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PubMed1991

Mechanisms of granulomatous lung disease from inhaled beryllium: the role of antigenicity in granuloma formation.

Granulomatous lung disease is a debilitating and sometimes fatal condition encountered in humans, for which the cellular and molecular mechanisms are poorly understood. Two patterns of granulomatous lung disease are recognized; foreign-body reactions and immune-mediated granulomas. Beryllium inhalation by humans results, in a small number of exposed individuals, in a chronic, granulomatous, immune-mediated pulmonary disease (chronic beryllium lung disease, CBD). Animal models used to study CBD have demonstrated significant species differences in the pathologic response to beryllium. While rats exposed to beryllium appear to develop a chronic, foreign-body response within the lung, dogs so exposed develop beryllium-specific immune responses within the lung and blood, accompanied by immune granulomas within the lung. At the heart of this difference appears to be the ability of the dog, but not the rat, to immunologically recognize the antigenicity of beryllium. This important difference further underscores the need to understand the mechanistic differences among similar disease syndromes, particularly if therapeutic regimens are to be used.

Administration, Inhalation↗
PubMed2001

Major histocompatibility locus genetic markers of beryllium sensitization and disease.

Hypersensitivity to beryllium (Be) is found in 1-16% of exposed workers undergoing immunological screening for beryllium disease using the beryllium lymphocyte proliferation test (BeLPT). However, only approximately 50% of BeLPT-positive workers present with lung granulomas (i.e. berylliosis). As berylliosis is associated with the human leukocyte antigen (HLA)-DP supratypic marker DPGlu69, the authors asked whether this marker is differentially associated with disease presentation. A population of 639 workers from a beryllium factory undergoing BeLPT screening was evaluated in a nested case-control study for the prevalence of HLA-DPGlu69, the HLA-DPB1, HLA-DQ and HLA-DR alleles and of the biallelic tumour necrosis factor (TNF)-alpha polymorphism TNF-alpha-308 in 23 individuals presenting as "sensitized" (i.e. BeLPT-positive without lung granulomas) and in 22 presenting as "diseased" (i.e. BeLPT-positive with granulomas in the lung biopsy). The HLA-DPGlu69 marker was associated with "disease" (odds ratio (OR) 3.7, p=0.016, 95% confidence interval (CI) 1.4-10.0), whilst the high TNF-alpha production-related TNF-alpha-308*2 marker was associated with both a positive BeLPT (OR 7.8, corrected p<0.0001, 95% CI 3.2-19.1) with no difference between "sensitization" and "disease". Furthermore, the HLA-DRArg74 marker was associated with "sensitization" without disease (OR 3.96, p=0.005, 95%, CI 1.5-10.1). The data indicate that tumour necrosis factor-alpha, human leukocyte antigen-DR and human leukocyte antigen-DP markers play different roles in beryllium sensitization and granuloma formation in beryllium-exposed workers.

Adult↗
PubMed1996

Significance of the blood beryllium lymphocyte proliferation test.

The blood beryllium lymphocyte proliferation test (BeLPT) is an in vitro measure of the beryllium antigen-specific cell-mediated immune response. This response to beryllium is now understood to play a central role in the immunopathogenesis of chronic beryllium disease (CBD). Although there remain some unresolved methodologic issues with testing, the blood BeLPT has already undergone sufficient development and field assessment to lead to a number of important conclusions: a) The BeLPT identifies beryllium sensitization and CBD earlier and better than any other clinical test presently available. b) The CBD cases identified with the blood test are clinically significant. c) A subset of the people identified by the BeLPT who do not yet have clinical disease will progress and require treatment with corticosteroids for impairing illness. d) The BeLPT can be used to improve clinical diagnostic accuracy and to correct mistaken diagnoses. e) The blood test can be used in screening large numbers of exposed workers because it is sensitive and specific and has high positive and negative predictive value for CBD. f) In every workforce studied to date, the BeLPT has identified beryllium sensitization and CBD that had been missed by conventional screening efforts. g) Worker populations that have been characterized using the BeLPT can help to elucidate the role of exposure genetics and dysregulated inflammation in the genesis of occupational lung disease.

