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PubMed2004

Analysis of time-dependent recovery from beryllium toxicity following chelation therapy and antioxidant supplementation.

Efforts have been made to minimize the toxic effect caused by beryllium. Adult cyclic rats of Sprague Dawley strain were administered a bolus dose of 50mg/kg beryllium nitrate intramuscularly. The chelation therapy with glutathione (GSH), dimercapto propane sulfonic acid (DMPS)+ selenium (Se) and D-Penicillamine (DPA) + Se was given for 3 days followed by a rest of 1,3 and 7 days respectively. The results revealed a significant fall in the blood sugar level, serum alkaline phosphatase activity, serum proteins. A significant rise in the transaminases i.e. aspartate aminotranferase and alanine aminotranferase pattern is indicative of leakage of enzymes from liver resulting in alterations in the cell permeability. A rise in the hepatic lipid peroxidation activity is a direct indication of oxidative damage resulting in free radical generation. Results of the distribution studies by atomic absorption spectrophotometry reveal an increased concentration of beryllium in liver and kidney followed by lung and uterus. The relative ability of 3 chelating agents to act as antagonists for acute beryllium poisoning have been examined in liver, kidney, lungs and uterus. The appreciable change in the beryllium concentration in various organs is duration-dependent during the entire period being highly significant after 7 days rest. From the biochemical assays, and distribution studies it can be assumed that DPA+Se was the most effective therapeutic agent followed by DMPS+Se and GSH. Thus it can be concluded that DPA+Se is a better therapeutic agent as compared to DMPS+Se and GSH.

Animals↗
PubMed1992

An immune model of beryllium-induced pulmonary granulomata in mice. Histopathology, immune reactivity, and flow-cytometric analysis of bronchoalveolar lavage-derived cells.

BACKGROUND: Beryllium compounds can cause acute and chronic lung injury in humans. Although models of chronic granulomatous lung disease have been established in various animal species, a murine model of beryllium-induced chronic lung disease has not been established. EXPERIMENTAL DESIGN: Beryllium was introduced intratracheally either as a soluble salt (BeSO4) or in particulate form (BeO). Various preimmunization protocols were used to enhance immune-mediated pulmonary changes. Cells obtained by bronchoalveolar lavage (BAL) were analyzed using flow cytometry, and the observations correlated with in vitro immune responses and with lung histopathology. RESULTS: Histologic changes were consistently found in mice preimmunized with BeSO4.4H2O plus syngeneic serum. Addition of complete or incomplete Freund's adjuvant to the preimmunization protocol was not necessary to induce granulomatous changes. BAL showed a significant increase in lymphocytes at 2, 4, and 8 weeks after intratracheal BeSO4. Approximately one-third of BAL lymphocytes expressed the gamma/delta T lymphocyte receptor at 2 weeks; at 4 weeks the lymphocytes were predominantly Thy1+, L3T4+ (CD4+) and expressed only the alpha/beta T lymphocyte receptor. Only BAL lymphocytes from mice preimmunized with BeSO4/serum and challenged with BeSO4/serum showed significant in vitro proliferation in response to BeSO4. Macrophage activation antigens (Mac-2, Mac-3) were expressed only during the acute inflammatory phase (2 weeks) whereas increased expression of a monocyte/macrophage antigen (Mac-1) remained elevated beyond the inflammatory period in some instances. Attempts to induce similar lesions in BALB/c and C57BL6/J mice were unsuccessful. Genetic differences at the H-2 major histocompatibility complex gene complex may account for the differential responses to BeSO4 among various mouse strains. A single exposure to BeO also induced histopathologic changes in the lung which correlated with BAL cellularity, but these changes were only observed 8 months after exposure and did not proceed to frank granulomas. CONCLUSIONS: A murine model of granulomatous lung disease may prove useful in understanding the genetic and immunologic factors that determine the response to beryllium. The animal model may also have implications for pulmonary sarcoidosis, a disease of unknown cause(s), whose disease manifestations and BAL profiles are difficult to distinguish clinically and pathologically from chronic beryllium disease.

Animals↗
PubMed1979

Penetration of beryllium through the placenta and its distribution in the mouse.

