3.4 Chronic Beryllium Disease3.3e) RDRP Publications of Special Note Relating to Fiber-Induced Diseases | 3.4a) RDRP Publications of Special Note Relating to Chronic Beryllium Disease
Beryllium is a lightweight metal with many remarkable properties, such as heat resistance and conductance, electrical conductance, flexibility, formability, neutron moderation, x-ray transparency, and lubricity, among others. These properties enable many essential and/or unique applications in a variety of industries, including nuclear weapons and energy, medical devices, aerospace, and electronics. Beryllium’s use is steadily becoming more widespread and diverse.
As many as 134,000 current U.S. workers may be exposed to beryllium and it is likely that many times that number have been exposed at some time in their working lives.96
Exposure to beryllium can lead to sensitization, a cell-mediated allergic-type response, and cause chronic beryllium disease, an immunologic granulomatous lung disease. Chronic beryllium disease is incurable and can result in serious impairment and even death. Sensitization has been found in one to ten percent of workers in cross-sectional studies, with chronic beryllium disease diagnosed in ten to 100 percent of the sensitized.97 It is unknown whether all sensitized individuals will eventually develop disease. The routes and characteristics of beryllium exposure and its health outcomes can serve as a model for the millions of workers in manufacturing and emerging nanotechnologies who have unmeasured or unregulated exposures to a variety of hazardous occupational agents.
Compliance with the current OSHA PEL (2 µg/m3) does not assure prevention of sensitization and disease. Some jobs or work processes have demonstrated higher rates of sensitization and chronic beryllium disease.98 However, no consistent relationship has been found between workers’ estimated beryllium exposure and risk of either sensitization or disease. Also, in most studies, individual cases of sensitization or disease have been identified among workers whose exposure appeared to be minimal, such as secretaries and other clerical workers and security guards. In other words, workers with the highest estimated exposures were not necessarily at the highest risk, and higher-risk jobs or processes did not always have the highest beryllium exposure.
The lack of a consistent relationship between exposure and disease suggests that other characteristics of beryllium exposure (for example, particle size or chemical form) may be relevant, and penetration of particles through the skin may contribute to development of sensitization. Some individuals are inherently at greater risk of sensitization and chronic beryllium disease. One genetic marker has been studied extensively, and work on several other markers are in progress.99 In addition, there is also a need for highly sensitive field-portable detection methods for beryllium to enable fast, on-site analysis.
The ultimate intermediate goal of the chronic beryllium disease sub-program is to prevent and reduce the development of beryllium sensitization and chronic beryllium disease. To that end, we have developed a program of research to reach that intermediate goal by:
A 1997 request by Brush Wellman Inc., the sole U.S. beryllium manufacturer, to collaborate with RDRP scientists on beryllium research led to the development of the chronic beryllium disease sub-program. Through our collaboration with the sole U.S. producer of beryllium and beryllium-containing products, we have access to excellent “field laboratories” where we can conduct epidemiologic studies, collect airborne and other work process samples, and see the results of our research put into practice almost immediately.
The chronic beryllium disease sub-program has three major initiatives: medical surveillance and epidemiology; exposure assessment and bioavailability; and genetic studies. The major objectives within each major initiative and a very brief description of the approach taken to achieve these objectives are as follows:
Medical surveillance and epidemiology
From 1998 to 2001 RDRP conducted a series of cross-sectional plant-wide surveys. We screened almost 1200 workers for sensitization and collected medical and work histories, and evaluated historical beryllium air sampling data. At two facilities study results demonstrated no reduction in sensitization and chronic beryllium disease despite prior efforts to reduce air levels. At a third facility, which had very low air levels of beryllium, levels of sensitization and disease similar to those seen at other facilities were observed.
