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PubMed2003

Beryllium-stimulated neopterin as a diagnostic adjunct in chronic beryllium disease.

BACKGROUND: The diagnosis of chronic beryllium disease (CBD) relies on the beryllium lymphocyte proliferation test (BeLPT) to demonstrate a Be specific immune response. This test has improved early diagnosis, but cannot discriminate beryllium sensitization (BeS) from CBD. We previously found high neopterin levels in CBD patients' serum and questioned whether Be-stimulated neopterin production by peripheral blood cells in vitro might be useful in the diagnosis of CBD. METHODS: CBD, BeS, Be exposed workers without disease (Be-exp) normal controls and sarcoidosis subjects were enrolled. Peripheral blood mononuclear cells (PBMN) were cultured in the presence and absence of beryllium sulfate. Neopterin levels were determined from cell supernatants by enzyme linked immunosorbent assay (ELISA). Clinical evaluation of CBD subjects included chest radiography, pulmonary function testing, exercise testing, and the BeLPT. RESULTS: CBD patients produced higher levels of neopterin in both unstimulated and Be-stimulated conditions compared to all other subjects (P < 0.0001). Unstimulated neopterin mononuclear cell levels overlapped among groups, however, Be-stimulated neopterin levels in CBD showed little overlap. Using a neopterin concentration of 2.5 ng/ml as a cutoff, Be-stimulated neopterin had a sensitivity of 80% and specificity of 100% for CBD and was able to differentiate CBD from BeS. Be-stimulated neopterin was inversely related to measures of pulmonary function, exercise capacity, and gas exchange. CONCLUSIONS: Neopterin may be a useful diagnostic adjunct in the non-invasive assessment of CBD, differentiating CBD from BeS. Further studies will be required to determine how it performs in workplace screening.

Adult↗
PubMed2004

Measurement of beryllium in biological samples by accelerator mass spectrometry: applications for studying chronic beryllium disease.

A method using accelerator mass spectrometry (AMS) has been developed for quantifying attomoles of beryllium (Be) in biological samples. This method provides the sensitivity to trace Be in biological samples at very low doses with the purpose of identifying the molecular targets involved in chronic beryllium disease. Proof of the method was tested by administering 0.001, 0.05, 0.5, and 5.0 microg of 9Be and 10Be by intraperitoneal injection to male mice and removing the spleen, liver, femurs, blood, lungs, and kidneys after 24 h of exposure. These samples were prepared for AMS analysis by tissue digestion in nitric acid, followed by further organic oxidation with hydrogen peroxide and ammonium persulfate and, last, precipitation of Be with ammonium hydroxide and conversion to beryllium oxide at 800 degrees C. The 10Be/9Be ratio of the extracted beryllium oxide was measured by AMS, and Be in the original sample was calculated. Results indicate that Be levels were dose-dependent in all tissues and the highest levels were measured in the spleen and liver. The measured 10Be/9Be ratios spanned 4 orders of magnitude, from 10(-10) to 10(-14), with a detection limit of 3.0 x 10(-14), which is equivalent to 0.8 amol of 10Be. These results show that routine quantification of nanogram levels of Be in tissues is possible and that AMS is a sensitive method that can be used in biological studies to understand the molecular dosimetry of Be and mechanisms of toxicity.

Animals↗
PubMed1997

Beryllium-stimulated release of tumor necrosis factor-alpha, interleukin-6, and their soluble receptors in chronic beryllium disease.

