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PubMed2002

Target organ localization of memory CD4(+) T cells in patients with chronic beryllium disease.

Chronic beryllium disease (CBD) is caused by exposure to beryllium in the workplace, and it remains an important public health concern. Evidence suggests that CD4(+) T cells play a critical role in the development of this disease. Using intracellular cytokine staining, we found that the frequency of beryllium-specific CD4(+) T cells in the lungs (bronchoalveolar lavage) of 12 CBD patients ranged from 1.4% to 29% (mean 17.8%), and these T cells expressed a Th1-type phenotype in response to beryllium sulfate (BeSO(4)). Few, if any, beryllium-specific CD8(+) T cells were identified. In contrast, the frequency of beryllium-responsive CD4(+) T cells in the blood of these subjects ranged from undetectable to 1 in 500. No correlation was observed between the frequency of beryllium-responsive bronchoalveolar lavage (BAL) CD4(+) T cells as detected by intracellular staining and lymphocyte proliferation in culture after BeSO(4) exposure. Staining for surface marker expression showed that nearly all BAL T cells exhibit an effector memory cell phenotype. These results demonstrate a dramatically high frequency and compartmentalization of antigen-specific effector memory CD4(+) cells in the lungs of CBD patients. These studies provide insight into the phenotypic and functional characteristics of antigen-specific T cells invading other inaccessible target organs in human disease.

Berylliosis↗

PubMed1999

Partial IL-10 inhibition of the cell-mediated immune response in chronic beryllium disease.

Chronic beryllium disease (CBD) provides a human disorder in which to study the delayed type IV hypersensitivity response to persistent Ag that leads to noncaseating pulmonary granuloma formation. We hypothesized that, in CBD, failure of IL-10 to modulate the beryllium-specific, cell-mediated immune response would result in persistent, maximal cytokine production and T lymphocyte proliferation, thus contributing to the development of granulomatous lung disease. To test this hypothesis, we used bronchoalveolar lavage cells from control and CBD subjects to evaluate the beryllium salt-specific production of endogenous IL-10 and the effects of exogenous human rIL-10 (rhIL-10) on HLA expression, on the production of IL-2, IFN-gamma, and TNF-alpha, and on T lymphocyte proliferation. Our data demonstrate that beryllium-stimulated bronchoalveolar lavage cells produce IL-10, and the neutralization of endogenous IL-10 does not increase significantly cytokine production, HLA expression, or T lymphocyte proliferation. Second, the addition of excess exogenous rhIL-10 partially inhibited the beryllium-stimulated production of IL-2, IFN-gamma, and TNF-alpha; however, we measured no change in T lymphocyte proliferation or in the percentage of alveolar macrophages expressing HLA-DP. Interestingly, beryllium salts interfered with an IL-10-stimulated decrease in the percentage of alveolar macrophages expressing HLA-DR. We conclude that, in the CBD-derived, beryllium-stimulated cell-mediated immune response, low levels of endogenous IL-10 have no appreciable effect; exogenous rhIL-10 has a limited effect on cytokine production and no effect on T lymphocyte proliferation or HLA expression.

Adjuvants, Immunologic↗

PubMed2003

Misdiagnosis of sarcoidosis in patients with chronic beryllium disease.

BACKGROUND AND AIM: Sarcoidosis (SA) is a chronic systemic disorder characterized by infiltration of inflammatory cells in affected organs, resulting in the formation of granulomas. Granulomas are observed in numerous infectious diseases and hypersensitivity reactions (e.g., beryllium). Chronic beryllium disease (CBD) is a multisystem entity caused by dust, fumes or mists of beryllium metal or its salts. Although beryllium has been used for years by several industries in Israel, no case of CBD had ever been reported until recently when we described a 21-year-old female dental technician with CBD who was originally diagnosed as having SA. We launched the current investigation to test the hypothesis that other cases of CBD in Israel were not previously reported because these patients were misdiagnosed as having SA. METHODS: Forty-seven patients with confirmed-SA from our outpatient clinic were recalled in order to reevaluate their occupational exposure history. We performed the beryllium lymphocyte transformation test (BeLTT) on each patient with a potentially positive environmental exposure anamnesis to beryllium (14/47). RESULTS: Two of the 14 patients with evidence of granulomas in lung tissue (pulmonary involvement) and 1/14 with extrapulmonary involvement who all had a positive occupational exposure to beryllium and a positive BeLTT test had been erroneously diagnosed as having SA instead of CBD. CONCLUSION: Our findings emphasize the vital importance of taking a comprehensive occupational history in the clinical evaluation of patients suspected of having SA.