Subsequent to these surveys the company implemented a comprehensive preventive program at these facilities that included engineering and administrative controls, increased use of personal protective equipment, including dermal protection, and frequent comprehensive medical surveillance of newly-hired workers. At one facility, the rate of sensitization was less than half the rate observed in workers surveyed pre-program. This is the only documented example of prevention of sensitization in a beryllium production facility.
Exposure assessment and bioavailability
RDRP obtained extensive historical data for airborne beryllium levels and continues to use those data to estimate workers’ mass concentration exposure. However, mass based exposure estimates have not been linked to risk of sensitization or disease.
In order to determine the relevant aspects of exposure, RDRP continues to characterize physical and chemical properties of materials collected at representative work processes at four facilities. The goal of this work is to develop models of bioavailability using physical and chemical properties to create new approaches to exposure assessment.
There is evidence to suggest that dermal exposure to beryllium particles may contribute to development of sensitization. RDRP conducted one study that evaluated potential exposure pathways to beryllium-copper alloy.
Current methods for beryllium sample analysis take multiple days which prevents timely response to high air and surface levels. RDRP has invested in the development of better tools for detection of beryllium in workplace air and on surfaces, especially real-time (field-portable) monitors for rapid detection of hazards and timely response.
RDRP has, in tandem with epidemiologic studies, collected samples for genetic analysis from almost 1200 beryllium workers. We continue to identify the genetic markers responsible for differential risk of sensitization and chronic beryllium disease. Another goal is to understand the relationship between beryllium exposure and these genetic markers.
RDRP has used molecular epidemiology and computer modeling (computational chemistry) to identify critical variations in the one genetic marker that has been most strongly linked to sensitization and disease. These findings were essential to creating a transgenic mouse model for experimental studies of sensitization and chronic beryllium disease. This animal model will be made available to the research community when it has been properly validated.
This model system compliments the epidemiologic and exposure assessment research because it provides a mechanism for experimental validation of observational study findings. This tripartite approach (medical surveillance, exposure assessment, and genetics) was presented in the form of a program project, which recently received NORA funding support for FY 2007-2010).
Outputs and Transfer
Since 1996, the chronic beryllium disease sub-program has produced 54 peer-reviewed journal articles, and has presented more than 100 abstracts at national and international meetings of professional societies. Most of the journal articles (41) have been published in the last six to seven years. Listed below are important representative publications for each of our three major areas; a comprehensive list may be found in A3-116.
Highlights of each of the three initiatives in this sub-program are captured in seven key outputs:
Medical surveillance and epidemiology
A 2005 paper published in the “American Journal of Industrial Medicine” presented the results of the first plant-wide survey of a copper-beryllium alloy facility (1, A3-117). Copper-beryllium alloys are the most widely-used forms of beryllium, contain very little beryllium by weight (less than two percent), and had been considered by many to be of lower risk than other forms of the metal such as pure beryllium or beryllium oxide. Our results showed similar levels of sensitization and chronic beryllium disease and relatively low airborne beryllium concentrations compared to other types of beryllium facilities with much higher levels of airborne beryllium.
A recent report in “Occupational and Environmental Medicine,” (2, A3-118) demonstrates that the comprehensive preventive program that was implemented by Brush Wellman Inc. beginning in 2000 has successfully reduced the incidence of beryllium sensitization in the early years of employment (average 16 months, maximum four years) among beryllium-naïve newly-hired workers. We assessed the initial effectiveness of the comprehensive preventive program in preventing beryllium sensitization among workers at one facility who were hired during the program’s first five years (2000 to 2004). Incidence of sensitization was 0.7 cases per 1000 person-months employment. We compared these results to workers tested just before the program’s implementation, whose analogous rate of sensitization was 5.6 cases per 1000 person-months employment, or 8.2 times higher than the post intervention rate (95 percent confidence interval: 1.2-188.8). Airborne levels in production areas were similar during the two periods, which suggests that the comprehensive approach to control and prevention, including dermal protection, was key to its initial success. Further study at this facility and others is planned.
