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Experiments on animals have revealed that beryllium in toxic dose induces lesions of chromosomes in the bone marrow cells mostly because of chromosome aberrations. No mutagenic effect of beryllium on sex cells has been revealed.
After injection in the rat of a soluble beryllium salt, the distribution of this element was studied at the subcellular level by analytical ion microscopy. Beryllium is concentrated inside the nuclei with a particular affinity for the nuclei of the proximal tubule cells of the kidney. The same tissue was studied by electron microscopy and abnormal intranuclear inclusions were observed in the same variety of cells.
PULMONARY BERYLLIOSIS, A CHRONIC ALLERGIC PNEUMOSCLEROSIS RESULTING FROM INHALATION OF BERYLLIUM COMPOUNDS, MAY OCCUR IN TWO CLINICAL FORMS: interstitial, which is mild, slowly progressive, and presents moderate skin reactions of delayed-type hypersensitivity to haptens; and granulomatous, which is rapidly progressive after a short latent period and presents systemic lesions and significant allergic skin reactions. The investigation of experimental berylliosis in rats has revealed some factors that could lead to the abolition of natural tolerance. Six new beryllium-containing autoantigens, two of which accumulated in different tissues, were identified in the lung nucleoproteins accompanying a partial loss of normal tissue and serum antigens. Antibodies to the new antigens and to normal lung tissue (in smaller amounts) were found in the sera of rats with experimental berylliosis, as well as in patients. The patients with granulomatous berylliosis also had antibodies to DNA, RNA, and extracts of normal homologous heart, spleen, liver, and thyroid in quantities that correlated with the clinical picture and with the effectiveness of glucocorticoid therapy. The fact that natural tolerance mechanisms were interrupted in all cases and autoimmune granulomatous berylliosis developed only in some patients led to the assumption that the mechanism was effective under the influence of additional endogenous factors; diseases producing an accumulation of autoantibodies could provide the stimulus for the appearance of these factors.
When 5 mg doses of beryllium hydroxide, Be(OH)2, were injected intravenously (i.v.) into rats, much of the injected material was retained in the lungs. When the injection of Be(OH)2 was accompanied by particulate antigens such as killed B. abortus organisms or SRBC, immune responses took place in the intra-thoracic lymph nodes (ITLN) so that antibodies of the IgA class were generated and endowed the bile with significant agglutinating activity. This did not happen when the antigens were injected without the beryllium adjuvant. Similarly, a soluble antigen, bovine serum albumin (BSA) only gave rise to significant amounts of biliary and serum antibodies after i.v. injection if Be(OH)2 was used too. The highest titres occurred when the antigen followed the adjuvant after an interval of a few seconds but substantial titres still resulted if the injection of antigen was delayed for 24 hr. The amounts of biliary antibodies generated by the parenteral injection of antigen and adjuvant were comparable to those that occurred after the same materials were injected directly into the GALT. The adjuvant action of Be(OH)2 was able to induce in athymic (nude) rats the production of measurable amounts of both biliary and serum antibodies to SRBC.
Beryllium was injected subcutaneously (s.c.) into sheep in the form of a suspension of insoluble Be(OH)2 in isologous lymph plasma. Even in the absence of added antigen, doses of 50-150 mg induced rapid and vigorous proliferative responses in the regional lymph nodes so that large numbers of immunoblasts appeared in the efferent lymph within 4 days. Dendritic macrophages and dead white cells, which are excluded normally from efferent lymph, also appeared in significant numbers. When horseradish peroxidase was added to the injections of Be(OH)2, specific, high-affinity antibody appeared in the immunoblasts. This did not happen when the antigen was injected on its own or in combination with conventional, alum adjuvant. By the incorporation of radioactive 7Be in the injected material, it was shown that most of the Be(OH)2 remained at the site of injection and relatively little reached the node. In spite of this the cellular composition of peripheral lymph draining directly from the sites of injection showed no significant changes, and it was concluded that a 'depot' effect was unlikely to account for the heightened immune responses. These observations on the effects of beryllium are consistent with the view that its adjuvant action results from damage to intra-nodal macrophages, and that factors released from such cells caused intense immunoblastic proliferation.
