Managing Health Effects of Beryllium Exposure (2008) / Chapter Skim
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3 Epidemiologic and Clinical Studies of Beryllium Sensitization and Chronic Beryllium Disease
3 Epidemiologic and Clinical Studies of Beryllium Sensitization and Chronic Beryllium Disease
Pages 52-84
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From page 52... ...
EPIDEMIOLOGIC LITERATURE Exposure to airborne beryllium-containing particles 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 1940s, was observed in beryllium workers and was characterized by the onset of severe respiratory symptoms, usually over several weeks.
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From page 53... ...
The recent epidemiologic literature on BeS and CBD and their clinical presentation, diagnosis, and management are reviewed below. In the United States, acute beryllium disease was first reported in the early 1940s by Van Ordstrand et al.
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From page 54... ...
The committee took into account the results of the older epidemiologic studies, clinical studies, and case series that described clinically diagnosed CBD in the pre-BeLPT era to inform other sections of this chapter (see sections on "Presentation and Diagnosis of and Testing for Chronic Beryllium Disease" and "Progression and Management of Chronic Beryllium Disease")
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From page 55... ...
2006 Cross-sectional 1.1% 1.1% No Workers in three distribution centers Nuclear-weapons industry Rocky Flats nuclear-weapons facility Kreiss et al. 1989 Cross-sectional 11.8% 7.8% No Production, research and development machinists only (Continued)
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From page 56... ...
2004 Cross-sectional 0.8% 0.1% No Decontamination, decommissioning workers only Viet et al. 2000 Case-control N/A N/A Yes Current, former workers Hanford Nuclear Reservation, Oak Ridge Reservation, Savannah River site Welch et al.
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From page 57... ...
Natural History of Beryllium Lung Disease The committee found it useful to summarize the main pathologic processes that lead to CBD in a simplified schematic (Figure 3-1)
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From page 58... ...
There are a number of methodologic issues and differences between the epidemiologic studies, including study design, number of study participants, how exposure was quantified, diversity of physicochemical form of beryllium, genetic susceptibility to CBD, and the healthy-worker effect. The section "Challenges in Interpreting the Epidemiologic Literature on Beryllium Disease" later in this chapter elaborates on some of the challenges to understanding CBD risk and how they limit the interpretability of the epidemiologic studies.
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From page 59... ...
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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From page 60... ...
Many air sampling measurements were available for these workers, and five exposure metrics were estimated for each of the 27 cases; each metric represented a slightly different assumption about which aspect of an exposure profile is most important in predicting risk. For example, three of the five metrics attempted to estimate the time-weighted-average exposure in the year of highest exposure of each worker.
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From page 61... ...
Employment increased in 1996, and a second BeLPT screening was conducted in 1998. A detailed assessment of airborne exposures was carried out at the same time.
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From page 62... ...
of 734) of the workers on the basis of two abnormal BeLPT results.
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From page 63... ...
Those studies were all cross-sectional and based on health surveys of various worker cohorts. They share many of the limitations of other beryllium epidemiologic studies, including less than 100% participation of the target population, loss to followup, and inadequate exposure data or inadequate ability to link exposure data to specific study participants.
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From page 64... ...
BeS was defined on the basis of two abnormal BeLPTs and no evidence of pathologic changes (granulomas or mononuclear cell infiltrates) on transbronchial biopsy.
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From page 65... ...
. Family members of beryllium workers have developed CBD thought to have occurred from contact with contaminated clothing (Lieben and Metzner 1959; Eisenbud and Lisson 1983; Newman and Kreiss 1992)
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From page 66... ...
. Decades ago, workers developed contact dermatitis from skin exposure to soluble beryllium salts, which was confirmed with beryllium skin-patch testing (Curtis 1951)
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From page 67... ...
If skin exposure can lead to sensitization, regulatory standards based on air concentrations, even if very low, may not prevent sensitization. Challenges in Interpreting the Epidemiologic Literature on Beryllium Disease In reviewing the epidemiologic literature on BeS and CBD, the committee often found limitations in the current evidence base that made it difficult to respond confidently to a number of the questions in the committee's charge.
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From page 68... ...
Ideally, studies of beryllium cohorts include BeLPT testing of all cohort members before the first exposure, but that is usually not possible. Often, employment for at least several months precedes the first test, and this may be sufficient time for sensitization to have occurred.
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From page 69... ...