Adult↗

PubMed2005

[Chronic beryllium disease: a model of interaction between environmental exposure and genetic predisposition. Pathogenesis and clinical features (Part 2)].

INTRODUCTION: Chronic beryllium disease (CBD) is an occupational lung disease caused by the inhalation of beryllium dust, fumes or metallic salts. CURRENT DATA: Beryllium affects the lungs via particles deposited in the pulmonary alveoli. These are ingested by alveolar macrophages which act as antigen presenting cells to CD4+ T lymphocytes. T lymphocytes proliferate in response to beryllium antigens and combined with macrophages produce numerous epithelioid granulomas with the release of inflammatory cytokines (IFNgamma, IL-2, TNFalpha and IL6) and growth factors. Beryllium induces macrophage apoptosis which reduces its clearance from the lung which in turn contributes to the host's continual re-exposure and thus a chronic granulomatous disorder. Pulmonary granulomatous inflammation is the primary manifestation of CBD, but the disease occasionally involves other organs such as the liver, spleen, lymph nodes and bone marrow. The clinical, radiological, and histopathological features of CBD can be difficult to distinguish from sarcoidosis. The Beryllium lymphocyte proliferation test (BeLPT) demonstrates a beryllium specific immune response, confirms the diagnosis of CBD, and excludes sarcoidosis. CONCLUSIONS AND PERSPECTIVES: CBD provides a human model of pulmonary granulomatous disease produced by an occupational exposure, occurring more frequently in those with a genetic pre-disposition. It can be differentiated from sarcoidosis by specific immunological testing.

Berylliosis↗

PubMed1996

Cytokine production by bronchoalveolar lavage cells in chronic beryllium disease.

Chronic beryllium disease (CBD) begins as a sensitizing cell-mediated immune response to beryllium antigen that progresses to granulomatous lung disease. Previous studies demonstrated the involvement of proinflammatory cytokines in the disease process, but the pattern and regulation of cytokine release is unknown. Using bronchoalveolar lavage (BAL) cells from CBD patients in short-term tissue culture, we evaluated cytokine protein levels by enzyme-linked immunosorbent assay and T-lymphocyte proliferation by tritiated thymidine incorporation. We observed the beryllium-stimulated release of tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), interleukin-2 (IL-2), and interferon-gamma (IFN-gamma) but not interleukin-4 (IL-4). Beryllium-stimulated IFN-gamma release was sustained to 168 hr in culture, whereas IL-2 concentrations returned to baseline after 24 hr. Neutralization of IL-2 decreased beryllium-stimulated T-lymphocyte proliferation, but the level of proliferation remained elevated in comparison to unstimulated BAL cells. These data suggest that T helper 1 (Th1) lymphocytes participate in the beryllium disease process; that IFN-gamma levels remain elevated after IL-2 levels return to baseline; and that IL-2 participates directly in beryllium-stimulated T-cell proliferation, but other T-lymphocyte mitogenic cytokines may be involved.

Berylliosis↗

PubMed2004

Variable response to long-term corticosteroid therapy in chronic beryllium disease.

OBJECTIVES: Chronic beryllium disease (CBD) shares many of its characteristics with sarcoidosis and is often treated with corticosteroids. There is limited available literature regarding the effect of long-term corticosteroid therapy on the natural history of CBD. METHODS AND MATERIALS: We conducted an observational retrospective study of six patients with CBD who received prolonged corticosteroid treatment with a mean pulmonary function test follow-up period of 10.1 years. Five of the six patients were exposed to beryllium at the same workplace. The diagnosis in four of the six cases was confirmed by a positive beryllium lymphocyte proliferation test result on blood or BAL fluid. Periodic pulmonary function tests were analyzed in relation to removal from beryllium exposure and treatment with corticosteroids. MEASUREMENTS AND RESULTS: Two broad patterns of response were noted in these patients. The first pattern seen in two patients showed no improvement in FVC or diffusion capacity of the lung for carbon monoxide (Dlco) with corticosteroids. However, a significant improvement in these parameters was noted on cessation of beryllium exposure in one of the two patients. The second pattern showed an initial improvement in FVC and Dlco with corticosteroids, which was not sustained. An improvement was noted on stopping beryllium exposure. CONCLUSIONS: The response to long-term corticosteroids in CBD, quite like that in sarcoidosis, is variable. Significant lung function improvement may be seen following cessation of beryllium exposure.

