Beryllium Lymphocyte Proliferation Test Research Articles

Beryllium sensitivity among workers at a Norwegian aluminum smelter

Sensitivity to beryllium was investigated among workers at an aluminum smelter in Norway as a consequence of the findings in an occupational exposure survey. 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. 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. 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.

Beryllium contamination and exposure monitoring in an inhalation laboratory setting

Beryllium (Be) is used in several forms: pure metal, beryllium oxide, and as an alloy with copper, aluminum, or nickel. Beryllium oxide, beryllium metal, and beryllium alloys are the main forms present in the workplace, with inhalation being the primary route of exposure. Cases of workers with sensitization or chronic beryllium disease challenge the scientific community for a better understanding of Be toxicity. Therefore, a toxicological inhalation study using a murine model was performed in our laboratory in order to identify the toxic effects related to different particle sizes and chemical forms of Be. This article attempts to provide information regarding the relative effectiveness of the environmental monitoring and exposure protection program that was enacted to protect staff (students and researchers) in this controlled animal beryllium inhalation exposure experiment. This includes specific attention to particle migration control through intensive housekeeping and systematic airborne and surface monitoring. Results show that the protective measures applied during this research have been effective. The highest airborne Be concentration in the laboratory was less than one-tenth of the Quebec OEL (occupational exposure limit) of 0.15 microg/m(3). Considering the protection factor of 10(3) of the powered air-purifying respirator used in this research, the average exposure level would be 0.03 x 10(- 4) microg/m(3), which is extremely low. Moreover, with the exception of one value, all average Be concentrations on surfaces were below the Quebec Standard guideline level of 3 microg/100 cm(2) for Be contamination. Finally, all beryllium lymphocyte proliferation tests for the staff were not higher than controls.

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

BackgroundUp to 12% of beryllium-exposed American workers would test positive on beryllium lymphocyte proliferation test (BeLPT) screening, but the implications of sensitization remain uncertain.MethodsSeventy 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.ResultsBeyond 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.ConclusionsThe 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.

Advances in Identifying Beryllium Sensitization and Disease

Beryllium is a lightweight metal with unique qualities related to stiffness, corrosion resistance, and conductivity. While there are many useful applications, researchers in the 1930s and l940s linked beryllium exposure to a progressive occupational lung disease. Acute beryllium disease is a pulmonary irritant response to high exposure levels, whereas chronic beryllium disease (CBD) typically results from a hypersensitivity response to lower exposure levels. A blood test, the beryllium lymphocyte proliferation test (BeLPT), was an important advance in identifying individuals who are sensitized to beryllium (BeS) and thus at risk for developing CBD. While there is no true “gold standard” for BeS, basic epidemiologic concepts have been used to advance our understanding of the different screening algorithms.

Non-invasive diagnosis of chronic beryllium disease in workers exposed to hazardous dust in Israel

ObjectivesChronic beryllium disease (CBD) is caused by prolonged occupational exposure to beryllium and is characterised by various clinical presentations, mostly pulmonary. The inflammatory process involves non-caseous granulomas and proliferation of...

Efficacy of a Program to Prevent Beryllium Sensitization among New Employees at a Copper-Beryllium Alloy Processing Facility

