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1.  Chronic Beryllium Disease and Sensitization at a Beryllium Processing Facility 
Environmental Health Perspectives  2005;113(10):1366-1372.
We conducted a medical screening for beryllium disease of 577 former workers from a beryllium processing facility. The screening included a medical and work history questionnaire, a chest radiograph, and blood lymphocyte proliferation testing for beryllium. A task exposure and a job exposure matrix were constructed to examine the association between exposure to beryllium and the development of beryllium disease. More than 90% of the cohort completed the questionnaire, and 74% completed the blood and radiograph component of the screening. Forty-four (7.6%) individuals had definite or probable chronic beryllium disease (CBD), and another 40 (7.0%) were sensitized to beryllium. The prevalence of CBD and sensitization in our cohort was greater than the prevalence reported in studies of other beryllium-exposed cohorts. Various exposure measures evaluated included duration; first decade worked; last decade worked; cumulative, mean, and highest job; and highest task exposure to beryllium (to both soluble and nonsoluble forms). Soluble cumulative and mean exposure levels were lower in individuals with CBD. Sensitized individuals had shorter duration of exposure, began work later, last worked longer ago, and had lower cumulative and peak exposures and lower nonsoluble cumulative and mean exposures. A possible explanation for the exposure–response findings of our study may be an interaction between genetic predisposition and a decreased permanence of soluble beryllium in the body. Both CBD and sensitization occurred in former workers whose mean daily working lifetime average exposures were lower than the current allowable Occupational Safety and Health Administration workplace air level of 2 μg/m3 and the Department of Energy guideline of 0.2 μg/m3.
PMCID: PMC1281281  PMID: 16203248
beryllium; chronic beryllium disease; epidemiology; exposure–response; lymphocyte proliferation testing
2.  Low Prevalence of Chronic Beryllium Disease Among Workers at aNuclearWeaponsResearchandDevelopmentFacility 
To study the prevalence of beryllium sensitization (BeS) and chronic beryllium disease (CBD) in a cohort of workers from a nuclear weapons research and development facility.
We evaluated 50 workers with BeS with medical and occupational histories, physical examination, chest imaging with high-resolution computed tomography (N = 49), and pulmonary function testing. Forty of these workers also underwent bronchoscopy for bronchoalveolar lavage and transbronchial biopsies.
The mean duration of employment at the facility was 18 years and the mean latency (from first possible exposure) to time of evaluation was 32 years. Five of the workers had CBD at the time of evaluation (based on histology or high-resolution computed tomography); three others had evidence of probable CBD.
These workers with BeS, characterized by a long duration of potential Be exposure and a long latency, had a low prevalence of CBD.
PMCID: PMC3313491  PMID: 20523233
3.  Modulation of Lymphocyte Proliferation by Antioxidants in Chronic Beryllium Disease 
Rationale: Occupational exposure to beryllium (Be) can result in chronic granulomatous inflammation characterized by the presence of Be-specific CD4+ T cells. Studies show that oxidative stress plays a role in the pathogenesis of chronic inflammatory disorders.
Objectives: We hypothesized that Be-induced oxidative stress modulates the proliferation of Be-specific CD4+ T cells.
Methods: Thirty-three subjects with chronic beryllium disease (CBD), 15 subjects with beryllium sensitization, and 28 healthy normal control subjects were consecutively enrolled from the Occupational and Environmental Health Clinic of the National Jewish Medical and Research Center.