The fate of i.v. administered particles of beryllium phosphate (50 mumol/kg) has been investigated by electron microscopy in the liver of the rat. These particles were endocytosed by the Kupffer cells within 15 min of administration but they were never found in the endothelial or parenchymal cells of the liver. Endocytosed particles were rapidly degraded within vesicles which were identified as secondary lysosomes. Pronounced swelling of these lysosomes subsequently developed, within 60 min of administration, resulting in distension of the entire cell. This vacuolation was entirely restricted to the Kupffer cells, particularly those in the pericanalicular region of the hepatic lobules. Lysosomal swelling, or even rupture, probably resulted in the subsequent death of these cells by the intra-cytoplasmic release of beryllium.
The i.v. administration of suspensions of beryllium phosphate (5-50 mumol/kg) to rats resulted in the vacuolation of hepatic Kupffer cells within 3 h. After 6 h necrotic Kupffer cells were common throughout the sinusoids of the liver but no changes were detected in the hepatic parenchymal cells during this period. A significant reduction in the numbers of intrasinusoidal cells was observed 14 h after treatment but this population had reverted to normal within 24 h. The administration of colloidal carbon to treated animals at this time did, however, demonstrate a reduction in the complement of functional endocytic cells. These results demonstrate a selective destruction of endocytic cells in the liver by this particulate toxin and the limited response by the organ to this injury. These observations are the most probable explanation for the reticuloendothelial blockade known to be caused in vivo by beryllium phosphate.
An Ayurvedic medicine, Liv-52 has been studied as a prophylactic against beryllium induced toxicity in rats. Administration of beryllium per se caused severe degenerative and necrotic changes in liver, kidney, lungs and spleen. Its administration reduced glycogen content, activity of alkaline phosphatase and adenosine triphosphatase in these organs. On the contrary, activities of acid phosphatase and glucose-6-phosphatase were increased significantly. In Liv-52 primed rats significant recoupment was observed in all the parameters.
Beryllium chloride and/or zinc chloride were intraperitoneally injected into mice. The amount of beryllium (Be) injected corresponded to 1/10th of the LD50 dose intravenously administered. The amount of zinc (Zn) injected was the same as Be. The changes in porphyrin metabolism of the mice were studied. Delta-aminolevulinic acid dehydratase (ALA-D) activities in the blood were found to increase significantly in Zn and BeZn groups when compared to the control level. The blood porphobilinogen deaminase (PBG-D) activity in the Zn group was slightly less than that in the controls. The ALA-D and PBG-D activities in liver were higher in the Be and BeZn groups than in the controls. The splenic ALA-D activities were significantly higher in the Zn and BeZn groups than in the control and Be groups. The splenic PBG-D activities were markedly higher in the Be and/or Zn groups than in the controls. An increase in ALA-D activities in the blood and spleen was observed in the BeZn group, together with an increase in ALA-D activities caused by Zn administration. Furthermore, the increase in PBG-D activities in liver and spleen was observed in the Be and/or Zn groups. The results suggested that chemical similarity between Be and Zn brought about these phenomena.
Chronic beryllium disease (CBD) is a rare occupational, granulomatous lung disease clinically resembling sarcoidosis. The immune response to beryllium is thought to depend on genetic susceptibility. Although a glutamic acid in position 69 of the human leukocyte antigen-DP beta chain (HLA-DPB1-Glu69) is associated with the development of CBD, it cannot fully explain susceptibility. It is likely that additionally other genes are involved in regulating the immune and inflammatory response in the pathogenesis of this disease. Functional gene polymorphisms (PMs) of the tumor necrosis factor (TNF)A and transforming growth factor (TGF) beta(1) genes are suspected to modify the course of granulomatous disorders. We analyzed the TGF-beta(1) (codon 25) PM in 59 patients with CBD and 164 matched healthy controls, from two groups of European/Israeli and United States origin. Additionally, patients were genotyped for HLA class II gene variants and the TNFA (-308) PM. The most significant results were found for the TGF-beta(1) (codon 25) PM with a shift towards the low producing non-GG genotypes in the subgroup of European and Israeli patients with CBD (62.50% vs. 13.82% in healthy controls; P<0.001). This phenomenon was not observed in the group from the United States. Moreover, TGF-beta(1) (codon 25) PM genotype frequencies from United States CBD patients differed significantly from those of European and Israeli patients. In contrast, increased frequencies for the high producing TNFA2 allele were found only in the patients from the United States (28.20% vs. 8.96% in healthy controls; P<0.005) but not in the group of Europe and Israel. In conclusion, the increase in TGF-beta(1) (codon 25) PM genotype frequency associated with a low TGF-beta release suggests that immunoregulatory cytokines such as TGF-beta are involved in the pathogenesis of CBD. Moreover, based on the interaction of gene PMs associated with the control of the immune response, such as TNF-alpha and TGF-beta(1), with a specific immune response gene such as HLA-DPB1-Glu69 or other HLA-class II PMs driving the immune response to Be, the present data suggest that a combination of different genetic backgrounds determine susceptibility for the same immunopathological reaction and disease.