Berylliosis↗
PubMed2005

Beryllium presentation to CD4+ T cells is dependent on a single amino acid residue of the MHC class II beta-chain.

Chronic beryllium disease (CBD) is characterized by a CD4+ T cell alveolitis and granulomatous inflammation in the lung. Genetic susceptibility to this disease has been linked with HLA-DP alleles, particularly those possessing a glutamic acid at position 69 (Glu69) of the beta-chain. However, 15% of CBD patients do not possess a Glu69-containing HLA-DP allele, suggesting that other MHC class II alleles may be involved in disease susceptibility. In CBD patients without a Glu69-containing HLA-DP allele, an increased frequency of HLA-DR13 alleles has been described, and these alleles possess a glutamic acid at position 71 of the beta-chain (which corresponds to position 69 of HLA-DP). Thus, we hypothesized that beryllium presentation to CD4+ T cells was dependent on a glutamic acid residue at the identical position of both HLA-DP and -DR. The results show that HLA-DP Glu69- and HLA-DR Glu71-expressing molecules are capable of inducing beryllium-specific proliferation and IFN-gamma expression by lung CD4+ T cells. Using fibroblasts expressing mutated HLA-DP2 and -DR13 molecules, beryllium recognition was dependent on the glutamic acid at position 69 of HLA-DP and 71 of HLA-DR, suggesting a critical role for this amino acid in beryllium presentation to Ag-specific CD4+ T cells. Thus, these results demonstrate that a single amino acid residue of the MHC class II beta-chain dictates beryllium presentation and potentially, disease susceptibility.

Alleles↗
PubMed1989

The induction of chromosome damage in CHO cells by beryllium and radiation given alone and in combination.

Studies were conducted to determine the effects of BeSO4 or X rays, alone and in combination, on cell cycle kinetics, cell killing, and the production of chromosome aberrations in Chinese hamster ovary (CHO) cells. The concentration of BeSO4 required to kill 50% of CHO cells exposed to BeSO4 for 20 h was determined to be 1.1 mM with 95% confidence intervals of 0.72 to 1.8 mM. During the last 2 h of the 20-h beryllium treatment (0.2 and 1.0 mM), cells were exposed to 0.0, 1.0, or 2.0 Gy of X rays. Exposure to either BeSO4 or X rays produced a change in cell cycle kinetics which resulted in an accumulation of cells in the G2/M stage of the cell cycle. However, combined exposure to both agents resulted in a block similar to that observed following exposure to X rays only. The background level of chromosome damage was 0.05 +/- 0.015 aberrations/cell in the CHO cells. Seven hours after the end of exposure to 0.2 and 1.0 mM beryllium, 0.03 +/- 0.003 and 0.09 +/- 0.02 aberrations/cell, respectively, were observed. The data for chromosome aberrations following X-ray exposure were fitted to a linear model with a coefficient of 0.14 +/- 0.01 aberrations/cell/Gy. When beryllium was combined with the X-ray exposure the interactive response was predicted by a multiplicative model and was significantly higher (P less than 0.05) than predicted by an additive model. The influence of time after radiation exposure on the interaction between beryllium and X rays was also determined. No interaction between beryllium and X-ray exposure in the induction of chromosome-type aberrations (P greater than 0.05) was detected. The frequency of chromatid-type exchanges and total aberrations was significantly higher (P less than 0.05) in the radiation plus beryllium-exposed cells when compared to cells exposed to X rays only, at both 9 and 12 h after X-ray exposure. These data suggest that the multiplicative interaction may be limited to cells in the S and G2 stages of the cell cycle.

Animals↗
PubMed1988

Selective intracellular beryllium localization in rat tissue by mass-resolved ion microprobe imaging.