Exposure assessment and bioavailability
Three papers detail significant findings in the area of physicochemical characterization of airborne beryllium. The first two, one published in the “AIHA Journal” in 2003 and the other published in the “Journal of Environmental Monitoring” in 2004, present the differences we found in chemical form and surface area among samples collected at work processes associated with different risks of chronic beryllium disease (3-4, A3-119, A3-120). The third, published in “Applied Occupational and Environmental Hygiene” in 2001, discusses how the number concentration of particles collected at various work processes diverges from mass concentration at the same processes. (5, A3-121). All three articles won awards: the first received the 2004 AIHA David L. Swift Memorial Award for Outstanding Contribution to Aerosol and Industrial Hygiene Research; the second was recognized by the Royal Society of Chemistry as a “Very Significant” paper; and the third received the 2002 NIOSH Alice Hamilton Award, the 2001 AIHA Award for Best Publication in Aerosol Science, and a 2002 nomination for the CDC’s prestigious Charles C. Shepard Science Award.
RDRP scientists have authored four papers describing the RDRP-developed, highly sensitive, field-portable analytical method for determining trace beryllium in workplace air and surface samples this method and its validation—two in the “Journal of Environmental Monitoring” (one in 2006 and one in press) and two in the “Journal of the American Society for Testing and Materials (ASTM) International” (both in 2005), (A3-116) (6, A3-122). The method relies on a novel combination of field-based extraction and fluorescence detection.
A notable 2003 paper published in “Environmental Health Perspectives” was based on a combination of computational chemistry and molecular epidemiology; it provided an understanding of the underlying basis for immunogenetic observations of chronic beryllium disease risk (7, A3-123).
We use several other methods for disseminating the results of our research, beyond the traditional publications in peer-reviewed journals and formal presentations at professional meetings. To ensure that findings are immediately available for application in the workplace, we hold bimonthly meetings with Brush Wellman research staff to discuss ongoing projects and plan new work. We also conduct an annual worker-focused meeting, which is held over two half-days and attended by several dozen employees of Brush Wellman (hourly, supervisory, and management), RDRP researchers, and other interested parties (unions, other industries dealing with similar workplace issues, government agencies [e.g. OSHA], and university researchers). At the annual meetings, researchers provide updates on ongoing and completed research, and workforce representatives make presentations on the ways research results are being applied in the facilities. This meeting is also a forum for workers to express the concerns and questions of fellow employees. Company participants in the annual meeting are responsible for conveying what they learn to their fellow workers, both in presentations and informally; Brush Wellman’s health and safety staff makes regular presentations at plant meetings, and RDRP research staff makes presentations at the facilities.
Brush Wellman’s health and safety and product stewardship staff then provides information to their customers through presentations and written materials. Their customers run the gamut from very large (e.g. major aerospace companies) to very small (e.g. small machine shops with few employees). The former have their own health and safety groups, but the latter must rely on information provided by the beryllium supplier to keep their workers safe. One approach to making comprehensive information available to all is a personal computer-based software program that will permit a risk-based approach to control; among other factors, workplace-specific decisions can be made based upon the chemical forms of beryllium that are used and the types of processing those materials undergo. This program is in the developmental stages and members of RDRP staff are working with Brush Wellman to develop a user-friendly tool to assist with decision-making.
RDRP is producing a NIOSH Alert:“Preventing Beryllium Sensitization and Chronic Beryllium Disease.” The NIOSH Alert provides an update on the current state of knowledge and recommendations for protecting worker health. The NIOSH Alert will be mailed in hard copy to all known beryllium-using workplaces, and will also be posted electronically on the NIOSH Web site. It will be sent directly to other government agencies, beryllium disease support groups, the external (peer and stakeholder) reviewers and other constituents (e.g. unions). We will work with the NIOSH OHC to notify prior press contacts when the document is available.