In 2000, 7% of workers at a copper-beryllium facility were beryllium sensitized. Risk was associated with work near a wire annealing/pickling process. The facility then implemented a preventive program including particle migration control, respiratory and dermal protection, and process enclosure. We assessed the program's efficacy in preventing beryllium sensitization. In 2000, the facility began testing new hires (program workers) with beryllium lymphocyte proliferation tests (BeLPTs) at hire and at intervals during employment. We compared sensitization incidence rates (IRs) and prevalence rates for workers hired before the program (legacy workers) with rates for program workers, including program worker subgroups. We also examined trends in BeLPTs from a single laboratory. In all, five of 43 legacy workers (IR = 3.8/1,000 person-months) and three of 82 program workers (IR = 1.9/1,000 person-months) were beryllium sensitized, for an incidence rate ratio (IRR) of 2.0 (95% confidence interval [CI] 0.5, 10.1). Two of 37 pre-enclosure program workers (IR = 2.4/1,000 person-months) and one of 45 post-enclosure program workers (IR = 1.4/1,000 person-months) were beryllium sensitized, for IRRs of 1.6 (95% CI 0.3, 11.9) and 2.8 (95% CI 0.4, 66.2), respectively, compared with legacy workers. Test for trend in prevalence rates was significant. Among 2,159 first-draw BeLPTs during 95 months, we identified seven months when high numbers of redraws were required, with one possible misclassification in this facility. Fewer workers became sensitized after implementation of the preventive program. However, low statistical power due to the facility's small workforce prevents a definitive conclusion about the program's efficacy. These findings have implications for other copper-beryllium facilities, where program components may merit application.

A Reconsideration of Acute Beryllium Disease

ContextAlthough chronic beryllium disease (CBD) is clearly an immune-mediated granulomatous reaction to beryllium, acute beryllium disease (ABD) is commonly considered an irritative chemical phenomenon related to high exposures. Given reported new cases of ABD and projected increased demand for beryllium, we aimed to reevaluate the patho physiologic associations between ABD and CBD using two cases identified from a survey of beryllium production facility workers.Case PresentationWithin weeks after exposure to beryllium fluoride began, two workers had systemic illness characterized by dermal and respiratory symptoms and precipitous declines in pulmonary function. Symptoms and pulmonary function abnormalities improved with cessation of exposure and, in one worker, recurred with repeat exposure. Bronchoalveolar lavage fluid analyses and blood beryllium lymphocyte proliferation tests revealed lymphocytic alveolitis and cellular immune recognition of beryllium. None of the measured air samples exceeded 100 μg/m3, and most were < 10 μg/m3, lower than usually described. In both cases, lung biopsy about 18 months after acute illness revealed noncaseating granulomas. Years after first exposure, the workers left employment because of CBD.DiscussionContrary to common understanding, these cases suggest that ABD and CBD represent a continuum of disease, and both involve hypersensitivity reactions to beryllium. Differences in disease presentation and progression are likely influenced by the solubility of the beryllium compound involved.Relevance to PracticeABD may occur after exposures lower than the high concentrations commonly described. Prudence dictates limitation of further beryllium exposure in both ABD and CBD.

Beryllium hypersensitivity and chronic beryllium lung disease

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). 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. 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.

Use of proliferation tests to evaluate the effects of complexing agents on beryllium toxicity

Occupational exposure to beryllium may cause chronic beryllium disease (CBD), a granulomatous interstitial pneumonitis caused by a cell-mediated immune response with delayed hypersensitivity initiated by an electrostatic interaction with the MHC class II human leukocyte antigen (HLA). Increased research efforts focus on the development of a CBD treatment by chelation therapy. This work presents an in vitro evaluation of the beneficial effects of beryllium chelation with different organic substrates. We have used a standard beryllium lymphocyte proliferation test (BeLPT) adapted for mouse splenocytes. Three complexing agents, 4,5-dihydroxy-1,3-benzenedisulfonic acid (tiron), nitrilotripropionic acid (NTP) and nitrilotriacetic acid (NTA), were tested using different protocols of the splenocyte proliferation test (SPT). We studied their corrective effect (beryllium pre-exposed splenocytes), their protective effect (ligand pre-exposed splenocytes) and their combined effects at fixed Be:L ratio of 1:2, at fixed Be concentration and at fixed L concentration. We also studied the effect of tiron in preventing splenocyte sensitization to beryllium. All three complexing agents showed a corrective effect and proved efficient in the combined effects, except NTA in the fixed Be:L ratio. Only NTP and tiron showed a significant protection at lower beryllium concentrations, while NTA was not significant. Splenocytes pre-exposed to chelated beryllium did not show sensitization while splenocytes pre-exposed to beryllium were sensitized. We observed a strong correlation between the efficiency of the complexing agent and its affinity towards beryllium. Both tiron and NTP showed a similar affinity towards the beryllium ion that is 10(7) higher than that of NTA.