Chronic beryllium disease (CBD) provides a model system in which to evaluate the antigen-stimulated, cell-mediated, immune response that leads to granulomatous lung disease. We hypothesized that beryllium salts would stimulate bronchoalveolar lavage (BAL) cell release of tumor necrosis factor-alpha (TNF-alpha) and lnterleukin-6 (IL-6), and their soluble receptors, soluble TNF receptor I (sTNF RI), sTNF RII, and sIL-6R and that chronic exposure to antigen would increase production of soluble receptors in the serum and BAL fluid (BALF) of beryllium-sensitized and CBD patients. We have demonstrated (1) similar constitutive TNF-alpha, IL-6, and soluble receptor production by control subjects and CBD patients, (2) a BeSO4-stimulated increase in TNF-alpha and IL-6 production by CBD-derived BAL cells, and (3) a BeSO4-induced decrease in sTNF RII production by BAL cells from control subjects. We measured increased serum sTNF RI and serum and BALF sIL-6R in beryllium-sensitized subjects and increased sTNF RI and RII in serum and sIL-6R and sTNF RII and BALF in CBD patients. These changes correlated with pulmonary lymphocytosis and clinical measures of disease severity, indicating that soluble receptors may reflect disease status.

Adult↗
PubMed1996

The natural history of beryllium sensitization and chronic beryllium disease.

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.

Berylliosis↗
PubMedDate not supplied

Chronic beryllium disease and beryllium sensitization at Rocky Flats: a case-control study.

A case-control study was conducted to evaluate the risk of chronic beryllium disease (CBD) and beryllium sensitization (SENS) associated with various levels of historical beryllium exposure at the Rocky Flats nuclear weapons facility. Fifty CBD and 74 SENS cases were matched to controls of the same age group, race, gender, and smoking status. A job exposure matrix was developed from job history data and fixed airhead (FAH) exposure data available from 1960 to 1988. Job titles and building areas were assigned factors based on exposure relative to a machinist in the Building 444 Beryllium Shop. Concurrence on these factors was obtained from past and present Rocky Flats industrial hygienists. Using the matrix, long-term mean and cumulative exposures were estimated for each subject. Both exposure estimates (p < 0.0001) and years of employment (p = 0.010) were found to be significantly higher for CBD cases as compared with their controls, but not so for the SENS cases as compared with their controls. Logistic regression analyses showed statistically significant relationships between both cumulative and mean exposure and CBD, but not for SENS. These findings suggest that reduced worker exposures might lower the future incidence of CBD, but may not necessarily lower the incidence of SENS.

Adult↗
PubMed1982

Development of beryllium lymphocyte transformation tests in chronic beryllium disease.

We found that optimal conditions for the beryllium transformation test required the use of purified lymphocyte suspensions in 20% human serum, with beryllium sulphate at concentrations of 10(-6) to 10(-7) M. Using these conditions, all 15 chronic beryllium patients tested gave a stimulation index of more than 2. Despite the above, 10(-5) and 10(-6)M, BeSO4 inhibited spontaneous thymidine incorporation and lymphocyte transformation to PHA and PPD in normal subjects. Alternative methods, using whole blood, venous and thumb-prick samples, gave fewer and less reproducible positive results.

Berylliosis↗
PubMed1984

Lymphocyte beryllium binding: relationship to development of delayed beryllium hypersensitivity.

Beryllium binding to human and both inbred and outbred guinea pig lymphocytes has been characterized by Scatchard binding analysis. In isotonic media, only one class of binding sites, presumed to be located on the outer cell surface, was identified with a relatively low affinity (KA3-4 X 10(5) M-1). In hypotonic media in which the cells rupture, an additional class of binding sites, probably in the cell nucleus, is revealed with a higher affinity (KA1-2 X 10(6) M-1). Preliminary investigation of the high affinity binding in strain XIII guinea pig peripheral blood lymphocytes provides evidence that a greater level of beryllium binding may be predictive of the potential to express delayed beryllium hypersensitivity.

Animals↗
PubMed2001

High beryllium-stimulated TNF-alpha is associated with the -308 TNF-alpha promoter polymorphism and with clinical severity in chronic beryllium disease.

