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.

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.

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.

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.

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.

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.

Chronic beryllium disease, HLA-DPB1, and the DP peptide binding groove.

Multiple epidemiologic studies demonstrate associations between chronic beryllium disease (CBD), beryllium sensitization (BeS), and HLA-DPB1 alleles with a glutamic acid residue at position 69 (E69). Results suggest that the less-frequent E69 variants (non-*0201/*0202 alleles) might be associated with greater risk of CBD. In this study, we sought to define specific E69-carrying alleles and their amino acid sequences in the DP peptide binding groove, as well as their relationship to CBD and BeS risk, using the largest case control study to date. We enrolled 502 BeS/CBD subjects and 653 beryllium-exposed controls from three beryllium industries who gave informed consent for participation. Non-Hispanic white cases and controls were frequency-matched by industry. HLA-DPB1 genotypes were determined using sequence-specific primer PCR. The E69 alleles were tested for association with disease individually and grouped by amino acid structure using logistic regression. The results show that CBD cases were more likely than controls to carry a non-*02 E69 allele than an *02 E69, with odds ratios (95% confidence interval) ranging from 3.1 (2.1-4.5) to 3.9 (2.6-5.9) (p < 0.0001). Polymorphic amino acids at positions 84 and 11 were associated with CBD: DD versus GG, 2.8 (1.8-4.6), p < 0.0001; GD versus GG, 2.1 (1.5-2.8), p < 0.0001; LL versus GG, 3.2 (1.8-5.6), p < 0.0001; GL versus GG, 2.8 (2.1-3.8), p < 0.0001. Similar results were found within the BeS group and CBD/BeS combined group. We conclude that the less frequent E69 alleles confer more risk for CBD than does *0201. Recent studies examining how the composition and structure of the binding pockets influence peptide binding in MHC genes, as well of studies showing the topology of the TCR to likely bind DPB1 preferentially, give plausible biological rationale for these findings.

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.

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.

CD27 expression on CD4+ T cells differentiates effector from regulatory T cell subsets in the lung.

Beryllium exposure in the workplace can result in chronic beryllium disease, a granulomatous lung disorder characterized by CD4(+) T cell alveolitis and progressive lung fibrosis. A large number of the CD4(+) T cells recruited to the lung in chronic beryllium disease recognize beryllium in an Ag-specific manner and express Th1-type cytokines following T cell activation. Beryllium-responsive CD4(+) T cells in the bronchoalveolar lavage (BAL) express an effector memory T cell phenotype and recognize beryllium in a CD28-independent manner. In this study, we show that the majority of beryllium-responsive CD4(+) T cells in BAL have lost CD27 expression, whereas a subset of beryllium-responsive cells in blood retains expression of this costimulatory molecule. In addition, loss of CD27 on BAL CD4(+) T cells inversely correlates with markers of lung inflammation. A small population of BAL CD4(+) T cells retains CD27 expression, and these CD4(+)CD27(+) T cells contain the FoxP3-expressing, naturally occurring regulatory T (T(reg)) cell subset. Coexpression of CD27 and CD25 identifies the majority of FoxP3-expressing T(reg) cells in blood and BAL, and these cells express potent suppressor function. Taken together, these findings suggest that CD27 is differentially expressed between effector T cells from the inflamed lung and can be used in conjunction with CD25 to isolate T(reg) cells and assess their functional capacity in an ongoing adaptive immune response in a target organ.

Search for chronic beryllium disease among sarcoidosis patients in Ontario, Canada.

Chronic beryllium disease (CBD) is clinically similar to other granulomatous diseases such as sarcoidosis. It is often misdiagnosed if a thorough occupational history is not taken. When appropriate, a beryllium lymphocyte proliferation tests (BeLPT) need to be performed. We aimed to search for CBD among currently diagnosed pulmonary sarcoidosis patients and to identify the occupations and exposures in Ontario leading to CBD. Questionnaire items included work history and details of possible exposure to beryllium. Participants who provided a history of previous work with metals underwent BeLPTs and an ELISPOT on the basis of having a higher pretest probability of CBD. Among 121 sarcoid patients enrolled, 87 (72%) reported no known previous metal dust or fume exposure, while 34 (28%) had metal exposure, including 17 (14%) with beryllium exposure at work or home. However, none of these 34 who underwent testing had positive test results. Self-reported exposure to beryllium or metals was relatively common in these patients with clinical sarcoidosis, but CBD was not confirmed using blood assays in this population.

Contact allergy to beryllium chloride: report of 12 cases.

BACKGROUND: Isolated cases of allergic contact dermatitis, gingivitis and stomatitis caused by beryllium have been previously reported. We have been able to study a series of 12 patients with patch test reactions to beryllium chloride. OBJECTIVES: The study was aimed at defining the clinical and patch testing characteristics in this group of patients, and determining whether some were delayed elicitation reactions or late reactions of active sensitizations by patch testing. MATERIAL AND METHODS: We performed a 5-year retrospective study of patients tested with a metal series, and studied a subgroup who showed reactions to beryllium chloride. RESULTS: A total of 1799 patients were patch tested, 62 of whom were also tested with a specific metal series; 12 of them reacted to beryllium chloride. Eight of the 12 patients showed reactions to other metals. Based on the time of positive reaction to beryllium chloride, three patterns emerged: (i) 3 patients showed positive reactions on D2-D4; (ii) 6 patients showed positive reactions between D7 and D10; and (iii) 3 patients showed positive reactions later than D10. CONCLUSIONS: Contact allergy to beryllium chloride may not be as unusual as the literature suggests. In order to avoid undetected contact allergies, we recommend performing later readings, between D7 and D10, whenever patch testing is performed with beryllium chloride. Active sensitization may occur.

