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PubMed1988

Beryllium disease.

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.

Berylliosis↗
PubMed1999

Angiotensin-1 converting enzyme polymorphisms in chronic beryllium disease.

To test the hypothesis that the angiotensin converting enzyme (ACE) genotype is associated with chronic beryllium disease (CBD) and disease severity, we studied 50 cases of CBD and compared their ACE genotype to that of two different control groups, consisting of: (1) 50 participants from a beryllium machining facility; and (2) 50 participants from a non-beryllium-associated workplace. We found no statistically significant difference in the frequency of the I or D allele or of the DD genotype among cases of CBD and either control group. The odds ratio (OR) for the CBD DD genotype as compared with the non-DD genotype was 1.58 (95% confidence interval [CI]: 0.68 to 3.66, p = 0.12) for the beryllium-exposed control group, and 1.09 (95% CI: 0.48 to 2.46, p = 0.56) for the non-beryllium-exposed controls. We found an association between serum ACE activity and the ACE genotype, with DD cases having the highest median serum ACE activity (p = 0.005). We evaluated the beryllium lymphocyte proliferation test (BeLPT), bronchoalveolar lavage (BAL) cell components, chest radiography, pulmonary function test results, and exercise physiology in our CBD cases. No statistically significant associations with these disease markers were found for the CBD cases with the DD genotype. Although the difference was not statistically significant, the DD cases had a shorter median duration of exposure to beryllium before diagnosis of CBD, and tended to have a weaker response in their blood and BAL BeLPT than did the non-DD cases. These findings may indicate that the ACE genotype is important in the immune response to beryllium and in progression to beryllium disease.

Adult↗
PubMed2006

Diagnoses of chronic beryllium disease within cohorts of sarcoidosis patients.

An increase in chronic beryllium disease (CBD) has been suggested due to higher industrial use of beryllium alloys. Since occupational CBD is a perfect phenocopy of sarcoidosis, it might be misdiagnosed as sarcoidosis. In the current it was hypothesised that CBD exists in cohorts of sarcoidosis patients. In a prospective case study, sarcoidosis patients were evaluated for potential beryllium exposure. In those patients in whom beryllium exposure was confirmed and beryllium hypersensitivity demonstrated, the diagnosis of sarcoidosis was rejected and corrected to CBD. In 84 patients seen for re-evaluation or making a diagnosis of sarcoidosis, beryllium exposure was recognised and a diagnosis of CBD was made in 34 out of 84 patients. The time lag between clinical diagnosis of sarcoidosis and the final diagnosis of CBD ranged 0-18 yrs (median 3 yrs) and the mean (range) age at time of diagnosis of CBD was 43.9(25-80) yrs. Beryllium-contaminated workplaces causing disease encompassed a wide spectrum of industries and technical trades in which beryllium-exposure is generally not perceived as a health hazard. In conclusion, chronic beryllium disease still belongs to the spectrum of differential diagnoses of granulomatous disorders.

Adult↗
PubMed1977

Beryllium carcinogenesis.

Beryllium is a proven bone carcinogen in rabbits, and proven pulmonary carcinogen in rats. Median effective doses or concentrations can be computed only with considerable uncertainty; they appear to be in the 10 mg area (as total dose, in divided intravenous injections, expressed as Be for zinc beryllium silicate) for rabbits, and in the 20 alpha/m3 area (as atmospheric concentration for inhalation exposures lasting for at least three months, expressed as Be for beryllium sulfate) for rats. It is also proven that, at least from inhalation, guinea pigs do not develop beryllium cancers. Epidemiologic studies in humans are thus far unconfirmed but do not show increased cancer morbidity among beryllium workers. Current research is aimed at explaining the mechanism of carcinogenic action in the susceptible species, which seems to involve nucleic acid transcriptional interference, or the species specificity, which seems to involve immune mechanisms. No experiments were reported thus far besides the carcinogenesis studies to show that beryllium is a chemical mutagen. In the species thus far tested, there appeared to be mutual exclusion of development of a delayed (cell-mediated) hypersensitivity to beryllium and development of neoplasia from beryllium. Further research on this subject might lead to new possibilities in the understanding of cancer susceptibility.

Adenocarcinoma↗
PubMed1992

Modulation of tubulin-nucleotide interactions by metal ions: comparison of beryllium with magnesium and initial studies with other cations.