Beryllium (Be)-antigen stimulates tumor necrosis factor-alpha (TNF-alpha) from bronchoalveolar lavage (BAL) cells in chronic beryllium disease (CBD). This study tested the hypothesis that high concentrations of Be-stimulated TNF-alpha are related to polymorphisms in the TNF-alpha promoter and clinical markers of disease severity in CBD. Demographic and clinical information was obtained from patients with CBD (n = 20). TNF-alpha concentrations were measured in BAL cell culture supernatant by ELISA. A priori, we categorized CBD subjects as either high or low TNF-alpha producers using a cutoff of 1,500 pg/ml. The TNF-alpha promoter sequence, +64 to -1045, was determined by direct sequencing. Human leukocyte-associated antigen (HLA)-DPB1 and -DRB1 genotyping was determined by polymerase chain reaction (PCR). High Be-stimulated TNF-alpha was associated with TNF2 alleles, Hispanic ethnicity, presence of HLA-DPB1 Glu69, and absence of HLA-DR4. Be-stimulated TNF-alpha concentrations correlated with markers of disease severity, including chest radiograph, beryllium lymphocyte proliferation, and spirometry. We found no novel TNF-alpha promoter polymorphisms. These data suggest that the TNF2 A allele at -308 in the TNF-alpha promoter region is a functional polymorphism, associated with a high level of Be-antigen-stimulated TNF-alpha and that these high TNF-alpha levels indicate disease severity in CBD.

Antigens↗
PubMed2004

Beryllium-ferritin: lymphocyte proliferation and macrophage apoptosis in chronic beryllium disease.

A beryllium (Be)-ferritin adduct containing 270 pm of Be stimulated proliferation of bronchoalveolar lavage (BAL) lymphocytes from subjects with chronic beryllium disease (CBD) at concentrations 5-6 logs lower than the amounts of beryllium sulfate (BeSO4) needed to induce proliferation. We observed increased apoptotic CBD BAL macrophages after exposure to both BeSO4 (50 +/- 6%, mean +/- SEM, P <0.05 versus unstimulated controls) and Be-ferritin (40 +/- 2%), whereas only 2.0 +/- 0.2% of BAL lymphocytes underwent activation-induced cell death. Be-ferritin also induced apoptosis in BAL macrophages from subjects with Be sensitization (25 +/- 3%) and in the H36.12j hybrid macrophage cell line (15 +/- 2%). Be-ferritin induced lung macrophage CD95 (Fas) expression and the activation of intracellular caspase-3, -8 and -9. Thus, lung macrophages take up Be-ferritin, delivering physiologically relevant levels of Be that promote Be antigen presentation and macrophage apoptosis. Be-ferritin thereby serves as a "Trojan Horse," triggering proliferation of Be-ferritin-specific CBD BAL T cells. We hypothesize that Be-ferritin exposure may result in persistent antigen exposure inducing Be-specific T cell clonal expansion and T cell helper type 1-type cytokine production and potentially explains the chronicity of CBD and its development years after environmental Be exposure has ceased.

Adult↗
PubMed2006

Beryllium-induced TNF-alpha production is transcription-dependent in chronic beryllium disease.

Beryllium (Be)-antigen presentation to Be-specific CD4(+) T cells from the lungs of patients with chronic beryllium disease (CBD) results in T cell proliferation and TNF-alpha secretion. We tested the hypothesis that Be-induced, CBD bronchoalveolar lavage (BAL) T cell, transcription-dependent, TNF-alpha secretion was accompanied by specific transcription factor upregulation. After 6 h of Be stimulation, CBD BAL cells produced a median of 883 pg/ml TNF-alpha (range, 608-1,275 pg/ml) versus 198 pg/ml (range, 116-245 pg/ml) by unstimulated cells. After 12 h CBD BAL cells produced a median of 2,963 pg/ml (range, 99-9,424 pg/ml) TNF-alpha versus 55 pg/ml (range, 0-454) by unstimulated cells. Using real-time RT-PCR, Be-stimulated TNF-alpha production at 6 h was preceded by a 5-fold increase in TNF-alpha pre-mRNA copy number:beta-actin copy number (Be median ratio 0.21; unstimulated median ratio 0.04). The median ratio of mature TNF-alpha mRNA:beta-actin mRNA was upregulated 1.4-fold (Be median ratio 0.17; unstimulated median ratio 0.12). Be exposure in the presence of the transcription inhibitor pentoxifylline (PTX) decreased CBD BAL cell TNF-alpha pre-mRNA levels > 60%, whereas treatment with the mRNA splicing inhibitor 2-aminopurine (2AP) decreased levels 40% relative to Be exposure alone. PTX treatment decreased mature TNF-alpha mRNA levels 50% while 2AP decreased levels > 80%, relative to Be exposure alone. Beryllium exposure specifically upregulated transcription factors AP-1 and NF-kappaB. The data suggest that Be exposure induces transcription-dependent TNF-alpha production, potentially due to upregulation of specific transcription factors.

