mice appeared to be more resistant to the toxic effects of inhaled Be than rats.

Animals↗

PubMed1998

Chronic cigarette smoke exposure increases the pulmonary retention and radiation dose of 239Pu inhaled as 239PuO2 by F344 rats.

As a portion of a study to examine how chronic cigarette smoke exposure might alter the risk of lung tumors from inhaled 239puO2 in rats, the effects of smoke exposure on alpha-particle lung dosimetry over the life-span of exposed rats were determined. Male and female rats were exposed to inhaled 239PuO2 alone or in combination with cigarette smoke. Animals exposed to filtered air alone served as controls for the smoke exposure. Whole-body exposure to mainstream smoke diluted to concentrations of either 100 or 250 mg total particulate matter m(-3)(LCS or HCS, respectively) began at 6 wk of age and continued for 6 h d(-1), 5d wk(-1), for 30 mo. A single, pernasal, acute exposure to 239PuO2 was given to all rats (control, LCS and HCS) at 12 wk of age. Exposure to cigarette smoke caused decreased body weight gains in a concentration dependent manner. Lung-to-body weight ratios were increased in smoke-exposed rats. Rats exposed to cigarette smoke before the 239PuO2 exposure deposited less 239Pu in the lung than did controls. Except for male rats exposed to LCS, exposure to smoke retarded the clearance of 239Pu from the lung compared to control rats through study termination at 870 d after 239PuO2 exposure. Radiation doses to lungs were calculated by sex and by exposure group for rats on study for at least 360 d using modeled body weight changes, lung-to-body weight ratios, and standard dosimetric calculations. For both sexes, estimated lifetime radiation doses from the time of 239PuO2 exposure to death were 3.8 Gy, 4.4 Gy, or 6.7 Gy for the control, LCS, or HCS exposure groups, respectively. Assuming an approximately linear dose-response relationship between radiation dose and lung neoplasm incidence, approximate increases of 20% or 80% in tumor incidence over controls would be expected in rats exposed to 239PuO2 and LCS or 239PuO2 and HCS, respectively.

Administration, Inhalation↗

PubMed1997

Immunologic specificity of lymphocyte cell lines from dogs exposed to beryllium oxide.

We have reported that dogs exposed twice to aerosols of beryllium oxide (BeO) developed Be-specific immune responses within the lung, along with granulomatous and fibrotic lung lesions. To evaluate the specificity of the immune response, lymphocytes from lungs and blood of BeO-exposed dogs were co-cultured over an irradiated blood monocyte layer, alternately with interleukin 2 and BeSO4. Resultant cell lines were then tested for their response to different metal cations, common canine recall antigens, and BeSO4 in an in vitro cell proliferation assay. The cell lines responded to BeSO4 in a dose-dependent fashion, with mean stimulation indices of 7, 58, 119, and 112 at concentrations of 0.01, 1.0, 10, and 100 microM BeSO4 respectively. Cells not proliferate when incubated with ZnSO4 or NiSO4, or with canine distemper, leptospira, adenovirus 2, parvovirus, or parainfluenza antigens. Lymphocytes from normal vaccinated dogs proliferated markedly when cultured with these antigens. Cells from the cultured cell lines (91%) stained with Thy-1 (a pan T-cell marker) and 96% stained with DT2 (a helper T-cell marker). Furthermore, the Be-induced proliferative response was restricted by major histocompatibility (MHC) class II antigens. These data reinforce the premise that inhalation exposure of dogs to BeO produces lung lesions and MHC class II restricted immunologic responses mediated by Be-specific, helper T-Cells. These data further confirm the hypothesis that antigen localized to the lung results in the recruitment of T-cells to the lung, followed by localized antigen-specific, cell-mediated immune responses.

Administration, Inhalation↗

PubMed1996

Animal models of beryllium-induced lung disease.