With microtubule-associated proteins (MAPs) BeSO4 and MgSO4 stimulated tubulin polymerization as compared to a reaction mixture without exogenously added metal ion, while beryllium fluoride had no effect (E. Hamel et al., 1991, Arch. Biochem. Biophys. 286, 57-69). Effects of both cations were most dramatic at GTP concentrations in the same molar range as the tubulin concentration. We have now compared effects of beryllium and magnesium on tubulin-nucleotide interactions in both unpolymerized tubulin and in polymer. Polymer formed with magnesium had properties similar to those of polymer formed without exogenous cation, except for a 20% lower stoichiometry of exogenous GTP incorporated into the latter. In both polymers the incorporated GTP was hydrolyzed to GDP. Stoichiometry of GTP incorporation into polymers formed with beryllium or magnesium was identical, but much of the GTP in the beryllium polymer was not hydrolyzed. The beryllium polymer was more stable than the magnesium polymer. Beryllium also differed from magnesium in only weakly enhancing the binding of GTP in the exchangeable site of unpolymerized tubulin, while neither cation affected GDP exchange at the site. If both cations were present in a reaction mixture, polymer stability was little changed from that of the beryllium polymer, but most of the GTP incorporated into polymer was hydrolyzed. Six additional metal salts (AlCl3, CdCl2, CoCl2, MnCl2, SnCl2, and ZnCl2) also stimulated MAP-dependent tubulin polymerization, but enhanced polymer stability did not correlate with polymer GTP content. We postulate that enhanced polymer stability is a consequence of cation binding directly to tubulin and/or polymer while deficient GTP hydrolysis in the presence of beryllium, as well as aluminum and tin, is a consequence of tight binding of cation to GTP in the exchangeable site.

Beryllium↗
PubMed2005

Characterization of phagolysosomal simulant fluid for study of beryllium aerosol particle dissolution.

A simulant of phagolysosomal fluid is needed for beryllium particle dissolution research because intraphagolysosomal dissolution is believed to be a necessary step in the cellular immune response associated with development of chronic beryllium disease. Thus, we refined and characterized a potassium hydrogen phthalate (KHP) buffered solution with pH 4.55, termed phagolysosomal simulant fluid (PSF), for use in a static dissolution technique. To characterize the simulant, beryllium dissolution in PSF was compared to dissolution in the J774A.1 murine cell line. The effects of ionic composition, buffer strength, and the presence of the antifungal agent alkylbenzyldimethylammonium chloride (ABDC) on beryllium dissolution in PSF were evaluated. Beryllium dissolution in PSF was not different from dissolution in the J774A.1 murine cell line (p = 0.78) or from dissolution in another simulant having the same pH but different ionic composition (p = 0.73). A buffer concentration of 0.01-M KHP did not appear adequate to maintain pH under all conditions. There was no difference between dissolution in PSF with 0.01-M KHP and 0.02-M KHP (p = 0.12). At 0.04-M KHP, beryllium dissolution was increased relative to 0.02-M KHP (p = 0.02). Use of a 0.02-M KHP buffer concentration in the standard formulation for PSF provided stability in pH without alteration of the dissolution rate. The presence of ABDC did not influence beryllium dissolution in PSF (p = 0.35). PSF appears to be a useful and appropriate model of in vitro beryllium dissolution when using a static dissolution technique. In addition, the critical approach used to evaluate and adjust the composition of PSF may serve as a framework for characterizing PSF to study dissolution of other metal and oxide particles.

Aerosols↗
PubMed2000

Detection of beryllium sensitivity using a flow cytometric lymphocyte proliferation test: the Immuno-Be-LPT.

Measurement of lymphocyte proliferation to detect hypersensitivity to beryllium (Be-LPT) in vitro is done presently using a method based on tritiated thymidine incorporation. Although this method is sensitive it gives no information on cell viability or responding lymphocyte subsets. We have developed reliable and simple flow cytometric assays for lymphocyte proliferation testing (Immuno-Be-LPT) by combining immunophenotyping with bromodeoxyuridine (BrdU) incorporation or DNA content using propidium iodide (PI) or 4'6'-diimidazolin-2-phenylindole (DAPI). Evaluation of beryllium-induced lymphocyte proliferation in blood cells from seven patients with chronic beryllium disease (CBD) and 120 beryllium workers by both the Bc-LPT and the Immuno-Be-LPT showed agreement between the tests. The Immuno-Bc-LPT provided additional information about the specific type of lymphocytes responding. CD4+ lymphocytes proliferated in response to beryllium in blood samples from all seven CBD individuals and CD8+ lymphocytes proliferated in six of the seven. Four beryllium workers without CBD had positive responses to beryllium primarily in the CD8+ cells. The use of the individual's own plasma supported a greater beryllium or tetanus-induced proliferation of CD4+ lymphocytes when compared to commercial human serum. The response of CD4+ lymphocytes measured in the Immuno-Be-LPT may provide a new marker for the diagnosis of CBD.

