Mortality Among Individuals Diagnosed With Chronic Beryllium Disease and Beryllium Sensitization.

OBJECTIVE: The aim of the study is to investigate the cause of death among individuals diagnosed with chronic beryllium disease (CBD) or beryllium sensitization (BeS). METHODS: Vital status, cause of death, and standardized mortality ratios for the underlying cause of death were determined for a cohort of 354 individuals with CBD and 290 individuals with BeS. RESULTS: Among 216 deceased individuals, 153 had CBD and 63 had BeS. Nonmalignant respiratory deaths and other causes of death were significantly increased among those with CBD. No cause of death was significantly increased for BeS. Mortality from lung cancer was not increased. CONCLUSIONS: Individuals with CBD had an overall increased mortality risk due to increased respiratory mortality regardless of their duration of exposure to beryllium. Individuals with BeS did not have increased respiratory mortality. No increased risk of lung cancer was seen among this cohort.

Beryllium disease among construction trade workers at Department of Energy nuclear sites: A follow-up.

BACKGROUND: Construction workers at U.S. Department of Energy (DOE) nuclear weapons facilities are screened to identify DOE-related occupational illnesses, including beryllium sensitization (BeS) and chronic beryllium disease (CBD). The study objectives were to estimate beryllium disease risks and the CBD claims acceptance rate in the energy workers' benefits program. METHODS: Workers diagnosed with BeS via beryllium lymphocyte proliferation test (BeLPT) included in screening examinations were interviewed about subsequent diagnosis of CBD. We estimated the proportion who developed CBD based on the ratio of CBD cases, based on self-reported compensation claim status, to all workers with BeS interviewed. We used stratified analyses to explore trends in disease frequency by age, race, sex, DOE employment duration, site, trade group, and cigarette smoking history. RESULTS: Between 1998 and 2020, 21,854 workers received a BeLPT; 262 (1.20%) had BeS (two abnormals or one abnormal plus one borderline test); 212 (0.97%) had a single abnormal BeLPT. Of 177 BeS workers interviewed, 35 (19.8%) reported an accepted CBD compensation claim. The claims acceptance rate among BeS workers increased with years of DOE employment, from 8.4% with <5 years to 33.3% for >25 or more years. Five of 68 interviewed workers with a single positive BeLPT reported CBD claim acceptance; an additional CBD case was confirmed by chart review (8.8%). CONCLUSIONS: Years of DOE work predict the risk of developing CBD among those sensitized and getting a claim for CBD accepted. Ongoing surveillance and increased awareness of the risk of beryllium exposure and CBD as an occupational disease among construction workers are needed.

[Sarcoidosis and berylliosis]. / Sarkoidose und Berylliose.

Sarcoidosis and berylliosis (chronic beryllium disease, CBD) are granulomatous diseases and are phenocopies which cannot be differentiated based on the clinical presentation. Whereas for sarcoidosis the eliciting agent is unknown, for berylliosis an exposure to beryllium (mostly as occupational exposure) can be confirmed that therefore induces a sensitization against beryllium. The diagnosis is generally made in patients with a typical clinical presentation, the histological proof of a non-necrotizing granuloma and the exclusion of other diseases causing granulomas. In most cases, granulomas can be detected in the lungs and/or (intrathoracic) lymph nodes. The proof of sensitization to beryllium for the differential diagnosis can be performed with a so-called beryllium lymphocyte proliferation test in peripheral mononuclear blood cells or cells from a bronchoalveolar lavage. The objectives of treatment are avoidance of functional organ impairment and symptom control. Immunosuppressive therapy (initially mostly with corticosteroids) and supportive measures can prove beneficial; however, in many cases clinical observation can be sufficient because of stable disease or spontaneous resolution. In addition, further beryllium exposure must be avoided, which mostly necessitates a change of the workplace.

A Cluster of Beryllium Sensitization Traced to the Presence of Beryllium in Concrete Dust.

