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1.  Beryllium Metal I. Experimental Results on Acute Oral Toxicity, Local Skin and Eye Effects, and Genotoxicity 
Annals of Occupational Hygiene  2010;55(1):30-42.
The toxicity of soluble metal compounds is often different from that of the parent metal. Since no reliable data on acute toxicity, local effects, and mutagenicity of beryllium metal have ever been generated, beryllium metal powder was tested according to the respective Organisation for Economical Co-Operation and Development (OECD) guidelines. Acute oral toxicity of beryllium metal was investigated in rats and local effects on skin and eye in rabbits. Skin-sensitizing properties were investigated in guinea pigs (maximization method). Basic knowledge about systemic bioavailability is important for the design of genotoxicity tests on poorly soluble substances. Therefore, it was necessary to experimentally compare the capacities of beryllium chloride and beryllium metal to form ions under simulated human lung conditions. Solubility of beryllium metal in artificial lung fluid was low, while solubility in artificial lysosomal fluid was moderate. Beryllium chloride dissolution kinetics were largely different, and thus, metal extracts were used in the in vitro genotoxicity tests. Genotoxicity was investigated in vitro in a bacterial reverse mutagenicity assay, a mammalian cell gene mutation assay, a mammalian cell chromosome aberration assay, and an unscheduled DNA synthesis (UDS) assay. In addition, cell transformation was tested in a Syrian hamster embryo cell assay, and potential inhibition of DNA repair was tested by modification of the UDS assay. Beryllium metal was found not to be mutagenic or clastogenic based on the experimental in vitro results. Furthermore, treatment with beryllium metal extracts did not induce DNA repair synthesis, indicative of no DNA-damaging potential of beryllium metal. A cell-transforming potential and a tendency to inhibit DNA repair when the cell is severely damaged by an external stimulus were observed. Beryllium metal was also found not to be a skin or eye irritant, not to be a skin sensitizer, and not to have relevant acute oral toxic properties.
PMCID: PMC3020675  PMID: 21196457
acute toxicity; beryllium; genotoxicity; mutagenicity; sensitization; solubility
2.  Beryllium Metal II. A Review of the Available Toxicity Data 
Annals of Occupational Hygiene  2010;55(1):43-56.
Beryllium metal was classified in Europe collectively with beryllium compounds, e.g. soluble salts. Toxicological equivalence was assumed despite greatly differing physicochemical properties. Following introduction of the Registration, Evaluation, Authorization and Restriction of Chemicals (REACH) regulation, beryllium metal was classified as individual substance and more investigational efforts to appropriately characterize beryllium metal as a specific substance apart from soluble beryllium compounds was required. A literature search on toxicity of beryllium metal was conducted, and the resulting literature compiled together with the results of a recently performed study package into a comprehensive data set. Testing performed under Organisation for Economic Co-Operation and Development guidelines and Good Laboratory Practice concluded that beryllium metal was neither a skin irritant, an eye irritant, a skin sensitizer nor evoked any clinical signs of acute oral toxicity; discrepancies between the current legal classification of beryllium metal in the European Union (EU) and the experimental results were identified. Furthermore, genotoxicity and carcinogenicity were discussed in the context of the literature data and the new experimental data. It was concluded that beryllium metal is unlikely to be a classical nonthreshold mutagen. Effects on DNA repair and morphological cell transformation were observed but need further investigation to evaluate their relevance in vivo. Animal carcinogenicity studies deliver evidence of carcinogenicity in the rat; however, lung overload may be a species-specific confounding factor in the existing studies, and studies in other species do not give convincing evidence of carcinogenicity. Epidemiology has been intensively discussed over the last years and has the problem that the studies base on the same US beryllium production population and do not distinguish between metal and soluble compounds. It is noted that the correlation between beryllium exposure and carcinogenicity, even including the soluble compounds, remains under discussion in the scientific community and active research is continuing.
PMCID: PMC3020676  PMID: 21196456
acute toxicity; beryllium; carcinogenicity; classification; epidemiology; genotoxicity; inhalation; sensitization
3.  Lung function, biological monitoring, and biological effect monitoring of gemstone cutters exposed to beryls 
OBJECTIVES—Gemstone cutters are potentially exposed to various carcinogenic and fibrogenic metals such as chromium, nickel, aluminium, and beryllium, as well as to lead. Increased beryllium concentrations had been reported in the air of workplaces of beryl cutters in Idar-Oberstein, Germany. The aim of the survey was to study the excretion of beryllium in cutters and grinders with occupational exposure to beryls—for example, aquamarines and emeralds—to examine the prevalence of beryllium sensitisation with the beryllium lymphocyte transformation test (BeLT), to examine the prevalence of lung disease induced by beryllium, to describe the internal load of the respective metals relative to work process, and to screen for genotoxic effects in this particular profession.