Antibodies, Monoclonal↗
PubMed1970

Effects of beryllium on deoxyribonucleic acid-synthesizing enzymes in regenerating rat liver.

1. The incorporation of thymidine into DNA of regenerating rat liver was measured at various times after partial hepatectomy. A single intravenous injection of 30mumol of beryllium/kg given immediately after the operation inhibited DNA synthesis 12, 16, 20, 24 and 28h later. 2. The activity of several enzymes critical to DNA synthesis (thymidine kinase, thymidylate kinase, thymidylate synthetase, deoxycytidylate deaminase and DNA polymerase) increased in control rats 20-24h after partial hepatectomy severalfold over the activity found in resting livers. After beryllium treatment this rise in activity was much less and it seemed as if beryllium would partially block the induction of DNA-synthesizing enzymes after partial hepatectomy. 3. Enzymes whose activities do not rise during liver regeneration were not affected by beryllium (aspartate transcarbamoylase, carbamoyl phosphate synthetase, uridine kinase and glucose 6-phosphatase). 4. No evidence was found in vitro that beryllium would specifically inhibit thymidine kinase or DNA polymerase. 5. The time-effect relationship between beryllium administration and thymidine kinase activity in vivo was examined. Measured 24h after partial hepatectomy, thymidine kinase activity was only affected if beryllium was given within the first 9-12h after partial hepatectomy. Beryllium given later, even in greatly increased doses, failed to have any effect on thymidine kinase. The possibility is discussed that beryllium inhibits enzyme induction at the transcriptional level.

Animals↗
PubMed2006

Assessment of the beryllium lymphocyte proliferation test using statistical process control.

Despite more than 20 years of surveillance and epidemiologic studies using the beryllium blood lymphocyte proliferation test (BeBLPT) as a measure of beryllium sensitization (BeS) and as an aid for diagnosing subclinical chronic beryllium disease (CBD), improvements in specific understanding of the inhalation toxicology of CBD have been limited. Although epidemiologic data suggest that BeS and CBD risks vary by process/work activity, it has proven difficult to reach specific conclusions regarding the dose-response relationship between workplace beryllium exposure and BeS or subclinical CBD. One possible reason for this uncertainty could be misclassification of BeS resulting from variation in BeBLPT testing performance. The reliability of the BeBLPT, a biological assay that measures beryllium sensitization, is unknown. To assess the performance of four laboratories that conducted this test, we used data from a medical surveillance program that offered testing for beryllium sensitization with the BeBLPT. The study population was workers exposed to beryllium at various facilities over a 10-year period (1992-2001). Workers with abnormal results were offered diagnostic workups for CBD. Our analyses used a standard statistical technique, statistical process control (SPC), to evaluate test reliability. The study design involved a repeated measures analysis of BeBLPT results generated from the company-wide, longitudinal testing. Analytical methods included use of (1) statistical process control charts that examined temporal patterns of variation for the stimulation index, a measure of cell reactivity to beryllium; (2) correlation analysis that compared prior perceptions of BeBLPT instability to the statistical measures of test variation; and (3) assessment of the variation in the proportion of missing test results and how time periods with more missing data influenced SPC findings. During the period of this study, all laboratories displayed variation in test results that were beyond what would be expected due to chance alone. Patterns of test results suggested that variations were systematic. We conclude that laboratories performing the BeBLPT or other similar biological assays of immunological response could benefit from a statistical approach such as SPC to improve quality management.

Air Pollutants, Occupational↗
PubMed2001

Identifying an apppropriate occupational exposure limit (OEL) for beryllium: data gaps and current research initiatives.