The inhalation Toxicology Research Institute (ITRI) is conducting research to improve the understanding of chronic beryllium disease (CBD) and beryllium-induced lung cancer. Initial animal studies examined beagle dogs that inhaled BeO calcined at either 500 or 1000 degrees C. At similar lung burdens, the 500 degrees C BeO induced more severe and extensive granulomatous pneumonia, lymphocytic infiltration into the lung, and positive Be-specific lymphocyte proliferative responses in vitro than the 1000 degrees C BeO. However, the progressive nature of human CBD was not duplicated. More recently, Strains A/J and C3H/Hej mice were exposed to Be metal by inhalation. This produced a marked granulomatous pneumonia, diffuse infiltrates, and multifocal aggregates of interstitial lymphocytes with a pronounced T helper component and pulmonary in situ lymphocyte proliferation. With respect to lung cancer, at a mean lung burden as low as 17 micrograms Be/g lung, inhaled Be metal induced benign and/or malignant lung tumors in over 50% of male and female F344 rats surviving > or = 1 year on study. Substantial tumor multiplicity was found, but K-ras and p53 gene mutations were virtually absent. In mice, however, a lung burden of approximately 60 micrograms (-300 micrograms Be/g lung) caused only a slight increase in crude lung tumor incidence and multiplicity over controls in strain A/J mice and no elevated incidence in strain C3H mice. Taken together, this research program constitutes a coordinated effort to understand beryllium-induced lung disease in experimental animal models.

Animals↗

PubMed1994

The comparative pulmonary toxicity of beryllium metal and beryllium oxide in cynomolgus monkeys.

Inhalation of beryllium (Be) may result in an immune-mediated, chronic granulomatous pulmonary disorder known as chronic beryllium disease (CBD). The physicochemical form of Be may affect the incidence and severity of CBD. We exposed cynomolgus monkeys, by bronchoscopic, intrabronchiolar instillation, to either beryllium oxide (BeO; heat-treated at 500 degrees C) or Be metal at concentrations selected to achieve equimolar concentrations of available Be2+ ions dissolving from the particles. Monkeys underwent bronchoalveolar lavage of the right and left diaphragmatic lobes at 14, 30, 60, 90, and 120 days post exposure (dpe). Monkeys were sacrificed at 80 and 180 dpe for evaluation of histopathological pulmonary changes. Numbers of lymphocytes from lung lobes of Be metal-exposed, but not BeO-exposed, monkeys were increased at 14, 30 and 90 dpe. Lung lymphocytes were increased for BeO exposed monkeys only at 60 dpe. In vitro, Be-specific, lung lymphocyte proliferation occurred at 14, 60, and 90 dpe for lymphocytes from Be metal-exposed lung lobes only. At no time were values from BeO-exposed lung lobes different from values from control lobes. Lung lesions in Be metal-exposed monkeys were characterized by focally intense, interstitial fibrosis, marked Type II cell hyperplasia, and variable lymphocyte infiltration. Some Be-metal-exposed monkeys had discrete immune granulomas consisting of tightly organized lymphocytic cuffs surrounding nodular aggregates of epithelioid macrophages. Lesions were rarely present in BeO-exposed monkeys and were much less severe. These data suggest that Be metal produces more severe pulmonary lesions than does BeO and that these lesions are accompanied by Be-specific immune responses.

Animals↗

PubMed1993

Disposition of polycyclic aromatic hydrocarbons in the respiratory tract of the beagle dog. I. The alveolar region.

Clearance of polycyclic aromatic hydrocarbons (PAHs) from the respiratory tract follows a biphasic pattern, with a rapid clearance of most of the PAH followed by a slow clearance of a small fraction. In previously published models, it was predicted that the rapid phase represents clearance through the thin epithelial barriers in the alveoli, the slow clearance is through the thicker epithelium of the airways, and the rate of clearance from either region will be slowed if the PAH has a high degree of lipophilicity. The objective of this first study in a series of three was to validate model predictions for rates of alveolar clearance of PAHs of different lipophilicities. A new method was developed to expose dogs to a bolus of aerosolized crystals of either benzo[a]pyrene (BaP) or phenanthrene (Phe) in a single breath. A bolus of PAH crystals was formed by condensation from a heated vapor and was injected into the pulmonary region. The bloodborne clearance of the PAHs was monitored by repeatedly sampling blood through catheters in the ascending aorta and the right atrium of the dog. Half of the Phe and the BaP cleared within 1 min and 2.4 min, respectively. The data indicated that the clearance of the highly lipophilic BaP was limited by diffusion of the PAH through the alveolar septa, while clearance of the moderately lipophilic Phe was limited mostly by the rate of perfusion of the blood. The results indicate that inhaled PAHs of sufficient lipophilicity to limit diffusion through cells have a greater potential for toxicity to the lung than less lipophilic PAHs. Because of thicker epithelia, bronchi should be at greater risk than the alveoli for PAH-induced toxicity exerted at the portal of entry.