Adult↗
PubMed2001

Marked tachypnea in siblings with chronic beryllium disease due to copper-beryllium alloy.

Two biological sisters working at the same factory for > 9 years developed chronic beryllium disease (CBD) from a copper-beryllium alloy. Both had marked tachypnea (36 breaths/min and 45 breaths/min at rest, respectively), persisting over 8 years. Ventilation during exercise (assessed in one sibling) was grossly excessive (57 L/min, expected 23 L/min) with a respiratory rate of 64 breaths/min even with normal baseline routine pulmonary function tests. Blood beryllium lymphocyte transformation test and lung biopsies confirmed the diagnosis. No other cases of CBD have been reported from this plant among about 120 workers. These cases support the genetic basis for berylliosis and illustrate the marked tachypnea that may accompany this disease.

Alloys↗
PubMed1994

The comparative pulmonary toxicity of beryllium metal and beryllium oxide in cynomolgus monkeys.

Inhalation of beryllium (Be) may result in an immune-mediated, chronic granulomatous pulmonary disorder known as chronic beryllium disease (CBD). The physicochemical form of Be may affect the incidence and severity of CBD. We exposed cynomolgus monkeys, by bronchoscopic, intrabronchiolar instillation, to either beryllium oxide (BeO; heat-treated at 500 degrees C) or Be metal at concentrations selected to achieve equimolar concentrations of available Be2+ ions dissolving from the particles. Monkeys underwent bronchoalveolar lavage of the right and left diaphragmatic lobes at 14, 30, 60, 90, and 120 days post exposure (dpe). Monkeys were sacrificed at 80 and 180 dpe for evaluation of histopathological pulmonary changes. Numbers of lymphocytes from lung lobes of Be metal-exposed, but not BeO-exposed, monkeys were increased at 14, 30 and 90 dpe. Lung lymphocytes were increased for BeO exposed monkeys only at 60 dpe. In vitro, Be-specific, lung lymphocyte proliferation occurred at 14, 60, and 90 dpe for lymphocytes from Be metal-exposed lung lobes only. At no time were values from BeO-exposed lung lobes different from values from control lobes. Lung lesions in Be metal-exposed monkeys were characterized by focally intense, interstitial fibrosis, marked Type II cell hyperplasia, and variable lymphocyte infiltration. Some Be-metal-exposed monkeys had discrete immune granulomas consisting of tightly organized lymphocytic cuffs surrounding nodular aggregates of epithelioid macrophages. Lesions were rarely present in BeO-exposed monkeys and were much less severe. These data suggest that Be metal produces more severe pulmonary lesions than does BeO and that these lesions are accompanied by Be-specific immune responses.

Animals↗
PubMed2003

Influence of MHC class II in susceptibility to beryllium sensitization and chronic beryllium disease.