[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.

Long-term follow-up of beryllium sensitized workers from a single employer.

BACKGROUND: Up to 12% of beryllium-exposed American workers would test positive on beryllium lymphocyte proliferation test (BeLPT) screening, but the implications of sensitization remain uncertain. METHODS: Seventy two current and former employees of a beryllium manufacturer, including 22 with pathologic changes of chronic beryllium disease (CBD), and 50 without, with a confirmed positive test were followed-up for 7.4 +/-3.1 years. RESULTS: Beyond predicted effects of aging, flow rates and lung volumes changed little from baseline, while DLCO dropped 17.4% of predicted on average. Despite this group decline, only 8 subjects (11.1%) demonstrated physiologic or radiologic abnormalities typical of CBD. Other than baseline status, no clinical or laboratory feature distinguished those who clinically manifested CBD at follow-up from those who did not. CONCLUSIONS: The clinical outlook remains favorable for beryllium-sensitized individuals over the first 5-12 years. However, declines in DLCO may presage further and more serious clinical manifestations in the future. These conclusions are tempered by the possibility of selection bias and other study limitations.

Beryllium sensitivity among workers at a Norwegian aluminum smelter.

BACKGROUND: Sensitivity to beryllium was investigated among workers at an aluminum smelter in Norway as a consequence of the findings in an occupational exposure survey. METHODS: Three hundred and sixty-two employees and 31 reference persons were tested for sensitization to beryllium with the beryllium lymphocyte proliferation test (BeLPT) based on specifications by the US Department of Energy in 2001. The results are reported as abnormal, borderline, or normal. RESULTS: One person (0.28%) from the aluminum smelter was found to have abnormal results in two separate blood samples and is sensitized to beryllium. Three other persons had one abnormal test that was not confirmed by a second test. One person in the reference group had one abnormal and one normal test result. No borderline samples were detected. None of the employees with one or more abnormal sample results had pot room asthma. The sensitized individual worked in a Soederberg line in 1972-1974. The beryllium concentration in the work atmosphere is estimated to have been similar as today (0.1-0.3 microg/m(3)), but work routines, etc. would cause higher total exposures. CONCLUSIONS: Only one sensitized person of 362 is in line with what is found in other studies in the aluminum industry. The low number, compared with the beryllium handling industry, may be attributable to lower work atmosphere concentrations, beryllium speciation effects, or use of respiratory protection equipment. Pot room asthma does not appear to be associated with beryllium sensitization.

Toxic metal fumes from mantle-type camp lanterns.

The mantle of a gas lantern contains about 600 micrograms of toxic beryllium metal. Most of the beryllium is volatilized and becomes airborne during the first 15 minutes of use of a new mantle. The inhalation of this quantity of beryllium can be hazardous.

HLA-DPB1 glutamate 69: a genetic marker of beryllium disease.

Chronic beryllium disease (CBD) is a lung disorder related to beryllium exposure and is characterized by the accumulation in the lung of beryllium-specific CD4+ major histocompatibility complex (MHC) class II-restricted T lymphocytes. Evaluation of MHC class II genes in 33 CBD cases and 44 controls has shown a negative association with HLA-DPB1*0401 (P < 0.001) and a positive association with HLA-DPB1*0201 (P < 0.05) alleles, which differ at residues 36, 55 to 56, and 69 of the beta 1 chain. Among CBD cases, 97 percent expressed the HLA-DPB1*0201-associated glutamic acid (unaffected population, 30 percent; P < 0.001) at residue 69, a position involved in susceptibility to autoimmune disorders. This suggests that HLA-DP has a role in conferring susceptibility and that residue 69 of HLA-DPB1 could be used in risk assessment for CBD.

Beryllium hypersensitivity and chronic beryllium lung disease.

PURPOSE OF REVIEW: This review aims to present the clinician with a synthesis of recent studies that have enhanced our understanding of the epidemiology and pathogenesis of beryllium hypersensitivity (BeH) and chronic beryllium disease (CBD). RECENT FINDINGS: Lower occupational limit levels to beryllium exposure and more stringent preventive measures can decrease the risk for development of BeH and CBD. Beryllium sensitization is determined by a positive beryllium lymphocyte proliferation test (BeLPT). Longitudinal data suggest that BeH progresses to CBD. Together with a comprehensive history the BeLPT may help identify berylliosis in patients erroneously diagnosed to have sarcoidosis. HLA-DPB1-Glu69 marker is associated with increased susceptibility to development of BeH and CBD but poor positive predictive value limits its use; other genetic markers are being investigated. Recent investigations augment our understanding on the role of T-lymphocytes and chemokines in the pathogenesis of beryllium-associated disease. However, the basis for treatment strategies remains scarce. SUMMARY: Our enhanced understanding of beryllium-associated lung disease potentially provides a window to unraveling other granulomatous diseases. However, even more questions beg to be elucidated and additional efforts are needed to translate this body of knowledge into better prevention and treatment.