Administration, Inhalation↗

PubMed1993

Disposition of polycyclic aromatic hydrocarbons in the respiratory tract of the beagle dog. II. The conducting airways.

Physiological models have predicted that the lipophilicity of solutes such as polycyclic aromatic hydrocarbons (PAHs) will delay clearance from the respiratory tract. This clearance consists of a delayed penetration of the mucous lining layer (MLL), allowing mucociliary clearance, followed by a slow penetration of PAHs through walls of the conducting airways. To test this prediction, mucociliary clearance and retention in the mucosa of PAHs deposited in the conducting airways of the Beagle dog were measured. Mucociliary clearance of particles and dissolved PAHs was measured by instilling onto the MLL in a main stem bronchus or the distal trachea small volume of saline containing either dissolved benzo(a)pyrene (BaP) or phenanthrene (Phe), or a suspension of particulate solvent green (SG) or macroaggregated albumin (MAA). Sequential lavage of the mucous-retained materials followed the instillations. Retention of BaP in the airway walls of the bronchial tree was studied by instilling the hydrocarbon in an ethanol/saline solution at precise locations of the upper bronchial tree, and measuring the concentration of BaP and its major metabolites in the tissues. Results indicated that mucociliary clearance of SG and MAA particles in the trachea of the Beagle dog occurred at average rates of 27-30 mm/min. Of the two solutes, only the highly lipophilic BaP was sufficiently retained within the MLL to be transported with the mucociliary escalator. In addition, a fraction of the lipophilic materials cleared at a very rapid rate, in excess of 90 mm/min. This may indicate that one monolayer of pulmonary surfactant at the air interface is spreading out of the lungs on top of the MLL ata faster rate than mucociliary clearance. However, despite the protective properties of the MLL, fractions of BaP penetrating to the bronchial epithelium had a clearance half-time in the range of 1.4 hr, a period during which considerable metabolism of the PAH occurred. This long retention indicates a diffusion-limited uptake of BaP by the airways, and underscores the potential for local toxicity of highly lipophilic toxicants in the bronchial epithelium.

Animals↗

PubMed1993

A microspray nozzle for local administration of liquids or suspensions to lung airways via bronchoscopy.

A microspray nozzle has been developed for the localized administration of solutions or suspensions to discrete pulmonary airway regions via bronchoscopy. Toxicants or tracer particles can be administered to single or multiple, specific lung airway segments. This permits studies of local-airway, whole-lung, and systemic responses to inhaled materials. The nozzle is fabricated by ultra-precision machining, has an overall length of 1 mm, and a diameter small enough to fit in the end of a 1.1-mm inner diameter, 1.2-mm outer diameter catheter. In vitro studies demonstrated the delivery efficiency for 99mTc solutions (98 +/- 1% SD) and for suspensions of 99mTc sulfur colloid or 3-mum 85Sr-labeled microspheres (55 +/- 15%). Photographic and gamma camera images of material deposited in the airways of Beagle dogs demonstrated in vivo that the deposition patterns are compact and uniform. The technique may also have therapeutic medical applications.

Administration, Inhalation↗

PubMed1993

Sequential analysis of the pathogenesis of plutonium-induced pulmonary neoplasms in the rat: morphology, morphometry, and cytokinetics.

Light microscopy, morphometry, and cytokinetic techniques were used to examine the dynamics of plutonium-induced pulmonary proliferative lesions and neoplasms in rats at several intervals to 450 days after inhalation exposure to aerosols of 239PuO2. Maximal increases in alveolar and bronchiolar epithelial cell labeling were seen at 30 days; decreasing subsequently, the levels remained elevated above control indices. Focal proliferative epithelial lesions developed in the lung by 180 days and before the onset of pulmonary neoplasms. Pulmonary neoplasms, predominantly adenocarcinomas and squamous cell carcinomas, were initially observed at 308 days. The proliferative lesions progressed through a succession of morphological changes leading to the development of neoplasms. The volume density (fraction) and epithelial surface area of foci of alveolar epithelial hyperplasia increased progressively between 180 and 450 days after exposure, in contrast to the other proliferative lesions. We conclude that plutonium-induced pulmonary neoplasms develop through a succession of focal proliferative lesions that represent developmental preneoplastic lesions. Progressive increases in volume and epithelial surface area of the alveolar epithelial hyperplasias suggest that they may be more at risk for neoplastic transformation than the other histological types of proliferative foci.