Justification for screening for chronic beryllium disease: closer to reality

Chronic beryllium disease (CBD) appeared to be waning 30 yrs ago 1. In 1980, less than one case per year was reported and the incidence rate per ton of beryllium produced had declined from between five and 10, to less than 0.001. CBD appeared to be heading toward the medical archives as a success story of environmental control in the absence of understanding of the pathogenesis of the disease. However, in 1982, an immunological test performed on lymphocytes recovered from the bronchoalveolar lavage fluid demonstrated a marked increased in the number of beryllium-sensitive cells in the lung compared to the blood, strongly suggesting that CBD was a hypersensitivity to beryllium 2. The findings of that initial study were confirmed in larger studies 3 and by different investigators 4, 5. Around 10 yrs later, an immunological test (the beryllium lymphocyte proliferation test (BeLPT)) was initially used in cross-sectional studies and later in the surveillance and screening of current and former beryllium workers 6–8. Those studies demonstrated that CBD was not heading for the medical archives, but that the disease was present in much greater numbers than previously reported due to misdiagnosis of overt cases and the detection of early and …

Immunology of chronic beryllium disease

This review discusses the immunology of chronic beryllium disease. It addresses the importance of the interaction between class II molecules and the T cells that recognize beryllium, along with the subsequent immune response that results in sensitization and disease, and genetic factors leading to variation in this response. HLA-DPB1 with a glutamic acid at amino acid position 69 (Glu69) confers increased risk of beryllium sensitization and is not specific for chronic beryllium disease. The degree of negative surface charge of the molecule may increase risk of chronic beryllium disease but not sensitization. In the absence of Glu69, HLA-DRB1 alleles may function in beryllium presentation, increasing the risk of chronic beryllium disease. The T-cell response as assessed by the beryllium lymphocyte proliferation test is dependent on central memory T-cells, while Th1 cytokine secretion leading to granulomatous inflammation and chronic beryllium disease is dependent on the activity of effector memory T cells. Polymorphisms in cytokine genes, such as the TGF-beta1 gene, also affect the risk of chronic beryllium disease and more severe disease. The current diagnostic criteria for sensitization and chronic beryllium disease rely on the beryllium lymphocyte proliferation test. By understanding the novel immunologic mechanisms and genetic factors associated with sensitization and chronic beryllium disease, we may improve our ability to detect beryllium health effects with new diagnostics, and hopefully refine therapies for disease.

Immunological Responses in a Murine Model Following Inhalation Exposure to Be Metal, BeO, and AlBe