Penetration of beryllium through the placenta and its distribution in the organs after intravenous administration of BeCl2 in a dose of 0.1 mg/kg was studied in a series of experiments on ICR SPF mice. To trace the fate of beryllium, an isotope in the form of 7BeCl2 in an amount of 111kBq per animal was used. This dose was administered to a group of females before fertilization, on the 7th and 14th day of pregnancy, and to control animals. The animals were killed on the 18th to 19th day of pregnancy and the content of beryllium in the foetuses and its distribution in the organs of the mothers were determined by measuring activity. It has been found that beryllium penetrates through the placenta with difficulty, however, part of the dose administered circulated in the blood long enough for Be to penetrate the foetuses. Of interest is the finding that beryllium in the dose administered influenced the number of foetuses of the exposed females. This finding deserves detailed evaluation in the test of dominant lethal mutations.

Animals↗
PubMed1994

The epidemiological evidence on the carcinogenicity of beryllium in humans.

Authoritative reviews of the question of whether occupational exposure to beryllium compounds is associated with increased risk of respiratory cancer were published in 1987 and were critical of the quality of the evidence available up to that time. No clear conclusion could be drawn from it as to the carcinogenicity of beryllium to humans. If studies published since 1987 are to lead to a revision of the regulatory status of beryllium compounds they must clearly be of high quality and scientific validity. These studies, as well as the earlier reports, are reviewed here. I argue that the small and inconsistent excess of lung cancer deaths in employees of one or two plants seen in two post-1987 studies is compatible with a number of explanations other than that they are attributable to occupational exposure to beryllium. Specifically, information on cigarette smoking is poor, and the data do not exist to rule out the possibility that the small number of excess deaths results from residual confounding by cigarette smoking patterns in the populations studied. Indeed, excess deaths from emphysema and ischemia heart disease in the same cohort suggest that confounding by cigarette smoking is a more likely explanation of the lung cancer excess than is occupational exposure to beryllium compounds.

Berylliosis↗
PubMed1997

Beryllium induces IL-2 and IFN-gamma in berylliosis.

Chronic beryllium disease (CBD) provides a model for study of the Ag-stimulated, cell-mediated immune response that, over time, progresses to granulomatous lung disease. Using cells obtained with bronchoalveolar lavage from patients with CBD and normal individuals, we evaluated beryllium salt-stimulated T lymphocyte proliferation and production of proinflammatory cytokines. Our findings demonstrate that beryllium sulfate stimulates production of both IL-2 and IFN-gamma, not IL-4 and IL-7. We observed a brief time course for IL-2 protein (6-48 h after BeSO4 stimulation) and mRNA production (3-6 h) and a protracted time course for IFN-gamma protein (24-168 h) and mRNA (0.25-168 h). Beryllium-stimulated T lymphocyte proliferation and IFN-gamma release were only partially inhibited by neutralization of IL-2. On the basis of these findings, we hypothesized that IFN-gamma and the IL-2/IFN-gamma-inducible alpha subunit of the soluble IL-2 receptor were elevated in serum and bronchoalveolar lavage fluid of individuals with disease and were molecular markers of granulomatous disease. The data demonstrate that levels of the alpha subunit of the soluble IL-2 receptor, but not IFN-gamma, are elevated in the serum (median = 1428 U/ml; interquartile range = 823-2137 U/ml) and bronchoalveolar lavage fluid (median = 1.56 U/ml, interquartile range = 1.04-4.22 U/ml) of patients with CBD and correlate with the degree of pulmonary lymphocytosis and clinical measures of disease severity. We conclude that IL-2 and IFN-gamma are produced in the beryllium-stimulated, cell-mediated immune response with different time courses and that the alpha subunit of the soluble IL-2 receptor may serve as a biomarker of disease progression.

Adult↗
PubMed2002

Clinical approach to chronic beryllium disease and other nonpneumoconiotic interstitial lung diseases.

Exposures in the workplace result in a diverse set of diseases ranging from the pneumoconiosis to other interstitial lung diseases to acute lung injury. Physician awareness of the potential disease manifestations associated with specific exposures is important in defining these diseases and in preventing additional disease. Most occupational diseases mimic other forms of lung disease, including pulmonary fibrosis, sarcoidosis, adult respiratory distress syndrome (ARDS), and bronchiolitis. A "sarcoidosis"-like syndrome, usually limited to the lungs, may result from exposure to bioaerosols and a number of metals. Exposure to beryllium in the workplace produces a granulomatous lung disease clinically indistinguishable from sarcoidosis, chronic beryllium disease (CBD). Beryllium's ability to produce a beryllium-specific immune response is used in the beryllium lymphocyte proliferation tests to confirm a diagnosis of CBD and exclude sarcoidosis. Exposure to other metals must also be considered in the differential diagnosis of sarcoidosis. When an individual presents acutely with ARDS or acute lung injury, an acute inhalational exposure must be considered. Exposure to a number of irritant substances at high levels may cause a "chemical pneumonitis" or acute lung injury, depending on the solubility and physicochemical properties of the substance. Some of the most notable agents include nitrogen and sulfur oxides, phosgene, and smoke breakdown products. Ingestion of paraquat may also result in an ARDS syndrome, with pulmonary fibrosis eventually resulting. Bronchiolitis is a rare manifestation of inhalational exposures but must also be considered in the clinical evaluation of inhalational exposure.