In many cases, however, there are very few quantitative exposure data and many other differences in the studies that make it difficult to reduce them to "natural experiments" with different physicochemical forms of beryllium. Limitations in the Study of Small Exposed Populations Although the estimates of the current numbers of workers exposed to beryllium are in the tens of thousands, workers in facilities with regularly quantifiable exposure are far fewer.
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From page 70... ...
Diagnosis of and Testing for Beryllium Sensitization As described above, beryllium exposure can cause chronic granulomatous disease in the lungs that is associated with the presence of lymphocytes that specifically respond to beryllium. Before the advent of the BeLPT, CBD typically was diagnosed when a worker presented with clinical symptoms and an abnormal chest radiograph or lung function.
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From page 71... ...
. A great majority of patients with CBD have a positive BeLPT result when peripheral blood or BAL cells are used, whereas patients with sarcoidosis or other interstitial lung diseases do not.
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From page 72... ...
At the Third International Conference on Beryllium Disease in October 2007, Brousseau et al. reported on a study of concordance between two laboratories in Quebec when BeLPT testing procedures were closely matched.
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From page 73... ...
. TABLE 3-2 Testing Characteristics in Two Laboratories Performing the BeLPT Characteristic Laboratory A Laboratory B Volume of blood 30 mL 30 mL Anticoagulant Sodium heparin Sodium heparin Transit time 24 h 24 h Gradient Ficoll-Pack Lympholyte H Medium preparation Phosphate-buffered saline Phosphate-buffered saline Culture medium RPMI-1640 RPMI-1640 Mitogen Phytohemagglutinin Phytohemagglutinin (10 µg/mL)
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From page 74... ...
HRCT can detect abnormalities consistent with CBD when a chest radiograph or lung function appears normal. Thus, it can be difficult to determine whether mild disease is truly "subclinical" or constitutes a clinically significant effect; the term subclinical CBD has been used (Kriebel et al.
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From page 75... ...
The pathologic findings are not specific for CBD and may occur in other lung diseases, including sarcoidosis and hypersensitivity pneumonitis. In addition to noncaseating granulomas in the lung, extrapulmonary granulomas have been described in skin, liver, lymph nodes, and muscle in patients with CBD (Stoeckle et al.
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From page 76... ...
Another 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 77... ...
. Progression and Management of Chronic Beryllium Disease As noted earlier, CBD has a clinical spectrum that can range from evidence of BeS and granulomas of the lung without clinically significant symptoms or deficits in lung function to end-stage lung disease.
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From page 78... ...
Possible risk factors for progression that have not been systematically assessed include magnitude and type of beryllium exposure (including particle size and solubility) , exposure duration, concurrent exposure to other lung toxicants, smoking, race, sex, life stresses, combat, surgery, and genetic factors (Newman 1996)
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From page 79... ...
The diagnosis of CBD or BeS may be associated with psychosocial stress or loss of income. A case presentation at the 2005 International Beryllium Disease Conference in Montreal described a young man with surveillanceidentified disease that resulted in job loss, major reactive depression, and unemployment (S.
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From page 80... ...
of the new hires had confirmed abnormal BeLPT results, but all six had 18-50 days of exposure to beryllium between the initial positive test and a confirmatory BeLPT, and this leaves open the possibility that sensitization occurred
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From page 81... ...
(2008) state, the PPV of the BeLPT can improve from 0.383 to 0.968 when a single abnormal BeLPT result is confirmed with a second abnormal result.
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From page 82... ...
Workers with positive BeLPT results should undergo further medical evaluation, which should generally include a medical and occupational questionnaire, pulmonary-function tests that include lung volumes and carbon monoxide diffusing capacity, and high-resolution computed tomography of the chest when indicated. After review of the test results, consideration should be given to performing bronchoscopy with bronchoalveolar lavage, transbronchial biopsy, and possibly other tests (see Chapter 7)
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From page 83... ...
The Air Force should evaluate the feasibility of requiring concordance in testing procedures between laboratories performing its BeLPTs, and the committee recommends the use of an algorithm for interpreting BeLPT results (see Appendix B)
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From page 84... ...
84 Managing Health Effects of Beryllium Exposure which would include workplace and exposure data and clinical information obtained as part of the beryllium exposure- and disease-management program. In addition to facilitating evaluation of the effectiveness of the program over time, the database could be appropriately designed to be used as a resource by researchers.
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