RationaleChronic beryllium disease (CBD) is a progressive granulomatous lung disease and characterized by mononuclear cell infiltration and granulomatous inflammation in the lung. Affected individuals have a Be-specific hypersensitivity response involving CD4+ T-lymphocytes and production of Th1 type cytokines.MethodsC3H/HeJ mice were exposed to Be metal, BeO, and AlBe, total and respirable particles. Beryllium lymphocyte proliferation test (BeLPT) was used to explore the presence of Be-specific immune responses in spleen. Cytokine assays were performed in bronchoalveolar lavage. Flow cytometry analysis was conducted to determine expression of T cell and intracellular IFN-γ. Standard histology of lung was used to explore cellular infiltration and granulomatous inflammation.ResultsExposure to Be compounds led to marked pulmonary inflammation. The expression of CD4+, CD8+, and IFN-γ stained with florescence labelled antibodies indicated a significantly greater expression among Be metal, BeO, and AlBe exposed mice, particularly respirable particles. Proliferation response as Stimulation Index was significantly higher for Be exposed mice than control. Cytokine assays of bronchoalveolar lavage revealed significant increased level of Th1 type cytokines including IL-2, TNF-α, and IFN-γ for mice exposed to Be compounds compared to control, predominantly respirable particles.ConclusionsCytokines production, expression of CD4+, and lung inflammation are in correlation with the immunological effects being seen in human with CBD. Our findings suggest that respirable particles may induce more pronounced immunological effects than total. This study provide a novel model as a basis for further study to investigate the importance role of particle size for identify a scientifically based threshold to protect workers against CBD. RationaleChronic beryllium disease (CBD) is a progressive granulomatous lung disease and characterized by mononuclear cell infiltration and granulomatous inflammation in the lung. Affected individuals have a Be-specific hypersensitivity response involving CD4+ T-lymphocytes and production of Th1 type cytokines. Chronic beryllium disease (CBD) is a progressive granulomatous lung disease and characterized by mononuclear cell infiltration and granulomatous inflammation in the lung. Affected individuals have a Be-specific hypersensitivity response involving CD4+ T-lymphocytes and production of Th1 type cytokines. MethodsC3H/HeJ mice were exposed to Be metal, BeO, and AlBe, total and respirable particles. Beryllium lymphocyte proliferation test (BeLPT) was used to explore the presence of Be-specific immune responses in spleen. Cytokine assays were performed in bronchoalveolar lavage. Flow cytometry analysis was conducted to determine expression of T cell and intracellular IFN-γ. Standard histology of lung was used to explore cellular infiltration and granulomatous inflammation. C3H/HeJ mice were exposed to Be metal, BeO, and AlBe, total and respirable particles. Beryllium lymphocyte proliferation test (BeLPT) was used to explore the presence of Be-specific immune responses in spleen. Cytokine assays were performed in bronchoalveolar lavage. Flow cytometry analysis was conducted to determine expression of T cell and intracellular IFN-γ. Standard histology of lung was used to explore cellular infiltration and granulomatous inflammation. ResultsExposure to Be compounds led to marked pulmonary inflammation. The expression of CD4+, CD8+, and IFN-γ stained with florescence labelled antibodies indicated a significantly greater expression among Be metal, BeO, and AlBe exposed mice, particularly respirable particles. Proliferation response as Stimulation Index was significantly higher for Be exposed mice than control. Cytokine assays of bronchoalveolar lavage revealed significant increased level of Th1 type cytokines including IL-2, TNF-α, and IFN-γ for mice exposed to Be compounds compared to control, predominantly respirable particles. Exposure to Be compounds led to marked pulmonary inflammation. The expression of CD4+, CD8+, and IFN-γ stained with florescence labelled antibodies indicated a significantly greater expression among Be metal, BeO, and AlBe exposed mice, particularly respirable particles. Proliferation response as Stimulation Index was significantly higher for Be exposed mice than control. Cytokine assays of bronchoalveolar lavage revealed significant increased level of Th1 type cytokines including IL-2, TNF-α, and IFN-γ for mice exposed to Be compounds compared to control, predominantly respirable particles. ConclusionsCytokines production, expression of CD4+, and lung inflammation are in correlation with the immunological effects being seen in human with CBD. Our findings suggest that respirable particles may induce more pronounced immunological effects than total. This study provide a novel model as a basis for further study to investigate the importance role of particle size for identify a scientifically based threshold to protect workers against CBD. Cytokines production, expression of CD4+, and lung inflammation are in correlation with the immunological effects being seen in human with CBD. Our findings suggest that respirable particles may induce more pronounced immunological effects than total. This study provide a novel model as a basis for further study to investigate the importance role of particle size for identify a scientifically based threshold to protect workers against CBD.

