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.

Neoplasia de pulmón en trabajadores expuestos al berilio y/o sus compuestos: revisión sistemática / Lung Neoplasm in Workers Exposed to Beryllium and/or its Compounds: Systematic Review

Introducción: El berilio es un metal que por sus propiedades físico-químicas es utilizado en la industria para la fabricación de diferentes productos comerciales y de alta tecnología. La exposición laboral al berilio se relaciona con la aparición de neoplasia de pulmón, siendo esta enfermedad la primera causa de muerte por cáncer a nivel mundial.Objetivos: Revisar la literatura científica existente en relación con la exposición laboral al berilio y/o sus compues-tos y la neoplasia de pulmón.Método: Revisión sistemática de la literatura científica recogida en las bases de datos bibliográficas MEDLINE (vía PubMed), EMBASE, Web Of Science, Scopus, Cochrane Library, Índice Bibliográfico Español en Ciencias de la Salud (IBECS), Literatura Latinoamericana y del Caribe en Ciencias de la Salud (LILACS) y Medicina en Español (MEDES). Los términos utilizados como descriptores fueron: “Occupational Exposure”, “Occupational Diseases”, “Beryllium” y “Lung Neoplasms”. La búsqueda se completó con otros términos en texto libre y no se emplearon filtros (límites). La determinación de la calidad de los artículos seleccionados se llevó a cabo empleando la guía STROBE.Resultados: Se recuperaron 180 referencias, de las que se seleccionaron a texto completo 11 artículos tras aplicar los criterios de inclusión y exclusión. En estos estudios se describe la asociación entre exposición laboral al berilio y el desarrollo de neoplasia de pulmón.Conclusiones: Existe una asociación entre la exposición laboral al berilio y/o sus compuestos y la neoplasia de pulmón. Considerando el bajo número de estudios publicados y sus limitaciones, sería necesario realizar nuevos estudios que se adapten a las condiciones de la industria actual del berilio, teniendo en cuenta la solubilidad de sus compuestos, así como la identificación de sectores industriales y colectivos de trabajadores expuestos al mismo que aún no hayan sido estudiados (AU)

Introduction: Beryllium is an element that, due to its physical and chemical characteristics, is used in the manufac-turing of different commercial products and the high-tech industry. Laboral exposure to beryllium is associated with higher incidence of lung cancer, being this disease the leading cause of cancer death worldwide.Objectives: To review the existing scientific literature on the occurrence of occupational exposure to beryllium and/or its compounds and lung cancer.Method: Systematic review of the scientific literature collected in the bibliographic databases MEDLINE (via PubMed), EMBASE, Web Of Science, Scopus, Cochrane Library, Spanish Bibliographic Index in Health Sciences (IBECS), Latin American and Caribbean Literature in Health Sciences (LILACS) and Medicine in Spanish (MEDES). The terms used as descriptors were: “Occupational Exposure”, “Occupational Diseases”, “Beryllium” and “Lung Neo-plasms”. The search was completed with other terms in free text and no filters (limits) were used. The determination of the quality of the selected articles was carried out using the STROBE guide.Results: 180 references were retrieved, of which 11 articles could be obtained in full text after applying the inclusion and exclusion criteria. These studies describe the association between occupational exposure to beryllium and the development of lung cancer.Conclusions: There is an association between exposure to beryllium and/or its compounds and the development of lung cancer. However, considering the low number of published studies and their limitations, further studies should be carried out, which may be adapted to the current circumstances of the beryllium industry, taking into account the solubility of the beryllium compounds and the identification of industries and populations of workers exposed to beryllium that have not yet been studied (AU)

Analysis of single nucleotide polymorphisms in chronic beryllium disease.

Sarcoidosis and chronic beryllium disease (CBD) are phenocopies, however the latter one has a clear trigger factor that is beryllium exposure. This study analyses single nucleotide polymorphisms (SNPs) in a large cohort for beryllium-exposed persons. SNPs were chosen for their relevance in sarcoidosis. Even though one of largest cohorts of beryllium-exposed persons was analysed, no statistically relevant association between any SNP and CBD could be verified. Notably, some SNPs exhibit inverse OR for beryllium sensitization and CBD with nominally statistical significance, which allows hypothesizing about pathophysiological role of genes for the disease triggering and development.

[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.

Health aspects of exposure to emissions from burning coal of high beryllium content: interactions with the immune system.

