Agency For Toxic Substances and Disease Registry (ATSDR) Case Studies in Environmental Medicine Beryllium Toxicity
Agency For Toxic Substances and Disease Registry (ATSDR) Case Studies in Environmental Medicine Beryllium Toxicity
Agency For Toxic Substances and Disease Registry (ATSDR) Case Studies in Environmental Medicine Beryllium Toxicity
Table of Contents
How to Use This Course ............................................................................................ 3
Initial Check............................................................................................................ 5
What Is Beryllium and How Are People Exposed To It? .................................................. 9
What Are the Standards and Regulations for Beryllium Exposure? ................................. 11
Who Is at Risk of Exposure to Beryllium?................................................................... 14
Who Is Susceptible to Beryllium Exposure? ................................................................ 17
How Does Beryllium Induce Pathogenic Changes?....................................................... 19
Clinical Assessment ................................................................................................ 22
Clinical Assessment - Other Diagnostic Tests.............................................................. 26
How Should Patients Exposed to Beryllium Be Treated and Managed? ............................ 29
Sources of Additional Information............................................................................. 32
Posttest Instructions............................................................................................... 38
Literature Cited ..................................................................................................... 44
Key Concepts
This educational case study document is one in a series of selfinstructional publications designed to increase the primary care
providers knowledge of hazardous substances in the environment and
to promote the adoption of medical practices that aid in the evaluation
and care of potentially exposed patients. The complete series of Case
Studies in Environmental Medicine is located on the ATSDR Web site at
URL: www.atsdr.cdc.gov/csem/. In addition, the downloadable PDF
version of this educational series and other environmental medicine
materials provides content in an electronic, printable format, especially
for those who may lack adequate Internet service.
Page 1 of 50
Beryllium Toxicity
Acknowledgements
Disclaimer
Page 2 of 50
Beryllium Toxicity
Available
Versions
Instructions
Instructional
Format
Section
Element
Title
Learning
Objectives
Text
Key Points
Progress Check
Answers
This course is designed to help you learn efficiently. Topics are clearly
labeled so that you can skip sections or quickly scan sections you are
already familiar with. This labeling will also allow you to use this training
material as a handy reference. To help you identify and absorb important
content quickly, each section is structured as follows:
Purpose
Serves as a focus question that you should be able to answer after
completing the section
Describes specific content addressed in each section and focuses your
attention on important points
Provides the information you need to answer the focus question(s) and
achieve the learning objectives
Highlights important issues and helps you review
Enables you to test yourself to determine whether you have mastered
the learning objectives
Provide feedback to ensure you understand the content and can locate
information in the text
Page 3 of 50
Content Area
Exposure Pathways
Standards and
Regulations
Populations at Risk
Health Effects
Clinical Assessment
Treatment and
Management
Beryllium Toxicity
Objectives
Describe berylliums properties.
Describe how people are exposed to beryllium.
Describe the Occupational Safety and Health
Administration (OSHA) permissible exposure limit (PEL)
for beryllium.
Describe the U.S. Environmental Protection Agency
(EPA) regulation for beryllium emissions in air .
Identify the populations most heavily exposed to
beryllium.
Identify who is at risk of exposure to beryllium in the
home.
Name a marker of genetic susceptibility to beryllium
exposure.
Describe two mechanisms of injury resulting from
beryllium exposure.
Describe the health conditions associated with beryllium
exposure.
Describe chest radiograph findings associated with
beryllium-related diseases.
Describe pulmonary function test findings associated
with beryllium-related diseases.
Identify other tests that can assist with diagnosis of
beryllium-related diseases.
Identify what patients should be treated .
Identify the primary drug for treatment of chronic
beryllium disease (CBD).
Describe possible sequelae of chronic beryllium disease.
Page 4 of 50
Beryllium Toxicity
Initial Check
Instructions
Case Study
This Initial Check will help you assess your current knowledge about
beryllium toxicity. Read the case study below, and then answer the
questions that follow.
A 14-year-old daughter of a dental technician has a cough, is
wheezing, and has a low-grade fever.
The patient has developed a troublesome cough and sometimes at night
cannot catch her breath. Her cough has recently worsened, with an
increase in sputum production and chest discomfort. Last night she had a
particularly rough time, but she had no wheezing or fever. Chart review
reveals no known history of asthma or allergies. The patients height and
weight are appropriate for her age. Her two siblings, aged 6 and 12
years, are in good health. History of previous illness reveals three
episodes of otitis media as a young child, but no other significant illness.