BACKGROUND: Chronic beryllium disease (CBD), a granulomatous disease with similarities to sarcoidosis, arises only in individuals exposed to beryllium. Inhaled beryllium can elicit a T-cell-dominated alveolitis leading nonnecrotizing granulomata. CBD can be distinguished from sarcoidosis by demonstrating beryllium sensitization in a lymphocyte proliferation test. RESEARCH QUESTION: Beryllium exposure usually occurs in an occupational setting. Because of the diagnosis of CBD in a patient without evident beryllium exposure, we performed a beryllium-lymphocyte proliferation test (BeLPT) among his work colleagues. STUDY DESIGN AND METHODS: This field study investigated a cohort of work colleagues without obvious beryllium exposure. Twenty-one of 30 individuals were assessed in our outpatient clinic for beryllium sensitization. Therefore, BeLPT was performed with freshly collected peripheral blood mononuclear cells. Data were extracted from clinical charts, including geographical data. Beryllium content in dust samples collected at the workplace was measured by graphite-furnace atomic absorption spectroscopy and was compared with samples from different areas of Germany. RESULTS: For the initial patient, the diagnosis of sarcoidosis was reclassified as CBD based on two positive BeLPT results. Assessment of his workplace did not identify a source of beryllium. However, BeLPTs performed on his workmates demonstrated beryllium sensitization in 5 of 21 individuals, suggesting a local beryllium source. Concrete dust obtained from the building yard, the workplace of the index patient, contained high amounts of beryllium (1138 ± 162 µg/kg), whereas dust from other localities (control samples) showed much lower beryllium content (range, 147 ± 18-452 ± 206 µg/kg). Notably, the control dust collected from different places all over Germany exhibit different beryllium concentrations. INTERPRETATION: We describe a cluster of beryllium-sensitized workers from an industry not related to beryllium caused by environmental exposure to beryllium-containing concrete dust, which exhibited markedly elevated beryllium content. Importantly, analyses of dust samples collected from different localities showed that they contain markedly different amounts of beryllium. Thus, besides workplace-related exposure, environmental factors also are capable of eliciting a beryllium sensitization.

[Management of occupational health for adverse health effects of beryllium and its compounds in workplaces - Recent trends and issues in Japan].

OBJECTIVES: Beryllium is primarily used in its metallic form, in alloys, or in beryllium oxide ceramics. Its physical and mechanical properties make it useful for many applications across a range of industries. Because beryllium is recognized as a sensitizing and carcinogenic agent, the management of occupational health for workers who may be occupationally exposed to beryllium has long been an important issue in the world. Under these circumstances, the U.S. Occupational Safety and Health Administration (OSHA) had published a rule in January 2017, to prevent the development of chronic beryllium disease and lung cancer. This rule strengthens the regulations governing the use of beryllium and its compounds. With the announcement of the OSHA rule in January 2017, the purpose of this study is to gain insight into the health problems and industrial hygiene associated with the use of beryllium and share the issues related to the management of occupational health for persons working with beryllium in Japan. METHODS: We collected information regarding the beryllium industry, beryllium exposure, beryllium-induced health disorders, OSHA rule of January 2017, and regulations for beryllium use in Japan. After reviewing them, we discussed the issues concerning occupational health management of workers exposed to beryllium in Japan. RESULTS: It has been reconfirmed that in recent years, the most serious health problem due to beryllium exposure is chronic beryllium disease caused by beryllium sensitization. Management of occupational health that emphasizes reduction of beryllium sensitization and early detection of beryllium-sensitized workers is important. CONCLUSIONS: It was suggested that the following should be considered as the issues of management of occupational health of workers exposed to beryllium in Japan: (1) Collect epidemiologic data on health hazards from beryllium exposure in Japan. (2) Review the diagnostic items of special medical check-ups. (3) Review the definition of beryllium and its compounds in the Ordinance on Prevention of Hazards due to Specified Chemical Substances.

Polymorphism of FCGR3A gene in chronic beryllium disease.

