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PubMed2003

Genetic factors modify the risk of developing beryllium disease.

Chronic beryllium disease (CBD) is a debilitating, granulomatous lung disease that occurs in 1 to 5% of exposed workers. Beryllium stimulates a major histocompatibility Class II-restricted, TH1, CD4+ T cell-mediated immune response. The immunological component of the illness, coupled with the small subset of beryllium workers who develop disease, led researchers to hypothesize that genetic factors modify risk of disease. Analysis of human leukocyte antigen (HLA) genes, the T cell receptor, and tumor necrosis factor (TNF)-alpha focused on three critical steps in the development of beryllium specific immunity. Molecular epidemiological analysis of the association of HLA-DP, -DR, and -DQ has implicated HLA-DPB1E69 allelic variants in disease; however, its role in sensitization is unclear. A single report suggested association between HLA-DQB1G86 and progression from sensitization to disease. A beryllium-specific binding motif was identified in CBD-derived T cell clones. Beryllium-stimulated proliferation using HLA-DPB1*0201 and TCRAV22S1/TCRBVb3 T cell receptors (TCRs) confirmed beryllium specificity of these molecules. The G/A transition at -308 in the TNF-alpha promoter was associated with high concentrations of TNF-alpha in bronchoalveolar lavage and to disease severity. Although these studies are continuing, the data confirm the role of genetic factors in the cellular response to beryllium.

Journal Article↗
PubMed2001

Chronic beryllium disease: a hypersensitivity disorder.

Chronic beryllium disease (CBD) is one of two pulmonary syndromes caused by environmental exposure to beryllium. Acute beryllium disease was first described in 1943 and is an acute toxic reaction to beryllium. CBD was first described in 1946 and the pathogenesis of this disorder was not fully appreciated until the development of fiberoptic bronchoscopy allowed sampling of bronchoalveolar lung cells. Because CBD was associated with a delayed skin test reaction to beryllium, occurred in only 1-5 percent of individuals, was not associated with a clear-cut dose-response curve, and was associated with a granulomatous reaction, a hypersensitivity to beryllium was suspected as the cause. The hypothesis that CBD was due to hypersensitivity was not proven until the 1980s when samples of bronchoalveolar cells obtained by bronchoscopy demonstrated that not only did every individual with CBD have lymphocytes that could respond to beryllium (lymphocyte proliferation assay), but, also, that there was an accumulation of these cells at the site of active disease. The immunological reaction in CBD was associated with CD4+ lymphocytes responding to a beryllium-influenced but unknown peptide(s) that was (were) presented by HLA molecules on antigen-presenting cells. Genetic studies also demonstrated an association of CBD with HLA-DPB1 alleles that contain glutamine at position 69 in up to 97 percent of subjects with CBD but also 30-40 percent of controls. The understanding that CBD is a hypersensitivity disorder has had important implications for the diagnosis, screening, and environmental control precautions necessary for its prevention.

Berylliosis↗
PubMed1996

Machining risk of beryllium disease and sensitization with median exposures below 2 micrograms/m3.

We examined the prevalence of beryllium sensitization in relation to work process and beryllium exposure measurements in a beryllia ceramics plant that had operated since 1980. We interviewed 136 employees (97.8% of the workforce), ascertained beryllium sensitization with the beryllium lymphocyte proliferation blood test, and reviewed historical industrial hygiene measurements. Of eight beryllium-sensitized employees (5.9%), six (4.4% of participating employees) had granulomatous disease on transbronchial lung biopsy. Machinists had a sensitization rate of 14.3% compared to a rate of 1.2% among other employees. Machining had significantly higher general area and breathing zone measurements than did other processes in the time period in which most beryllium-sensitized cases had started machining work. Daily weighted average (DWA) estimates of exposure for matching processes also exceeded estimates for other work processes in that time period, with a median DWA of 0.9 microgram/m3. Machining process DWAs accounted for the majority of DWAs exceeding the 2.0 micrograms/m3 OSHA standard, with 8.1% of machining DWAs above the standard. We conclude that lowering machining process-related exposures may be important to lowering risk of beryllium disease.

Air Pollutants, Occupational↗
PubMed2001

Estimating historical exposures of workers in a beryllium manufacturing plant.