Adult↗
PubMed1994

Alveolar macrophages from patients with beryllium disease and sarcoidosis express increased levels of mRNA for tumor necrosis factor-alpha and interleukin-6 but not interleukin-1 beta.

Recent evidence suggests that the alveolar macrophage-derived cytokines tumor necrosis factor-alpha (TNF-alpha), interleukin-1 beta (IL-1 beta), and interleukin-6 (IL-6) play important roles in granulomatous diseases. Our objective was to quantify the mRNA for these cytokines in beryllium disease, a human granulomatous disease of known etiology. We hypothesized that alveolar macrophages and bronchoalveolar lavage fluid from patients with beryllium disease and sarcoidosis would express increased levels of mRNA and proteins, respectively, for TNF-alpha, IL-1 beta, and IL-6 compared with those of normal individuals. We performed bronchoalveolar lavage and used a quantitative polymerase chain reaction to determine alveolar macrophage-derived cytokine gene expression. We determined lavage fluid cytokine levels by enzyme-linked immunosorbent assay. In patients with beryllium disease (n = 23), we observed elevated macrophage mRNA expression for TNF-alpha and IL-6 when compared with that of normal subjects (n = 7). Sarcoidosis patients (n = 6) also had increased expression for TNF-alpha and IL-6 compared with that of normal volunteers. IL-1 beta expression was similar in all three groups. In patients with beryllium disease (n = 39), lavage fluid TNF-alpha concentration was higher than that of 16 normal subjects. Lavage fluid IL-1 beta and IL-6 levels did not differ among the groups. This is the first report of macrophage cytokine expression in beryllium disease. These novel findings suggest that macrophage expression of TNF-alpha and IL-6 may be important in the human granulomatous inflammatory response.

Actins↗
PubMed1996

Chronic beryllium disease: diagnosis and management.

Chronic beryllium disease is predominantly a pulmonary granulomatosis that was originally described in 1946. Symptoms usually include dyspnea and cough. Fever, anorexia, and weight loss are common. Skin lesions are the most common extrathoracic manifestation. Granulomatous hepatitis, hypercalcemia, and kidney stones can also occur. Radiographic and physiologic abnormalities are similar to those in sarcoidosis. While traditionally the pathologic changes included granulomas and cellular interstitial changes, the hallmark of the disease today is the well-formed granuloma. Immunologic studies have demonstrated a cell-mediated response to beryllium that is due to an accumulation of CD4+ T cells at the site of disease activity. Diagnosis depends on the demonstration of pathologic changes (i.e., granuloma) and evidence that the granuloma was caused by a hypersensitivity to beryllium (i.e., positive lung proliferative response to beryllium). Using these criteria, the diagnosis of chronic beryllium disease can now be made before the onset of clinical symptoms. Whether, with early diagnosis, the natural course of this condition will be the same as when it was traditionally diagnosed is not known. Currently, corticosteroids are used to treat patients with significant symptoms or evidence of progressive disease.

Berylliosis↗
PubMed2001

Gene expression profile in BALB/c-3T3 cells transformed with beryllium sulfate.