To provide another distribution pathway for the results of our research, we have produced two newsletters written for current and former worker research participants and their families (“NIOSH Beryllium Research Highlights,”issued in June 2003 and July 2005, A3-124, A3-125); a third newsletter is in preparation for launch in FY 2008.
NIOSH co-sponsored meetings with the:
RDRP researchers are members of committees of the AIHA, the American Thoracic Society, and the Beryllium Health and Safety Committee (an independent international committee), among others. Members of RDRP staff have also organized and presented a professional development course for the AIHA for four years (in 2004 it was rated in the top seventh percentile of such courses).
OSHA is in the process of developing a new standard for beryllium and RDRP has given OSHA analysts access to our epidemiologic data to enable them to perform risk assessment. Due to confidentiality issues, OSHA researchers evaluate the data at NIOSH in Morgantown under the supervision of RDRP staff.
Medical surveillance and epidemiology
Joint research conducted by RDRP and Brush Wellman (which, as already noted, is the only U.S. beryllium producer), has had important impact on Brush Wellman’s work practices. RDRP findings showed that implementation of engineering controls targeted to reduce inhalation exposures associated with specific higher-risk work processes, did not, in themselves, reduce beryllium sensitization and chronic beryllium disease. RDRP published data in reports listed in A3-116 that were suggestive of skin exposure involvement in beryllium sensitization. In response to RDRP data, Brush Wellman took the results of our mutual research and implemented a comprehensive “Preventive Program” at its three main plants. This program followed the traditional “hierarchy of control” approach, including engineering controls, administrative controls, and use of personal protective equipment, and also included some aspects that were novel or unproven.
Exposure assessment and bioavailability
This work is in its early stages, but has strong potential to eventually affect the actions of others. Research by both RDRP scientists and others demonstrated no consistent relationship between individual estimates of beryllium exposure, as measured by the traditional approach (mass concentration), and risk of sensitization or chronic beryllium disease. In fact, those at highest risk sometimes had relatively low beryllium exposures. During the last decade, understanding of the immunopathology of chronic beryllium disease has improved and many now hypothesize that dissolved beryllium in ionic form, not particles, is the input to the chronic beryllium disease immune reaction at the cellular level. To better understand the quantitative translation of particle exposure (via inhalation, and potentially skin) into dissolved beryllium dose in the initiation of beryllium sensitization and chronic beryllium disease, investigators have been focusing on characterization of the physicochemical properties (size, surface area, and chemical form) of workplace aerosols that potentially affect dissolution. Research results thus far indicate that differences in these properties are relevant to disease risk. Ultimately we hope to provide a true estimate of beryllium “dose” relevant to disease risk, rather than the current estimates of beryllium “exposure” that do not predict risk. Dose estimates will inform standard-setting and efforts to control exposure in the workplace.
This work is in its early stages, but also has a strong potential to eventually affect the actions of others. In humans, our genetic research has led to a better understanding of susceptible subpopulations among beryllium-exposed workers, creating the potential that genetic counseling might eventually be a useful, helpful option. For example, earlier research demonstrated that one marker was highly prevalent among those with sensitization and chronic beryllium disease. Since that marker was also very common among the general population, it was of limited utility in predicting who was more likely to develop disease. However, our research has uncovered a hierarchy of risk among those with this marker, indicating that a much smaller proportion of the population is at extremely high risk.
Our genetic research, in partnership with Lawrence Berkeley National Laboratory, led to the development of a transgenic mouse model for use in experimental research. Identification of a hierarchy of risk led us to develop three transgenic mouse strains, containing a high-risk, a medium-risk, or a low-risk allele. This mouse model will be made available to interested researchers. Use of the mouse model will enable studies at many laboratories of the relationships among: routes of exposure (dermal versus respiratory); patterns of exposure (e.g. long-term low exposure versus short-duration high exposure), durations of exposure (e.g. chronic versus acute), and types of exposure (e.g. chemical forms and particle size). It will also allow validation that gene variants carry different degrees of genetic susceptibility to chronic beryllium disease.