Recent Chronic Beryllium Disease in Residents Surrounding a Beryllium Facility

Between 1948 and 1969, cases of community-acquired chronic beryllium disease (CA-CBD) were reported in neighborhoods surrounding beryllium facilities. Further surveillance was not performed in these communities, and additional cases have not been reported. To increase awareness of recently diagnosed cases of CA-CBD in residents surrounding a beryllium facility. Medical records were reviewed from individuals in a community surrounding a beryllium manufacturing facility in Reading, Pennsylvania. Definite cases of CBD required (1) an abnormal beryllium lymphocyte proliferation test in blood or bronchoalveolar lavage and (2) biopsy evidence of granulomatous inflammation. Probable cases of CBD either displayed an abnormal blood test to beryllium and radiographic evidence consistent with disease, or met epidemiologic criteria for CBD based on the Beryllium Case Registry criteria. Cases with occupational or potential paraoccupational exposure were excluded. Sixteen cases of potential community-acquired CBD were evaluated. From these, eight cases of community-acquired CBD were identified (five definite and three probable). The cases' initial year of residence began between 1943 and 1953 and continued until 1956-2001. Six of the eight cases required medical treatment and three of the cases died since diagnosis. Cases of CBD meeting current immunologic diagnostic criteria and attributable to industry-associated environmental exposure were detected among residents of a community surrounding a beryllium manufacturing facility. Most were diagnosed years after exposure cessation. The frequency and extent of beryllium disease in this community are unknown. We anticipate that not only have cases been misdiagnosed in this community but that more cases of CBD will be diagnosed in the future.

Optimizing BeLPT criteria for beryllium sensitization

The beryllium lymphocyte proliferation test (BeLPT) is used to identify persons sensitized to beryllium. ATSDR convened an expert panel of physicians and scientists in April 2006 to discuss this test and to consider what BeLPT test results actually establish beryllium sensitization. The three criteria proposed by panel members were (1)one abnormal result, (2)one abnormal and one borderline result, and (3)two abnormal results. Complete algorithms were developed for each of the three proposed criteria. Using single-test outcome probabilities developed by Stange et al. [2004. Am J Ind Med 46:453-462], we calculated and compared the sensitivity, specificity, and positive predictive values (PPVs) for each set of criteria. The overall sensitivity and specificity of the three criteria were similar. When the criteria required confirmation of an abnormal result the PPV was higher--whether the requirement was satisfied by a borderline result, or only by another abnormal result. Confirmation also reduced the likelihood of false positives. The differences between the three criteria decreased as the prevalence of sensitization increased. A single unconfirmed abnormal is usually insufficient to establish sensitization for an apparently healthy person. When the prevalence of beryllium sensitization in a group is high, however, even a single abnormal BeLPT can be a strong predictor.

Use of the Beryllium Lymphocyte Proliferation Test (BeLPT) for Screening

Use of the Beryllium Lymphocyte Proliferation Test (BeLPT) for Screening

Assessment of the Beryllium Lymphocyte Proliferation Test: Lessons Learned from a Long-Term Occupational Surveillance Program

Assessment of the Beryllium Lymphocyte Proliferation Test: Lessons Learned from a Long-Term Occupational Surveillance Program

Enhanced preventive programme at a beryllium oxide ceramics facility reduces beryllium sensitisation among new workers

Background: A 1998 survey at a beryllium oxide ceramics manufacturing facility found that 10% of workers hired in the previous 6 years had beryllium sensitisation as determined by the beryllium...

Assessment of the Beryllium Lymphocyte Proliferation Test Using Statistical Process Control