METHODS—In a cross sectional investigation, 57 out of 100 gemstone cutters working in 12 factories in Idar-Oberstein with occupational exposure to beryls underwent medical examinations, a chest radiograph, lung function testing (spirometry, airway resistance with the interrupter technique), and biological monitoring, including measurements of aluminium, chromium, and nickel in urine as well as lead in blood. Beryllium in urine was measured with a newly developed direct electrothermal atomic absorption spectroscopy technique with a measurement limit of 0.06 µg/l. Also, cytogenetic tests (rates of micronuclei and sister chromatid exchange), and a BeLT were performed. Airborne concentrations of beryllium were measured in three factories. As no adequate local control group was available, the cutters were categorised into those with an exposure to beryls of >4 hours/week (group A) and ⩽4 hours/week (group B).
RESULTS—Clinical, radiological, or spirometric abnormalities indicating pneumoconiosis were detected in none of the gemstone cutters. Metal concentrations in biological material were far below the respective biological limit values, and beryllium in urine was only measurable in subjects of group A. Cytogenetic investigations showed normal values which were independent of the duration of beryllium exposure. In one subject, the BeLT was positive. Beryllium stimulation indices were significantly higher in subjects with detectable beryllium in the urine than in those with beryllium concentrations below the detection limit (p<0.05). In one factory, two out of four measurements of airborne beryllium concentrations were well above the German threshold limit value of 2 µg/m3 (twofold and 10-fold), and all gemstone cutters working in this factory had measurable beryllium concentrations in urine.
CONCLUSION—No adverse clinical health effects were found in this cross sectional investigation of gemstone cutters working with beryls. However, an improvement in workplace hygiene is recommended, accompanied by biological monitoring of beryllium in urine.

Keywords: gemstone cutter; beryllium in urine; lymphocyte transformation test
PMCID: PMC1739907  PMID: 10711282
4.  Pulmonary berylliosis on corticosteroid therapy, with cavitating lung lesions and aspergillomata--report on a fatal case. 
Postgraduate Medical Journal  1987;63(743):797-799.
A fatal case of pulmonary berylliosis in a 42 year old male is described. The patient was exposed to beryllium while working in a chemical plant over a 9 year period, and presented two years after ceasing such employment. The berylliosis was diagnosed on open lung biopsy in 1971. The patient was commenced on steriod therapy at that time. He suffered progressive dyspnoea from severe restrictive lung disease over the next 14 years. A chest X-ray of June 1985 revealed a lesion in the left upper lobe suggestive of a mycetoma. Before any therapy could be instituted he suffered a massive haemoptysis and died. Post-mortem examination revealed two large mycetomata in the right and left upper lobes. Parenchymal histology showed evidence of chronic inflammation with non-caseating granulomata and the cavity wall showed localized invasion by Aspergillus fumigatus. It is possible that the long term steroid therapy with multiple boosters of treatment may have contributed to the development of the mycetoma. This is the first case report known to the authors of a fatal aspergilloma in association with chronic berylliosis treated with steroids.
PMCID: PMC2428527  PMID: 3328191
5.  Chronic Pulmonary Berylliosis in a Female Chemist 
A chronic progressive granulomatous disease of the lungs is described in a female chemist who worked for about two years with a beryllium compound in the manufacture of fluorescent lighting tubes. The level of beryllium in the laboratory atmosphere was found to be 2·7 μg. per cu.m. and in other parts of the factory up to 39·1 μg. per cu.m. were recorded. Symptoms began about two years after she left this work and she died three years later. A diagnosis of chronic pulmonary berylliosis was made, and confirmation was obtained by lung biopsy when early in the course of the disease a large cyst attached to the right middle lobe was removed by thoracotomy. Tests of lung function showed that there was a low arterial saturation at rest and a normal Pco2 in spite of marked hyperventilation. Both elastance and resistance of the lungs were greater than normal and total work of breathing was six times the normal. Pregnancy was associated with relief of symptoms which persisted for some months after a normal birth. Death occurred about seven years after exposure to beryllium ceased. At necropsy beryllium was detected in the lungs chemically and demonstrated in histological sections by special stains. Microscopic examination of the lung showed conchoidal bodies and doubly refractile crystals and the pathogenesis of these lesions is discussed. It is suggested that there is a sensitivity reaction to beryllium, which is probably combined with protein to form an antigen, and that the breakdown of necrotic foci provokes a further reaction in the lung with the repeated appearance of fresh lesions.
PMCID: PMC1038106  PMID: 13773748
6.  Skin as a route of exposure and sensitization in chronic beryllium disease. 
Environmental Health Perspectives  2003;111(9):1202-1208.