She has no history of eczema or food intolerance.
In response to your questions, the mother tells you that her husband, a
dental technician, has been diagnosed with sarcoidosis. He recently had
flu-like symptoms similar to those of his daughter, including fatigue,
nasal congestion, sneezing, and cough. Although her husband, who
smokes cigarettes, has had a cough for several years, the mother states
that her daughter developed symptoms a few days after her husbands
latest bout. She wonders if her husbands sarcoidosis could have been
transmitted to their daughter.
Initial Check
Questions
Page 5 of 50
Initial Check
Answers
1.
Beryllium Toxicity
2.
Initially, you would want to know the fathers general state of health,
his full work history, smoking habits, and history of respiratory
problems. You may also wish to explore his hobbies and home
environment. As a dental laboratory technician, the father may be at
risk of exposure to beryllium (during casting and grinding of alloys
used in dental prostheses), as well as to mercury (during mixing of
dental amalgams). Chronic cough is a common symptom of chronic
beryllium disease, which can be misdiagnosed as sarcoidosis unless
an immunological test specific to beryllium sensitization is used.
The information for this answer comes from section How Should
Patients Exposed to Beryllium Be Evaluated?
3.
Page 6 of 50
Beryllium Toxicity
6.
7.
8.
chest radiograph,
pulmonary function tests,
carbon monoxide diffusion, and
exercise physiology with arterial blood gases.
Page 7 of 50
Beryllium Toxicity
Page 8 of 50
Beryllium Toxicity
What Is
Beryllium?
How Are
People
Exposed to
Beryllium?
Key Points
Page 9 of 50
Beryllium Toxicity
Page 10 of 50
Beryllium Toxicity
Introduction
Workplace
Standards
Environmental
Standards
Page 11 of 50
National Institute
for Occupational
Safety and
Health (NIOSH)
Air: workplace
for Beryllium
Level
3
2 g/m
0.05 g/m3
0.2 g/m3
0.5 g/m3
Beryllium Toxicity
Comments
Advisory; TLV-TWA*
Notice of Intended Change,
2007; TLV-TWA*
Notice of Intended Change,
2007: STEL
Advisory; 10-hour TWA;
REL**
Occupational
Regulation; PEL as TWA
Air: workplace
2 g/m3
3
Safety and
5 g/m
Regulation; Ceiling
25 g/m3
Health
Regulation; STEL
30-minute maximum peak
Administration
(OSHA)
U.S.
Air emissions
10 g/24 hours
Regulation
Environmental
Protection
Agency (EPA)
*
TLV-TWA (threshold limit value-time-weighted average): time-weighted average
concentration to which nearly all workers may be repeatedly exposed for a normal workday
and a 40-hour workweek.
PEL (permissible exposure limit): highest level of beryllium in air to which a worker may
be exposed, averaged over an 8-hour workday.
Key Points
Page 12 of 50
Beryllium Toxicity
Relatively new.
Not meant to be strictly enforced.
Lower than the NIOSH advisory level.
Unchanged since the 1940s and may not be protective.
10
10
10
10
g in a 24-hour period.
g in a 24-hour period.
g averaged over an 8-hour workday.
g averaged over an 8-hour workday.
Page 13 of 50
Beryllium Toxicity
Overview of
Risk of
Exposure
Occupational
Exposure
In What
Industries
Might Workers
Be Exposed to
Beryllium?
Beryllium disease was first noted in the 1930s in Europe. In the 1940s,
reports of disease related to beryllium surfaced among workers exposed
to beryllium-containing phosphors in the fluorescent lamp industry and
the nuclear weapons industry (Kress and Crispell 1944). Industry
standards and environmental controls for beryllium were initially
established in the late 1940s.
At least 134,000 current U.S. workers are estimated to be exposed to
beryllium, though precise numbers for the total number of workers
exposed to beryllium are unavailable (Henneberger et al. 2004). This
count does not include former workers, contract workers, and
construction workers exposed in beryllium using facilities. Outside the
United States, more and more industries are being identified with current
or former beryllium exposure (Newman et al. 2005; Glazer and Newman
2003).