Beryllium absorption sites in the kidney and liver of rats have been located and imaged at approximately 70 nm lateral resolution with a scanning ion microprobe utilizing secondary ion mass spectrometry. Embedded sections and lyophilized cryosections of these organs were prepared after in vivo administration of beryllium in soluble form. Beryllium distribution images were correlated with the histological microstructure revealed by CN- images. In the kidney, beryllium concentrates selectively within the nuclei of proximal tubule cells and occasionally within modified podocytes or mesangial cells in the glomerulus. In the liver, beryllium is seen to localize within severely altered lysosomal structures as well as within hepatocyte nuclei. These observations are relevant to understanding aspects of the toxic and carcinogenic properties of absorbed beryllium compounds.

Animals↗
PubMed1984

[Effects of beryllium chloride on cultured cells].

The effects of beryllium on cultured cells were investigated. Three cell-lines (HeLa-S3, Vero, HEL-R66) were used in these experiments and they were cultured in Eagle's MEM plus 5 or 10% FBS (Fetal Bovine Serum) containing beryllium in various concentrations. HeLa cells or Vero cells were able to grow in the medium with 10 micrograms Be/ml (1.1 mM). On the other hand, the growth of HEL cells were strongly inhibited, even when cultured in the medium with 1 microgram Be/ml (1.1 X 10(-1) mM) and the number of living cells showed markedly low level as compared to that of the control samples cultured in the medium without beryllium. The cytotoxic effects of beryllium on these cells, which were cultured for three days in the medium with beryllium, were observed. None of cytotoxic effects were found on HeLa cells cultured with 0.5 micrograms/ml (5.5 X 10(-2) mM) and on Vero cells cultured with 0.05 micrograms Be/ml (5.5 X 10(-3) mM), while HEL cells received cytotoxic effects even when cultured in the medium containing 0.05 micrograms Be/ml (5.5 X 10(-3) mM), and these effects on the cells appeared strong when cultured in the medium without FBS. It was revealed from these experiments that HEL cells are very sensitive in terms of toxic effects of beryllium. Therefore, there cells can be used for the toxicological study on low level concentrations of the metal.

Animals↗
PubMed2001

Beryllium sensitivity is linked to HLA-DP genotype.

Chronic beryllium disease (CBD) appears to arise from a combination of both exposure and genetic risk factors. A distinguishing feature of CBD is beryllium hypersensitivity, which can be measured in vitro by a lymphocyte proliferation test. The objective of this study was to determine whether certain allelic variations of the HLA-DPB1 gene, which had been observed previously in CBD, could be found in a group of individuals having beryllium hypersensitivity, but no symptoms of CBD. A flow cytometry-based Lymphocyte Proliferation Test combined with immunophenotyping (Immuno-LPT) was used to detect CD4+ and CD8+ T cell proliferation in response to in vitro stimulation with beryllium. The HLA-DPB1 haplotypes of the same individuals were determined by automated DNA sequencing. Twenty-two out of 25 beryllium-sensitive, non-CBD individuals were found to be carriers of the HLA-DPB1 gene having a substitution of a glutamic acid at position 69 in Exon 2 (Glu69), and a significantly high percentage (24%) were Glu69 homozygotes. Most of the CD4+ responders on the Immuno-LPT (10/14) carried rare, non-*0201 Glu69 DPB1 alleles; while most of the non-CD4+ responders (9/11) were common Glu69 carriers (*0201 or *0202) or non-Glu69 individuals (non-Glu69/non-Glu69). This is the first direct evidence that HLA-DP genotype is linked to a phenotypic response that occurs in beryllium sensitization in the absence of clinical CBD.

Berylliosis↗
PubMed2001

The quest for beryllium peroxides.