Chronic beryllium disease is an occupational lung disease that begins as a cell-mediated immune response to beryllium. Although respiratory and engineering controls have significantly decreased occupational beryllium exposures over the last decade, the rate of beryllium sensitization has not declined. We hypothesized that skin exposure to beryllium particles would provide an alternative route for sensitization to this metal. We employed optical scanning laser confocal microscopy and size-selected fluorospheres to demonstrate that 0.5- and 1.0- micro m particles, in conjunction with motion, as at the wrist, penetrate the stratum corneum of human skin and reach the epidermis and, occasionally, the dermis. The cutaneous immune response to chemical sensitizers is initiated in the skin, matures in the local lymph node (LN), and releases hapten-specific T cells into the peripheral blood. Topical application of beryllium to C3H mice generated beryllium-specific sensitization that was documented by peripheral blood and LN beryllium lymphocyte proliferation tests (BeLPT) and by changes in LN T-cell activation markers, increased expression of CD44, and decreased CD62L. In a sensitization-challenge treatment paradigm, epicutaneous beryllium increased murine ear thickness following chemical challenge. These data are consistent with development of a hapten-specific, cell-mediated immune response following topical application of beryllium and suggest a mechanistic link between the persistent rate of beryllium worker sensitization and skin exposure to fine and ultrafine beryllium particles.
PMCID: PMC1241575  PMID: 12842774
7.  Chronic beryllium disease and cancer risk estimates with uncertainty for beryllium released to the air from the Rocky Flats Plant. 
Environmental Health Perspectives  1999;107(9):731-744.
Beryllium was released into the air from routine operations and three accidental fires at the Rocky Flats Plant (RFP) in Colorado from 1958 to 1989. We evaluated environmental monitoring data and developed estimates of airborne concentrations and their uncertainties and calculated lifetime cancer risks and risks of chronic beryllium disease to hypothetical receptors. This article discusses exposure-response relationships for lung cancer and chronic beryllium disease. We assigned a distribution to cancer slope factor values based on the relative risk estimates from an occupational epidemiologic study used by the U.S. Environmental Protection Agency (EPA) to determine the slope factors. We used the regional atmospheric transport code for Hanford emission tracking atmospheric transport model for exposure calculations because it is particularly well suited for long-term annual-average dispersion estimates and it incorporates spatially varying meteorologic and environmental parameters. We accounted for model prediction uncertainty by using several multiplicative stochastic correction factors that accounted for uncertainty in the dispersion estimate, the meteorology, deposition, and plume depletion. We used Monte Carlo techniques to propagate model prediction uncertainty through to the final risk calculations. We developed nine exposure scenarios of hypothetical but typical residents of the RFP area to consider the lifestyle, time spent outdoors, location, age, and sex of people who may have been exposed. We determined geometric mean incremental lifetime cancer incidence risk estimates for beryllium inhalation for each scenario. The risk estimates were < 10(-6). Predicted air concentrations were well below the current reference concentration derived by the EPA for beryllium sensitization.
PMCID: PMC1566450  PMID: 10464074
8.  Alterations in the K-ras and p53 genes in rat lung tumors. 
Environmental Health Perspectives  1997;105(Suppl 4):901-906.
Activation of the K-ras protooncogene and inactivation of the p53 tumor suppressor gene are events common to many types of human cancers. Molecular epidemiology studies have associated mutational profiles in these genes with specific exposures. The purpose of this paper is to review investigations that have examined the role of the K-ras and p53 genes in lung tumors induced in the F344 rat by mutagenic and nonmutagenic exposures. Mutation profiles within the K-ras and p53 genes, if present in rat lung tumors, would help to define some of the molecular mechanisms underlying cancer induction by various environmental agents. Pulmonary adenocarcinomas or squamous cell carcinomas were induced by tetranitromethane (TNM), 4-methylnitrosamino-1-(3-pyridyl)-1-butanone (NNK), beryllium metal, plutonium-239, X-ray, diesel exhaust, or carbon black. These agents were chosen because the tumors they produced could arise via different types of DNA damage. Mutation of the K-ras gene was determined by approaches that included DNA transfection, direct sequencing, mismatch hybridization, and restriction fragment length polymorphism analysis. The frequency for mutation of the K-ras gene was exposure dependent. Only two agents, TNM and plutonium, led to mutation frequencies of > 10%. In both cases, the transition mutations formed could have been derived from deamination of cytosine. The identification of non-ras transforming genes in rat lung tumors induced by mutagenic and nonmutagenic exposures such as NNK and beryllium would help define some of the mechanisms underlying cancer induction by different types of DNA damage. Alteration in the p53 gene was assessed by immunohistochemical analysis for p53 protein and single-strand conformation polymorphism (SSCP) analysis of exons 4 to 9. None of the 93 adenocarcinomas examined was immunoreactive toward the anti-p53 antibody CM1. In contrast, 14 to 71 squamous cell carcinomas exhibited nuclear p53 immunoreactivity with no correlation to type of exposure. However, SSCP analysis only detected mutations in 2 of 14 squamous cell tumors that were immunoreactive, suggesting that protein stabilization did not stem from mutations within the p53 gene. Thus, the p53 gene does not appear to be involved in the genesis of most rat lung tumors.