Progress Towards End Outcomes
Implementation of Brush Wellman’s comprehensive Preventive Program has already been markedly effective in reducing beryllium sensitization rates. Thus far, we have assessed the initial effectiveness of the Preventive Program at one facility. We found an incidence rate of 0.7 cases of sensitization per 1000 person-months of employment. We then compared this rate to analogous data from workers hired in a similar interval just prior to implementation of the Preventive Program, who had 6.5 cases per 1000 person-months, more than eight times greater than the rate under the new Preventive Program (A3-118). These results demonstrate primary prevention of beryllium sensitization in an industrial setting. They are the first known success story, short of eliminating use of this strategic metal altogether. While these results are encouraging, they are preliminary and necessitate further investigation. Longer-term follow-up is needed to determine if the reduction in sensitization is maintained with time, or if the Preventive Program merely delays (rather than prevents) onset of sensitization. Longer-term follow-up may also potentially provide information on the effectiveness of various programmatic components, which were not all introduced at the same time. Another limitation to these preliminary findings is that they included only workers who remained employed at the facility at the time of testing. Testing former workers, who have past, but not ongoing, exposure to beryllium will provide a more complete description of the program’s effectiveness and provide valuable information to current workers concerned about their risk of developing sensitization (and ultimately, chronic beryllium disease) after leaving employment. Including former workers who were tested at hire but who left prior to the first test interval (three months) should also assist in providing a more complete picture of risk associated with work at facilities after implementation of the preventive program.
We are continuing to analyze data collected since the Beryllium Program’s inception in 1998. The products will include: epidemiologic analyses of the largest Brush Wellman facility (prevalence of sensitization and chronic beryllium disease among workers employed at the plant in 1999, prevalence of sensitization and chronic beryllium disease among current and former workers from the 1993-94 worker cohort, risks related to work processes, and risks related to quantified beryllium exposure); a second epidemiologic analysis of the copper-beryllium alloy facility (risks related to quantified beryllium exposure); physicochemical characterization of beryllium materials collected in 1999; and genetic analyses (prevalence of various genetic markers among the sensitized, those with chronic beryllium disease, and those not affected; the relationships between various genetic markers, and the relationships between quantified beryllium exposure and various genetic markers).
In March 2006, RDRP scientists submitted a program proposal for funding through fiscal year 2010. The proposal includes four projects that carry our program forward:
This project was funded for the period FY 2007-2010.
Members of the Beryllium Health and Safety Committee are currently working with the AIHA to enable laboratories using field methods such as the portable real-time monitor to become accredited. The AIHA is presently in the process of amending their laboratory accreditation policy to accommodate on-site analysis. It is expected that the portable beryllium method will see wider use when accreditation /certification is realized; this is expected within the calendar year. Concomitantly, OSHA is considering a revision (lowering) of the OSHA PEL, and this new method will enable quantitative measurement of beryllium at the very low levels that are likely to be required.
Intermediate Goal and Objectives Moving Forward
The intermediate goal is to prevent and reduce beryllium sensitization and chronic beryllium disease. The objectives to accomplish this are to:
96. Henneberger PK, Goe SK, Miller WE, Doney B, Groce DW . Industries in the U.S. with airborne beryllium exposure and estimates of the number of current workers potentially exposed. J Occ Env Hyg 1:648-659.
97. Henneberger PK, Cumro D, Deubner DD, Kent MS, McCawley M, Kreiss K . Beryllium sensitization and disease among long-term and short-term workers in a beryllium ceramics plant. Int Archives of Occ Env Hlth 74(3):167-76.
98. Schuler CR, Kent MS, Deubner DC, Berakis MT, McCawley M, Henneberger PK, Rossman MD, Kreiss K . Process-related risk of beryllium sensitization and disease in a copper-beryllium alloy facility. Am J Ind Med 47:195-205.