Differential gene expression was studied to understand the potential molecular mechanism responsible for cell transformation and tumorigenesis induced by beryllium. Cell lines were derived from tumors developed in nude mice injected subcutaneously with BALB/c-3T3 cells morphologically transformed with beryllium sulfate. Using the Atlas mouse 1.2 cDNA expression microarray, the expression profiles of 1176 genes, belonging to several different functional categories, were studied in the tumor cells as well as in the nontransformed control cells. Expression of 18 genes belonging to two functional groups was found to be consistently and reproducibly different (at least twofold) in the tumor cells compared with the control cells. The functional groups and the differentially expressed genes are as follows: The cancer-related genes (nine genes) were the ets-related transcription factor activated by ras, colony-stimulating factor, A-myb, sky, cot1, c-fos, c-jun, c-myc, and R-ras proto-oncogenes. The DNA synthesis, repair, and recombination genes (nine genes) were the DNA replication licensing factor MCM4, the DNA replication licensing factor MCM5, the DNA mismatch repair gene PMS2, the DNA excision repair gene, the DNA mismatch repair gene MSH2, the ultraviolet excision repair gene Rad23 DNA ligase 1, Rad51, and Rad52. The differential gene expression profile was confirmed with reverse transcription-polymerase chain reaction using primers specific for the differentially expressed genes. In general, expression of the cancer-related genes was upregulated, while expression of genes involved in DNA synthesis, repair, and recombination was downregulated in the tumor cells compared with the control cells. Using c-fos and c-jun, two of the differentially expressed genes, as model genes, we have found that in the nontransformed BALB/c-3T3 cells, the beryllium-induced transcriptional activation of these genes was dependent on pathways of protein kinase C and mitogen-activated protein kinase and independent of reactive oxygen species. These results indicate that beryllium-induced cell transformation and tumorigenesis are accompanied by and are possibly a product of alterations in expression of genes related to cancer and to DNA synthesis, repair, and recombination.

3T3 Cells↗
PubMed1991

Fluoride, beryllium and ADP combine as a ternary complex in aqueous solution as revealed by a multinuclear NMR study.

Different kinds of nucleotide binding enzymes are sensitive to fluoroberyllate complexes (BeFx) and fluoroaluminate complexes (AlFy). It has been hypothesized that the effects of these fluorometals are related to the generation at a nucleotide binding site of a pseudo nucleoside triphosphate, consisting of a fluorometal moiety bound to the beta phosphate group of a molecule of nucleoside diphosphate (Bigay et al. 1985; Lunardi et al. 1985). In order to establish whether ternary complexes comprising ADP, beryllium and fluoride can exist in slightly alkaline solution in the absence of enzyme, we have carried out a multinuclear (31P, 9Be and 19F) NMR study. In preliminary experiments, pyrophosphate (PPi) was substituted for ADP and taken as a simpler analog of nucleoside diphosphate. In the absence of fluoride, three types of PPi-Be complexes were generated: two of these were bidentate chelates with either one or two pyrophosphate molecules bound per beryllium; the third one was a monodentate complex. It is probable that the same types of combination exist between the polyphosphate chain of ADP and Be. In the presence of fluoride, both ADP and PPi combined with beryllium to form ternary complexes. These complexes consisted of monofluoroberyllate(-BeF) or difluoroberyllate(-BeF2) bound to the two phosphates of one molecule of ADP or PPi as a bidentate chelate. We failed to observe the formation of complexes between ADP and trifluoroberyllate(-BeF3). The relevance of this study to the biological effects of fluoride and beryllium on various enzymic reactions is discussed.

Adenosine Diphosphate↗
PubMed1977

Effect of iron-beryllium antagonism on the growth of Pseudomonas fluorescens type S.

Studies of the growth of Pseudomonas fluorescens type S in acidified peptone nutrient broth supplemented with potassium dioxalatoberyllate show that the inhibitory action of beryllium on the lag phase can be strongly counteracted by an increase in the iron content of the medium. In terms of relative concentrations, Fe3+ is up to 250 times more effective than Mg2+ as an antagonist of beryllium under the conditions employed. Conversely, evidence of the effect of beryllium on iron-dependent constituents of the cell is provided by the fact that cultures of Pseudomonas fluorescens adapted to relatively high concentrations of beryllium show a marked decrease in cytochrome c content.

Beryllium↗
PubMed1990

Studies on the genotoxicity of beryllium sulphate in vitro and in vivo.

There is limited evidence that beryllium is a lung carcinogen to man, and several compounds of beryllium are carcinogenic to the lungs of the rat, rabbit and monkey. One such compound is beryllium sulphate (BeSO4.4H2O). This soluble salt has been evaluated in a range of genotoxicity tests. It was non-mutagenic to Salmonella typhimurium (strains TA1535, 1537, 1538, 98 and 100) when evaluated in the plate-incorporation assay at dose levels up to 5 mg/plate (+/- induced rat-liver S9 mix). It was also non-clastogenic to Chinese hamster lung (CHL) cells cultured in vitro. When dosed to male CBA mice via oral gavage at dose levels of 80% and 50% of the medium lethal dose (2.3 and 1.4 g/kg, respectively) it failed to increase the incidence of micronucleated polychromatic erythrocytes in the bone marrow (sampled at 24, 48 and 72 h post-dosing). However, a marked depression of erythropoiesis was evident 24 h after dosing suggestive of beryllium-mediated bone-marrow toxicity. When tested in the strain A mouse lung tumour bioassay, BeSO4 induced a significant increase in the number of tumour-bearing animals but not in the number of lung tumours per animal. These findings are discussed within the contexts of other genotoxicity data published for BeSO4, and of current strategies for the detection of possible human carcinogens.