PMCID: PMC1470039  PMID: 9255578
9.  Up-Regulation of Programmed Death-1 Expression on Beryllium-Specific CD4+ T Cells in Chronic Beryllium Disease1 
Chronic beryllium disease (CBD) is caused by workplace exposure to beryllium and is characterized by the accumulation of memory CD4+ T cells in the lung. These cells respond vigorously to beryllium salts in culture by producing proinflammatory Th1-type cytokines. The presence of these inflammatory cytokines leads to the recruitment of alveolar macrophages, alveolitis, and subsequent granuloma development. It has been shown that chronic exposure to conventional Ags leads to up-regulation in the expression of negative regulators of T cells such as programmed death-1 (PD-1). Due to the persistence of beryllium in the lung after the cessation of exposure, aberrant regulation of the PD-1 pathway may play an important role in CBD development. In the present study, PD-1 expression was measured on blood and bronchoalveolar lavage (BAL) CD4+ T cells from beryllium-sensitized and CBD subjects. PD-1 expression was significantly higher on BAL CD4+ T cells compared with those cells in blood, with the highest expression on the beryllium-specific T cell subset. In addition, the expression of PD-1 on BAL CD4+ T cells directly correlated with the severity of the T cell alveolitis. Increased expression of the PD-1 ligands, PD-L1 and PD-L2, on BAL CD14+ cells compared with blood was also seen. The addition of anti-PD-1 ligand mAbs augmented beryllium-induced CD4+ T cell proliferation, and an inverse correlation was seen between PD-1 expression on beryllium-specific CD4+ T cells and beryllium-induced proliferation. Thus, the PD-1 pathway is active in beryllium-induced disease and plays a key role in controlling beryllium-induced T cell proliferation.
PMCID: PMC4347847  PMID: 18250483
10.  Study on the effects of nitrilotriproprionic acid and 4,5-dihydroxy-1,3-benzene disulphonate on the fractionation of beryllium in human serum using graphite furnace atomic absorption spectrometry 
Occupational exposure to beryllium may cause Chronic Beryllium Disease (CBD), a lung disorder initiated by an electrostatic interaction with the MHC class II human leukocyte antigen (HLA). Molecular studies have found a significant correlation between the electrostatic potential at the HLA-DP surface and disease susceptibility. CBD can therefore be treated by chelation therapy. In this work, we studied the effect of two complexing agents, nitrilotriproprionic acid (NTP) and 4,5-dihydroxy-1,3-benzene disulphonate (Tiron), on the fractionation of beryllium in human serum analysed by graphite furnace atomic absorption spectrometry (GFAAS).
We found the average serum beryllium concentration of fourteen non-exposed individuals to be 0.53 (± 0.14) μg l-1, with 21 (± 3)% of the beryllium mass bound to the low molecular weight fraction (LMW), and 79 (± 3)% bound to the high molecular weight fraction (HMW). The addition of Tiron increased the beryllium mass in the HMW fraction, while NTP was not seen to have any influence on the fractionation of beryllium between the two fractions. NTP was, however, shown to complex 94.5% of the Be mass in the LMW fraction. The beryllium GFAAS detection limit, calculated as three times the standard deviation of 10 replicates of the lowest standard (0.05 μg L-1), was 6.0 (± 0.2) ng L-1.
The concentration of beryllium or its fractionation in human serum was not affected by sex or smoking habit. On average, three quarters of the beryllium in serum were found in the HMW fraction. Of the two ligands tested, only Tiron was effective in mobilising beryllium under physiological conditions, thus increasing the Be content in the HMW fraction.
PMCID: PMC2396160  PMID: 18479524
11.  A Reconsideration of Acute Beryllium Disease 
Environmental Health Perspectives  2009;117(8):1250-1256.
Although chronic beryllium disease (CBD) is clearly an immune-mediated granulomatous reaction to beryllium, acute beryllium disease (ABD) is commonly considered an irritative chemical phenomenon related to high exposures. Given reported new cases of ABD and projected increased demand for beryllium, we aimed to reevaluate the patho physiologic associations between ABD and CBD using two cases identified from a survey of beryllium production facility workers.
Case Presentation
Within weeks after exposure to beryllium fluoride began, two workers had systemic illness characterized by dermal and respiratory symptoms and precipitous declines in pulmonary function. Symptoms and pulmonary function abnormalities improved with cessation of exposure and, in one worker, recurred with repeat exposure. Bronchoalveolar lavage fluid analyses and blood beryllium lymphocyte proliferation tests revealed lymphocytic alveolitis and cellular immune recognition of beryllium. None of the measured air samples exceeded 100 μg/m3, and most were < 10 μg/m3, lower than usually described. In both cases, lung biopsy about 18 months after acute illness revealed noncaseating granulomas. Years after first exposure, the workers left employment because of CBD.