Adult↗

PubMed2002

Protective effect of Tiron (4,5-dihydroxybenzene-1,3-disulfonic acid disodium salt) against beryllium-induced maternal and fetal toxicity in rats.

The efficacy of Tiron (4,5-dihydroxybenzene 1,3-disulfonic acid disodium salt) was examined in the treatment of beryllium-induced maternal and developmental toxicity in rats. Single administration of beryllium nitrate at a dose of 50 mg/kg (i.m.) on day 13 of gestation caused reductions in fetal and placental weights, the number of implantation sites and number of corpora lutea, as well as causing post-implantation loss, stunted growth, increase in the number of resorptions, and also a disturbed sex ratio. Maternal toxicity was demonstrated by reduction in body weight gain. Administration of beryllium also showed significant alteration in the hematological and biochemical indices of the mother as well as the fetus. Marked decreases were recorded in hemoglobin percentage, blood sugar levels, serum protein contents and serum alkaline phosphatase activity. By contrast, significant elevation was found in the activity of transaminases (aspartate aminotransferase and alanine aminotransferase). Tissue protein contents, glycogen contents, activities of alkaline phosphatase, adenosine triphosphatase and succinic dehydrogenase of kidney, lungs and uterus, and maternal and fetal liver all showed significantly decreased values after beryllium exposure, and remarkable elevation was observed in acid phosphatase, glucose-6-phosphatase and hepatic lipid peroxidation. These parameters were restored considerably with administration of 471 mg/kg i.m. Tiron from days 14 to 18 of gestation. Atomic absorption spectrophotometry also revealed a high concentration of beryllium in different organs of pregnant rats. Interestingly, a small amount of metal ion was also detected in the fetus and reduced accumulation of beryllium was noticed after Tiron treatment.

1,2-Dihydroxybenzene-3,5-Disulfonic Acid Disodium ↗

PubMed2006

A theoretical framework for evaluating analytical digestion methods for poorly soluble particulate beryllium.

Complete digestion of all chemical forms and sizes of particulate analytes in environmental samples is usually necessary to obtain accurate results with atomic spectroscopy. In the current study, we investigate the physicochemical properties of beryllium particles likely to be encountered in samples collected from different occupational environments and present a hypothesis that a dissolution theory can be used as a conceptual framework to guide development of strategies for digestion procedures. For monodisperse single-chemical constituent primary particles, such as those encountered when handling some types of beryllium oxide (BeO) powder, theory predicts that a digestion procedure is sufficient when it completely dissolves all primary particles, independent of cluster size. For polydisperse single-chemical constituent particles, such as those encountered during the handling of some types of beryllium metal powder, theory predicts that a digestion procedure is sufficient only when it completely dissolves the largest particle in the sample. For samples with unknown or multi-chemical constituent particles and with particles having undefined sizes, e.g., fume emissions from a copper-beryllium alloy furnace operation or dust from a beryl ore crushing operation, a surface area-limited and single-constituent-dependent dissolution theory may not predict complete dissolution, thereby requiring non-routine robust treatment procedures with post-digestion filtration, followed by examination of residual particulate material. Additionally, for beryllium, and likely other poorly soluble materials, particulate reference materials of various chemical forms and size distributions are needed to better evaluate and harmonize analytical digestion procedures. Figure Generation of aerosol particles during machining of beryllium oxide.

Aerosols↗

PubMed1991

A novel enzyme-linked immunosorbent assay (ELISA) for the detection of beryllium antibodies.

A novel immunological method has been developed for detecting antibodies (IgG molecules) specific to beryllium, a light metal used in industry and capable of causing chronic beryllium disease. Beryllium metal was vacuum deposited onto commercially available immunological microsticks, which were then exposed to test plasma containing the putative antibodies. Antigen-antibody complexes were located using a biotin-avidin amplification method. One employee diagnosed with chronic beryllium disease and one diagnosed as "sensitized" (lymphocyte transformation positive) exhibited antibody titers graphically and statistically different and higher than a pooled baseline control population. Plasma from these two employees (former beryllium workers) was used in four different approaches to validate the presence of beryllium antibodies. The assay proved to be reproducible.