BACKGROUND: Beryllium is known to be toxic to the lungs, causing beryllium lung disease and associated with increased lung cancer risk. Airborne beryllium exposures have been monitored since the 1940s. This study describes methods used to measure airborne beryllium concentrations and how historical measurements from a beryllium manufacturing plant were used to estimate workers' exposures in a lung cancer case-control study. METHODS: Airborne beryllium concentrations had been measured using all-glass impingers, high-volume air filters, and personal respirable and total dust samplers. To provide consistency in exposure estimates over time, measurements collected by the other monitoring methods were converted to approximate the most frequently used high-volume, time-weighted average measurements. Because industrial hygiene measurements were not collected in every year for all jobs throughout the duration of the case-control study, exposure estimates had to be extrapolated from the existing measurements over time and across jobs. RESULTS: Over 7,000 historical measurements were available to estimate beryllium exposures of workers over time. Average exposures between jobs varied considerably and exposures for all jobs decreased dramatically between the 1940s and 1970s due to major plant production changes. CONCLUSIONS: Although error in the exposure metrics for the cases and controls likely occurred due to limitations of the exposure assessment data, the exposure estimates for each job over time provided a reasonable, objective mechanism for categorizing workers by the relative exposures they were likely to have encountered during their tenure. Published 2001 Wiley-Liss, Inc.

Air Pollutants, Occupational↗
PubMed1992

A mortality study of workers at seven beryllium processing plants.

The International Agency for Research on Cancer (IARC) has found that the evidence for the carcinogenicity of beryllium is sufficient based on animal data but "limited" based on human data. This analysis reports on a retrospective cohort mortality study among 9,225 male workers employed at seven beryllium processing facilities for at least 2 days between January 1, 1940, and December 31, 1969. Vital status was ascertained through December 31, 1988. The standardized mortality ratio (SMR) for lung cancer in the total cohort was 1.26 (95% confidence interval [CI] = 1.12-1.42); significant SMRs for lung cancer were observed for two of the oldest plants located in Lorain, Ohio (SMR = 1.69; 95% CI = 1.28-2.19) and Reading, Pennsylvania (SMR = 1.24; 95% CI = 1.03-1.48). For the overall cohort, significantly elevated SMRs were found for "all deaths" (SMR = 1.05; 95% CI = 1.01-1.08), "ischemic heart disease" (SMR = 1.08; 95% CI = 1.01-1.14), "pneumoconiosis and other respiratory diseases" (SMR = 1.48; 95% CI = 1.21-1.80), and "chronic and unspecified nephritis, renal failure, and other renal sclerosis" (SMR = 1.49; 95% CI = 1.00-2.12). Lung cancer SMRs did not increase with longer duration of employment, but did increase with longer latency (time since first exposure). Lung cancer was particularly elevated (SMR = 3.33; 95% CI = 1.66-5.95) among workers at the Lorain plant with a history of (primarily) acute beryllium disease, which is associated with very high beryllium exposure. The lung cancer excess was not restricted to plants operating in the 1940s, when beryllium exposures were known to be extraordinarily high. Elevated lung cancer SMRs were also observed for four of the five plants operating in the 1950s for workers hired during that decade. Neither smoking nor geographic location fully explains the increased lung cancer risk. Occupational exposure to beryllium compounds is the most plausible explanation for the increased risk of lung cancer observed in this study. Continued mortality follow-up of this cohort will provide a more definitive assessment of lung cancer risk at the newer plants and among cohort members hired in the 1950s or later at the older plants. Further clarification of the potential for specific beryllium compounds to induce lung cancer in humans, and the possible contribution of other exposures in specific processes at these plants, would require a nested case-control study. We are currently assessing whether available industrial hygiene data would support such an analysis.

Berylliosis↗
PubMed2004

Flow cytometric test for beryllium sensitivity.