Contrary to common understanding, these cases suggest that ABD and CBD represent a continuum of disease, and both involve hypersensitivity reactions to beryllium. Differences in disease presentation and progression are likely influenced by the solubility of the beryllium compound involved.
Relevance to Practice
ABD may occur after exposures lower than the high concentrations commonly described. Prudence dictates limitation of further beryllium exposure in both ABD and CBD.
PMCID: PMC2721869  PMID: 19672405
acute; beryllium; beryllium disease; granuloma; hypersensitivity; immune sensitization; pneumonitis
12.  The carcinogenicity of beryllium. 
Beryllium, some of its alloys, and a variety of its compounds have induced malignant tumors of the lung and osteogenic sarcoma in experimental animals. Three animal species, monkeys, rabbits, and rats, have been shown to be susceptible. Beryllium induces morphological transformation in mammalian cells and enhances viral transformation of mammalian cells. It has been shown to decrease fidelity of DNA synthesis. It has been recognized that exposure to compounds of this metal will, in some individuals, result in a chronic granulomatous disease of the lung. A series of overlapping recent human epidemiological studies have been suggestive of an increase in the incidence of lung cancer in populations occupationally exposed to beryllium. Such studies, together with animal and in vitro studies, argue for the strong presumption of a carcinogenic hazard to man in occupational beryllium exposures.
PMCID: PMC1568815  PMID: 7023926
13.  A long-term follow-up of workers exposed to beryllium 
ABSTRACT The relationship of features of beryllium disease to the estimated exposure to beryllium has been investigated over a 30-year period at a factory manufacturing beryllium products. The factory opened in 1952. Of the 146 men who had worked there for more than six months up to 1963, 89% were seen at that time and were followed up in 1973. The nine who continued to work in the factory and those who were engaged subsequently were examined in 1977. On each occasion a clinical interview, occupational history, chest radiograph, and assessment of lung function were carried out. The findings of the main survey were related to the beryllium content of the dust measured by mass spectrometry for 1952-60 when over 3000 determinations were made. In no part of the plant did the estimated average daily exposure exceed 2 μg m-3, and only 9% of individual determinations exceeded this level. Twenty determinations exceeded 25 μg m-3. During the period under review, four men developed the clinical, radiographic, and physiological features of beryllium disease. Two men acquired abnormal chest radiographs consistent with beryllium disease but without other features, and one developed probable beryllium disease despite the diagnosis not being confirmed at necropsy. The affected men were all exposed to beryllium oxide or hydroxide but in a wide range of estimated doses. In six the changes developed after exposure had ceased; trigger factors including patch testing may have contributed to their illness. Seventeen men recalled episodes of brief exposure to high concentrations of dust, two developed pneumonitis from which they recovered completely, and one developed chronic beryllium disease after a further 23 years' exposure. In subjects without clinical or radiographic evidence of disease no convincing evidence was obtained for any association between the lung function and the estimated exposure to beryllium.
PMCID: PMC1009111  PMID: 6824594
14.  4-1BB Enhances Proliferation of Beryllium-Specific T Cells in the Lung of Subjects with Chronic Beryllium Disease1 
In contrast to naive T cells, reactivation of memory cells is less dependent on CD28-mediated costimulation. We have shown that circulating beryllium-specific CD4+ T cells from chronic beryllium disease patients remain CD28-dependent, while those present in the lung no longer require CD28 for T cell activation. In the present study, we analyzed whether other costimulatory molecules are essential for beryllium-induced T cell function in the lung. Enhanced proliferation of a beryllium-responsive, HLA-DP2-restricted T cell line was seen after the induction of 4-1BB ligand expression on the surface of HLA-DP2-expressing fibroblasts. Following beryllium exposure, CD4+ T cells from blood and bronchoalveolar lavage of chronic beryllium disease patients up-regulate 4-1BB expression, and the majority of beryllium-responsive, IFN-γ-producing CD4+ T cells in blood coexpress CD28 and 4-1BB. Conversely, a significant fraction of IFN-γ-producing bronchoalveolar lavage (BAL) T cells express 4-1BB in the absence of CD28. In contrast to blood, inhibition of the 4-1BB ligand-4-1BB interaction partially blocked beryllium-induced proliferation of BAL CD4+ T cells, and a lack of 4-1BB expression on BAL T cells was associated with increased beryllium-induced cell death. Taken together, these findings suggest an important role of 4-1BB in the costimulation of beryllium-responsive CD4+ T cells in the target organ.