Previously we showed that alveolar macrophages (AMs) from patients with chronic beryllium disease (CBD) and beryllium sensitization (BeS) demonstrated significantly greater cell surface CD16 (encoded by the FCGR3A gene) than controls. We hypothesized that these differences were related to polymorphisms in the FCGR3A gene. This study was to determine the association between FCGR3A polymorphisms in CBD, BeS versus controls as well as clinical data, providing potential information about disease pathogenesis, risk, and activity. A total of 189 CBD/154 BeS/150 controls (92 Be-exposed non-diseased and 58 healthy controls) were included in this study. Sequence-specific primers polymerase chain reaction (PCR-SSP) was used to determine FCGR3A 158V/F polymorphisms. We found significantly higher frequencies of the 158V allele (OR: 1.60 (CI: 1.17-2.19), p = 0.004) and 158VV homozygotes (OR: 2.97 (CI: 1.48-5.97) p = 0.007) in CBD versus controls. No differences were found in the frequencies of FCGR3A alleles or genotypes between BeS versus controls and CBD versus BeS. Average changes in exercise testing maximum workload (Wlm), maximum oxygen consumption (VO2m), and diffusion capacity of carbon monoxide (DLCO) demonstrated greater decline over time in those CBD cases with the 158VV gene, modeled between 10 and 40 years from first beryllium exposure. The FCGR3A V158F polymorphism is associated with CBD compared to BeS and controls and may impact lung function in CBD.

Occupational Exposure to Beryllium. Final rule.

The Occupational Safety and Health Administration (OSHA) is amending its existing standards for occupational exposure to beryllium and beryllium compounds. OSHA has determined that employees exposed to beryllium at the previous permissible exposure limits face a significant risk of material impairment to their health. The evidence in the record for this rulemaking indicates that workers exposed to beryllium are at increased risk of developing chronic beryllium disease and lung cancer. This final rule establishes new permissible exposure limits of 0.2 micrograms of beryllium per cubic meter of air (0.2 [mu]g/m\3\) as an 8-hour time-weighted average and 2.0 [mu]g/m\3\ as a short-term exposure limit determined over a sampling period of 15 minutes. It also includes other provisions to protect employees, such as requirements for exposure assessment, methods for controlling exposure, respiratory protection, personal protective clothing and equipment, housekeeping, medical surveillance, hazard communication, and recordkeeping. OSHA is issuing three separate standards--for general industry, for shipyards, and for construction--in order to tailor requirements to the circumstances found in these sectors.

Beryllium in exhaled breath condensate as a biomarker of occupational exposure in a primary aluminum production plant.

OBJECTIVE: Low beryllium exposure can induce pulmonary granulomatosis, so called berylliosis. For occupational health monitoring, it is more relevant to assess the internal dose of Be received by the lungs than urinary or atmospheric Be. Exhaled breath condensate (EBC) is a matrix collected non-invasively that derives from the airway lining fluid. EBC beryllium (Be) levels were evaluated as a marker of occupational exposure in a primary aluminum production plant. METHODS: We collected urine and EBC from controls and workers recently exposed to beryllium in the pot room and the anode repair sectors, and calculated a cumulative beryllium exposure index (CBEI) summing the number of years of employment in each task and multiplying by the estimated average beryllium exposure for the task. Concentrations of beryllium and aluminum were measured in EBC (Be-EBC and Al-EBC) and in urine (Be-U and Al-U) by ICP-MS. RESULTS AND CONCLUSION: We have shown that it was possible to measure Be and Al in workers' EBC. Compared with controls and after adjustment for smoking status, levels of Be-EBC and Al-EBC were higher in pot room workers and exposed subjects, respectively. Due to its relationship with CBEI, but not with Be-U, it appears that Be-EBC could be a promising marker of occupational exposure and provide additional toxicokinetic information in occupational health studies.

Metal-specific CD4+ T-cell responses induced by beryllium exposure in HLA-DP2 transgenic mice.