BACKGROUND: Chronic beryllium disease (CBD) is an occupational granulomatous disorder characterized by hypersensitivity to beryllium, mediated by CD4+ T lymphocytes, and predominantly affects the lungs. In this disorder, lymphocyte proliferative responses to beryllium, measured by 3H thymidine incorporation, are used for diagnosis of CBD, for screening asymptomatic workers or former workers to detect unrecognized disease, and for surveillance as a bioassay to detect abnormal exposures. Problems with test variability and the use of radioactivity have recently led to the search for alternative methods. METHODS: We applied a 5,6-carboxyfluorescein diacetate succinimidyl ester flow cytometric technique for measurement of mitogen- and antigen-induced T-lymphocyte proliferation to a group of beryllium-exposed sensitized individuals and beryllium-unexposed controls. RESULTS: We detected mitogen and antigen proliferative responses in CD3+, CD4+, and CD8+ subpopulations. Phytohemagglutinin and Candida stimulated CD4+ and CD8+ T-cell responses, but beryllium appeared to stimulate only CD3+/CD4+ responses. CONCLUSIONS: This technique may provide a sensitive, nonradioactive alternative to the traditional proliferation tests that measure beryllium sensitivity. It offers the added specificity of enabling phenotypic description of the responding cell type and may prove to be easier to standardize for clinical use.

Air Pollutants, Occupational↗
PubMedDate not supplied

Beryllium-induced biochemical alterations and their prevention following co-administration of meso-2,3-dimercaptosuccinic acid or 2,3-dimercaptopropane sulphonate in rats.

The effects of meso-2,3-dimercaptosuccinic acid (DMSA) and 2,3-dimercaptopropane sulphonate (DMPS) on body beryllium burden, hepatic lipid peroxidation, glutathione, alkaline and acid phosphatase and some biochemical variables of porphyrin metabolism were studied in beryllium-poisoned rats. It was observed that beryllium poisoning is associated with a slight increase in lipid peroxidation, significant depletion of alkaline phosphatase and elevation of acid phosphatase activities in the liver and increased beryllium concentration in blood and other soft organs. Evidence is presented that both DMSA and DMPS during concomitant administration prevented most of the above beryllium-induced biochemical alterations. Tissue beryllium concentration and histopathological lesions in liver and kidneys were also significantly less marked following simultaneous administration of DMPS compared to beryllium-exposed controls; DMSA was comparatively less effective.

Animals↗
PubMed1990

The acute toxicity of inhaled beryllium metal in rats.

We exposed rats once by nose only for 50 min to a mean concentration of 800 micrograms/m3 of beryllium metal (initial lung burden, 625 micrograms) to characterize the acute toxic effects within the lung. Histological changes within the lung and enzyme changes within bronchoalveolar lavage (BAL) fluid were evaluated at 3, 7, 10, 14, 31, 59, 115, and 171 days postexposure (dpe). Beryllium metal-exposed rats developed acute, necrotizing, hemorrhagic, exudative pneumonitis and intraalveolar fibrosis that peaked at 14 dpe. By 31 dpe, inflammatory lesions were replaced by minimal interstitial and intraalveolar fibrosis. Necrotizing inflammation was observed again at 59 dpe which progressed to chronic-active inflammation by 115 dpe. This inflammation worsened progressively, as did alveolar macrophage and epithelial hyperplasia, becoming severe at 171 dpe. Low numbers of diffusely distributed lymphocytes were also present but they were not associated with granulomas as is observed in beryllium-induced disease in man. Throughout the experiment, total numbers of cells were elevated within the BAL samples due primarily to increased numbers of neutrophils. Lymphocytes were not elevated in BAL samples collected from beryllium-exposed rats at any time after exposure. Lactate dehydrogenase (LDH), beta-glucuronidase, and protein levels were elevated in BAL fluid from 3 through 14 dpe but returned to near normal levels by 31 dpe. LDH increased once again at 59 dpe and remained elevated at 171 dpe. beta-Glucuronidase and protein levels were slightly, but not significantly, elevated from 31 through 171 dpe. Results indicate that inhalation of beryllium metal by rats results in severe, acute chemical pneumonitis that is followed by a quiescent period of minimal inflammation and mild fibrosis. Progressive, chronic-active, fibrosing pneumonitis is observed later. Chronic beryllium lung disease of man is an immunologically mediated granulomatous lung disease, whereas beryllium-induced lung lesions in rats appear to be due to direct chemical toxicity and foreign-body-type reactions.