PMCID: PMC3057106  PMID: 18768897
15.  Beryllium Alters Lipopolysaccharide-Mediated Intracellular Phosphorylation and Cytokine Release in Human Peripheral Blood Mononuclear Cells 
Beryllium exposure in susceptible individuals leads to the development of chronic beryllium disease, a lung disorder marked by release of inflammatory cytokine and granuloma formation. We have previously reported that beryllium induces an immune response even in blood mononuclear cells from healthy individuals. In this study, we investigate the effects of beryllium on lipopolysaccharide - mediated cytokine release in blood mononuclear and dendritic cells from healthy individuals. We find that in vitro treatment of beryllium sulfate inhibits the secretion of lipopolysaccharide-mediated interleukin 10, while the release of interleukin 1β is enhanced. Additionally, not all lipopolysaccharide - mediated responses are altered, as interleukin 6 release in unaffected upon beryllium treatment. Beryllium sulfate treated cells show altered phosphotyrosine levels upon lipopolysaccharide stimulation. Significantly, beryllium inhibits the phosphorylation of signal transducer and activator of transducer 3, induced by lipopolysaccharide. Finally, inhibitors of phosphoinositide-3 kinase mimic the effects of beryllium in inhibition of interleukin 10 release, while they have no effect on interleukin 1β secretion. This study strongly suggests that prior exposures to beryllium could alter host immune responses to bacterial infections in healthy individuals, by altering intracellular signaling.
PMCID: PMC3607438  PMID: 19894180
Beryllium; Cytokines; Human; Lipopolysaccharide
16.  A Novel Alternative to Environmental Monitoring to Detect Workers at Risk for Beryllium Exposure-Related Health Effects 
The purpose of this study was to describe a methodology for surveillance and monitoring of beryllium exposure using biological monitoring to complement environmental monitoring. Eighty-three Israeli dental technicians (mean age 41.6 ± 1.36 years) and 80 American nuclear machining workers (54.9 ± 1.21 years) were enrolled. Biological monitoring was carried out by analyzing particle size (laser technique) and shape (image analysis) in 131/163 (80.3%) induced sputum samples (Dipa Analyser, Donner Tech, Or Aquiva, Israel). Environmental monitoring was carried out only in the United States (Sioutas impactor, SKC, Inc., Eighty Four, Pa.). Pulmonary function testing performance and induced sputum retrieval were done by conventional methods. Sixty-three Israeli workers and 37 American workers were followed up for at least 2 years.
Biological monitoring by induced sputum indicated that a >92% accumulation of <5 µm particles correlated significantly to a positive beryllium lymphocyte proliferation test result (OR 3.8, 95% CI 1.2–11.4, p = 0.015) among all participants. Environmental monitoring showed that beryllium particles were <1 µm, and this small fraction (0.1–1 µ) was significantly more highly accumulated in nuclear machining workers compared to dental technicians. The small fractions positively correlated with induced sputum macrophages (r = 0.21 p = 0.01) and negatively correlated with diffusion lung carbon monoxide single breath (DLCO-SB r = 0.180 p = 0.04) in all subjects. Years of exposure were positively correlated to the number of accumulated particles 2–3 µ in diameter (r = 0.2, p = 0.02) and negatively correlated to forced expiratory volume in one second/forced vital capacity findings (r = −0.18, p = 0.02). DLCO was decreased in both groups after two years of monitoring.
Biological monitoring is more informative than environmental monitoring in the surveillance and monitoring of workers in beryllium industries. Induced sputum is a feasible and promising biomonitoring method that should be included in the surveillance of exposed workers.
PMCID: PMC4347844  PMID: 24856577
induced sputum; exposure assessment; biological monitoring; particulate matter; hazardous dust
17.  Differences in estimates of size distribution of beryllium powder materials using phase contrast microscopy, scanning electron microscopy, and liquid suspension counter techniques 
Accurate characterization of the physicochemical properties of aerosols generated for inhalation toxicology studies is essential for obtaining meaningful results. Great emphasis must also be placed on characterizing particle properties of materials as administered in inhalation studies. Thus, research is needed to identify a suite of techniques capable of characterizing the multiple particle properties (i.e., size, mass, surface area, number) of a material that may influence toxicity. The purpose of this study was to characterize the morphology and investigate the size distribution of a model toxicant, beryllium. Beryllium metal, oxides, and alloy particles were aerodynamically size-separated using an aerosol cyclone, imaged dry using scanning electron microscopy (SEM), then characterized using phase contrast microscopy (PCM), a liquid suspension particle counter (LPC), and computer-controlled SEM (CCSEM). Beryllium metal powder was compact with smaller sub-micrometer size particles attached to the surface of larger particles, whereas the beryllium oxides and alloy particles were clusters of primary particles. As expected, the geometric mean (GM) diameter of metal powder determined using PCM decreased with aerodynamic size, but when suspended in liquid for LPC or CCSEM analysis, the GM diameter decreased by a factor of two (p < 0.001). This observation suggested that the smaller submicrometer size particles attached to the surface of larger particles and/or particle agglomerates detach in liquid, thereby shifting the particle size distribution downward. The GM diameters of the oxide materials were similar regardless of sizing technique, but observed differences were generally significant (p < 0.001). For oxides, aerodynamic cluster size will dictate deposition in the lung, but primary particle size may influence biological activity. The GM diameter of alloy particles determined using PCM became smaller with decreasing aerodynamic size fraction; however, when suspended in liquid for CCSEM and LPC analyses, GM particle size decreased by a factor of two (p < 0.001) suggesting that alloy particles detach in liquid. Detachment of particles in liquid could have significance for the expected versus actual size (and number) distribution of aerosol delivered to an exposure subject. Thus, a suite of complimentary analytical techniques may be necessary for estimating size distribution. Consideration should be given to thoroughly understanding the influence of any liquid vehicle which may alter the expected aerosol size distribution.
