1. Beryllium Disease: Increasing Awareness/Protecting Worker Health L.B. Sandy Rock, MD, MPH Risk Communicator

2. Beryllium Disease  Hazards o Beryllium o Asbestos o Hexavalent Chromium o Silica (dust)? o Allergens o (Tobacco) o Fumes/exhaust Potential Causes of Occupational Lung Disease at the Hanford Site (in order of worker concern 2011)

3. What is CBD?  Beryllium o What and where (and why?)  Exposure o How and how much  Sensitization o BeLPT  Lung disease o “Systemic granulomatous disease” o Chronic lung disease---varying severity  Also…Class IA carcinogen Beryllium Disease

4. Outcome objectives:  After actively participating in this discussion, attendees will be able to o 1) describe the characteristics of chronic beryllium disease (and how it is diagnosed); o 2) explain how and where exposure to beryllium can occur (and the importance of occupational history); o 3) identify the uncertainties inherent in delineating environmental testing, exposure, diagnostic testing, treatment, and all levels of prevention (thus, why it is so challenging an occupational disease). Beryllium Disease

5. Case Study 1  A 52-year-old male former Health Physics Technician at Hanford worked in several areas now known to have been beryllium contaminated. Ten years ago he developed a mild to moderate pneumonitis after exposure to chemical vapors from a storage tank; chest x-ray revealed hilar adenopathy compatible with sarcoidosis and biopsy confirmed the diagnosis. He was treated with systemic corticosteroids initially, and, later, by inhalation. Because of work history and sarcoidosis diagnosis, beryllium sensitization blood test was performed and was negative for four consecutive years; on the fifth year, he had a positive test followed by a positive confirmatory test “just a few months after stopping inhaled cortisone.” Beryllium Disease

6. Case Study 2  A 50-year-old male power operator worked for many years in the 300 Area at Hanford, a known beryllium- contaminated area. He heard about the Voluntary Beryllium Program but was reluctant at first to join it. He had no health problems. At coworkers’ urging, he later entered the program and had a negative initial blood test for beryllium sensitization; one year later, he had positive tests. He is angry that his first test was negative since he “continued to work in possible beryllium contaminated buildings.” Beryllium Disease

7. Pre/Post Quiz Both of the above patients were referred to a major medical center known for expertise in beryllium disease and both were diagnosed with CBD. Neither one has developed symptoms or required any treatment to date. Questions: 1.Patients with a work history in all but which job category and presenting with a sarcoidosis-like syndrome should be tested for Beryllium Disease? o Nuclear o Sporting equipment o Ceramic o Fast Food o Electronic 2.What test distinguishes Chronic Beryllium Disease from sarcoidosis? o BeLPT o LeBPT o Lipotropin, blood o Speckled macrophage test o Transbronchial biopsy 3.Many workers express anxiety about being tested for CBD. Which of the following is the least of their concerns? o Job loss o Loss of insurability o Lack of compensation programs o Lack of specific treatment o Uncertainty in diagnosis Beryllium Disease

8. Quiz (cont’d) 4. What nationally-recognized center is considered the most knowledgeable about CBD? o Scripps Memorial Hospital o National Jewish MC, Denver o University of Virginia o Tulane University Medical Center o Mayo Clinic 5. An evaluation for Chronic Beryllium Disease would include all of the following EXCEPT: o Chest x-ray (PA/Lat) o Bronchoscopy with lavage and biopsy o Node biopsy for beryllium particle spectroscopy o D L CO diffusion o Spirometry Beryllium Disease

9. Beryllium Beryllium is amazingly versatile as a metal alloy and is used in dental appliances, golf clubs, non- sparking tools, wheelchairs, automobiles, bicycle frames and electronics. Beryllium Disease Atomic number = 4 Atomic weight = 9 High tensile strength High heat capacity Excellent electrical conductivity High stiffness (modulus of elasticity)

10. Main industries  nuclear production/fabrication facilities  aerospace  aircraft manufacture and maintenance  computer  dental laboratories/ceramics  telecommunications  foundries and metal reclamation Beryllium Disease