Administration, Inhalation↗
PubMed2006

T cell recognition in chronic beryllium disease.

Chronic beryllium disease (CBD) is a granulomatous lung disorder caused by beryllium exposure in the workplace and is characterized by the accumulation of beryllium-specific CD4(+) T cells. Depending on genetic susceptibility and the nature of the exposure, CBD occurs in up to 20% of exposed workers. Genetic susceptibility has been associated with particular HLA-DP alleles, especially those possessing a negatively charged glutamic acid residue at the 69th position of the beta-chain. The mechanism for this association lies in the ability of these HLA-DP molecules to bind and present beryllium to pathogenic CD4(+) T cells. Large numbers of effector memory, beryllium-specific CD4(+) T cells are recruited to the lung of these subjects and secrete Th1-type cytokines upon beryllium recognition. The presence of circulating beryllium-specific CD4(+) T cells directly correlates with the severity of lymphocytic alveolitis. With the presence of a known antigenic stimulus, CBD serves as an important model of immune-mediated, organ destruction. Thus, our findings in CBD have important implications for studies in autoimmune diseases, in particular those with an unknown inciting antigen and an inaccessible target organ.

Antigen Presentation↗
PubMed2003

Identification of an abnormal beryllium lymphocyte proliferation test.

The potential hazards from exposure to beryllium or beryllium compounds in the workplace were first reported in the 1930s. The tritiated thymidine beryllium lymphocyte proliferation test (BeLPT) is an in vitro blood test that is widely used to screen beryllium exposed workers in the nuclear industry for sensitivity to beryllium. The clinical significance of the BeLPT was described and a standard protocol was developed in the late 1980s. Cell proliferation is measured by the incorporation of tritiated thymidine into dividing cells on two culture dates and using three concentrations of beryllium sulfate. Results are expressed as a 'stimulation index' (SI) which is the ratio of the amount of tritiated thymidine (measured by beta counts) in the simulated cells divided by the counts for the unstimulated cells on the same culture day. Several statistical methods for use in the routine analysis of the BeLPT were proposed in the early 1990s. The least absolute values (LAV) method was recommended for routine analysis of the BeLPT. This report further evaluates the LAV method using new data, and proposes a new method for identification of an abnormal or borderline test. This new statistical-biological positive (SBP) method reflects the clinical judgment that: (i) at least two SIs show a 'positive' response to beryllium; and (ii) that the maximum of the six SIs must exceed a cut-point that is determined from a reference data set of normal individuals whose blood has been tested by the same method in the same serum. The new data is from the Y-12 National Security Complex in Oak Ridge (Y-12) and consists of 1080 workers and 33 non-exposed control BeLPTs (all tested in the same serum). Graphical results are presented to explain the statistical method, and the new SBP method is applied to the Y-12 group. The true positive rate and specificity of the new method were estimated to be 86% and 97%, respectively. An electronic notebook that is accessible via the Internet was used in this work and contains background information and details not included in the paper.

Berylliosis↗
PubMed2002

Immobilisation of beryllium in solid waste (red-mud) by fixation and vitrification.

The objective of this study was to obtain information on the immobilization of beryllium (Be) in solid waste generated in the extraction process of beryllium from its ore, Beryl. This solid waste, termed red-mud, contains oxides of iron, aluminium, calcium, magnesium and beryllium. The red-mud waste contains beryllium at levels above the permissible limit, which prevents its disposal as solid waste. The total beryllium content in the red-mud analysed showed value ranging from 0.39 to 0.59% Be The studies showed that 50% of the total beryllium in red-mud can be extracted by water by repeated leaching over a period of 45 days. The cement mix, casting into cement blocks, was subjected to leachability studies over a period of 105 days and immobilization factor (IF factor) was determined. These IF values, of the order of 102, were compared with those obtained by performing leachability study on vitrified red-mud masses produced at different temperature conditions. Direct heating of the red-mud gave the gray coloured, non-transparent vitreous mass (as 'bad glass') showed effective immobilisation factor for beryllium in red-mud of the order of 10(4).

Beryllium↗
PubMed2001

Beryllium(II) complexes of the Kläui tripodal ligand cyclopentadienyltris(diethylphosphito-p)cobaltate(-).