There is no experimental proof documented in the literature for the existence of any beryllium peroxide compound. All recent pertinent preparative attempts described in this work, using a range of beryllium salts with various peroxides as reagents under mild conditions, were equally unsuccessful. (1)H and (9)Be NMR investigations of aqueous solutions containing beryllium salts and hydrogen peroxide in a broad pH range also gave no definite evidence for the presence of peroxoberyllates as components of the manifold equilibria in such solutions. Quantum chemical calculations have therefore been carried out to delineate the energetics and structures of various beryllium peroxide model compounds. Standard Hartree-Fock and density functional methods were employed at various levels of sophistication. The series of prototypes considered consists of [BeOH](+), Be(OH)(2), Be(OH)(OOH), Be(OOH)(2), [Be(O(2))(2)](2-), [BeO(2)(OH(2))(2)], and [Be(2)(O(2))(2)(OH(2))(4)] (all in the gas phase). Surprisingly, the triatomic cation [BeOH](+) has been found to have a linear structure. All the Be-O(peroxide) bonds are found to be rather long, suggesting weaker bonding compared to the Be-O bonds in aquo, hydroxo, or oxo complexes. Hydrogen peroxide or anions derived therefrom are therefore not able to compete successfully with water (hydroxide anions) in aqueous solution. In the mononuclear beryllium peroxide molecules, the peroxide groups form chelating units at tetrahedrally 4-coordinate metal atoms. The binuclear compound [Be(2)(O(2))(2)(OH(2))(4)] has a puckered six-membered-ring structure, close to the standard chair conformation. A significant lengthening of the O-O bonds upon coordination to the Be(2+) centers has been calculated, but it is unlikely that the polarization of the peroxide group by the high positive charge density at Be(2+) is significant to cause an intrinsic instability of beryllium peroxides. All structures represent distinct local minima on the potential energy surface and are predicted to be (meta)stable species in nonaqueous media. The field of aluminum peroxides is a similar gray area on the map of metal and metalloid peroxides and is reminiscent of the well-established "diagonal-relation" of Be and Al in the periodic table of the elements.

Journal Article↗
PubMed2003

HLA-DPB1 and chronic beryllium disease: a HuGE review.

The human leukocyte antigen (HLA) complex is a series of genes located on chromosome 6 that are important in normal immune function. Susceptibility to chronic beryllium disease, a granulomatous lung disease that appears in workers exposed to beryllium, is modified by genetic variants of the HLA-DP subregion. Evaluation of HLA-DPB1 sequence motifs in current and former beryllium workers implicated a glutamic acid residue at position 69 (HLA-DPB1(Glu69)) in chronic beryllium disease. This finding has since been extended to specific HLA-DPB1(Glu69) alleles. Specific job tasks have also been implicated in degree of risk, and in this paper the authors explore gene-environment interaction. The utility of this genetic information for prospective, current, and former beryllium workers must be weighed against the potential for employment and insurance discrimination. Continued research in the beryllium-exposed population will be important for improving personal risk assessment and identifying high-risk genes associated with disease progression.

Berylliosis↗
PubMed1991

Lung cancer incidence among patients with beryllium disease: a cohort mortality study.

We have conducted a cohort mortality study on 689 patients with beryllium disease who were included in a case registry. An earlier mortality study on 421 of these patients was limited to males and resulted in a determination of a nonsignificant twofold lung cancer excess based on only seven lung cancer deaths. We have extended this earlier study by including females and by adding 13 years of follow-up. Comparison of the 689 beryllium disease patients with the U.S. population resulted in a lung cancer standardized mortality ratio (SMR) of 2.00 (95% confidence interval = 1.33-2.89) based on 28 observed lung cancer deaths. Adjustment for smoking did not change these results. All causes of mortality were also significantly elevated (SMR = 2.19), largely because of the very high rate of deaths due to pneumoconioses (primarily beryllium disease) (SMR = 34.23; 158 deaths). No other causes of death were significantly elevated. The excess of lung cancer was consistent for both sexes and did not appear to increase with duration of exposure to beryllium or with time elapsed since first exposure to this element. The case registry included those with acute beryllium disease, which resembles a chemical pneumonitis, and those with chronic beryllium disease, which resembles other pneumoconioses. The lung cancer excess was more pronounced among those with acute disease (SMR = 2.32) than among those with chronic disease (SMR = 1.57).

Adult↗
PubMed1993

Chronic beryllium disease in a dental laboratory technician.