11. Industrial Uses  Gyroscopes, guidance systems, accelerometers  Reactor rods (controls fission reactions)  X-ray windows  Spark-free tools (strengthens copper)  Consumer products: Mountain bikes, golf clubs, baseball bats, electronics, ceramics, fishing rods, space shuttle/aviation, brakes  [Fluorescent lights] Beryllium Disease

12. What and…  Beryllium in the environment o Ash Volcanic – Mt St Helens Fly Ash – Coal-fired power plants – Incinerators  Beryl o Gemstone Emerald, aquamarine, goshenite, and davidsonite  Beryllium particles (fine) and beryllium oxide o Likely sensitizers o Occur in refining and other processing of beryllium metal Beryllium Disease

13. … how much?  Do we know? o Probably THE most contentious issue  Genetics-- HLA-DPB polymorphisms o “Glu69” HLA-DPB1-Glu69 marker – glutamine residue at position 69 (Glu 69+) of the B1 chain of the HLA-DPB molecule  Permissible Exposure Level o A workplace determination OSHA ACGIH DOE/CBDPP Beryllium Disease

14. Numbers (aka “epidemiology”)  CBD in the general population? o = Sarcoidosis + BeLPT positivity  CBD in workers o Industries Nuclear weapons production among many others Ceramics o DOE sites Hanford Rocky Flats Others  History o First described 1933 Germany/discovered 1943 in U.S./ Fluorescent lamp manufacturing (more acute lung disease known since 1930’s) Beryllium Disease

15. …at Hanford… from 11/97-1/11---  Sensitized: 113  CBD: 32  Workers tested: 5752 (through 10/1/10)  Workers in Be medical programs: 4476 ( 1/11/11) o Be-Worker—3257 o Be-Program-Voluntary (formerly “Previous Worker”) —1219 Beryllium Disease

16. Newly Diagnosed Beryllium Sensitized Workers, FY10 Beryllium Disease  16 newly diagnosed Beryllium Sensitized workers in FY10 o 4 on initial screening for beryllium work clearance with no prior Hanford work history and with significant other DOE/DOD work history Including previous employment in facilities such as Palo Verde, Shearon Harris, INL moving beryllium waste containers, non-Hanford radioactive waste disposal, o 2 with prior Hanford work history and potential significant non-Hanford DOE/DOD experience Including previous employment in facilities such as INL from 1989- 1993, US Navy o 10 with no reported non-Hanford (or any other) work experience

17. Insidious  Exposure o Dust---processing, grinding, etching  Sensitization o No stigma  CBD o Mild symptoms in most, at first Beryllium Disease

18. What happens…  Exposure-  Sensitization o Lung o Skin (significance?) o 2-15%?  Sensitization  Granuloma formation in lungs (CBD) o 20-100%?  CBD  diminished pulmonary function o Variable course: obstruction; restriction; ↓ gas transport (O 2, CO 2 ) (↓D L CO) Beryllium Disease

19. Evaluation  Laboratory Studies o Blood BeLPT test of choice – beryllium sensitization – peripheral blood mononuclear cells exposed in vitro to beryllium salts at varying concentrations for variable time intervals – cell proliferation in the presence of beryllium indicates a positive test result. – performed only in selected specialized laboratories (Oak Ridge; U Penn; Nat’l Jewish, Denver; Cleveland Clinic) Beryllium Disease

20. Evaluation, cont’d  Imaging Studies o Chest x-ray: normal in about half of the patients with documented chronic beryllium disease (CBD) hilar adenopathy and/or increased interstitial markings. o High-resolution CT (HRCT) scan, chest more sensitive ground glass opacification (see the image next slide), parenchymal nodules, or septal lines negative in 25% of patients with documented CBD. Beryllium Disease

21. A high-resolution CT scan of the chest showing the typical ground glass appearance in a patient with chronic beryllium disease, or berylliosis. Beryllium Disease