The occupational exposure limit of 2.0 microg/m3 for beryllium has been used in the workplace since the late 1940s. In particular, the adequacy of the American Conference of Governmental Industrial Hygienists (ACGIH) Threshold Limit Value (TLV) for beryllium has recently come into question. The symposium "Beryllium: Effect on Worker Health" was convened in September 1999, to bring together leading scientists to present and discuss current research activities on beryllium exposure and chronic beryllium disease (CBD). One of the key questions to be resolved at the symposium was, "Is there a sufficient understanding of exposure and the cause of CBD that would allow us to develop a TLV that we believe would prevent disease?" Seven scientists presented information regarding the current understanding of the disease, possible causes, and ongoing research. The topics were (1) biomonitoring approaches and their relationship with clinical effects, (2) historical and current exposure assessments, (3) sampling methods and aerosol characterization, and (4) epidemiology. Six basic hypotheses regarding the relationship between exposure to beryllium and CBD were generated from the information presented at the symposium. The six hypotheses that are related to issues such as beryllium form, particle size, industrial hygiene practices, extrapulmonary routes of exposure, and genetic susceptibility also appear to be the focus of ongoing and likely future research initiatives. This article summarizes both the presentations made at the meeting and the hypotheses generated. It is expected that an understanding of these issues should explain the inconsistent dose-response relationship observed between exposure and CBD. The ongoing and planned research is anticipated to provide sufficient data within two to three years to develop one or more scientifically sound TLVs for the different chemical forms of beryllium.

Air Pollutants, Occupational↗
PubMed1996

Retrospective beryllium exposure assessment at the Rocky Flats Environmental Technology Site.

The purpose of this study was to determine how two types of sampling data could be used for an exposure assessment in a beryllium shop at the Department of Energy's Rocky Flats Plant. Beryllium exposure was assessed via fixed airhead (FAH) sampling, in which the filter cassette was affixed to the machine, generally within a few feet of the worker's breathing zone. Approximately 500,000 FAH samples were collected for beryllium over three decades at the site. From 1984 to 1987, personal breathing zone (PBZ) samples also were collected as part of the evaluation of a new high velocity/lcw volume local exhaust ventilation system in the beryllium shop. FAH data indicated that four statistically different exposure periods existed from 1970 to 1988, as the FAH annual arithmetic means varied with changes in the local exhaust ventilation system and production levels. A matched comparison between the FAH and PBZ sample data found no direct linear correlation (R2 = 0.014); however, the mean PBZ results were higher than the mean FAH results (p = 0.0001). The mean PBZ level was 1.04 micrograms/m3 while the FAH average was 0.16 microgram/m3 (permissible exposure limit for beryllium: 2 micrograms/m3). A health surveillance program to identify cases of chronic beryllium disease (CBD) and beryllium sensitization has been implemented at Rocky Flats. To date, 53 cases of CBD and 86 cases of sensitivity to beryllium have been diagnosed. Continuing studies are evaluating semiquantitative dose response relationships for CBD using the exposure data discussed herein.

Air Pollutants, Occupational↗
PubMed1991

Blood cell proliferation response to beryllium: analysis by receiver-operating characteristics.

As testing for beryllium-induced proliferation of bronchoalveolar lavage cells is not suitable for screening, we evaluated the proliferative response of blood cells to beryllium. Twenty-seven patients with chronic beryllium disease, documented by histology and a positive lung proliferative response to beryllium, were compared to 30 controls. A significant difference (p less than .05) was observed between beryllium disease patients and controls with 100 or 10 microM beryllium salts. To evaluate the optimum test parameters and stimulation index cutoff, receiver operating characteristic curves (true positive v false positive) were generated. Maximum predictive value positive (26%) was observed at a stimulation index cutoff of 2.5 which corresponds to a 38% sensitivity and 97% specificity. This suggests that the blood cell proliferation response to beryllium has a limited role in screening for chronic beryllium disease.

Berylliosis↗
PubMed1994

Novel in vitro method for identification of individuals at risk for beryllium hypersensitivity.

Beryllium-specific lymphocytes were generated by in vitro immunization of peripheral blood mononuclear cells (PBMC) from healthy unexposed individuals. Measurement of blastogenic responses of PBMC by [3H]thymidine uptake demonstrated that sensitization of PBMC with beryllium salts followed by stimulation with unrelated salts resulted in a negative response, whereas sensitization and restimulation of PBMC with beryllium salts produced a positive response. Flow cytometric and cell depletion analyses showed that all of the responding cells were CD4+ T cells. The in vitro immunization system was used to screen 52 human subjects for susceptibility to beryllium sensitization in vitro. The results show that of the 52 healthy unexposed subjects tested, only 1 (2%) was highly responsive, 4 subjects (8%) were moderately responsive, 20 subjects (39%) were low-level responders, and 27 subjects (52%) were nonresponders. The results showing 2% high-level responsiveness to beryllium sensitization in vitro correlate with the 1 to 5% prevalence of chronic beryllium disease in individuals sensitized to beryllium dust in vivo and thus support the thesis that the in vitro immunization system may permit the identification of individuals at risk for beryllium hypersensitivity.

