Health Effects of Beryllium Exposure A Literature Review (2007) / Chapter Skim
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3 Sensitization and Chronic Beryllium Disease
3 Sensitization and Chronic Beryllium Disease
Pages 32-59
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From page 32... ...
EPIDEMIOLOGY AND CLINICAL DISEASE Exposure to beryllium can cause two distinct types of pulmonary disease, a pneumonitis referred to as acute beryllium disease and a chronic granulomatous disease called CBD. Acute beryllium disease, first reported in the 1930s, was observed in beryllium workers and was characterized by the onset of respiratory symptoms usually over several weeks.
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From page 33... ...
By 1948, the known cases totaled more than 400, and the basic clinical features of the disease were understood. It was established that the risk of disease among beryllium workers rose with the intensity of airborne exposure and that risk varied with the physicochemical properties of the beryllium exposure (Machle et al.
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From page 34... ...
1993b Cross-sectional 1.9% 1.7% No Stratified random sample with probable beryllium exposure Stange et al. 1996b Longitudinal 2.4% 0.7% No Current and former workers Stange et al.
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From page 35... ...
Bertrandite ore (containing an average of 0.23% beryllium) is mined at the Utah facility, and an extraction mill at the same site produces beryllium hydroxide, which is shipped elsewhere to be made into beryllium oxide ceramics and beryllium metal.
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Beryllium Oxide Ceramics Beryllium oxide ceramics production workers in two facilities have been studied: one that produced ceramics until 1975 (Kreiss et al.
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Despite their limitations, they provide useful data on risks in a fairly large and diverse group of workers in the nuclear industry. BeS and CBD were reported in each of the studies in workers who handled beryllium metal and alloy and in those who performed various tasks involved in cleaning up former weapons facilities where beryllium was handled.
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From page 38... ...
Cumulative and average exposure estimates were fit to case-control status in logistic-regression models. There was strong evidence of increasing risk of CBD with increasing beryllium exposure, particularly as measured by cumulative exposure.
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From page 39... ...
. BeS has also been produced in mice by skin exposure to beryllium oxide particles (Tinkle et al.
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From page 40... ...
The BeLPT, like other cell-culture assays, is associated with intratest, intertest, and interlaboratory variability; therefore, a positive, or abnormal, BeLPT result is generally confirmed with a second analysis, either by testing of the same blood sample in a different laboratory or by testing of a later sample before the subject is considered sensitized. The BeLPT of peripheral blood or BAL cells is used as part of the diagnostic workup of patients who have interstitial lung disease and possible beryllium exposure when CBD is in the differential diagnosis.
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From page 41... ...
Presentation and Diagnosis of and Testing for CBD Clinically, CBD can be difficult to distinguish from sarcoidosis and other interstitial lung diseases, especially if, as is common, the history of beryllium exposure is not obtained. Since its pathogenesis involves a beryllium-specific, cell-mediated immune response, CBD cannot occur without sensitization.
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From page 42... ...
CBD presents as a clinical spectrum in sensitized people that ranges from the presence of granulomas on lung biopsy without respiratory symptoms, radiographic abnormalities, or decrements in pulmonary-function or exercise tests to end-stage lung disease with severe dyspnea, severe pulmonary function changes, radiographic changes, arterial oxygen desaturation, and cor pulmonale. Between those extremes, there may be mild to severe changes in one or more of the tests.
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From page 43... ...
A study of 21 patients with CBD (defined as beryllium exposure, consistent biopsy results, and abnormal BeLPT results) identified through screening at their plants showed that 14 had normal pulmonary-function test results and 10 had normal physiologic measures on maximal exercise (Pappas and Newman 1993)
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From page 44... ...
Possible risk factors for progression that have not been systematically assessed include smoking status, race, sex, genetic factors, exposure duration, magnitude and type of beryllium exposure (including particle size and solubility) , concurrent exposures, and life stresses, such as pregnancy and lactation, combat, and surgery (Newman 1996)
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From page 45... ...