22. Evaluation, cont’d  Other Tests o Pulmonary function tests include the following: Spirometry Lung volumes Diffusing capacity of lung for carbon monoxide (DLCO) o Arterial blood gases o Cardiopulmonary exercise  With disease progression, spirometry may show evidence of obstruction, restriction, or both. (In an early study in 40 patients with advanced CBD, an obstructive pattern was observed in 39% of patients, a restrictive pattern in 20%, and a low DLCO in 36%.)  The DLCO declines over the course of the disease. The most sensitive test is abnormalities in gas exchange during exercise.  Laser microprobe mass spectrographic (LAMMS) analysis can be used to detect beryllium in histologic sections from lung biopsy specimens. This test is not necessary for the diagnosis and is not widely available. Beryllium Disease

23. Evaluation  Procedures o Flexible fiberoptic bronchoscopy with BAL and transbronchial biopsies (TBBX) to confirm a suspected diagnosis of CBD. – Patients with CBD usually have BAL lymphocytosis (>20% lymphocytes). – The BeLPT test also can be performed on BAL cells. – A minimum of 6 high-quality biopsies should be obtained to optimize the yield. If TBBX results are negative but suspicion high, consider repeat bronchoscopy. o Open lung biopsy may need to be performed if repeat bronchoscopy findings still are negative.  Histologic Findings o The hallmark of CBD is the presence of nonnecrotizing granulomas on lung biopsy (see the image below). These granulomas are histopathologically indistinguishable from sarcoid granulomas Beryllium Disease

24. Normal lung tissue ~200x Beryllium Disease

25. Granulomatous lung tissue ~200x Beryllium Disease

26. How is it treated?  Sensitization o Prevent further exposure o Evaluate and re-evaluate Referrals – National Jewish Medical Center (NJH;Denver)  Chronic Beryllium Disease o A type of chronic lung disease o Specialist evaluation & directed care o No controlled studies for CBD therapy are available. Based on the pathogenesis of the disease (immune-mediated) and due to the similarities with sarcoidosis, CBD is treated with corticosteroids. When corticosteroid therapy fails or in patients who develop significant adverse effects, methotrexate (MTX) may be considered  Maintain good general health! Beryllium Disease

27. How is it prevented?  The usual o Administrative Controls o Engineering Controls o PPE o Training/Work practices o Pre-planning/Hazard Awareness  The unusual o Sampling/monitoring (specifically for Be; controversy over “safe” levels) o CBDPP enhances worker protection by detailing guidance and standards for monitoring, prevention of exposure, medical surveillance, and work practices Beryllium Disease

28. CBDPP  Chronic Beryllium Disease Prevention Program  10 CFR 850 (DOE program rule)  AMH, DOE, Site contractors committee  Site-wide Beryllium Disease

29. Necessary research  Quantifying levels of sensitization and chronic beryllium disease in various work settings and worker populations  Understanding airborne beryllium exposure and the characteristics associated with risk of disease among exposed workers (as well as risk of aggravating disease)  Understanding how different routes of exposure contribute to disease risk  Understanding the genetic risk factors associated with disease Beryllium Disease

30. BHSC The Beryllium Health and Safety Committee (BHSC) is committed to preventing beryllium sensitization and chronic Beryllium Disease (CBD) and other adverse health effects that can be cased by workplace exposure to beryllium. The Mission of the BHSC will be accomplished by:  Promoting the safe use of beryllium  Obtaining a better understanding of exposure risks  Improving exposure monitoring  Fostering improved controls  Accumulating and disseminating information concerning beryllium process best work practices, as well as, data from the health studies concerning the hazards associated with beryllium  Training / mentoring of beryllium health professionals  Identifying and promoting research that has the potential to enhance or improve our worker safety programs Beryllium Disease