Measurements and Main Results: All studies were performed with Ficoll-Hypaque–isolated peripheral blood mononuclear cells from subsets of the study subjects. Decreased intracellular levels of the thiol antioxidants, glutathione and cysteine, were observed in peripheral blood mononuclear cells from subjects with beryllium sensitization and CBD, as compared with healthy control subjects. Beryllium stimulation decreased intracellular thiol antioxidants by more than 40%, accompanied by increased reactive oxygen species levels and the proliferation of Be-specific blood CD4+ T cells from subjects with CBD. Be-induced T-cell proliferation was inhibited by treatment with the thiol antioxidant N-acetylcysteine or the catalytic antioxidant manganese(III) 5,10,15,20-tetrakis(4-benzoic acid)porphyrin (MnTBAP). MnTBAP treatment also inhibited T-cell proliferation in response to the unrelated, MHC class II–restricted antigen tetanus toxoid. Treatment of CBD blood lymphocytes, but not antigen-presenting cells, with MnTBAP decreased Be-induced T-cell proliferation by more than 40%.
Conclusions: Beryllium can mediate a thiol imbalance leading to oxidative stress that may modulate the proliferation and clonal expansion of Be-specific blood CD4+ T cells. These data suggest that Be-induced oxidative stress plays a role in the pathogenesis of granulomatous inflammation in CBD.
PMCID: PMC2361422  PMID: 18218990
T cells; reactive oxygen species; glutathione; N-acetylcysteine; oxidative stress
4.  Impact of negatively charged patches on the surface of MHC class II antigen-presenting proteins on risk of chronic beryllium disease 
Chronic beryllium disease (CBD) is a granulomatous lung disease that occurs primarily in workers who are exposed to beryllium dust or fumes. Although exposure to beryllium is a necessary factor in the pathobiology of CBD, alleles that code for a glutamic acid residue at the 69th position of the HLA-DPβ1 gene have previously been found to be associated with CBD. To date, 43 HLA-DPβ1 alleles that code for glutamic acid 69 (E69) have been described. Whether all of these E69 coding alleles convey equal risk of CBD is unknown. The present study demonstrates that, on the one hand, E69 alleloforms of major histocompatibility complex class II antigen-presenting proteins with the greatest negative surface charge convey the highest risk of CBD, and on the other hand, irrespective of allele, they convey equal risk of beryllium sensitization (BeS). In addition, the data suggest that the same alleles that cause the greatest risk of CBD are also important for the progression from BeS to CBD. Alleles convey the highest risk code for E26 in a constant region and for E69, aspartic acid 55 (D55), E56, D84 and E85 in hypervariable regions of the HLA-DPβ1 chain. Together with the calculated high binding affinities for beryllium, these results suggest that an adverse immune response, leading to CBD, is triggered by chemically specific metal–protein interactions.
PMCID: PMC2607452  PMID: 17956852
HLA-DP; genetic epidemiology; beryllium sensitization; granulomas; free energy perturbation; molecular dynamics
5.  Linking Genetic Susceptibility and T Cell Activation in Beryllium-induced Disease 
Chronic beryllium disease (CBD) is a granulomatous lung disorder caused by beryllium (Be) exposure in the workplace. It is characterized by the accumulation of Be-specific CD4+ T cells in the lung as well as persistent lung inflammation, culminating in the development of lung fibrosis. CBD occurs in 2 to 16% of Be-exposed workers depending on the individuals' genetic susceptibility and the characteristics of the exposure. Genetic susceptibility to Be-induced disease has been linked to major histocompatibility complex class II molecules. In particular, HLA-DP alleles possessing a glutamic acid at the 69th position of the β-chain (βGlu69) are most strongly linked to disease susceptibility. The HLA-DP alleles that present Be to T cells match those implicated in the genetic susceptibility, suggesting that the HLA contribution to disease is based on the ability of those molecules to bind and present Be to T cells. However, the structural features of βGlu69-containing HLA-DP molecules that explain the disease association remain unknown. We have recently crystallized HLA-DP2, which is the most prevalent of the βGlu69-containing HLA-DP molecules. Its unique structure, which includes surface exposure of βGlu69, provides an explanation of the genetic linkage between βGlu69-containing HLA-DP alleles and Be-induced disease.