Adult↗
PubMed2005

Frequency of beryllium-specific, central memory CD4+ T cells in blood determines proliferative response.

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+ T(EM) 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.

Aged↗
PubMed1988

A human cell beryllium acute toxicity assay.

A rapid, inexpensive beryllium acute toxicity assay using human erythrocyte ATP levels has been developed. The assay uses a photometric measurement of the luciferin-luciferase reaction in erythrocytes incubated in HEPES buffer with the tested toxicant. Incubation in HEPES significantly increases the sensitivity of erythrocytes to beryllium when compared to incubation in either plasma or physiological saline. After a one-hour incubation period in HEPES buffer and beryllium there is a loss of 50% of the erythrocyte ATP at 3 micrograms/ml of beryllium, and an 80% loss of ATP at 5 micrograms/ml of beryllium. The source of human erythrocytes does not appear to influence the test. Erythrocytes from 10 individuals, one with chronic beryllium disease and another with an acute sensitivity to beryllium, all gave similar biphasic dose-response curves to beryllium.

Adenosine Triphosphate↗
PubMed1987

Beryllium metal solubility in the lung, comparison of metal and hot-pressed forms by in vivo and in vitro dissolution bioassays.

The solubility of two industrial forms of beryllium, i.e. particles of metal powder and particles of hot-pressed beryllium, was investigated using in vivo and in vitro models. In the in vivo model, baboons and rats were used and were injected via the trachea with amounts of beryllium equivalent to 100,500 and 1000 fold the maximum permissible concentration (MPC) recommended by the US Occupational Safety and Health Administration. In vivo experiments showed that in both species the daily beryllium solubility rates were about 5 X 10(-6) for metal particles and that in rats the daily beryllium solubility rate was about 5 X 10(-5) for the hot-pressed particles. During the 10 months of the experiment with baboons, urinary excretion of beryllium was proportional to the amount administered. With regard to results for the in vitro models, the outcome of the acellular dissolution test using a serum simulant was not consistent with the in vivo results, though a cellular model using cultured macrophages showed the same trends in the dissolution rates for the two forms of beryllium as those observed in vivo. This result suggest that a cellular rather than an acellular dissolution model would be better a predicting solubility of beryllium compounds in the lungs.

Animals↗
PubMed1980

Beryllium toxicity testing in the suspension culture of mouse fibroblasts.

Suspension culture of mouse fibroblast cell line L-A 115 was used to test beryllium toxicity in the presence of magnesium ions. Beryllium added to the MEM cultivation medium was bound in a complex with sulphosalicylic acid BeSSA complex, because the use of beryllium chloride turned out to yield ineffective beryllium phosphate that formed macroscopically detectable insoluble opacities. The BeSSA complex was used in the concentration range: 10(-3)--10(-9)M, magnesium was used in 3 concentrations: 10(-1)M, 5 x 10(-2)M and 10(-2)M. Growth curve analysis revealed pronounced beryllium toxicity at the concentration of 10(-3)M, magnesium-produced toxic changes were observed only at the concentration of 10(-1)M. No competition between the beryllium and magnesium ions was recorded. It is assumed that the possible beryllium-magnesium competition was significantly modified by the use of BeSSA complex-bound beryllium.

Animals↗
PubMed2003

Chronic beryllium disease: immune-mediated destruction with implications for organ-specific autoimmunity.

Chronic beryllium disease (CBD) is caused by exposure to beryllium in the workplace and is characterized by an accumulation of beryllium-specific CD4+ T cells with granulomatous inflammation in the lung. Owing to its unique physical properties, beryllium is used in a variety of high-technology industries, and CBD continues to be an important public health concern. CBD develops in up to 16% of exposed workers, depending on genetic susceptibility and the nature of the exposure. Increased susceptibility has been associated with particular HLA-DP alleles, especially those possessing negatively charged residues at certain positions of the peptide-binding pocket. The mechanism for this disease association lies in the ability of certain HLA-DP molecules, with associated peptides, to bind and present beryllium to pathogenic CD4+ T cells. In patients with CBD, large numbers of effector memory CD4+ T cells are compartmentalized to the lung, and these cells are poised to release T helper 1-type cytokines upon beryllium recognition. In the same patients, however, beryllium-specific T cells are barely detectable in the circulation. As opposed to those present in blood, beryllium-specific cells in the lung no longer require the engagement of CD28 for optimal T-cell activation and in fact frequently lose the expression of CD28. These findings in CBD have important implications for studies in autoimmune diseases, including those in which the antigen is unknown and the target organ is inaccessible.

Autoimmune Diseases↗