Risk to workers depends considerably on their work tasks. For example,
machinists in both ceramics and nuclear weapons manufacture have
been found to have an increased risk of developing sensitization. This is
probably due to small respirable particles of beryllium (<10 microns) that
may be better able to deposit deep in the lungs. Other studies have
shown that laboratory workers and construction workers in berylliumusing facilities are also at increased risk. However, numerous individuals
with apparently trivial exposure, such as security guards, secretaries,
and bystanders, have also developed disease. This suggests that a linear
dose response may be absent. Inhaling metallic beryllium, beryllium
oxide, beryllium-copper and other alloys, or beryllium salts are the major
exposure risks leading to disease (Martyny et al. 2000; Sawyer et al.
2002; Willis and Florig 2002).
Industries and occupations with potential beryllium exposure include
aerospace,
automotive parts,
computers,
construction trades,
dental supplies and prosthesis manufacture,
electronics,
industrial ceramics,
laboratory workers,
metal recycling,
mining of beryl ore (beryl ore extraction),
nuclear weapons,
precision machine shops,
smelting/foundry,
tool and die manufacture, and
welding.
Page 14 of 50
Chronic
Beryllium
Disease (CBD)
Key Points
Progress
Check
Beryllium Toxicity
Page 15 of 50
Beryllium Toxicity
Page 16 of 50
Beryllium Toxicity
Overview of
Susceptibility
The Genetics
of Beryllium
Sensitization
and Disease
Key Points
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Beryllium Toxicity
9. The HLA-DP1 genes with the supratypic marker Glu69 may lead to
an increased risk to those exposed to beryllium by as much as
A.
B.
C.
D.
2-fold
20-fold
2-20-fold
No increased risk.
Page 18 of 50
Beryllium Toxicity
Acute versus
Chronic
Disease
Disorder
Bronchiolitis
Acute pneumonitis
Chronic beryllium disease
Lung cancer
Pulmonary hypertension*
Pneumothorax*
Skin
Contact dermatitis
Subcutaneous granulomatous nodules
Ulceration
Delayed wound healing
Lymphatic/ Hematologic
Page 19 of 50
Beryllium Toxicity
Respiratory
Effects: Acute
Respiratory
Effects: Chronic
Dermal Effects
Carcinogenic
Effects
Page 20 of 50
Beryllium Toxicity
those with acute beryllium disease (SMR = 2.32) than among those with
CBD (SMR = 1.57) (Steenland and Ward 1991). Increased lung cancer
among workers with higher beryllium exposures and lack of evidence for
confounding by cigarette smoking, provide further evidence that
beryllium is a human lung carcinogen (Sanderson et al. 2001).
Some researchers have disputed reported increased risk of lung cancer
in beryllium workers in published epidemiologic studies (Levy et al.
2002). In addition, mutation and chromosomal aberration assays have
yielded somewhat contradictory results. Only a limited number of
studies have addressed the underlying mechanisms of the
carcinogenicity and mutagenicity of beryllium.
Key Points
Progress Check
Page 21 of 50
Beryllium Toxicity
Clinical Assessment
Learning
Objectives
Introduction
History and
Physical
Examination
Signs and
Symptoms
nonproductive cough,
fatigue,
exertional dyspnea,
weight loss,
fever, and
myalgias.
The earliest clinical signs are scattered bibasilar crackles and wheezing.
As the disease progresses, lymphadenopathy may develop, along with
cyanosis, digital clubbing, and other signs of chronic lung disease (Glazer
and Newman 2003).
Beryllium can cause contact dermatitis. If beryllium penetrates the
patient's skin or enters open cuts, ulceration or subcutaneous tender
nodules can be seen, especially on exposed areas of skin. Cutaneous
granulomas can eventually appear. Although rare, cutaneous granulomas
can also be a manifestation of the systemic process of CBD, not
necessarily related to direct dermal contamination (Berlin et al. 2003).
Page 22 of 50
Beryllium Toxicity
asbestosis,
fungal disease,
hypersensitivity pneumonitis,
lymphangitic spread of carcinoma,
pulmonary hemosiderosis,
sarcoidosis,
silicosis, and
tuberculosis (Muller-Quernheim 2005).
CBD is often managed well with corticosteroids, but some patients do not respond to this
treatment and experience progressive fibrosis.
Initial
Laboratory
Evaluation
Page 23 of 50
BeLPT
Results
Reliability and
Sensitivity
Key Points
Beryllium Toxicity
The BeLPT is an in vitro immunologic test that can detect individuals who are
sensitized to beryllium and are at risk of progressing to CBD (Stange et al. 2004). The
BeLPT has revolutionized the approach to the diagnosis, screening, and surveillance of
beryllium health effects. The test is based on the development of a beryllium-specific,
cell-mediated immune response. The BeLPT has allowed us to define early health
effects of beryllium, including BeS, and CBD at an early stage (Maier 2001).