PMCID: PMC3266018  PMID: 20427584
beryllium; granuloma; human; lung; T cells
6.  Identification of beryllium-dependent peptides recognized by CD4+ T cells in chronic beryllium disease 
The Journal of Experimental Medicine  2013;210(7):1403-1418.
Identification of peptides that form complexes with beryllium and class II HLA molecules and are recognized by CD4+ T cells from patients with chronic beryllium disease.
Chronic beryllium disease (CBD) is a granulomatous disorder characterized by an influx of beryllium (Be)-specific CD4+ T cells into the lung. The vast majority of these T cells recognize Be in an HLA-DP–restricted manner, and peptide is required for T cell recognition. However, the peptides that stimulate Be-specific T cells are unknown. Using positional scanning libraries and fibroblasts expressing HLA-DP2, the most prevalent HLA-DP molecule linked to disease, we identified mimotopes and endogenous self-peptides that bind to MHCII and Be, forming a complex recognized by pathogenic CD4+ T cells in CBD. These peptides possess aspartic and glutamic acid residues at p4 and p7, respectively, that surround the putative Be-binding site and cooperate with HLA-DP2 in Be coordination. Endogenous plexin A peptides and proteins, which share the core motif and are expressed in lung, also stimulate these TCRs. Be-loaded HLA-DP2–mimotope and HLA-DP2–plexin A4 tetramers detected high frequencies of CD4+ T cells specific for these ligands in all HLA-DP2+ CBD patients tested. Thus, our findings identify the first ligand for a CD4+ T cell involved in metal-induced hypersensitivity and suggest a unique role of these peptides in metal ion coordination and the generation of a common antigen specificity in CBD.
PMCID: PMC3698527  PMID: 23797096
7.  Deficient and Dysfunctional Regulatory T Cells in the Lungs of Chronic Beryllium Disease Subjects 
Rationale: Chronic beryllium disease (CBD) is a CD4+ T cell–mediated disorder characterized by persistent lung inflammation. Naturally occurring regulatory T (Treg) cells modulate adaptive immune responses. The role of this T-cell subset in beryllium-induced lung disease is unknown.
Objectives: The aim of this study was to determine whether dysfunctional Treg cells in the lung contribute to the “unchecked” inflammatory response that characterizes CBD.
Methods: Using blood and bronchoalveolar lavage (BAL) cells from normal control subjects and individuals with beryllium-induced disease, we determined the frequency and function of naturally occurring Treg cells.
Measurements and Main Results: A significantly decreased percentage and expression of FoxP3 in BAL CD4+ T cells from CBD patients compared with beryllium-sensitized subjects was seen, and the percentage of FoxP3-expressing CD4+ Treg cells in BAL inversely correlated with disease severity. In contrast to blood Treg cells derived from beryllium-sensitized subjects and patients with CBD that completely suppressed blood responder T-cell proliferation, BAL FoxP3-expressing Treg cells from patients with CBD are unable to suppress anti–CD3-mediated BAL T-cell proliferation. Mixing studies showed that blood Treg cells are capable of suppressing autologous BAL responder T cells. Conversely, BAL CD4+ Treg cells are incapable of suppressing blood T cells, confirming that the failure of BAL Treg cells to suppress T-cell proliferation is caused by a dysfunctional Treg cell subset and not by resistance of BAL effector T cells to suppression.
Conclusions: These findings suggest that the deficient and dysfunctional Treg cells in the lung of patients with CBD contribute to the persistent inflammatory response in this disease.
PMCID: PMC2891494  PMID: 20299529
fibrosis; human; granuloma; inflammation
8.  Electrostatic potential on human leukocyte antigen: implications for putative mechanism of chronic beryllium disease. 
Environmental Health Perspectives  2003;111(15):1827-1834.