Antibodies↗

PubMed1987

Mutagenicity, carcinogenicity and teratogenicity of beryllium.

The carcinogenicity of a number of beryllium compounds has been confirmed in experiments on laboratory animals and this metal has to be treated as a possible carcinogenic threat to man. These carcinogenic properties are associated with mutagenic activity as shown by the results of short-term tests performed in vitro with beryllium chloride and beryllium sulfate. These soluble beryllium compounds can produce some infidelity of in vitro synthesis, forward gene mutations in microorganisms and in mammalian cells. They are also able to induce cell transformation. In addition to the positive results obtained in several short-term assays beryllium compounds have been found to bind to nucleoproteins, to inhibit certain enzymes needed for DNA synthesis, to bind nucleic acids to cell membranes and to inhibit microtubule polymerization. The teratogenicity of beryllium salts is relatively unknown and needs additional investigation.

Animals↗

PubMed1989

Liv-52 protection against beryllium toxicity in female albino rats.

Toxic effects of beryllium salts on the reproductive organs of cyclic adult female albino rats have been studied. An attempt was made to overcome these effects using an Ayurvedic medicine Liv-52 (Himalaya Drug Co., Bombay). Liv-52-primed rats (1 mL/rat/day for 15 days) were exposed to beryllium nitrate intravenously and were sacrificed at different time intervals. At autopsy ovary, uterus, cervix, and vagina were processed for biochemical and histopathologic examination. Histoarchitecture of the ovary, uterus, cervix, and vagina revealed severe necrotic changes with beryllium nitrate treatment. Tissue glycogen content and the activity of alkaline phosphatase were inhibited significantly after beryllium treatment. Total and esterified cholesterol levels increased significantly in these organs when exposed to beryllium salts. However, a significant improvement was observed in the biochemical parameters and histoarchitecture of these organs when beryllium was injected into Liv-52-primed animals.

Acid Phosphatase↗

PubMed1975

Factors affecting airborne beryllium concentrations in dental spaces.

Air sampling for beryllium concentrations produced during finishing procedures for a beryllium-containing alloy was conducted in two rooms with capacities of 700 and 10,000 cubic feet. The clearance rate of beryllium in the air and the effect of ventilation and room size on these concentrations were investigated. With local lathe ventilation, no beryllium was found. Without local lathe ventilation, mean 10 minutes concentrations of about 23 mug per cubic meter were found at the breathing zone of the lathe operator in both rooms. At 4 and 8 feet from the breathing zone, sizable concentrations of beryllium above the maximum acceptable standard were found only in the small room. These levels decreased to zero 10 minutes after completion of the finishing and polishing procedure. It was concluded that there was little hazard to dental personnel when local lathe ventilation was used; however, our finding of high concentrations of beryllium in the air when lathe ventilation was not used indicates that continued vigilance must be maintained.

Air↗

PubMed2003

Potential binding modes of beryllium with the class II major histocompatibility complex HLA-DP: a combined theoretical and structural database study.

In an effort to understand the molecular basis of chronic beryllium disease (CBD), a study of the chemical relationship between beryllium, antigen, and the major histocompatibility complex II, HLA-DP, was undertaken. A homology model of the HLA-DP protein was developed. An analysis of the sequences of HLA-DPB1 and HLA-DPA1 alleles most common among CBD patients revealed several carboxylate rich regions in the peptide-binding cleft. These regions contain many hard Lewis base sites that may provide bonding opportunities for beryllium, a hard Lewis acid. Quantum chemistry calculations and structural database results support the presence of beryllium clusters, bridged by carboxylate, hydroxo, and/or oxo ligands, in the HLA-DP binding cleft. These results strongly suggest that beryllium clusters are an integral part of the antigen, and may even act solely as antigen. This work provides an initial model for thinking about beryllium interactions with proteins relevant to CBD and other metal-induced diseases.

Amino Acid Sequence↗

PubMed2006

Trace-level beryllium analysis in the laboratory and in the field: state of the art, challenges and opportunities.