Beryllium has an impact on the human health of professionally or non-occupationally exposed people. Current evidence suggests that beryllium acts as a hapten with limited antigenic properties and is presented by antigen presenting cells to CD4+ T cells, which possess specific antigen receptors. The immunological changes in humoral immunoreactivity were considered biomarkers of beryllium exposure. In the present, due to the development of immunologic knowledge, tests of cellular immunity have promising potential for further research in this field. The historical view of the immune response to beryllium in acute and/or chronic beryllium disease is an example of the development of the interaction between mechanisms of innate and adaptive (specific), humoral and cellular immunity. The authors emphasize the increasing importance of immunological aspects in the studies of health impacts of human exposure to environmental pollutants.

Immunoreactivity to metal and silica associates with sarcoidosis in Dutch patients.

BACKGROUND: Involvement of metals or silica in the pathogenesis of sarcoidosis has been suggested by several case reports and specific epidemiological studies. However, the combination of occupational exposure and an immunological reaction has not been studied before in a group of sarcoidosis patients and non-sarcoidosis controls. METHODS: In 256 sarcoidosis patients and 73 control patients with obstructive sleep apnea, exposure to metal and silica was assessed using a questionnaire consisting of a complete occupational history subsequently linked to job-exposure matrices. Next, immunoreactivity to aluminium, beryllium, zirconium and silica was determined in 33 sarcoidosis and 19 control patients using a lymphocyte proliferation test. RESULTS: In sarcoidosis, 83 out 256 patients (32.4%) had occupational exposure to metals or silica, compared to 24.7% in the control group (p = 0.21). A significantly higher percentage of the sarcoidosis patients tested showed immunoreactivity to metals or silica compared to the control group (21.2 and 0% respectively, p = 0.039). CONCLUSIONS: Immunoreactivity to silica and metals was only found in sarcoidosis patients, supporting the hypothesis that these antigens may be involved in the pathogenesis of a distinct subgroup of sarcoidosis patients. This indicates that when searching for causative agents in sarcoidosis patients, besides beryllium, also zirconium, aluminium and silica deserve clinical investigation.

Associations of Metrics of Peak Inhalation Exposure and Skin Exposure Indices With Beryllium Sensitization at a Beryllium Manufacturing Facility.

OBJECTIVES: Peak beryllium inhalation exposures and exposure to the skin may be relevant for developing beryllium sensitization (BeS). The objective of this study was to identify risk factors associated with BeS to inform the prevention of sensitization, and the development of chronic beryllium disease (CBD). METHODS: In a survey of short-term workers employed at a primary beryllium manufacturing facility between the years 1994-1999, 264 participants completed a questionnaire and were tested for BeS. A range of qualitative and quantitative peak inhalation metrics and skin exposure indices were created using: personal full-shift beryllium exposure measurements, 15 min to 24 h process-specific task and area exposure measurements, glove measurements as indicator of skin exposure, process-upset information gleaned from historical reports, and self-reported information on exposure events. Hierarchical clustering was conducted to systematically group participants based on similarity of patterns of 16 exposure variables. The associations of the exposure metrics with BeS and self-reported skin symptoms (in work areas processing beryllium salts as well as in other work areas) were evaluated using correlation analysis, log-binomial and logistic regression models with splines. RESULTS: Metrics of peak inhalation exposure, indices of skin exposure, and using material containing beryllium salts were significantly associated with skin symptoms and BeS; skin symptoms were a strong predictor of BeS. However, in this cohort, we could not tease apart the independent effects of skin exposure from inhalation exposure, as these exposures occurred simultaneously and were highly correlated. Hierarchical clustering identified groups of participants with unique patterns of exposure characteristics resulting in different prevalence of BeS and skin symptoms. A cluster with high skin exposure index and use of material containing beryllium salts had the highest prevalence of BeS and self-reported skin symptoms, followed by a cluster with high inhalation and skin exposure index and a very small fraction of jobs in which beryllium salts were used. A cluster with low inhalation and skin exposure and no workers using beryllium salts had no cases of BeS. CONCLUSION: Multiple pathways and types of exposure were associated with BeS and may be important for informing BeS prevention. Prevention efforts should focus on controlling airborne beryllium exposures with attention to peaks, use of process characteristics (e.g. the likelihood of upset conditions to design interventions) minimize skin exposure to beryllium particles, and in particular, eliminate skin contact with beryllium salts to interrupt potential exposure pathways for BeS risk.