The pathobiology of chronic beryllium disease (CBD) involves the major histocompatibility complex class II human leukocyte antigen (HLA). Although occupational exposure to beryllium is the cause of CBD, molecular epidemiologic studies suggest that specific (Italic)HLA-DPB1(/Italic) alleles may be genetic susceptibility factors. We have studied three-dimensional structural models of HLA-DP proteins encoded by these genes. The extracellular domains of HLA-DPA1*0103/B1*1701, *1901, *0201, and *0401, and HLA-DPA1*0201/B1*1701, *1901, *0201, and *0401 were modeled from the X-ray coordinates of an HLA-DR template. Using these models, the electrostatic potential at the molecular surface of each HLA-DP was calculated and compared. These comparisons identify specific characteristics in the vicinity of the antigen-binding pocket that distinguish the different HLA-DP allotypes. Differences in electrostatics originate from the shape, specific disposition, and variation in the negatively charged groups around the pocket. The more negative the pocket potential, the greater the odds of developing CBD estimated from reported epidemiologic studies. Adverse impact is caused by charged substitutions in positions 55, 56, 69, 84, and 85, namely, the exact same loci identified as genetic markers of CBD susceptibility as well as cobalt-lung hard metal disease. These findings suggest that certain substitutions may promote an involuntary cation-binding site within a putatively metal-free peptide-binding pocket and therefore change the innate specificity of antigen recognition.
PMCID: PMC1241746  PMID: 14630515
9.  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
10.  CC chemokine receptor 5 gene polymorphisms in beryllium disease 
CC chemokine receptor 5 (CCR5) is expressed on type-1 T-helper cells, which are involved in the pathogenesis of the granulomatous lung disease chronic beryllium disease (CBD). CCR5 gene (CCR5) polymorphisms are associated with sarcoidosis severity. The present study explores associations between CCR5 polymorphisms and CBD and its disease progression.
Eight CCR5 polymorphisms were genotyped in CBD (n = 88), beryllium sensitisation (BeS; n = 86) and beryllium-exposed nondiseased controls (n = 173) using PCR with sequence-specific primers. Pulmonary function and bronchoalveolar lavage data were examined for associations with genotypes.
There were no significant differences in genotype and allele frequency between CBD, BeS individuals and controls. In CBD, associations were found with decline in forced expiratory volume in 1 s and forced vital capacity and the CCR5 -3458 thymidine (T)T genotype (p<0.0001), and an increase in alveolar–arterial oxygen tension difference at rest (p = 0.003) and at maximum exercise (p = 0.01) and the -5663 adenine allele. Increased bronchoalveolar lavage lymphocyte numbers were associated with CCR5 -2459 guanine/-2135T (p = 0.01) only in the combined CBD and BeS group.
This is the first study showing that CCR5 polymorphisms are associated with worsening pulmonary function over time in CBD, suggesting that CCR5 is important in the progression of pulmonary function in CBD. Further studies would be useful to clarify the mechanism whereby CCR5 polymorphisms affect progression of CBD.
PMCID: PMC3061572  PMID: 20075058
Broncholaveolar lavage; CC chemokine receptor 5; chronic beryllium disease; lung function tests; polymorphism
11.  Sulfasalazine and Mesalamine Modulate Beryllium-Specific Lymphocyte Proliferation and Inflammatory Cytokine Production 
Occupational exposure to beryllium (Be) results in Be sensitization (BeS) that can progress to pulmonary granulomatous inflammation associated with chronic Be disease (CBD). Be-specific lymphocytes are present in the blood of patients with BeS and in the blood and lungs of patients with CBD. Sulfasalazine and its active metabolite, mesalamine, are clinically used to ameliorate chronic inflammation associated with inflammatory bowel disease. We tested whether sulfasalazine or mesalamine could decrease Be-stimulated peripheral blood mononuclear cell (PBMC) proliferation in subjects with CBD and BeS and Be-induced cytokine production in CBD bronchoalveolar lavage (BAL) cells. CBD (n = 25), BeS (n = 12) and healthy normal control (n = 6) subjects were enrolled and ex vivo proliferation and cytokine production were assessed in the presence of Be and sulfasalazine or mesalamine. Be-stimulated PBMC proliferation was inhibited by treatment with either sulfasalazine or mesalamine. Be-stimulated CBD BAL cell IFN-γ and TNF-α cytokine production was decreased by treatment with sulfasalazine or mesalamine. Our data suggest that both sulfasalazine and mesalamine interfere with Be-stimulated PBMC proliferation in CBD and BeS and dampens Be-stimulated CBD BAL cell proinflammatory cytokine production. These studies demonstrate that sulfasalazine and mesalamine can disrupt inflammatory pathways critical to the pathogenesis of chronic granulomatous inflammation in CBD, and may serve as novel therapy for human granulomatous lung diseases.