Control of workplace exposure to beryllium is a growing issue in the United States and other nations. As the health risks associated with low-level exposure to beryllium are better understood, the need increases for improved analytical techniques both in the laboratory and in the field. These techniques also require a greater degree of standardization to permit reliable comparison of data obtained from different locations and at different times. Analysis of low-level beryllium samples, in the form of air filters or surface wipes, is frequently required for workplace monitoring or to provide data to support decision-making on implementation of exposure controls. In the United States and the United Kingdom, the current permissible exposure level is 2 microg m(-3) (air) and the United States Department of Energy has implemented an action level of 0.2 microg m(-3) (air) and 0.2 microg/100 cm(2) (surface). These low-level samples present a number of analytical challenges, including (1) a lack of suitable standard reference materials, (2) unknown robustness of sample preparation techniques, (3) interferences during analysis, (4) sensitivity (sufficiently low detection limits), (5) specificity (beryllium speciation) and (6) data comparability among laboratories. Additionally, there is a need for portable, real-time (or near real-time) equipment for beryllium air monitoring and surface wipe analysis that is both laboratory-validated and field-validated in a manner that would be accepted by national and/or international standards organizations. This paper provides a review of the current analytical requirements for trace-level beryllium analysis for worker protection and also addresses issues that may change those requirements. The current analytical state of the art and relevant challenges facing the analytical community will be presented, followed by suggested criteria for real-time monitoring equipment. Recognizing and addressing these challenges will present opportunities for laboratories, research and development organizations, instrument manufacturers and others.

Accreditation↗

PubMed1983

Epidemiological aspects of beryllium-induced nonmalignant lung disease: a 30-year update.

The unusual epidemiology of beryllium disease observed in the early studies of beryllium disease led in 1951 to the hypothesis that the chronic form of the disease is the result of an acquired sensitization to beryllium or its compounds. After 30 years, the role of sensitization has been confirmed in a number of laboratory and clinical studies. The unusual epidemiological features first summarized by Sterner and Eisenbud continue to be evident. The early studies also led to formulation of standards that have resulted in effective control of both the acute and chronic pulmonary forms of beryllium disease. No case of acute chemical pneumonitis has been reported among beryllium workers in about 15 years, and the number of chronic cases has diminished greatly despite a marked increase in the use of beryllium.

Berylliosis↗

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↗

PubMed1995

Experimental evidence for the existence of non-nuclear maxima in the electron-density distribution of metallic beryllium. A comparative study of the maximum entropy method and the multipole refinement method.

The electron-density distribution (EDD) of metallic beryllium has been derived from the structure factors of Larsen & Hansen [(1984). Acta Cryst. B40, 169-179] using the maximum entropy method (MEM). Subsequent topological analysis reveals non-nuclear maxima (NNM) in the EDD. Plots of the gradient field of the electron density illustrates this finding. A possible critical-point network for the hexagonal close-packed (h.c.p.) structure of beryllium is suggested. It is thus demonstrated that it is possible to obtain detailed topological information about the electron density in metallic beryllium without the use of a structural model. In order to test the findings of the MEM, the same set of structure factors were analysed using the multipole refinement method (MRM). Use of the MRM also reveals NNM. The results of the two different approaches to electron-density analysis are contrasted and discussed. Expressed within the framework of the theory of atoms in molecules, our results suggest that the h.c.p. structure of beryllium has no Be atoms directly bonded to other Be atoms. The structure is held together through a three-dimensional network of bonds between the NNM and Be atoms as well as between different NNM. The topological analysis thus reveals that the beryllium structure has important interactions connecting Be atoms of different basal plane layers. The breaking of these interactions when forming a surface may explain the abnormally large expansion of the inter-layer distance in the beryllium surface structure.

Beryllium↗

PubMed1988

Pulmonary function in beryllium workers: assessment of exposure.

The inhalation of beryllium causes a serious lung disease characterised by pronounced radiographic and functional impairments and occurs in workers engaged in the extraction and manufacture of the metal. This paper describes the beryllium exposure levels and refining processes in a large beryllium factory operating since the 1930s. Lifetime beryllium exposure histories were estimated for the 309 workers present at a health survey conducted in 1977. Beryllium exposure levels in the plant were high for many years, with some estimated exposure levels in excess of 100 micrograms/m3. As late as 1975, there were exposures to beryllium above 10 micrograms/m3 in some jobs. After about 1977, the plant was in compliance with the permissible exposure limit of 2.0 micrograms/m3. The median cumulative exposure in this cohort was 65 micrograms/m3-years and the median duration of exposure was 17 years. From these data a series of exposure parameters, functions of the exposure histories that characterise biologically important dimensions of exposure were calculated for each worker.

Beryllium↗