Adenoma↗
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↗
PubMed1986

Studies on the effects of dietary beryllium at two different calcium concentrations in Achatina fulica (Pulmonata).

The mortality was highest in snails fed beryllium in the diet containing the sub-optimal concentration of calcium. There was no increase in weight over an 8 week period. Snails fed the diet containing the optimal concentration of calcium without added beryllium showed maximum weight increase but calcium alone may not be responsible for elevated growth rate. Dietary calcium enhancement appears to be responsible for the reduced concentration of zinc, magnesium, phosphate and beryllium in the tissues. Beryllium treatment did not affect the calcium concentration in the digestive gland tissue but increased zinc and magnesium in the shell. The results are discussed in relation to uptake studies and possible enzyme systems involved.

Animals↗
PubMed2005

Genetic susceptibility and immune-mediated destruction in beryllium-induced disease.

Chronic beryllium disease (CBD) is a hypersensitivity disorder caused by beryllium exposure in the workplace and is characterized by the accumulation of beryllium-specific CD4(+) T cells in the lung and granulomatous inflammation. This disorder occurs in 2-16% of exposed workers, depending on genetic susceptibility and the nature of the exposure. Susceptibility has been associated with HLA-DP alleles possessing a glutamic acid at the 69th position (Glu(69)) of the beta-chain. The mechanism for this association lies in the ability of these HLA-DP molecules to present beryllium to pathogenic CD4(+) T cells. These findings in CBD have important implications for studies in autoimmune diseases, including those in which the inciting antigen is unknown and the target organ is inaccessible.

Berylliosis↗
PubMed1998

Effect of beryllium on the castability and resistance of ceramometal bonds in nickel-chromium alloys.

STATEMENT OF PROBLEM: Castability and ceramometal bond resistance play an important role in accepting nickel-chromium alloys as a substitute for gold alloys in dentistry. PURPOSE: This study was developed to verify the effect of beryllium on these factors in several compositions of nickel-based alloys by submitting them to castability and ceramometal bonding resistance tests. MATERIAL AND METHODS: Three experimental compositions of Ni-Cr alloys with different amounts of beryllium were used. One beryllium-free alloy was used as the control. RESULTS: Analysis of variance and Tukey's test showed significant differences (alpha = .001) for the castability test results and significant differences (alpha = .05) for ceramometal bond resistance between alloys. CONCLUSIONS: Although the amounts of chromium, manganese, and niobium were maintained, the variations in the amounts of beryllium allowed the estimation that Be-containing alloys presented better castability than Be-free alloys. The 0.9% Be-containing alloy demonstrated higher resistance of the ceramometal bond than the Be-free alloy.

Analysis of Variance↗
PubMed2003

Beryllium dermatitis.

Chronic beryllium disease is a granulomatous disorder characterized by a cell-mediated immune response to beryllium. Most reports of chronic beryllium disease discuss pulmonary and noncutaneous immunologic findings. This report of occupational chronic beryllium disease emphasizes cutaneous findings and discusses the potential role of skin exposure in the disease.

Adult↗
PubMed2003

Spectrofluorimetric determination of trace amounts of beryllium in mineral water and human's hair.

A new fluorescent reagent, 2-hydroxy-1-naphthaldehydene-8-aminoquinoline (HNAAQ), was synthesized. The fluorescent reaction of this reagent with beryllium was also studied. Based on this chelation, a highly sensitive spectrofluorimetric method was developed for determination of trace amounts of beryllium at pH 9.2. Under these conditions, the Be-HNAAQ complex has excitation and emission maxima at 410 and 450 nm, respectively. The linear range of the method is from 0 to 35 microg l(-1) and detection limit is 0.099 microg l(-1) of beryllium. Interference of other ions was studied. It is necessary to remove the interfering cations through concealing by EDTA and extraction separation techniques. The selectivity of the method can be increased remarkably. The procedure can be easily performed and affords good precision and accuracy. This method has been successfully applied to the determination of beryllium in mineral water and human's hair.

Aminoquinolines↗