This test is performed in only a small number of specialized laboratories. The Where
Can I Find More Information? section lists some laboratories that perform this test in
the United States. Use of trade names and commercial sources is for
identification only and does not imply endorsement by the Agency for
Toxic Substances and Disease Registry or the U.S. Department of Health
and Human Services.
The clinical significance of the BeLPT was described, and a standard
protocol developed, in the late 1980s (Frome et al. 2003; Kreiss et al.
1989). In the BeLPT, a patients mononuclear cells are collected from
blood or bronchoalveolar lavage fluid and then cultured in vitro with and
without beryllium salts. Cell proliferation is measured by the
incorporation of tritiated thymidine in dividing cells. The berylliumspecific cellular immune response is then quantified and reported as a
stimulation index, which is the ratio of the counts per minute of
radioactivity in the cells stimulated by beryllium salts divided by the
counts per minute for that persons cells that have not been stimulated
with any beryllium (Barna et al. 2003).
Results may be reported as abnormal, uninterpretable, or negative. Two
or more abnormal results constitute possible sensitization of the patient
and warrant further work-up by a pulmonologist.
As in other immunologic tests, occasionally results are uninterpretable or
may not be perfectly reproducible (Newman 1996). Inter - and intralaboratory disagreement in results may exist between and within
laboratories that conduct this test (Bobka et al. 1997; Deubner et al.
2001). Nonetheless, the BeLPT is the best available assay and is
efficacious in medical surveillance of beryllium-exposed individuals.
The sensitivity of the BeLPT is estimated at 68%, with a specificity of
nearly 97% (Stange et al. 2004). (Confirmation of an abnormal result is
recommended to assure appropriate referral for CBD medical evaluation.)
The positive predictive value of the BeLPT is comparable to other widely
accepted medical tests and is better than other screening tools, including
pulmonary function testing, the chest radiograph, and the symptom
questionnaire (Glazer and Newman 2003; Stange et al. 2004).
CBD is often misdiagnosed as sarcoidosis.
The BeLPT provides a specific test to diagnose BeS and CBD.
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Beryllium Toxicity
Chest radiograph.
Pulmonary function tests.
ABGs.
All of the above.
Page 25 of 50
Beryllium Toxicity
Bronchoscopy
with Lavage
and Biopsy
Other Tests
Follow-Up
Laboratory
Tests
Patch testing: Patch testing for BeS has been used in the past.
However, beryllium patch testing fell out of favor, in part because of
a potential risk of inducing sensitization and a theoretical risk of
aggravating underlying disease.
Flow cytometric assays (immuno-BeLPT): T-lymphocyte flow
cytometry may provide a sensitive alternative to the traditional
BeLPT. It offers a test for sensitization without the use of radioactivity
and may prove to be easier to standardize for clinical use (Farris et
al. 2000; Milovanova et al. 2004).
Beryllium stimulated serum neopterin: Neopterin may be a
useful diagnostic adjunct in the noninvasive assessment of CBD.
Elevated levels differentiate CBD from BeS (Maier et al. 2003).
ELISPOT analysis: The frequency of beryllium-specific T cells in the
blood of beryllium-exposed subjects is measured using ELISPOT
analysis and may be a useful biomarker that helps discriminate
between BeS and progression to CBD (Pott et al. 2005).
Beryllium Toxicity
may be seen. Importantly, the HRCT may not show evidence of CBD
in many cases identified by BeLPT screening (Meyer 1994).
Overall
Approach to
the Workup of
CBD
Page 27 of 50
Beryllium Toxicity
Key Points
Bronchoscopy.
BAL.
Transbronchial biopsy.
All of the above.
Page 28 of 50
Beryllium Toxicity
Introduction
Who Should
Be Treated?
Indications for
Treatment
Treatment
with
Prednisone
Monitoring the
Disease
Page 29 of 50
Possible
Sequelae and
Management
Considerations
Importance of
Early
Detection and
Treatment
Preventive
Measures
Dermatologic
Management
Beryllium Toxicity
Page 30 of 50
Progress
Check
Beryllium Toxicity
Aspirin.
Prednisone.
MAO inhibitors.