PMCID: PMC2951876  PMID: 19901345
granulomatous inflammation; IFN-γ; TNF-α; lymphocyte proliferation; berylliosis
12.  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
13.  Beryllium Lymphocyte Proliferation Test Surveillance Identifies Clinically Significant Beryllium Disease 
Workplace surveillance identifies chronic beryllium disease (CBD) but it remains unknown over what time frame mild CBD will progress to a more severe form.
We examined physiology and treatment in 229 beryllium sensitization (BeS) and 171 CBD surveillance-identified cases diagnosed from 1982 to 2002. Never smoking CBD cases (81) were compared to never smoking BeS patients (83) to assess disease progression. We compared CBD machinists to non-machinists to examine effects of exposure.
At baseline, CBD and BeS cases did not differ significantly in exposure time or physiology. CBD patients were more likely to have machined beryllium. Of CBD cases, 19.3% went on to require oral immunosuppressive therapy. At 30 years from first exposure, measures of gas exchange were significantly worse and total lung capacity was lower for CBD subjects. Machinists had faster disease progression as measured by pulmonary function testing and gas exchange.
Medical surveillance for CBD identifies individuals at significant risk of disease progression and impairment with sufficient time since first exposure.
PMCID: PMC3063521  PMID: 19681064
beryllium; chronic beryllium disease; medical surveillance
14.  Beryllium-Specific CD4+ T Cells in Blood as a Biomarker of Disease Progression 
CD4+ T cells are responsible for the progressive lung damage seen in patients with chronic beryllium disease (CBD), a granulomatous lung disorder in which antigen-specific, Th1-type cytokine-secreting T cells have been characterized. Compared to beryllium (Be)-sensitized subjects, an increased number of Be-responsive T cells are present in the blood of CBD patients.
The aim of this study was to determine whether the number of Be-specific T cells in blood predicted the development of CBD in a cohort of Be-exposed subjects.
Using IFN-γ ELISPOT and proliferation-based assays, we determined the frequency and proliferative capacity of Be-responsive T cells in blood.
Compared with the Be lymphocyte proliferation test which detected an abnormal Be-induced proliferative response in 11 of 260 (4.2%) workers from a Be-machining facility, IFN-γ ELISPOT detected a sensitization rate of 10% (χ2 = 55.7; P < 0.0001). A significant positive correlation was also noted between the number of Be-responsive CD4+ T cells in blood and lung of CBD patients. Importantly, the transition from Be sensitization to CBD was associated with an increased number of antigen-specific T cells in blood.
These findings have important implications for Be-induced disease and potentially other immune-mediated disorders, suggesting that the frequency of antigen-specific T cells in blood can serve as a noninvasive biomarker to predict disease development and severity of the Be-specific CD4+ T cell alveolitis.
Clinical implications
These findings suggest that the number of Be-responsive T cells in the circulation can serve as a biomarker of disease progression and as an estimate of the severity of Be-induced lung inflammation.
PMCID: PMC3205205  PMID: 21943943
Human; Lung; CD4-Positive T-Lymphocytes; Beryllium; Cytokines; Granuloma; ELISPOT
15.  Progression from Beryllium Exposure to Chronic Beryllium Disease: An Analytic Model 
Environmental Health Perspectives  2009;117(6):970-974.