Despite more than 20 years of surveillance and epidemiologic studies using the beryllium blood lymphocyte proliferation test (BeBLPT) as a measure of beryllium sensitization (BeS) and as an aid for diagnosing subclinical chronic beryllium disease (CBD), improvements in specific understanding of the inhalation toxicology of CBD have been limited. Although epidemiologic data suggest that BeS and CBD risks vary by process/work activity, it has proven difficult to reach specific conclusions regarding the dose-response relationship between workplace beryllium exposure and BeS or subclinical CBD. One possible reason for this uncertainty could be misclassification of BeS resulting from variation in BeBLPT testing performance. The reliability of the BeBLPT, a biological assay that measures beryllium sensitization, is unknown. To assess the performance of four laboratories that conducted this test, we used data from a medical surveillance program that offered testing for beryllium sensitization with the BeBLPT. The study population was workers exposed to beryllium at various facilities over a 10-year period (1992–2001). Workers with abnormal results were offered diagnostic workups for CBD. Our analyses used a standard statistical technique, statistical process control (SPC), to evaluate test reliability. The study design involved a repeated measures analysis of BeBLPT results generated from the company-wide, longitudinal testing. Analytical methods included use of (1) statistical process control charts that examined temporal patterns of variation for the stimulation index, a measure of cell reactivity to beryllium; (2) correlation analysis that compared prior perceptions of BeBLPT instability to the statistical measures of test variation; and (3) assessment of the variation in the proportion of missing test results and how time periods with more missing data influenced SPC findings. During the period of this study, all laboratories displayed variation in test results that were beyond what would be expected due to chance alone. Patterns of test results suggested that variations were systematic. We conclude that laboratories performing the BeBLPT or other similar biological assays of immunological response could benefit from a statistical approach such as SPC to improve quality management.

The BeLPT: Algorithms and implications

The beryllium lymphocyte proliferation test (BeLPT) is used to identify persons with beryllium sensitization. The variability of laboratory results and lack of a "gold standard" have led to questions about the test's performance. Fortunately, a recently published study has credibly estimated standard epidemiologic parameters for the BeLPT. Information from this recent study was used to assess the performance of two common algorithms for BeLPT testing. Standard epidemiologic parameters were determined for two common algorithms and then compared. One of the two algorithms was more sensitive than the other (86% vs. 66%). The specificity of both algorithms (99.8% or greater) was high. At an estimated 2% prevalence, the positive predictive value of both algorithms for beryllium sensitization remained high (90% or higher). A priori characterization of the testing algorithm under consideration can enhance public health decision-making.

Immunogenetic factors in beryllium sensitization and chronic beryllium disease

Exposure to beryllium in the workplace can cause beryllium sensitization and chronic beryllium disease. Sensitization to beryllium can be detected in the laboratory using the beryllium lymphocyte proliferation test. It was shown that anti-HLA antibodies could block the beryllium-specific response in the beryllium lymphocyte proliferation test, thereby implicating HLA genes in chronic beryllium disease. A supratypic genetic marker, HLA-DPB1*E69, was found to be strongly associated with immunologic sensitization to beryllium and chronic beryllium disease in beryllium workers. However, there are 40 HLA-DPB1 gene variants that have E69 but that also have other DNA sequence variations. The purpose of the study was to evaluate the evidence for potential differential susceptibility that may be associated with the physical characteristics of HLA protein molecules for which different HLA-DPB1*E69 variants code; that is, do some HLA-DPB1*E69 variants convey higher risk of beryllium sensitization and chronic beryllium disease than others. To do this, two approaches were pursued: first, detailed analysis of the findings from the published literature was performed, and second, computational chemistry was used to seek clues concerning the physical properties of the HLA protein molecules for which these alleles code. Among the 40 HLA-DPB1 gene variants that code for E69, molecular epidemiological studies have suggested a risk hierarchy, where some variants appear to convey low to moderate risk of chronic beryllium disease (e.g., HLA-DPB1*0201, ∼3-fold increased risk), some convey an intermediate risk (e.g., HLA-DPB1*1901, ∼5-fold) and others convey high risk (e.g., HLA-DPB1*1701, >10-fold). Molecular modeling has been used to further investigate a potential mechanistic basis for these observations. We found a strong correlation between the hierarchical order of risk of chronic beryllium disease associated with specific alleles and the predicted surface electrostatic potential and charge of the corresponding isotypes. Therefore, when alleles were grouped by the relative negative charge on the molecules for which they code, the data suggest that those alleles associated with the most negatively charged proteins carry the greatest risk of beryllium sensitization and disease.