PMCID: PMC1810321  PMID: 17328812
18.  The natural history of beryllium sensitization and chronic beryllium disease. 
Environmental Health Perspectives  1996;104(Suppl 5):937-943.
With the advent of in vitro immunologic testing, we can now detect exposed individuals who are sensitized to beryllium and those who have chronic beryllium disease (CBD) with lung pathology and impairment. Earlier detection and more accurate diagnostic tools raise new questions about the natural history of sensitization and granulomatous disease. Preliminary data suggest that early detection identifies people who are sensitized to beryllium and that these individuals are at risk for progressing into clinical disease. This article discusses the historical, recent, and ongoing studies germane to our understanding of CBD natural history, including the immunologic and inflammatory basis of the disease, the environmental and host risk factors for disease progression, biological markers of disease severity and activity that may help predict outcome, and the implications for broad-based workplace screening to identify patients at the earliest stages of beryllium sensitization and disease.
PMCID: PMC1469683  PMID: 8933038
19.  Animal models of beryllium-induced lung disease. 
Environmental Health Perspectives  1996;104(Suppl 5):973-979.
The inhalation Toxicology Research Institute (ITRI) is conducting research to improve the understanding of chronic beryllium disease (CBD) and beryllium-induced lung cancer. Initial animal studies examined beagle dogs that inhaled BeO calcined at either 500 or 1000 degrees C. At similar lung burdens, the 500 degrees C BeO induced more severe and extensive granulomatous pneumonia, lymphocytic infiltration into the lung, and positive Be-specific lymphocyte proliferative responses in vitro than the 1000 degrees C BeO. However, the progressive nature of human CBD was not duplicated. More recently, Strains A/J and C3H/Hej mice were exposed to Be metal by inhalation. This produced a marked granulomatous pneumonia, diffuse infiltrates, and multifocal aggregates of interstitial lymphocytes with a pronounced T helper component and pulmonary in situ lymphocyte proliferation. With respect to lung cancer, at a mean lung burden as low as 17 micrograms Be/g lung, inhaled Be metal induced benign and/or malignant lung tumors in over 50% of male and female F344 rats surviving > or = 1 year on study. Substantial tumor multiplicity was found, but K-ras and p53 gene mutations were virtually absent. In mice, however, a lung burden of approximately 60 micrograms (-300 micrograms Be/g lung) caused only a slight increase in crude lung tumor incidence and multiplicity over controls in strain A/J mice and no elevated incidence in strain C3H mice. Taken together, this research program constitutes a coordinated effort to understand beryllium-induced lung disease in experimental animal models.
PMCID: PMC1469700  PMID: 8933044
20.  CD27 Expression on CD4+ T Cells Differentiates Effector from Regulatory T Cell Subsets in the Lung1 
Beryllium exposure in the workplace can result in chronic beryllium disease, a granulomatous lung disorder characterized by CD4+ T cell alveolitis and progressive lung fibrosis. A large number of the CD4+ T cells recruited to the lung in chronic beryllium disease recognize beryllium in an Ag-specific manner and express Th1-type cytokines following T cell activation. Beryllium-responsive CD4+ T cells in the bronchoalveolar lavage (BAL) express an effector memory T cell phenotype and recognize beryllium in a CD28-independent manner. In this study, we show that the majority of beryllium-responsive CD4+ T cells in BAL have lost CD27 expression, whereas a subset of beryllium-responsive cells in blood retains expression of this costimulatory molecule. In addition, loss of CD27 on BAL CD4+ T cells inversely correlates with markers of lung inflammation. A small population of BAL CD4+ T cells retains CD27 expression, and these CD4+CD27+ T cells contain the FoxP3-expressing, naturally occurring regulatory T (Treg) cell subset. Coexpression of CD27 and CD25 identifies the majority of FoxP3-expressing Treg cells in blood and BAL, and these cells express potent suppressor function. Taken together, these findings suggest that CD27 is differentially expressed between effector T cells from the inflamed lung and can be used in conjunction with CD25 to isolate Treg cells and assess their functional capacity in an ongoing adaptive immune response in a target organ.