Chronic beryllium disease (CBD) is a granulomatous lung disorder that is associated with the accumulation of beryllium (Be)-specific CD4(+) T cells into the lung. Genetic susceptibility is linked to HLA-DPB1 alleles that possess a glutamic acid at position 69 (ßGlu69), and HLA-DPB1*02:01 is the most prevalent ßGlu69-containing allele. Using HLA-DP2 transgenic (Tg) mice, we developed a model of CBD that replicates the major features of the human disease. Here we characterized the T-cell receptor (TCR) repertoire of Be-responsive CD4(+) T cells derived from the lungs of Be oxide-exposed HLA-DP2 Tg mice. The majority of Be-specific T-cell hybridomas expressed TCR Vß6, and a subset of these hybridomas expressed identical or nearly identical ß-chains that were paired with different α-chains. We delineated mimotopes that bind to HLA-DP2 and form a complex recognized by Be-specific CD4(+) T cells in the absence of Be. These Be-independent peptides possess an arginine at p5 and a tryptophan at p7 that surround the Be-binding site within the HLA-DP2 acidic pocket and likely induce charge and conformational changes that mimic those induced by the Be(2+) cation. Collectively, these data highlight the interplay between peptides and Be in the generation of an adaptive immune response in metal-induced hypersensitivity.

An official American Thoracic Society statement: diagnosis and management of beryllium sensitivity and chronic beryllium disease.

RATIONALE: Beryllium continues to have a wide range of industrial applications. Exposure to beryllium can lead to sensitization (BeS) and chronic beryllium disease (CBD). OBJECTIVES: The purpose of this statement is to increase awareness and knowledge about beryllium exposure, BeS, and CBD. METHODS: Evidence was identified by a search of MEDLINE. The committee then summarized the evidence, drew conclusions, and described their approach to diagnosis and management. MAIN RESULTS: The beryllium lymphocyte proliferation test is the cornerstone of both medical surveillance and the diagnosis of BeS and CBD. A confirmed abnormal beryllium lymphocyte proliferation test without evidence of lung disease is diagnostic of BeS. BeS with evidence of a granulomatous inflammatory response in the lung is diagnostic of CBD. The determinants of progression from BeS to CBD are uncertain, but higher exposures and the presence of a genetic variant in the HLA-DP ß chain appear to increase the risk. Periodic evaluation of affected individuals can detect disease progression (from BeS to CBD, or from mild CBD to more severe CBD). Corticosteroid therapy is typically administered when a patient with CBD exhibits evidence of significant lung function abnormality or decline. CONCLUSIONS: Medical surveillance in workplaces that use beryllium-containing materials can identify individuals with BeS and at-risk groups of workers, which can help prioritize efforts to reduce inhalational and dermal exposures.

Considerations for the development of health-based surface dust cleanup criteria for beryllium.

The exposure-response patterns with beryllium sensitization (BeS), chronic beryllium disease (CBD) and lung cancer are influenced by a number of biological and physicochemical factors. Recent studies have suggested dermal exposure as a pathway for BeS. In light of the current non-health-based DOE Beryllium Rule surface criteria, the feasibility of deriving a human health-based surface dust cleanup criteria (SDCC) for beryllium was assessed based on toxicology and health risk factors via all potential routes of exposure. Beryllium-specific and general exposure factors were evaluated, including (1) beryllium physicochemical characteristics, bioavailability and influence on disease prevalence, and (2) chemical dissipation, resuspension and transfer. SDCC for non-cancer (SDCC) and cancer (SDCC) endpoints were derived from a combination of modern methods applied for occupational, residential and building reentry surface dust criteria. The most conservative SDCC estimates were derived for dermal exposure (5-379 µg/100 cm for 0.1-1% damaged skin and 17-3337 µg/100 cm for intact skin), whereas the SDCC for inhalation exposure ranged from 51 to 485 µg/100 cm. Considering this analysis, the lowest DOE surface criterion of 0.2 µg/100 cm is conservative for minimizing exposure and potential risks associated with beryllium-contaminated surfaces released for non-beryllium industrial or public sector use. Although methodological challenges exist with sampling and analysis procedures, data variability and interpretation of surface dust information in relation to anthropogenic and natural background concentrations, this evaluation should provide useful guidance with regard to cleanup of manufacturing equipment or remediation of property for transfer to the general public or non-beryllium industrial facilities.