Workers involved in the manufacture of dental prostheses are exposed to a number of potentially harmful substances capable of inducing lung disease. In this report, we describe a dental laboratory technician who developed chronic beryllium disease as a result of exposure in the workplace. The diagnosis of chronic beryllium disease was suspected from the clinical, radiographic, and histologic features and confirmed by the in vitro proliferation of lung lymphocytes to beryllium salts. The potential risks of beryllium use in the dental industry have been recognized for some time, but this is the first documentation of chronic beryllium disease in this population of workers. Since chronic beryllium disease may be easily confused with sarcoidosis, awareness of this occupational association is essential in preventing misdiagnosis and in providing appropriate management.

Adult↗
PubMed1993

Early pulmonary physiologic abnormalities in beryllium disease.

By using the beryllium-specific blood lymphocyte transformation test (BeLT) as a screening tool, it is possible to identify beryllium disease before clinical symptoms or radiographic abnormalities develop. Little is known about the early pulmonary physiologic abnormalities in granulomatous lung diseases. We compared two groups: (1) "surveillance-identified" early beryllium disease patients, detected using the blood BeLT in workplace screening projects (n = 21), and (2) "clinically identified" beryllium disease patients who presented with symptoms or radiographic abnormalities (n = 15). We measured spirometry, lung volumes, diffusing capacity for carbon monoxide, arterial blood gases, and maximal exercise capacity. Physiologic abnormalities occurred in 12 of 21 (57%) surveillance-identified patients. The most common derangement was a rise in the dead space to tidal volume ratio (VD/VT) during exercise, suggesting a pulmonary vascular abnormality. None of the surveillance-identified patients had pure restriction, and only one of 21 had an abnormal diffusing capacity. In comparison, 93% of clinically identified beryllium disease patients had one or more abnormalities, the most sensitive indicator being the exercise capacity. One-third had airflow limitation. Resting arterial blood gas analysis was abnormal in seven of 15 (47%), whereas diffusing capacity was low in only five of 15 (33%). Clinically identified patients performed less work, had more severe gas exchange abnormalities, and had higher VD/VT at maximal exercise than did surveillance-identified patients. We conclude that alterations in gas exchange and the pulmonary vascular bed occur early in beryllium disease.

Adult↗
PubMedDate not supplied

Influence of chelating agents on the toxicity and distribution of beryllium in rats.

The effect of two new chelating agents-Tiron (4,5-dihydroxy-1,3-benzene disulphonic acid disodium salt) and succinic acid--on the mobilization of beryllium was studied. Animals were exposed to beryllium nitrate (1 mg kg(-1) i.p.) daily for 21 days. Administration of beryllium nitrate showed a marked decrease in haemoglobin percentage, blood sugar, serum alkaline phosphatase and serum protein and a significant increase in the activity of transaminases. Tissue protein and glycogen contents and the activity of alkaline phosphatase, adenosine triphosphatase and succinic dehydrogenase showed significantly decreased values, but beryllium nitrate provoked a considerable increase in the activity of acid phosphatase and glucose-6-phosphatase in the vital and reproductive organs. Significant improvement in the haematological and biochemical parameters was observed with Tiron but no therapeutic effect was seen with succinic acid. Atomic absorption spectrophotometry (AAS) also showed a decreased level of beryllium concentration in the liver and kidney after Tiron therapy.

1,2-Dihydroxybenzene-3,5-Disulfonic Acid Disodium ↗
PubMed1997

Toxicological effects of beryllium on platelets and vascular endothelium.

Although ample research has described the toxic effects of the metal beryllium on the respiratory apparatus, less is known about its effects on the vascular apparatus, including pulmonary blood vessels. We investigated the in vitro effects of beryllium on endothelial vascular adenosine diphosphatase activity and prostacyclin production in bovine aortic endothelium, and on nitric oxide release in isolated rabbit arteries. Rabbit and human platelet responsiveness was also evaluated. Beryllium inhibited vascular endothelial adenosine diphosphatase activity, prostacyclin production, and nitric oxide release, thus inducing functional alterations in vascular endothelial cells. It also induced platelet hyperreactivity to arachidonic acid, as shown by a lowering of the threshold of aggregating concentration and by concurrently increasing thromboxane production. In contrast, beryllium left the response to aggregating and nonaggregating concentrations of ADP and collagen unchanged. These findings show that beryllium may impair some vascular endothelial functions and alter the interaction between platelet and endothelial mediators.