A case presentation at the 2005 International Beryllium Disease Conference in Montreal described a young man with subclinical disease that resulted in job loss, major reactive depression, and unemployment (S. Tarlo, University of Toronto, personal commun., April 23, 2007)
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From page 46... ...
Any estimate of the rate of a confirmed abnormal BeLPT in people with no exposure to beryllium is confounded by the fact that CBD (and hence a sensitivity to beryllium) has been found after relatively low exposures, and that there is no independent measure of beryllium exposure.
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From page 47... ...
. Two observations illustrate the primary importance of CD4+ T cells in the pathogenesis of CBD: the development of granulomatous inflammation in the lung is associated with the accumulation of CD4+ T cells in the BAL fluid, and sensitization to beryllium is detected in the ability of CD4+ T cells to proliferate in response to beryllium salts in culture.
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From page 48... ...
In many people, particularly CBD patients in the ceramics industry exposed to beryllium oxides, the T cells found in the BAL fluid express TCRBV3 genes with identical or homologous complementary-determining region 3 sequences. As further evidence that these are oligoclonal expansions, the beryllium-responsive T cells coexpress only a few homologous TCRα genes (Fontenot et al.
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From page 49... ...
(2005) reported that dissolution of beryllium oxide particles in macrophage phagolysosomes may be an important source of dissolved beryllium for input to the cell-mediated immune reaction characteristic of beryllium disease.
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Beryllium-Sensitization Progression to Chronic Beryllium Disease The immunologic mechanisms underlying the progression from BeS to CBD are not well understood. Beryllium-sensitized people demonstrate a beryllium-specific immune response and show no evidence of lung disease.
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From page 51... ...
that are involved in antigen presentation and processing. The notion of a role of these genes in CBD arose from experiments that used lymphocytes derived from blood and BAL fluid of patients with the disease.
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was expressed in 97% of the CBD patients examined and 30% of the controls. HLA-DPB1 Glu69 appeared to be a definitive marker of susceptibility to beryllium disease.
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TABLE 3-2 Summary of Association Studies on HLA-DPB1 Glu69 and TNF-α As Susceptibility Factors in Chronic Beryllium Disease and Beryllium Sensitization HomozyAuthor N Frequency gocity Alleles HLA-DPB1 Glu69 Glu69 Richeldi et al. 1993 CBD 33 97% N/A 0201: 52% Controls 44 30% 18% Richeldi et al.
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. The process appears to be transcription-dependent, in that beryllium exposure specifically upregulates the AP-1 and NF-κB transcription factors (Sawyer et al.
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From page 55... ...
They reported that the high TNF-α-producing variant was present at increased frequency in CBD patients in the United States but not in those in Europe and Israel, but it is likely that the two groups had different beryllium exposure and disease severity. Recent large-scale studies have cast doubt on earlier findings of the importance of TNF-α polymorphisms in CBD.
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From page 56... ...
. The distribution of radioactive beryllium oxide and beryllium sulfate instilled in the lungs of guinea pigs (strain 13 and albino)
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BAL fluid had increased numbers of inflammatory cells and enzyme concentrations. The authors concluded that human CBD is "an immunologically mediated granulomatous lung disease, whereas beryllium-induced lung lesions in rats appear to be due to direct chemical toxicity and foreign-body-type reactions" (p.
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From page 58... ...
or beryllium metal by bronchoscopic instillation. Lymphocytes were increased in the BAL fluid after 14, 30, or 90 days in monkeys treated with beryllium metal and after 60 days in monkeys treated with beryllium oxide.
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From page 59... ...
There are currently no adequate animal models of CBD. However, efforts are under way to create mouse models with human alleles associated with a range of BeS and CBD risk that may be useful in experimental study of beryllium dose-response, beryllium type and characteristics conferring risk, dose rate, and therapeutic approaches to beryllium diseases.
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