A glutamic acid at residue 69(Glu(69)) in the HLA-DPB1 gene (Glu(69)) is associated with chronic beryllium disease (CBD) and possibly beryllium sensitization (BeS). This study tested the hypothesis that MHC class II polymorphisms are important in susceptibility to BeS and CBD and that the Glu(69) variant is related to markers of disease severity. Genomic DNA was obtained from BeS (n = 50), CBD (n = 104), and beryllium-exposed nondiseased (Be-nondiseased) (n = 125) subjects. HLA-DPB1, -DRB1, and -DQB1 genotypes were determined by (sequence-specific primers) PCR. Disease severity was assessed by pulmonary function and exercise testing. A higher frequency of the DPB1 Glu(69) gene was found in CBD and BeS compared with the Be-nondiseased subjects, with odds ratios of 10.1 for CBD vs Be-nondiseased and 9.5 for BeS vs Be-nondiseased. The majority of BeS and CBD subjects displayed non-0201 Glu(69) alleles. Glu(69) homozygosity was higher in the CBD subjects, while BeS subjects were intermediate and Be-nondiseased lowest. DRB1*01 and DQB1*05 phenotypes were reduced in CBD vs Be-nondiseased subjects, while DRB1*13 and DQB1*06 were associated with CBD in the absence of Glu(69). Markers of disease severity, including a lower forced vital capacity, diffusion capacity for carbon monoxide, PaO(2) at rest, maximum workload on exercise testing, and a higher arterial-alveolar gradient at rest, were associated with Glu(69) homozygosity. We conclude that DPB1 Glu69 is a marker of sensitization and not specific for disease. Glu(69) homozygosity acts as a functional marker associated with markers of CBD severity.

Adult↗
PubMed1984

Experimental beryllium-induced lung disease. I. Differences in immunologic responses to beryllium compounds in strains 2 and 13 guinea pigs.

Granulomatous lung disease was produced in strain 2 but not strain 13 guinea pigs by endotracheal injection of beryllium oxide (BeO), although isolated multinucleated giant cells containing crystalline material were found in lungs of both strains. Disease was also produced in (2 x 13) F1 hybrids, but of a milder form than in strain 2. In BeO-treated strain 2 and F1 animals, challenge with beryllium salts produced delayed hypersensitivity skin reactivity, and in vitro, enhanced tritiated thymidine uptake and lymphokine production by lymph node cells. No evidence was found for involvement of humoral immunity in the disease. Responses were not seen in BeO-treated strain 13 guinea pigs, and immunization of animals with BeO in complete Freund's adjuvant produced similar immunologic findings. These data emphasize the involvement of genetically determined cellular immune mechanisms in beryllium lung disease.

Animals↗
PubMed2002

Nitric oxide attenuates beryllium-induced IFNgamma responses in chronic beryllium disease: evidence for mechanisms independent of IL-18.

In chronic beryllium disease (CBD), a granulomatous lung disease characterized by hypersensitivity to beryllium salts (BE), BE challenge of bronchoalveolar lavage cells induces IFNgamma. Although nitric oxide (NO) is elevated in CBD airways, the effects of NO on CBD IFNgamma responses are unknown. Here we report that BE-stimulated IFNgamma production in CBD lavage cells was markedly reduced (74%) by the NO generator DETA NONOate. Investigation of IFNgamma-stimulatory cytokine involvement indicated that lavage cell IL-18 was significantly increased (fourfold) by BE and reduced (64%) by DETA NONOate but IL-12 was undetectable. IL-18 production was caspase-1-dependent but caspase 1 inhibition reduced IFNgamma only partially (43%). Specific antibody depletion of lavage cell IL-18 yielded marginal reduction (19%) of IFNgamma. Data are the first to show that: (1) BE stimulates IL-18 as well as IFNgamma in CBD; (2) BE cytokine responses are NO-sensitive; and (3) NO down-regulation of IFNgamma involves other sites in addition to IL-18.

Berylliosis↗
PubMed2001

Ultrafine beryllium number concentration as a possible metric for chronic beryllium disease risk.