Animals↗
PubMed1986

Fluoride and beryllium interact with the (Na + K)-dependent ATPase as analogs of phosphate.

Fluoride irreversibly inhibits the (Na + K)-ATPase, and this inactivation requires divalent cations (Mg2+, Mn2+, or Ca2+), is augmented by K+, but is diminished by Na+ and by ATP. Prior incubation with the aluminum chelator deferoxamine markedly slows inactivation, whereas adding 1 microM AlCl3 speeds it, consistent with AlF-4 being the active species. Prior incubation of the enzyme with vanadate also blocks inactivation by fluoride added subsequently. Fluoride stimulates ouabain binding to the enzyme, and thus the analogy between AlF-4 and both orthophosphate and orthovanadate is reflected not only in the similar dependence on specific ligands for their enzyme interactions and their apparent competition for the same sites, but also in their common ability to promote ouabain binding. Beryllium also irreversibly inhibits the enzyme, and this inactivation again requires divalent cations, is augmented by K+, but is diminished by Na+ and by ATP. Similarly, prior incubation of the enzyme with vanadate blocks inactivation by beryllium added subsequently. Inactivation by beryllium, however, does not require a halide, and, unlike inactivation by fluoride, increases at basic pHs. These observations suggest that beryllium, as beryllium hydroxide complexes, acts as a phosphate analog, similar to AlF-4 and vanadate.

Aluminum↗
PubMed1991

Reexamination of the blood lymphocyte transformation test in the diagnosis of chronic beryllium disease.

The T cell response to beryllium, measured in bronchoalveolar lavage by the lymphocyte transformation test (LTT), is a critical diagnostic test for discriminating between chronic beryllium disease (CBD) and other granulomatous diseases. We examined the sensitivity, reproducibility, and methods of a less invasive, peripheral blood LTT in 17 patients with CBD and in 18 beryllium-exposed control subjects. Ninety-four percent of CBD cases (16/17) had abnormal blood LTT results, and all 18 beryllium-exposed control subjects had normal blood LTT results. Split samples for 10 beryllium disease cases and eight control subjects demonstrated that the blood LTT was reproducible between two separate laboratories. The LTT was equally sensitive with 10% and 20% serum in the culture medium. We conclude that an abnormal blood LTT can be used to diagnose CBD in patients with compatible lung pathology.

Adult↗
PubMed2005

Beryllium binding at neutral pH: the importance of the Be-O-Be motif.

Beryllium speciation at physiological conditions is critical to understanding chronic beryllium disease (CBD). The MHC-class II receptor alleles that have been linked to CBD have more than six carboxylates in a short 20 amino acid segment of the binding pocket and it has been suggested that beryllium may bind within the MHC-class II receptor via the carboxylates. Previous reports also show that citric acid binds beryllium significantly stronger than similar carboxylate ligands such as tartaric acid and is one of the few ligands that can compete with hydrolysis to solubilize beryllium across the entire pH range at molar concentrations. We have characterized the binding of Be to citric acid and shown using a combination of NMR, mass spectrometry and ligand competition studies that Be2L and Be4L2 species dominate. A Be-O-Be linkage with the bridging oxygen coming from the aliphatic alcohol is critical to the stability of the complex. We show through competition experiments that the most stable Be-O-Be arrangement has one Be in a five-member ring and the other Be in a six-member ring. The unusual deprotonation of an aliphatic alcohol (pK(a) = 18) at neutral pH has significant ramifications on the potential interactions of Be with biological ligands such as carbohydrates and Ser and Thr residues.

Beryllium↗