Adenocarcinoma↗

PubMed1992

In vitro activity of silicon carbide whiskers in comparison to other industrial fibers using four cell culture systems.

Silicon carbide whiskers (SiCW) and continuous glass filaments are important components of composite materials having potentially widespread use in the automotive, aerospace, and power generation industries. We determined the in vitro activity of three well-characterized samples of silicon carbide whiskers and a continuous glass filament sample in four different cellular assays and compared this to the activities of UICC crocidolite, JM Code 100 glass microfiber, and erionite in the same assay systems. The SiCW had a diameter range of 0.32-0.75 microns and a length range of 4.5-20.1 microns. The SiCW was significantly toxic; on a mass basis, one SiCW sample was more toxic than crocidolite; however, JM Code 100 glass microfiber, which is not toxic in vivo (i.e., it does not cause fibrogenesis or carcinogenesis when inhaled), was also more toxic than crocidolite. The glass filament sample was the least cytotoxic of all the samples tested. On a fiber number basis, all three SiCW samples were more toxic than crocidolite. The results of our study showed that SiCW exhibits significant in vitro biological reactivity. Thus, despite the caution that must be exercised in extrpolating the results of in vitro studies to conclusions about in vivo health effects, SiCW should be considered toxic until further toxicological data are available.

Aluminum Silicates↗

PubMed1992

Beryllium-induced lung disease in the dog following two exposures to BeO.

We have shown previously that dogs exposed once to aerosols of beryllium oxide (BeO) calcined at 500 or 1000 degrees C developed granulomatous lung lesions as well as Be-specific immune responses in the blood and lung. In this report, we investigate the immunopathologic consequences of exposing dogs twice to aerosols of BeO. Dogs previously exposed to aerosols of 500 or 1000 degrees C calcined BeO to achieve an initial lung burden (ILB) of either 50 or 17 micrograms/kg body wt were exposed a second time to BeO calcined at 500 degrees C, 2.5 years after the first exposure, to achieve an ILB of about 50 micrograms/kg body wt. Immune responses of peripheral blood and lung lymphocytes were measured at 0, 14, 30, 60, 90, 120, 150, 165, 180, and 210 days postexposure (dpe), and dogs were euthanized at 210 dpe. Be-specific immune responses occurred in blood at 30 dpe and again at 150 to 210 dpe. Only sporadic positive responses were seen among lung lymphocytes when cells were cultured in 10% fetal bovine serum. In contrast, samples collected at 165, 180, and 210 dpe and incubated with 10% dog serum showed a large number of positive responses in both blood and lung. Histologic lesions were characterized by perivascular and interstitial infiltrates of lymphocytes and macrophages with progression to patchy granulomatous pneumonia accompanied by focal septal fibrosis. We conclude that Be-induced granulomatous and fibrotic lung lesions are accompanied by Be-specific immune responses within the lung but these changes do not appear to be cumulative if enough time has elapsed between exposures.

Aerosols↗

PubMed1992

Species differences in urinary butadiene metabolites; identification of 1,2-dihydroxy-4-(N-acetylcysteinyl)butane, a novel metabolite of butadiene.

1,3-Butadiene (BD) is used in the manufacture of styrene-BD and polybutadiene rubber. Differences seen in chronic toxicity studies in the susceptibility of B6C3F1 mice and Sprague-Dawley rats to BD raise the question of how to use the rodent toxicology data to predict the health risk of BD in humans. The purpose of this study was to determine if there are species differences in the metabolism of BD to urinary metabolites that might help to explain the differences in the toxicity of BD. The major urinary metabolites of BD in F344/N rats, Sprague-Dawley rats, B6C3F1 mice, Syrian hamsters, and cynomolgus monkeys were identified as 1,2-dihydroxy-4-(N-acetylcysteinyl)-butane (I) and the N-acetylcysteine conjugate of BD monoxide [1-hydroxy-2-(N-acetylcysteinyl)-3-butene] (II). These mercapturic acids are formed by addition of glutathione at either the double bond (I) or the epoxide (II) respectively. When exposed to approximately 8000 p.p.m. of BD for 2 h, the mice excreted 3-4 times as much metabolite II as I, the hamster and the rats produced approximately 1.5 times as much metabolite II as I, while the monkeys produced primarily metabolite I. The ratio of formation of metabolite I to the total formation of the two mercapturic acids correlated well with the known hepatic epoxide hydrolase activity in the different species. These data suggest that (i) the availability of the monoepoxide for conjugation with glutathione is highest in the mouse, followed by the hamster and the rat, and is lowest in the monkey; and (ii) the epoxide availability is inversely related to the hepatic activity of epoxide hydrolase, the enzyme that removes the epoxide by hydrolysis. The ratio of the two mercapturic acids in human urine following BD exposure may indicate the pathways of BD metabolism in humans and may aid in the determination of the most appropriate animal model for BD toxicity.