Beryllium Standard Update.

The updated Occupational Safety and Health Administration's (OSHA) beryllium standard for general industry, construction, and shipyards reduced exposure limits for this known human carcinogen and became effective in 2018. Occupational and environmental health nurses need to monitor updates recently proposed for general industry to clarify implementation of the standard.

Is beryllium-induced lung cancer caused only by soluble forms and high exposure levels?

OBJECTIVES: The US Occupational Safety and Health Administration (OSHA) recently proposed a permissible exposure limit of 0.2 µg/m3 for beryllium, based partly on extrapolated estimates of lung cancer risk from a pooled occupational cohort. The purpose of the present analysis was to evaluate whether cohort members exposed at lower levels to mainly insoluble forms of beryllium exhibit increased risk of lung cancer. METHODS: We conducted Cox proportional hazards regression analyses among 75 lung cancer cases in age-based risk sets within two lower exposure plants in the pooled cohort followed from 1940 to 2005. We used categorical and power models to evaluate exposure-response patterns for mean and cumulative beryllium exposures in the two-plant cohort, comparing findings with the full pooled cohort. We also evaluated the distribution of exposure-years in each cohort by solubility class (soluble, insoluble and mixed). RESULTS: 98% of workers in the two-plant cohort were hired between 1955 and 1969. The mean beryllium exposure averaged 1.3 µg/m3 and the predominant form was insoluble. Adjusting for confounders, we observed a monotonic increase in lung cancer mortality across exposure categories in the two-plant cohort. The exposure-response coefficients (per unit ln exposure) were 0.270 (p=0.061) for mean exposure and 0.170 (p=0.033) for cumulative exposure, compared with 0.155 and 0.094 (respectively) in the full cohort. CONCLUSION: The low-exposure levels at these two plants and the predominance of insoluble beryllium suggest that the overall pooled cohort findings on which OSHA's lung cancer risk assessment is based are relevant for current workers exposed to any form of beryllium.

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.

A mortality study of beryllium workers.

We aimed at investigating mortality among beryllium-exposed workers, according to solubility of beryllium and beryllium compounds. We conducted an historical cohort study of 16,115 workers employed during 1925-2008 in 15 facilities, including eight entailing exposure to insoluble beryllium and seven entailing exposure to soluble/mixed beryllium compounds, who were followed up for mortality until 2011. Data were analyzed using indirect standardization and Cox regression modeling. Lung cancer standardized mortality ratio (SMR, national reference rates) was 1.02 (95% confidence interval [CI]: 0.94-1.10) in the whole cohort, 0.88 (95% CI: 0.75-1.03) in the insoluble beryllium subcohort, and 1.09 (95% CI: 0.99-1.09) in the soluble/mixed beryllium subcohort. For lung cancer, there was an association with period of hire in soluble/mixed beryllium plants but not in insoluble plants, and, conversely, employment in soluble/mixed plants was associated with increased mortality only among workers hired before 1955. There was no trend with duration of employment. Mortality from chronic beryllium disease increased, in particular, among workers hired before 1955 in soluble/mixed beryllium facilities. There was no increase in lung cancer mortality in the entire cohort and lung cancer mortality was not increased among beryllium workers hired in 1955 or later in soluble/mixed beryllium facilities, or at any time among those employed in insoluble beryllium facilities.

Beryllium-induced lung disease exhibits expression profiles similar to sarcoidosis.

A subset of beryllium-exposed workers develop beryllium sensitisation (BeS) which precedes chronic beryllium disease (CBD). We conducted an in-depth analysis of differentially expressed candidate genes in CBD.We performed Affymetrix GeneChip 1.0 ST array analysis on peripheral blood mononuclear cells (PBMCs) from 10 CBD, 10 BeS and 10 beryllium-exposed, nondiseased controls stimulated with BeSO4 or medium. The differentially expressed genes were validated by high-throughput real-time PCR in this group and in an additional group of cases and nonexposed controls. The functional roles of the top candidate genes in CBD were assessed using a pharmacological inhibitor. CBD gene expression data were compared with whole blood and lung tissue in sarcoidosis from the Gene Expression Omnibus.We confirmed almost 450 genes that were significantly differentially expressed between CBD and controls. The top enrichment of genes was for JAK (Janus kinase)-STAT (signal transducer and activator of transcription) signalling. A JAK2 inhibitor significantly decreased tumour necrosis factor-α and interferon-γ production. Furthermore, we found 287 differentially expressed genes overlapped in CBD/sarcoidosis. The top shared pathways included cytokine-cytokine receptor interactions, and Toll-like receptor, chemokine and JAK-STAT signalling pathways.We show that PBMCs demonstrate differentially expressed gene profiles relevant to the immunnopathogenesis of CBD. CBD and sarcoidosis share similar differential expression of pathogenic genes and pathways.