Release of beryllium into artificial airway epithelial lining fluid.

Inhaled beryllium particles that deposit in the lung airway lining fluid may dissolve and interact with immune-competent cells resulting in sensitization. As such, solubilization of 17 beryllium-containing materials (ore, hydroxide, metal, oxide, alloys, and process intermediates) was investigated using artificial human airway epithelial lining fluid. The maximum beryllium release in 7 days was 11.78% (from a beryl ore melter dust), although release from most materials was < 1%. Calculated dissolution half-times ranged from 30 days (reduction furnace material) to 74,000 days (hydroxide). Despite rapid mechanical clearance, billions of beryllium ions may be released in the respiratory tract via dissolution in airway lining fluid. Beryllium-containing particles that deposit in the respiratory tract dissolve in artificial lung epithelial lining fluid, thereby providing ions for absorption in the lung and interaction with immune-competent cells in the respiratory tract.

Sensitization and chronic beryllium disease at a primary manufacturing facility, part 2: validation of historical exposures.

OBJECTIVE: The aim of this study was to evaluate the validity of a job exposure matrix (JEM) constructed for the period 1994-1999. Historical exposure estimates (HEE) for the JEM were constructed for all job and year combinations by applying temporal factors reflecting annual change in area air measurements (1994-1998) to the personal baseline exposure estimates (BEE) collected in 1999. The JEM was generated for an epidemiologic study to examine quantitative exposure-response relationships with sensitization and chronic beryllium disease. METHODS: The validity of the BEE and HEE was evaluated by comparing them with a validation dataset of independently collected personal beryllium exposure measurements from 1999 and 1994-1998, respectively. Agreement between the JEM and validation data was assessed using relative bias and concordance correlation coefficients (CCC). RESULTS: The BEE and HEE overestimated the measured exposures in their respective validation datasets by 8% and 6%, respectively. The CCC reflecting the deviation of the fitted line from the concordance line, showed good agreement for both BEE (CCC=0.80) and HEE (CCC=0.72). Proportional difference did not change with exposure levels or by process area and year. Overall, the agreement between the JEM and validation estimates (from combined HEE and BEE) was high (CCC=0.77). CONCLUSIONS: This study demonstrated that the reconstructed beryllium exposures at a manufacturing facility were reliable and can be used in epidemiologic studies.

Sensitization and chronic beryllium disease at a primary manufacturing facility, part 3: exposure-response among short-term workers.

OBJECTIVES: Exposure-response relations for beryllium sensitization (BeS) and chronic beryllium disease (CBD) using aerosol mass concentration have been inconsistent, although process-related risks found in most studies suggest that exposure-dependent risks exist. We examined exposure-response relations using personal exposure estimates in a beryllium worker cohort with limited work tenure to minimize exposure misclassification. METHODS: The population comprised workers employed in 1999 with six years or less tenure. Each completed a work history questionnaire and was evaluated for immunological sensitization and CBD. A job-exposure matrix was combined with work histories to create individual estimates of average, cumulative, and highest-job-worked exposure for total, respirable, and submicron beryllium mass concentrations. We obtained odds ratios from logistic regression models for exposure-response relations, and evaluated process-related risks. RESULTS: Participation was 90.7% (264/291 eligible). Sensitization prevalence was 9.8% (26/264), with 6 sensitized also diagnosed with CBD (2.3%, 6/264). A general pattern of increasing sensitization prevalence was observed as exposure quartile increased. Both total and respirable beryllium mass concentration estimates were positively associated with sensitization (average and highest job), and CBD (cumulative). Increased sensitization prevalence was identified in metal/oxide production, alloy melting and casting, and maintenance, and for CBD in melting and casting. Lower sensitization prevalence was observed in plant-area administrative work. CONCLUSIONS: Sensitization was associated with average and highest job exposures, and CBD was associated with cumulative exposure. Both total and respirable mass concentrations were relevant predictors of risk. New process-related risks were identified in melting and casting and maintenance.

Sensitization and chronic beryllium disease at a primary manufacturing facility, part 1: historical exposure reconstruction.