PMCID: PMC3061566  PMID: 19454729
21.  Beryllium disease. 
Postgraduate Medical Journal  1988;64(753):511-516.
The increasing use of beryllium in a variety of industries continues to be a hazard. New cases are still being reported to the UK Beryllium Case Registry, now numbering 60 in the period 1945-1988. The majority of cases follow inhalation which results in acute beryllium disease (chemical pneumonitis) or more commonly chronic beryllium disease--a granulomatous pneumonitis. Granulomatous skin nodules also occur following local implantation. The clinical and radiological features are briefly described with the emphasis on pathology and immunology. Laser microprobe mass spectrometry analysis of tissue sections is a major advance in diagnosis. Detection of beryllium distinguishes the granulomas of chronic beryllium disease from other diseases, in particular sarcoidosis. The role of beryllium lymphocyte transformation tests is discussed. Chronic beryllium disease is steroid dependent and local excision of skin lesions appears to be curative. There is no evidence that beryllium is carcinogenic.
PMCID: PMC2428897  PMID: 3074283
22.  Frequency of beryllium-specific, central memory CD4+ T cells in blood determines proliferative response 
Journal of Clinical Investigation  2005;115(10):2886-2893.
Beryllium exposure can lead to the development of beryllium-specific CD4+ T cells and chronic beryllium disease (CBD), which is characterized by the presence of lung granulomas and a CD4+ T cell alveolitis. Studies have documented the presence of proliferating and cytokine-secreting CD4+ T cells in blood of CBD patients after beryllium stimulation. However, some patients were noted to have cytokine-secreting CD4+ T cells in blood in the absence of beryllium-induced proliferation, and overall, the correlation between the 2 types of responses was poor. We hypothesized that the relative proportion of memory T cell subsets determined antigen-specific proliferation. In most CBD patients, the majority of beryllium-specific CD4+ T cells in blood expressed an effector memory T cell maturation phenotype. However, the ability of blood cells to proliferate in the presence of beryllium strongly correlated with the fraction expressing a central memory T cell phenotype. In addition, we found a direct correlation between the percentage of beryllium-specific CD4+ TEM cells in blood and T cell lymphocytosis in the lung. Together, these findings indicate that the functional capability of antigen-specific CD4+ T cells is determined by the relative proportion of memory T cell subsets, which may reflect internal organ involvement.
PMCID: PMC1199530  PMID: 16151531
23.  Impaired Function of CTLA-4 in the Lungs of Patients with Chronic Beryllium Disease Contributes to Persistent Inflammation1 
Chronic beryllium disease (CBD) is an occupational lung disorder characterized by granulomatous inflammation and the accumulation of beryllium-responsive CD4+ T cells in the lung. These differentiated effector memory T cells secrete IL-2, IFN-γ, and TNF-α upon in vitro activation. Beryllium-responsive CD4+ T cells in the lung are CD28 independent and have increased expression of the coinhibitory receptor, programmed death 1, resulting in antigen-specific T cells that proliferate poorly yet retain the ability to express Th1-type cytokines. To further investigate the role of coinhibitory receptors in the beryllium-induced immune response, we examined the expression of CTLA-4 in blood and bronchoalveolar lavage cells from subjects with CBD. CTLA-4 expression was elevated on CD4+ T cells from the lungs of study subjects compared to blood. Furthermore, CTLA-4 expression was greatest in the beryllium-responsive subset of CD4+ T cells that retained the ability to proliferate and express IL-2. Functional assays show that the induction of CTLA-4 signaling in blood cells inhibited beryllium-induced T cell proliferation while having no effect on the proliferative capacity of beryllium-responsive CD4+ T cells in lung. Collectively, our findings suggest a dysfunctional CTLA-4 pathway in the lung and its potential contribution to the persistent inflammatory response that characterizes CBD.
PMCID: PMC3750981  PMID: 23851684
Human; T Cells; Cell Surface Molecules; Cytokines; Lung
24.  Target organ localization of memory CD4+ T cells in patients with chronic beryllium disease 
The Journal of Clinical Investigation  2002;110(10):1473-1482.
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 (BeSO4). 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 BeSO4 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.
PMCID: PMC151812  PMID: 12438445
25.  Cytokine production by bronchoalveolar lavage cells in chronic beryllium disease. 
Environmental Health Perspectives  1996;104(Suppl 5):969-971.
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.
PMCID: PMC1469699  PMID: 8933043

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