Beryllium is a lightweight metal which causes a chronic granulomatous lung disease among workers who become sensitized to it. Recent research has shown a persistence of the disease despite efforts at control with mean exposures below the Occupational Safety and Health Administration (OSHA) occupational exposure limit of 2 microg/m3. Results of our current research confirm a previous finding in certain plants that particle number concentrations are higher in areas where historical estimate of risk showed a high risk of disease despite relatively lower mass concentrations. By providing side-by-side measurements of both particle number and mass, this research adds support to the proposal that particle number rather than particle mass may be more reflective of target organ dose and subsequently a more appropriate measure of exposure for chronic beryllium disease. Our evidence also shows that particle mass exposure measurements and particle number exposure measurements were not correlated.

Air Pollutants, Occupational↗
PubMed2001

Is total mass or mass of alveolar-deposited airborne particles of beryllium a better predictor of the prevalence of disease? A preliminary study of a beryllium processing facility.

Cases of chronic beryllium disease (CBD) and beryllium (Be) sensitization continue to be identified among Be industry workers. The currently accepted method for measuring exposure, which involves measuring the total mass of airborne Be per cubic meter, shows an inconsistent dose-response relationship with the prevalence of CBD. This study was conducted to evaluate which Be aerosol characteristics other than total mass may be more informative in understanding the dose-response relationship between exposure to Be and disease. Personal (n = 53) and general (n = 55) area airborne Be samples were collected in five furnace areas at a Be manufacturing facility where prevalence rates of CBD and Be sensitization had been previously studied among 535 employees with significant Be exposure. In the five furnace areas, particle-size specific personal samples and area samples were collected using an Andersen impactor and a microorifice uniform deposit impactor (MOUDI), respectively. The calculated concentrations were expressed in terms of total mass per cubic meter, and in forms of mass, number, and surface area of particles less than 10 microm or less than 3.5 microm mass median aerodynamic diameter per cubic meter that are predicted to deposit in the alveolar region of the lung. Tests for linear trend of the relationships of the various exposure metrics to prevalence of CBD and sensitization demonstrated highly significant associations between mass concentration (MOUDI) of particles less than 10 microm, and less than 3.5 microm, predicted to deposit in the alveolar region of the lung and CBD (p = 0.0004 and 0.000003, respectively) and sensitization (p = 0.025 and 0.003, respectively). However, no statistically significant association was found between these two exposure metrics and personal (Andersen) samples. The number and surface area concentration (MOUDI) of alveolar-deposited particles (less than 10 microm) also showed significant relationships with CBD (p = 0.03 and 0.03, respectively). No other exposure parameters showed significant relationships with CBD or Be sensitization. These results suggest that the concentration of alveolar-deposited particles less than 10 microm or, more particularly, the concentration of alveolar-deposited particles less than 3.5 microm may be a more relevant exposure metric for predicting the incidence of CBD or sensitization than the total mass concentration of airborne Be.

Adult↗
PubMed2005

Secondary ion mass spectroscopy demonstrates retention of beryllium in chronic beryllium disease granulomas.

OBJECTIVE: We hypothesized that beryllium (Be) might persist in lung granulomas in patients with chronic beryllium disease (CBD). METHODS: A total of 33 Be-exposed ceramics workers underwent transbronchial biopsy. They were classified based on histopathology and Be-lymphocyte proliferation test as CBD or other categories. Lung tissue sections were analyzed using secondary ion mass spectroscopy. RESULTS: Be was detected in the lungs of all Be-exposed groups. Be levels were increased within the granulomas of patients with CBD compared with the Be levels outside granulomas. Notably, Be was detectable in the lungs of CBD patients who had ceased exposure to Be an average of 9 years previously. CONCLUSIONS: Be was detected in the lungs of all Be-exposed subjects, with the highest levels of persistent Be inside CBD lung granulomas. Be antigen persistence may help explain the chronicity of this granulomatous disorder.

Adult↗