The interactions of the beryllium(II) ion with the cyclopentadienyltris(diethylphosphito-P)cobaltate monoanion, L(-), have been investigated, in aqueous solution, by synthetic methods, potentiometry, ESMS, and (1)H, (31)P, and (9)Be NMR spectroscopy. L(-) has been found able to displace either two or three water molecules in the beryllium(II) coordination sphere, to form mononuclear, dinuclear, and trinuclear derivatives, in which the metal ion is pseudotetrahedrally coordinated. The species [BeL(H(2)O)](+) and [Be(2)L(2)(mu-OH)](+) have been identified in solution while complexes of formula BeL(2) and [Be(3)L(4)](ClO(4))(2) have been isolated as solid materials. The species [BeL(OPPh(2))](+), closely related to [BeL(H(2)O)](+), has been characterized in acetone solution and isolated as tetraphenylborate salt. The structure of the unusual trimeric complex [Be(3)L(4)](2+) has been elucidated by an unprecedented 2D (9)Be-(31)P NMR correlation spectrum showing the presence of a single central beryllium nucleus and two equivalent terminal beryllium nuclei. The three beryllium centers are held together by four cobaltate ligands, which display two different bonding modes: two ligands are terminally linked with all the three oxygen donors to one terminal beryllium, and the other two bridge two metal centers, sharing the oxygen donors between central and terminal beryllium atoms.

Beryllium↗
PubMed1991

Effects of beryllium metal particles on the viability and function of cultured rat alveolar macrophages.

The physicochemical properties of particles influence their in vivo toxicity following deposition in the respiratory tract. To evaluate the relative contributions of mass and surface area to particle-induced toxicity, rat pulmonary alveolar macrophages (PAM) were exposed to four types of particles in vitro. We used three beryllium metal samples: relatively large (Be-II) and relatively small (Be-V) sized fractions of beryllium metal obtained from an aerosol cyclone, and a beryllium metal aerosol generated by laser vaporization of bulk beryllium metal in an argon atmosphere (Be-L). We also used glass beads (GB) as a negative control particle. End points examined included cell viability, determined by trypan blue dye exclusion, and changes in phagocytic ability, measured by counting the number of sheep red blood cells internalized by the PAM. Phagocytic ability was inhibited by exposure to beryllium particles at concentrations that did not cause appreciable cell death. Results describing effects based on the mass concentration of particles in culture medium were transformed by the amount of specific surface area of the particles to permit the expression of toxicity relative to the amount of particle surface per unit volume of culture medium. On a mass basis, the order of particle-related cytotoxicity was Be-L greater than Be-V greater than Be-II greater than GB, and for inhibition of phagocytosis, the order was Be-L approximately Be-V greater than Be-II greater than GB. When analyzed on a specific surface area basis, the cytotoxicity of the different materials became more similar in a fashion that was largely predicted by the amount of surface of the particles administered. However, because differences in specific surface area among the beryllium particle samples did not entirely predict cytotoxicity, we concluded that factors in addition to specific surface area influenced the expression of toxic effects in cultures of PAM exposed to beryllium metal.

Animals↗
PubMed1989

Screening blood test identifies subclinical beryllium disease.

We evaluated the beryllium-specific lymphocyte transformation test as a workplace screening tool for early beryllium disease. Fifty-one of 58 workers with current beryllium exposure completed questionnaires and gave blood specimens for the lymphocyte transformation test. Six workers (11.8%) had elevated test results ranging from 5.7-fold to 16.7-fold stimulation. Of five who underwent clinical evaluation, four had beryllium disease, demonstrated by granulomata on transbronchial lung biopsy and elevated lymphocyte transformation tests by bronchoalveolar lavage cells (ranging from 18.6-fold to 44.3-fold stimulation). Our data show that (1) minimally symptomatic cases of beryllium disease can be identified by this peripheral blood test, (2) not all individuals with a positive peripheral blood lymphocyte transformation test have beryllium disease at the time of their initial evaluation, and (3) lymphocyte transformation test reproducibility is good, justifying further evaluation of this test for screening. We conclude that the peripheral blood lymphocyte transformation test may prove useful in preventing clinical chronic beryllium disease by early diagnosis in a subclinical phase.