Four heterocycles containing hydroxy and keto functionalities have been tested as chelating agents of beryllium(II). These are in the order (i) 3-hydroxy-2-methyl-4H-pyran-4-one (maltol, Hma), (ii) 5-hydroxy-2-(hydroxymethyl)-4H-pyran-4-one (kojic acid, Hka), (iii) 3-hydroxy-1,2-dimethyl-4-pyridinone (Hdpp), (iv) 1-(3-hydroxy-2-furanyl)ethanone (isomaltol, Hima). Although the skeletons of the first three species, with one nitrogen or oxygen heteroatom at the six-membered ring, are almost superimposable, straightforward synthesis and crystallization is achieved only for the 1:2 adduct Be(dpp)(2), 1. Also the complex Be(ima)(2), 2, precipitates in high yield but the ima(-) ligand has a different skeletal structure. X-ray determinations of 1 and 2 showed that the Be(2+) ion is pseudotetrahedrally coordinated by two chelating ligands with slightly asymmetric Be-O(alkoxo) and Be-O(keto) bonds. The complex Be(ma)(2) precipitates in low yields together with large amounts of unreacted Hma while, under the same conditions, no trace of the analogous species Be(ka)(2) has been observed. This paper presents the results of potentiometric and NMR studies in the aqueous solutions as well as of DFT structural optimizations for all of the free acids, their associated bases, and the adducts of the type [BeL(H(2)O)(2)](+) and BeL(2) in the gas phase. It is consistently found that the basicity of the ligands and the stability of their complexes decrease in the order dpp(-) > ma(-) > ka(-) > ima(-). In solution, all of the anionic ligands form adducts of the type [BeL(H(2)O)(2)](+) at low pH values, whereas higher concentrations of the free anion are required to form 1:2 adducts. The pH, the basicity, and the stability constants of the complexes as well as the formation of competing beryllium hydroxide species are strictly correlated factors for the obtainment of the latter type of adduct. The DFT calculations account nicely for the different donor powers of the various chelates in terms of electronic redistribution and associated energetics.
Two bifunctional ligands, phenyl(carboxymethyl)phosphinate (ccp(2-) and P,P'-diphenylmethylenediphosphinate (pcp(2-)), have been tested as chelating agents of beryllium(II). Both ligands have the same charge and a similar chelating structure, but whereas the 1:1 adduct of pcp(2-), Be(pcp)(H(2)O)(2), could be isolated as a white powder, no pure compound could be isolated from solutions containing beryllium(II) and ccp(2-). Instead, the solutions were examined by means of potentiometry and (9)Be NMR spectroscopy. Analysis of the potentiometric titration data with the program HYPERQUAD suggested the formation of the complex species BeL, [BeHL](+), [BeL(2)](2-), and [BeHL(2)](-) (L = ccp). The formation constants for these species were determined at 25 degrees C and I = 0.5 mol dm(-3) NaClO(4). The (9)Be NMR spectra are consistent with this model. The formation constants found for the ccp(2-) complexes are lower than those reported for related phosphonate ligands. However, the effective stability constant (which gives a better indication of the intrinsic coordinating capacity of the ligand at a particular pH) of the complex [Be(ccp)(2)](2-) at pH < 4 is greater than the effective constants of the corresponding phosphonoacetate and methylenediphosphonate complexes. The structure of Be(pcp)(H(2)O)(2) was determined by X-ray powder diffraction methods and consists of discrete molecules interconnected by an extended 2D network of hydrogen bonds, resulting in a stacking of doublelayers with a polar core and a lipophilic surface. Crystal data: C(13)H(16)BeO(6)P(2), fw 339.21, monoclinic P2(1)/c, a = 16.174(1) A, b = 8.979(1) A, c = 10.929(1) A, beta = 90.398(9) degrees, V = 1587.2(3) A(3), Z = 4.