Occupational Cohort Time Scales.

PURPOSE: This study explores how highly correlated time variables (occupational cohort time scales) contribute to confounding and ambiguity of interpretation. METHODS: Occupational cohort time scales were identified and organized through simple equations of three time scales (relational triads) and the connections between these triads (time scale web). The behavior of the time scales was examined when constraints were imposed on variable ranges and interrelationships. RESULTS: Constraints on a time scale in a triad create high correlations between the other two time scales. These correlations combine with the connections between relational triads to produce association paths. High correlation between time scales leads to ambiguity of interpretation. CONCLUSIONS: Understanding the properties of occupational cohort time scales, their relational triads, and the time scale web is helpful in understanding the origins of otherwise obscure confounding bias and ambiguity of interpretation.

Beryllium and other metal-induced lung disease.

PURPOSE OF REVIEW: Metals can cause disease of the upper and lower respiratory tract that mirror disease due to other causes, such as asthma, rhinosinusitis, acute bronchitis, chronic bronchitis, acute pneumonitis, bronchogenic carcinoma, and interstitial lung disease. This article will describe some uncommon and unique lung diseases that can be induced by metals. RECENT FINDINGS: Our understanding of old occupational lung diseases, such as chronic beryllium disease, continues to increase. New exposures in the workplace, such as indium, have been identified as novel occupational hazards. New forms of exposure, such as titanium dioxide nanoparticles, create risk of lung disease that is not seen with larger particles. SUMMARY: Knowledge of several unusual and/or unique occupational lung diseases should prompt questioning about a patient's occupational history, which may uncover an occupational, rather than an idiopathic, lung disease.

Illness absences among beryllium sensitized workers.

OBJECTIVES: This study examined absence rates among US Department of Energy workers who had beryllium sensitization (BeS) or were diagnosed with chronic beryllium disease (CBD) compared with those of other workers. METHODS: We used the lymphocyte proliferation test to determine beryllium sensitivity. In addition, we applied multivariable logistic regression to compare absences from 2002 to 2011 between workers with BeS or CBD to those without, and survival analysis to compare time to first absence by beryllium sensitization status. Finally, we examined beryllium status by occupational group. Results. Fewer than 3% of the 19,305 workers were BeS, and workers with BeS or CBD had more total absences (odds ratio [OR] = 1.31; 95% confidence interval [CI] = 1.18, 1.46) and respiratory absences (OR = 1.51; 95% CI = 1.24, 1.84) than did other workers. Time to first absence for all causes and for respiratory conditions occurred earlier for workers with BeS or CBD than for other workers. Line operators and crafts personnel were at increased risk for BeS or CBD. Conclusions. Although not considered "diseased," workers with BeS have higher absenteeism compared with nonsensitized workers.

Unsuspected exposure to beryllium: potential implications for sarcoidosis diagnoses.

Exposure to Beryllium (Be) can cause sensitization (BeS) and chronic beryllium disease (CBD) in some individuals.  Even relatively low exposures may be sufficient to generate an asymptomatic, or in some cases a symptomatic, immune response. Since the clinical presentation of CBD is similar to that of sarcoidosis, it is helpful to have information on exposure to beryllium in order to reduce misdiagnosis. The purpose of this pilot study is to explore the occurrence of Be surface deposits at worksites with little or no previous reported use of commercially available Be products.  The workplaces chosen for this study represent a convenience sample of businesses in eastern Iowa. One hundred thirty-six surface dust samples were collected from 27 businesses for analysis of Be. The results were then divided into categories by the amount of detected Be according to U.S. Department of Energy guidelines as described in 10 CFR 850.30 and 10 CFR 850.31. Overall, at least one of the samples at 78% of the work sites tested contained deposited Be above the analytical limit of quantitation (0.035 µg beryllium per sample).  Beryllium was detected in 46% of the samples collected. Twelve percent of the samples exceeded 0.2 µg/100 cm² and 4% of the samples exceeded a Be concentration of 3 µg/100 cm². The findings from this study suggest that there may be a wider range and greater number of work environments that have the potential for Be exposure than has been documented previously.  These findings could have implications for the accurate diagnosis of sarcoidosis.