31. B.A.G.  Beryllium Awareness Group  Affected workers  Open and closed meetings, monthly o Open: 1 st Wed/mo @ HAMMER Rm 31, 1:30-4:30 PM o Closed: 3 rd Wed -------- ---Be Registry-- The DOE Beryllium-Associated Worker Registry is a complex-wide internal program to help DOE conduct and improve its [CBDPP]. 10 CFR 850.39 specifies beryllium recordkeeping and reporting requirements for both DOE federal and contractor employees. [It] contains data on DOE contractor and federal workers, the jobs they performed, their beryllium exposure monitoring results, results from screening tests for chronic beryllium diseases, and the results from subsequent medical diagnostic procedures. Beryllium Disease

32. Outcome objectives:  After actively participating in this discussion, attendees will be able to o 1) describe the characteristics of chronic beryllium disease (and how it is diagnosed); o 2) explain how and where exposure to beryllium can occur (and the importance of occupational history); o 3) identify the uncertainties inherent in delineating environmental testing, exposure, diagnostic testing, treatment, and all levels of prevention (thus, why it is so challenging an occupational disease). Beryllium Disease

33. Pre/Post Quiz Both of the above patients were referred to a major medical center known for expertise in beryllium disease and both were diagnosed with CBD. Neither one has developed symptoms or required any treatment to date. Questions: 1.Patients with a work history in all but which job category and presenting with a sarcoidosis-like syndrome should be tested for Beryllium Disease? o Nuclear o Sporting equipment o Ceramic o Fast Food o Electronic 2.What test distinguishes Chronic Beryllium Disease from sarcoidosis? o BeLPT o LeBPT o Lipotropin, blood o Speckled macrophage test o Transbronchial biopsy 3.Many workers express anxiety about being tested for CBD. Which of the following is the least of their concerns? o Job loss o Loss of insurability o Lack of compensation programs o Lack of specific treatment o Uncertainty in diagnosis Beryllium Disease

34. Quiz (cont’d) 4. What nationally-recognized center is considered the most knowledgeable about CBD? o Scripps Memorial Hospital o National Jewish MC, Denver o University of Virginia o Tulane University Medical Center o Mayo Clinic 5. An evaluation for Chronic Beryllium Disease would include all of the following EXCEPT: o Chest x-ray (PA/Lat) o Bronchoscopy with lavage and biopsy o Node biopsy for beryllium particle spectroscopy o D L CO diffusion o Spirometry Beryllium Disease

35. Beryllium Corrective Action Plan (BeCAP)  A result of concerns brought to DOE through the Hanford Advisory Board (HAB) o HAB influenced by various parties BAG Activists Elected government officials o Driven by perception that workers were becoming BeS  DOE HQ sent team from Health, Safety and Security office o Numerous interviews and records review (non-medical) o Evaluation took place for two weeks March 2010 o Report released to public June 2010  Corrective Action Plan (BeCAP) developed and approved o “Final” agreed-upon Corrective Action Plan August 30, 2010 and accepted by DOE on 9/22/2010  All Hanford contractors responsible for meeting deadlines to complete assigned “opportunities for improvement” over the coming months. Beryllium Disease

36. Summary  Beryllium exposure can cause a granulomatous lung disease in workers who develop a lymphocyte-mediated sensitization to the metal. Workers in diverse industries are at risk because beryllium's properties are critical to nuclear, aerospace, telecommunications, electronic, metal alloy, biomedical, and semiconductor industries. The occupational air concentration standard's failure to protect beryllium workers is driving many scientific and occupational health advances. These developments include study of bioavailability of different physicochemical forms of beryllium, medical surveillance to show effectiveness of skin protection in preventing sensitization in high-risk processes, gene-environment interaction, transgenic mice for use in experimental research, and risk-based management of industrial exposures in the absence of effective exposure-response information. Beryllium sensitization and disease prevention are paradigms for much broader public health action in both occupational and general population settings. Beryllium Disease

37. Practice Commitments I will make the following changes in my practice:  Include comprehensive work history in patient charts  Consider BeLPT in patients with sarcoidosis, particularly those with relevant work history  ****** (TBD by attendees) Beryllium Disease