Acetylcysteine↗

PubMed1991

Effects of beryllium metal particles on the viability and function of cultured rat alveolar macrophages.

The physicochemical properties of particles influence their in vivo toxicity following deposition in the respiratory tract. To evaluate the relative contributions of mass and surface area to particle-induced toxicity, rat pulmonary alveolar macrophages (PAM) were exposed to four types of particles in vitro. We used three beryllium metal samples: relatively large (Be-II) and relatively small (Be-V) sized fractions of beryllium metal obtained from an aerosol cyclone, and a beryllium metal aerosol generated by laser vaporization of bulk beryllium metal in an argon atmosphere (Be-L). We also used glass beads (GB) as a negative control particle. End points examined included cell viability, determined by trypan blue dye exclusion, and changes in phagocytic ability, measured by counting the number of sheep red blood cells internalized by the PAM. Phagocytic ability was inhibited by exposure to beryllium particles at concentrations that did not cause appreciable cell death. Results describing effects based on the mass concentration of particles in culture medium were transformed by the amount of specific surface area of the particles to permit the expression of toxicity relative to the amount of particle surface per unit volume of culture medium. On a mass basis, the order of particle-related cytotoxicity was Be-L greater than Be-V greater than Be-II greater than GB, and for inhibition of phagocytosis, the order was Be-L approximately Be-V greater than Be-II greater than GB. When analyzed on a specific surface area basis, the cytotoxicity of the different materials became more similar in a fashion that was largely predicted by the amount of surface of the particles administered. However, because differences in specific surface area among the beryllium particle samples did not entirely predict cytotoxicity, we concluded that factors in addition to specific surface area influenced the expression of toxic effects in cultures of PAM exposed to beryllium metal.

Animals↗

PubMed1991

Dosimetry of beryllium in cultured canine pulmonary alveolar macrophages.

This study was designed to determine the dosimetry within macrophages of beryllium compounds administered at sublethal doses. Information on the dosimetry of beryllium within macrophages is required to guide further efforts to isolate and characterize beryllium-containing haptens. Inhalation of beryllium aerosols can cause chronic berylliosis, a progressive, granulomatous fibrosis of the lung. Studies in laboratory animals indicate that alveolar macrophages take up beryllium compounds and participate in a hypersensitivity immune response to beryllium-containing antigen. Beagle dog macrophage cultures were incubated with 7BeSO4 in solution or with suspensions of 7BeO particles that had been calcined at 500 or 1000 degrees C. Beryllium-7 was measured in fractions collected from cultures after successive centrifugation and filtration steps at 2, 6, 20, and 48 h after addition. An insignificant percentage of BeSO4 was taken up by the cells and did not cause cytotoxicity. Maximum BeO uptake occurred within 6 h, was 60 +/- 6% of added BeO, and was independent of BeO calcination temperature or specific surface area. Approximately 22% of 500 degrees C BeO dissolved within 48 h after addition to cell culture, concurrent with 39% cell killing. Dissolved beryllium remained associated with cells until a cytotoxic concentration was reached (2.2 x 10(-5) M, 15 nmol Be/10(6) cells), when the beryllium was released into the medium. There was no significant dissolution of the 1000 degrees C BeO within 48 h, and no significant cell killing. The results indicate that beryllium dissolved from phagocytized BeO was more cytotoxic than soluble beryllium added extracellularly. The data support an interactive mechanism in which phagocytized BeO particles were dissolved, and dissolved beryllium remained associated with the macrophage until a cytotoxic concentration accumulated, whereupon the beryllium was released to the medium and not appreciably taken up by viable cells.

Animals↗