Understanding the progression from beryllium exposure (BeE) to chronic beryllium disease (CBD) is essential for optimizing screening and early intervention to prevent CBD.
We developed an analytic Markov model of progression to CBD that assigns annual probabilities for progression through three states: from BeE to beryllium sensitization and then to CBD. We used calculations of the number in each state over time to assess which of several alternative progression models are most consistent with the limited available empirical data on prevalence and incidence. We estimated cost-effectiveness of screening considering both incremental (cost/case) and cumulative program costs.
No combination of parameters for a simple model in which risk of progression remains constant over time can meet the empirical constraints of relatively frequent early cases and continuing development of new cases with long latencies. Modeling shows that the risk of progression is initially high and then declines over time. Also, it is likely that there are at least two populations that differ significantly in risk. The cost-effectiveness of repetitive screening declines over time, although new cases will still be found with long latencies. However, screening will be particularly cost-effective when applied to persons with long latencies who have not been previously screened.
To optimize use of resources, the intensity of screening should decrease over time. Estimation of lifetime cumulative CBD risk should consider the declining risk of progression over time.
PMCID: PMC2702415  PMID: 19590692
beryllium; beryllium sensitization; chronic beryllium disease; cost-effectiveness; screening
16.  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
17.  Value of beryllium lymphocyte transformation tests in chronic beryllium disease and in potentially exposed workers 
Thorax  1983;38(1):41-44.
The beryllium lymphocyte transformation test was performed on 16 patients with chronic beryllium disease, 10 subjects (seven patients and three young boys) who were under suspicion, and 117 healthy beryllium workers. The tests gave a positive response in all patients with definite disease and a negative response in the suspected group. Two of the healthy workers had a positive response, indicating both exposure and sensitisation. It is not known whether sensitised workers are more liable to develop disease. We consider that the test is of value in the diagnosis of beryllium disease and advocate its use in monitoring the health of potentially exposed workers.
PMCID: PMC459482  PMID: 6845261
18.  Beryllium exposure and pulmonary function: a cross sectional study of beryllium workers. 
A cross sectional study of 297 white male workers employed in a large beryllium plant was conducted to test the hypothesis that long term exposure to beryllium is associated with decrements in pulmonary function. Spirometric measurement of pulmonary function, chest radiographs, and arterial blood gas measurements were collected. After controlling for age, height, and smoking in multivariate regression models, decrements in FVC and FEV1 were found to be associated with cumulative exposure to beryllium in the period up until 20 years before the health survey. These decrements were observed in workers who had no radiographic abnormalities. The alveolar-arterial oxygen difference was associated with cumulative exposure in the 10 years immediately before survey, after controlling for age and smoking. These findings suggest that beryllium may have both short and long term pulmonary effects that are distinct from the classic forms of acute and chronic beryllium disease.
PMCID: PMC1007963  PMID: 3258161
19.  Enhanced preventive programme at a beryllium oxide ceramics facility reduces beryllium sensitisation among new workers 
A 1998 survey at a beryllium oxide ceramics manufacturing facility found that 10% of workers hired in the previous 6 years had beryllium sensitisation as determined by the beryllium lymphocyte proliferation test (BeLPT). In response, the facility implemented an enhanced preventive programme to reduce sensitisation, including increased respiratory and dermal protection and particle migration control.
To assess the programme's effectiveness in preventing sensitisation.
In 2000, the facility began testing newly hired workers for beryllium sensitisation with the BeLPT at time of hire and during employment. The sensitisation rate and prevalence for workers hired from 2000 to 2004 were compared with that for workers hired from 1993 to 1998, who were tested in the 1998 survey. Facility environmental conditions for both time periods were evaluated.