Complete relativistic and quantum electrodynamics corrections of order alpha(2) Ry and alpha(3) Ry are calculated for the ground state of the beryllium atom and its positive ion. A basis set of correlated Gaussian functions is used, with exponents optimized against nonrelativistic binding energies. The results for Bethe logarithms ln(k(0)(Be)=5.750 34(3) and ln(k(0)(Be+)=5.751 67(3) demonstrate the availability of high precision theoretical predictions for energy levels of the beryllium atom and light ions. Our recommended value of the ionization potential 75 192.514(80) cm(-1) agrees with equally accurate available experimental values.
About 2100 inorganic and organometallic compounds containing beryllium, magnesium and alkaline earth atoms (M) were investigated with Voronoi-Dirichlet polyhedra (VDPs). It is shown that the coordination numbers (CNs) of the M atoms in MO(n) coordination polyhedra can be determined by means of VDPs without crystal-chemical radii. The distributions of the M-O distances in the coordination spheres of the M atoms are bimodal for M = Be or Mg and monomodal for the other alkaline earth metals. Beryllium and magnesium coordination polyhedra containing weak M-O contacts were classified by variants of their distortions. It is found that the volume of the domains of the Mg, Ca, Sr and Ba atoms is independent of their CNs at CN >/= 6 (up to 16 for barium). The possibility of using the model of deformable spheres to describe the crystal structure of the compounds investigated is suggested.
Patients with suspected chronic beryllium disease underwent bronchoscopy and bronchoalveolar lavage. Their bronchoalveolar lymphocytes were incubated with beryllium salts, and quantitative lymphocyte transformation was measured. Seventeen patients with a positive lymphocyte proliferation test were evaluated radiographically with the International Labour Office classification. The most common radiographic abnormalities included diffuse small round and reticular opacities. Hilar adenopathy, linear scars, lung distortion, bullae, and pleural thickening were found less commonly. Specific radiographic findings were compared with pulmonary function abnormalities. The extent of radiographic profusion of small opacities and the presence of linear scars did not correlate with pulmonary function abnormalities. There was, however, a significant correlation between extensive pleural disease and reduced vital capacity in this small group of patients.
We report the first case from Scotland of chronic beryllium pneumonitis to be accepted into the UK Beryllium Case Register. The exposure was due to 'spot welding' and this source causing disease has not been described previously.
The pathobiology of chronic beryllium disease (CBD) involves the major histocompatibility complex class II human leukocyte antigen (HLA). Although occupational exposure to beryllium is the cause of CBD, molecular epidemiologic studies suggest that specific (Italic)HLA-DPB1(/Italic) alleles may be genetic susceptibility factors. We have studied three-dimensional structural models of HLA-DP proteins encoded by these genes. The extracellular domains of HLA-DPA1*0103/B1*1701, *1901, *0201, and *0401, and HLA-DPA1*0201/B1*1701, *1901, *0201, and *0401 were modeled from the X-ray coordinates of an HLA-DR template. Using these models, the electrostatic potential at the molecular surface of each HLA-DP was calculated and compared. These comparisons identify specific characteristics in the vicinity of the antigen-binding pocket that distinguish the different HLA-DP allotypes. Differences in electrostatics originate from the shape, specific disposition, and variation in the negatively charged groups around the pocket. The more negative the pocket potential, the greater the odds of developing CBD estimated from reported epidemiologic studies. Adverse impact is caused by charged substitutions in positions 55, 56, 69, 84, and 85, namely, the exact same loci identified as genetic markers of CBD susceptibility as well as cobalt-lung hard metal disease. These findings suggest that certain substitutions may promote an involuntary cation-binding site within a putatively metal-free peptide-binding pocket and therefore change the innate specificity of antigen recognition.
This report is based on 30 deaths from chronic beryllium disease (CBD) in the United Kingdom with details of 19 autopsies. The majority were fluorescent lamp workers and machinists who died from respiratory failure. There were no cases of lung cancer. The survival times ranged from less than 1 to 29 years and was longest in machinists. All of the workers showed interstitial pulmonary fibrosis with varying degrees of cystic change. The majority showed hyalinized, and a few active sarcoid-type, granulomas. Extrathoracic granulomas, as in a U.K. sarcoid autopsy series, were rare. A notable difference was the absence of myocardial involvement in CBD compared to an incidence of 20% in the sarcoid autopsies. The detection of beryllium in the criteria for diagnosis is emphasized and the cases classified as definite include 12 of 19 positive analysis, 6 of 19, negative or unavailable analysis. The remaining case was classified as dubious because, despite a positive analysis, granulomas were absent. The main differential diagnosis is sarcoidosis.