OBJECTIVES: Previous epidemiologic studies of beryllium sensitization (BeS) and chronic beryllium disease (CBD) have reported inconsistent exposure-response relationships, likely due to exposure misclassification. The objective of this study was to develop historical estimates of size-selective personal exposure to beryllium for an epidemiologic study. METHODS: In 1999, a cross-sectional survey of workers hired after 1 January 1994 was conducted at a beryllium production facility. Personal exposure data from two air sampling surveys conducted in 1999 were used to obtain total, respirable, and submicron particle baseline exposure estimates (BEE) for a job-exposure matrix (JEM). General area air samples collected from 1994-1999 were used to estimate annual changes in exposures (temporal factors) for 24 different process areas. Historical exposure estimates (HEE) were calculated by applying the temporal factors to the BEE. Workers were assigned HEE based on their work history, and their historical exposure profile was summarized as cumulative, average, or highest-ever job exposure. RESULTS: Changes in exposure over a 6-year period were observed in 10 of the 24 process areas with an overall mean decline of 18% per year. The overall total exposure for study participants over their work tenure ranged from: 0.001-34.44 µg/m(3)-year, 0.01-16.26 µg/m(3), and 0.01-17.54 µg /m(3) for cumulative, average, and highest-ever job, respectively. For respirable exposures, the ranges were: 0.001-15.54 µg/m(3)-year, 0.01-3.56 µg/m(3), 0.01-5.54 µg /m(3) for cumulative, average, and highest-ever job, respectively. CONCLUSIONS: Using this JEM, exposure-response relationships for BeS and CBD can be explored over a range of exposure metrics such as total, respirable, and submicron beryllium mass concentrations, including summary measures such as cumulative, average, or highest exposures, with the ultimate objective of elucidating a quantitative exposure-response relationship.

Chest wall shrapnel-induced beryllium-sensitization and associated pulmonary disease.

Chronic beryllium disease (CBD) is an exposure-related granulomatous disease mimicking sarcoidosis. Beryllium exposure-associated disease occurs mainly via inhalation, but skin may also be a source of sensitization. A 65-year-old male with a history of war-related shrapnel wounds was initially diagnosed with pulmonary sarcoidosis. Twenty years later, the possibility of a metal-related etiology for the lung disease was raised. A beryllium lymphocyte proliferation test, elemental analysis of removed shrapnel, and genetic studies were consistent with a diagnosis of CBD. This case demonstrates that retained beryllium-containing foreign bodies can be linked to a pathophysiologic response in the lung consistent with CBD.

[Structural and functional-metabolic criteria for studies of bronchial lavage cells in beryllium production workers].

The article presents results of cytomorphologic and cytochemical studies of bronchoalveolar lavage cells in experimental animals and in beryllium production workers having beryllium intoxication signs. Findings are increased counts of degenerated neutrophils and macrophages in bronchial lavage, high degree of microbial (streptococcal and staphylococcal) contamination in workers having atrophic bronchitis, low levels of catecholamines and esterase activity, high content of phospholipids, if compared to apparently healthy individuals. These tests are expedient to use in early diagnosis among beryllium production workers.

Solubility and chemistry of materials encountered by beryllium mine and ore extraction workers: relation to risk.

OBJECTIVE: Beryllium mine and ore extraction mill workers have low rates of beryllium sensitization and chronic beryllium disease relative to the level of beryllium exposure. The objective was to relate these rates to the solubility and composition of the mine and mill materials. METHOD: Medical surveillance and exposure data were summarized. Dissolution of BeO, ore materials and beryllium hydroxide, Be(OH)(2) was measured in synthetic lung fluid. RESULT: The ore materials were more soluble than BeO at pH 7.2 and similar at pH 4.5. Be(OH)(2) was more soluble than BeO at both pH. Aluminum dissolved along with beryllium from ore materials. CONCLUSION: Higher solubility of beryllium ore materials and Be(OH)(2) at pH 7.2 might shorten particle longevity in the lung. The aluminum content of the ore materials might inhibit the cellular immune response to beryllium.