Newly hired workers in both cohorts worked for a mean of 16 months. Of the 97 workers hired from 2000 to 2004 with at least one employment BeLPT result, four had abnormal results at time of hire and one became sensitised during employment. Of the 69 workers hired from 1993 to 1998 and tested in 1998, six were found to be sensitised. The sensitisation rate for the 2000–4 workers was 0.7–2.7/1000 person‐months of employment, and that for the 1993–8 workers was 5.6/1000 person‐months, at least 2.1 (95% confidence interval (CI) 0.6 to 8.4) and up to 8.2 (95% CI 1.2 to 188.8) times higher than that for the 2000–4 workers. The sensitisation prevalence for the 2000–4 workers was 1% and that for the 1993–8 workers was 8.7%, 8.4 (95% CI 1.04 to 68.49) times higher than that for the 2000–4 workers. Airborne beryllium levels for production workers for the two time periods were similar.
A comprehensive preventive programme reduced beryllium sensitisation in new workers during the first years of employment, despite airborne beryllium levels for production workers that were similar to pre‐programme levels.
PMCID: PMC2078442  PMID: 17043076
20.  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
21.  Chronic beryllium disease: uncommon disease, less common diagnosis. 
Environmental Health Perspectives  1998;106(12):765-767.
Chronic beryllium disease (CBD) is typically considered only when occupational exposure to beryllium is a certainty; however, CBD has also occurred in occupational and environmental settings where exposure was unexpected. When the etiology of a case of granulomatous pulmonary disease is not determined, sarcoidosis is the "diagnosis of exclusion." This diagnosis does not communicate much information about the patient's prognosis, the disease's etiology, or even what disease etiologies were specifically excluded. Some cases of CBD have been called sarcoidosis, allowing exposure to continue for the patient and (at times) other individuals. The granulomatous changes of sarcoidosis are thought to result from an abnormal immune response. While the etiologic agents that can initiate this response are largely unknown, the immunopathogenesis of CBD has been well described, and laboratory methods are available in a few centers that can (if used) identify beryllium hypersensitivity. The potential for exposure and disease to be widely separated in time and location makes it important for health-care and environmental health professionals to be aware of these new diagnostic methods.
PMCID: PMC1533257  PMID: 9831535
22.  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
23.  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
24.  Prevalence of beryllium sensitization among aluminium smelter workers 
Background Beryllium exposure occurs in aluminium smelters from natural contamination of bauxite, the principal source of aluminium.
Aims To characterize beryllium exposure in aluminium smelters and determine the prevalence rate of beryllium sensitization (BeS) among aluminium smelter workers.
Methods A population of 3185 workers from nine aluminium smelters owned by four different aluminium-producing companies were determined to have significant beryllium exposure. Of these, 1932 workers participated in medical surveillance programmes that included the serum beryllium lymphocyte proliferation test (BeLPT), confirmation of sensitization by at least two abnormal BeLPT test results and further evaluation for chronic beryllium disease in workers with BeS.
Results Personal beryllium samples obtained from the nine aluminium smelters showed a range of <0.01–13.00 μg/m3 time-weighted average with an arithmetic mean of 0.25 μg/m3 and geometric mean of 0.06 μg/m3. Nine workers were diagnosed with BeS (prevalence rate of 0.47%, 95% confidence interval = 0.21–0.88%).
Conclusions BeS can occur in aluminium smelter workers through natural beryllium contamination of the bauxite and further concentration during the refining and smelting processes. Exposure levels to beryllium observed in aluminium smelters are similar to those seen in other industries that utilize beryllium. However, compared with beryllium-exposed workers in other industries, the rate of BeS among aluminium smelter workers appears lower. This lower observed rate may be related to a more soluble form of beryllium found in the aluminium smelting work environment as well as the consistent use of respiratory protection.
PMCID: PMC3716328  PMID: 20610489
Aluminium; beryllium; sensitization; smelter; surveillance
25.  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

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