Division of Respiratory Disease Studies (DRDS) Research on Beryllium Sensitization and Chronic Beryllium Disease
Some workers exposed to beryllium dusts and/or fumes may develop an immune response known as sensitization, which can be detected in the blood with the beryllium lymphocyte proliferation test (BeLPT). Sensitized workers may have or may develop chronic beryllium disease (CBD), a slowly progressive respiratory disease characterized by the formation of lung lesions called granulomas. These granulomas and accompanying fibrosis cause impairment of the lung’s ability to expand fully and to oxygenate the blood. The rate of progression from less severe to severe disease can vary widely. There is no cure for CBD, although symptoms can be treated. Recent estimates indicate that as many as 134,000 current US workers in private industry and government may be exposed to beryllium (Henneberger 2004).
Since 1998, NIOSH has been conducting research in collaboration with the leading U.S. producer of beryllium and beryllium-containing products, under a Memorandum of Understanding. The goal of this research is to prevent sensitization and CBD by developing a better understanding of the work processes and exposures that may present a potential risk for workers, and to develop effective interventions that will reduce the risk for adverse health effects. NIOSH also conducts genetic research on sensitization and CBD, independently of this collaboration.
Longitudinal Surveillance for Beryllium Sensitization and CBD (Project Officers: Christine Schuler and Abbas Virji)
In 1998-2000, NIOSH and the beryllium producer conducted surveys of current workers at the company’s three main facilities: the primary production plant, which produces beryllium metal, various alloys, and beryllium oxide powder (Schuler 2011 submitted); the ceramics plant, which produces beryllium oxide ceramics from oxide powder (Henneberger 2001); and the copper-beryllium alloy plant, where further processing of rod and wire and strip materials takes place (Schuler 2005). In addition, NIOSH surveyed former workers who had participated in earlier surveys at the primary production plant in 1993-94 (Kreiss 1997) and the ceramics plant in 1992 (Kreiss 1996). Results from these surveys have demonstrated that engineering controls put in place at the highest risk operations in the mid- to late 1990s were not sufficient to reduce risk of sensitization and CBD (Henneberger 2001, Schuler 2011 submitted); that sensitization and CBD can occur under conditions of low beryllium exposure (Henneberger 2001, Schuler 2005); and that the true risk to beryllium-exposed workers has been underestimated by reliance on results from cross-sectional surveys (Schuler 2008).
Evaluation of exposure-response relations in these populations is ongoing. Earlier efforts at these facilities and elsewhere demonstrated no consistent exposure-response relationship. However, process-related risks have been identified in the absence of exposure-response (Kreiss 1996, Kreiss 1997, Henneberger 2001, Schuler 2005 ), suggesting that predictive exposure factors do exist but may not have been adequately characterized. Possible explanations may include: inclusion of irrelevant exposure due to uncertainty in ascertaining time of onset of sensitization or CBD in cross-sectional epidemiologic studies, use of airborne exposure metrics that do not address biological relevance rather than metrics that consider lung deposition (Stefaniak 2003, Stefaniak 2011, Virji 2011), and lack of consideration of alternate pathways of exposure (Day 2007), among others. We have created individual exposure estimates for one group of workers from extensive databases of full-shift personal lapel samples of total mass concentration of airborne beryllium (Virji 2011 submitted). In addition to total mass, we are investigating the role of particle size, chemical form of beryllium, material solubility (Stefaniak 2006, Stefaniak 2011), and potential dermal exposure (Day 2006) in risk for sensitization and CBD.Investigators in the Division of Respiratory Disease Studies and the Health Effects Laboratory are currently working on four research projects that were funded by the National Occupational Research Agenda (listed below).
Long-term Efficacy of a Program to Prevent Beryllium Disease (Project Officer: Carrie Thomas and Christine Schuler)
In response to the results of multiple epidemiologic surveys at the company's facilities, and especially in light of the failure of targeted engineering controls to reduce sensitization and CBD, the company began to implement a comprehensive preventive program in 2000-01. This program was designed to keep beryllium out of the lungs, off the skin, and at the work process, among other points, and emphasized a well-trained and prepared workforce. To that point, no preventive programs had demonstrated effectiveness in preventing beryllium sensitization and CBD among beryllium-exposed workers. NIOSH and the company evaluated the early effectiveness of this program by comparing medical surveillance data from groups of workers hired after the preventive program began to similar groups of workers hired just prior to the program. Early results were promising, showing substantial reductions in sensitization at the beryllium ceramics plant (Cummings 2007), the alloy finishing plant (Thomas 2009), and the primary production plant (Bailey 2010).
Although encouraging, these evaluations needed to be extended to include longer follow-up, and testing of workers after leaving employment. This study was designed to address these points, with up to nine years of follow-up and testing of former workers hired after the beginning of the preventive program. As of April 2011, data collection and analysis are complete and the final report is nearing completion.
To better understand beryllium exposures, researchers at NIOSH believe that in addition to measuring the concentration of beryllium in air, we should also estimate the amount of beryllium that may potentially get onto the skin (Day 2006). Estimates of both inhalation and skin exposure and how they are related will help to better understand total exposures and their associations with high-risk processes. NIOSH researchers also believe that contaminated surfaces, like tools and equipment, represent potential sources for both inhalation and skin exposures. Settled dust on surfaces can be re-suspended in air and/or transferred to workers’ clothing and skin. Therefore, we should also measure concentrations of beryllium on work surfaces throughout beryllium facilities. These estimates will help to better understand migration of beryllium within facilities (Day 2007), allowing for focused exposure measurement and control efforts in the riskiest areas. Reducing total exposure should help to reduce the risk of beryllium disease.
To better understand exposure to beryllium, researchers at NIOSH believe that in addition to the amount of beryllium in air, testing for other properties of beryllium particles are important. These particle properties are:
- Size- small particles can get deeper into the lung than big particles
- Chemistry- beryllium metal, oxide, ore, and alloys may not be equally toxic
- Surface area- may limit how much beryllium dissolves from particles
- Solubility- how much beryllium dissolves from particles may be important for immune response
Once we understand the best way to measure exposure to beryllium particles, we can focus our exposure measurement and control efforts on just the most important properties. By reducing exposure to those particle properties, it should help to reduce the risk of beryllium disease.
No animal gets CBD. It is important to have an animal model for laboratory experiments, since it is important to be able to validate dose-response information derived from job-exposure matrices and epidemiologic studies as well as being able to answer other basic toxicological questions. Genetic studies have led to the creation of an animal model where different human HLA-DP alleles have been inserted into mice; this is called a “transgenic” or “knock-in” model. The model comprises three different strains of this genetically engineered mouse: low risk, where the transgene codes for lysine residue at the 69th position of the B-chain; medium risk, where the transgene codes for glutamic acid residue at the 69th position of the B-chain and glycine residues at positions 84 and 85; and high risk, where the transgene codes for glutamic acid at the 69th position of the B-chain and aspartic acid and glutamic acid residues at positions 84 and 85, respectively (Tarentino-Hutchinson et al. 2009). This mouse model will eventually be used to compare: different types of beryllium (alloy versus metal versus oxide versus salts), different doses of beryllium, and routes of exposure (skin versus lung). A mouse model could also be used to test interventions in the sensitized and new therapeutic approaches to chronic beryllium disease.
Beryllium Research Highlights is a series of newsletters written for current and former workers in the beryllium production industry who participated in our beryllium research program. These newsletters provide information to study participants about completed studies, current research findings, and upcoming activities.
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