Our perspective of the treatment of naevus of Ota with 1,064-, 755- and 532-nm wavelength lasers.

Naevus of Ota (NO) is a disfiguring pigmentary disorder affecting the face. Q-switched neodymium-doped yttrium aluminium garnet (QS Nd:YAG)-1,064 nm is a standard laser treatment because it causes highly selective destruction of melanin within the aberrant dermal melanocytes. However, not all lesions respond. This study aims to evaluate the efficacy/safety of QS Nd:YAG-1,064 nm and the shorter wavelength QS Alexandrite-755 nm and QS Nd:YAG-532 nm lasers in treating NO. Data were evaluated from 21 patients treated in our laser centre from 2004 to 2012. Lesional skin was irradiated with QS-532 nm/QS-755 nm/QS-1,064 nm, with settings titrated according to responses. All received initial test patches to direct initial wavelength choice, with subsequent treatments at 3-monthly intervals until clearance/lack of further response. Laser modality was switched following repeated test patches if there was no or no sustained improvement. Two thirds of patients had ≥ 90% improvement compared to baseline photographs. In 20% of patients, QS-1,064 nm was most efficacious with 97% mean improvement. The mean improvement was 80% for those in whom QS-755 nm was superior, and 90% for QS-532 nm. Median number of overall laser treatments was 8 (range 4-13). Number of treatments required varied significantly according to lesional colour and site: grey lesions and those on the forehead/temple were most resistant. We confirm successful treatment of NO with QS Nd:YAG-1,064 nm and the shorter wavelength QS-755 nm/QS-532 nm lasers without serious or irreversible side effects. We recommend judicious test patch analysis before treatment and a modality switch if complete clearance is not obtained.

Radiological design aspects of the National Ignition Facility.

The National Ignition Facility (NIF) has been designed to accommodate some challenging radiological conditions. The high prompt neutron source (up to 1.6 × 10(19) neutrons per shot) results in the need for significant fixed shielding. Concrete shielding approximately 2 m thick is used for the primary (target bay) shield. Penetrations in this shield, including those required for 192 laser beams, utilities, diagnostics, and 19 shielded personnel access doors, make the design challenging. An additional 28 shield doors are part of the secondary shield. In addition, the prompt neutron pulse results in activated air within the target bay, requiring special ventilation considerations. Finally, targets can use a number of hazardous and radioactive materials including tritium, beryllium, and depleted uranium (the latter of which results in the generation of small quantities of fission products). Frequent access is required to the associated potentially contaminated volumes for experimental setup, facilitating the need for local exhaust ventilation to manage these hazards. This paper reviews some of these challenges, design considerations, and the engineering solutions to these design requirements.

Sparse-data bias accompanying overly fine stratification in an analysis of beryllium exposure and lung cancer risk.

PURPOSE: Beryllium's classification as a carcinogen is based on limited human data that show inconsistent associations with lung cancer. Therefore, a thorough examination of those data is warranted. We reanalyzed data from the largest study of occupational beryllium exposure, conducted by the National Institute of Occupational Safety and Health (NIOSH). METHODS: Data had been analyzed using stratification and standardization. We reviewed the strata in the original analysis, and reanalyzed using fewer strata. We also fit a Poisson regression, and analyzed simulated datasets that generated lung cancer cases randomly without regard to exposure. RESULTS: The strongest association reported in the NIOSH study, a standardized rate ratio for death from lung cancer of 3.68 for the highest versus lowest category of time since first employment, is affected by sparse-data bias, stemming from stratifying 545 lung cancer cases and their associated person-time into 1792 categories. For time since first employment, the measure of beryllium exposure with the strongest reported association with lung cancer, there were no strata without zeroes in at least one of the two contrasting exposure categories. Reanalysis using fewer strata or with regression models gave substantially smaller effect estimates. Simulations confirmed that the original stratified analysis was upwardly biased. Other metrics used in the NIOSH study found weaker associations and were less affected by sparse-data bias. CONCLUSIONS: The strongest association reported in the NIOSH study seems to be biased as a result of non-overlap of data across the numerous strata. Simulation results indicate that most of the effect reported in the NIOSH paper for time since first employment is attributable to sparse-data bias.