Adult↗
PubMed2003

A model for optimization of biomarker testing frequency to minimize disease and cost: example of beryllium sensitization testing.

A common problem with medical surveillance programs using biomarkers is determining the optimal frequency of testing to minimize adverse health effects and cost. In the case of beryllium-exposed workers, frequency of testing for beryllium sensitization may be especially important. Recent studies indicate a lack of dose response for beryllium sensitization, but do support a dose response for the development of chronic beryllium disease (CBD). Though unproven, this implies that early identification of sensitization and immediate removal from exposure may reduce development of CBD. A model is proposed to project the optimal frequency of sensitization testing using the current beryllium lymphocyte proliferation test (BeLPT) to minimize disease-related costs, assuming that a positive BeLPT will precede CBD. Conversion rates for cumulative exposure to disease development were adapted from the literature and used with testing costs and cost of disease estimates in the model. The model was run assuming several test frequency regimes. Results support the use of periodic testing in line with the annual schedule proposed in the Final Chronic Beryllium Disease Prevention Program Rule (1999) following initial testing within three months of first beryllium exposure. The financial and health benefits of reducing the time from exposure to detection of early disease was also explored with the model and demonstrated as a highly desirable characteristic for an alternative test or improved BeLPT. Limitations of the approach are discussed as well as options for adapting this biomarker optimization methodology to consider biomarkers of other exposure-associated diseases.

Berylliosis↗
PubMed1996

Patch testing with beryllium alloy samples in guinea pigs.

An experimental study was conducted in guinea pigs for the predictive assessment of the beryllium alloy hazard in occupational exposure of the skin to beryllium compounds. Guinea pigs were sensitized to beryllium sulfate according to the maximized Magnusson and Kligman test, and challenged with beryllium alloys and metallic copper, beryllium and aluminum samples. Results showed a delayed skin hypersensitivity reaction in 30 to 60% of pre-sensitized guinea pigs challenged with copper-beryllium alloys and aluminum-beryllium alloy. An inflammatory follicular reaction was induced by copper in both controls and pre-sensitized guinea pigs.

Allergens↗
PubMed1977

Role of in vitro and in vivo tests of hypersensitivity in beryllium workers.

The value of the beryllium macrophage migration inhibition (Be MIF) and Mantoux tests in the diagnosis of chronic beryllium disease and in the detection of hypersensitivity in healthy beryllium workers is demonstrated. In the absence of steroid treatment the Be MIF test is positive in chronic beryllium disease patients. Seven of 50 (14%) helathy beryllium workers were Be MIF positive, while all the control subjects, normal and sarcoidosis patients, were negative. Healthy beryllium workers tend to be more often Mantoux negative than a comparable group of non-exposed workers, and although not conclusive this finding correlates with a positive Be MIF test. Although the detection of hypersensitivity is not diagnostic of disease, the Be MIF test can be used as an additional method for monitoring the health of beryllium workers. The full significance of our results should be assessed by a long-term study.

Adult↗
PubMed1987

Mitogenic effect of beryllium sulfate on mouse B lymphocytes but not T lymphocytes in vitro.

Beryllium metal and its salts can produce disease in man and in animal models. Beryllium disease is thought to involve cell-mediated immunity and an antigen-dependent response by beryllium-specific T cells. Beryllium salts have been shown to stimulate lymphocyte proliferation and release of lymphokines, and to induce granuloma formation and delayed-type hypersensitivity reactions in mice, guinea pigs and man. The studies described here were designed to test the hypothesis that a second lymphocyte population, B cells, may be responding nonspecifically to beryllium. Different populations of BDF1 mouse lymphocytes were cultured in the presence of varying concentrations of beryllium sulfate (BeSO4), and the increase in 125-iodouracildeoxyriboside uptake after 72 h in culture was determined. The data show that BeSO4 is weakly mitogenic for normal mouse spleen cells. Furthermore, BeSO4 is mitogenic for normal and nude mouse spleen B cells and not for spleen T cells or thymocytes in vitro. These findings suggest that BeSO4 can stimulate B cells nonspecifically, and support the hypothesis that polyclonal activation of B cells by beryllium may occur.

Animals↗