Acyclovir.
Page 31 of 50
Beryllium Toxicity
Please refer to the following Web resources for more information on the
adverse effects of beryllium, the treatment of beryllium - associated
diseases, and management of persons exposed to beryllium.
CDC-INFO (www.bt.cdc.gov/coca/800cdcinfo.asp)
800-CDC-INFO (800-232-4636) TTY 888-232-6348 - 24
Hours/Day
E-mail: cdcinfo@cdc.gov
Page 32 of 50
General
Environmental
Health
Information
Beryllium Toxicity
o
o
o
o
The CDC works to protect public health and the safety of people,
by providing information to enhance health decisions, and
promotes health through partnerships with state health
departments and other organizations.
The CDC focuses national attention on developing and applying
disease prevention and control (especially infectious diseases),
environmental health, occupational safety and health, health
promotion, prevention and education activities designed to
improve the health of the people of the United States.
National Center for Environmental Health (NCEH)
(www.cdc.gov/nceh/)
Page 33 of 50
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Beryllium Toxicity
Page 35 of 50
Suggested
Reading
Beryllium Toxicity
Glazer CS, Newman LS. 2003. Chronic beryllium disease: dont miss the
diagnosis. J Respir Dis 24(8):35763.
Maier L, Newman LS. 1998. Beryllium disease. In: Rom WN (ed.),
Environmental and Occupational Medicine, 3rd Edition. Boston: Little,
Brown, and Company. pp. 102135.
Newman LS, Lloyd J, Daniloff E. 1996. The natural history of beryllium
sensitization and chronic beryllium disease. Environ Health Perspect
104(Suppl 5):93743.
Rossman MD. 2001. Chronic beryllium disease: a hypersensitivity
disorder. Appl Occup Environ Hyg 16(5): 6158.
Sawyer RT, Maier LA, Kittle LA, Newman LS. 2002. Chronic beryllium
disease: a model interaction between innate and acquired immunity. Int
Immunopharmacol 2(2-3): 24961.
Stange AW, Furman FJ, Hilmas DE. 2004. The Beryllium Lymphocyte
Proliferation Test: Relevant Issues in Beryllium Health Surveillance. Am J
Ind Med 46: 45362.
Laboratories
That Run the
Beryllium
Lymphocyte
Proliferation
Test
www.nationaljewish.org/dise
ase-info/diseases/occmed/beryllium/
Page 36 of 50
Beryllium Toxicity
www.specialtylabs.com/
Other CSEMs
Page 37 of 50
Beryllium Toxicity
Posttest Instructions
Introduction
ATSDR seeks feedback on this course so we can asses its usefulness and
effectiveness. We ask you to complete the assessment questionnaire
online for this purpose.
In addition, if you complete the assessment and posttest online, you can
receive continuing education credits as follows.
Accrediting
Credits Offered
Organization
Accreditation Council for The Centers for Disease Control and Prevention (CDC) is
Continuing Medical
accredited by the Accreditation Council for Continuing Medical
Education (ACCME)
Education (ACCME) to provide continuing medical education for
physicians. CDC designates this educational activity for a
maximum of 1.5 AMA PRA Category 1 Credit(s). Physicians
should only claim credit commensurate with the extent of their
participation in the activity.
American Nurses
This activity for 1.5 contact hours is provided by the Centers
Credentialing Center
for Disease Control and Prevention, which is accredited as a
(ANCC), Commission on provider of continuing education in nursing by the American
Accreditation
Nurses Credentialing Center's Commission on Accreditation.
National Commission for CDC is a designated provider of continuing education contact
Health Education
hours (CECH) in health education by the National Commission
Credentialing, Inc.
for Health Education Credentialing, Inc. The Centers for
(NCHEC)
Disease Control and Prevention is a designated provider of
continuing education contact hours (CECH) in health education
by the National Commission for Health Education Credentialing,
Inc. This program is a designated event for the Certified Health
Education Specialist (CHES) to receive 1.5 Category I contact
hours in health education, CDC provider number GA0082.
International
The Centers for Disease Control and Prevention (CDC) has
Association for
been reviewed and approved as an Authorized Provider by the
Continuing Education
International Association for Continuing Education and Training
and Training (IACET)
(IACET), Suite 800, McLean, VA 22102. CDC will award 0.15 of
CEU's to participants who successfully complete this program.
Disclaimer
Page 38 of 50
Instructions
Posttest
Beryllium Toxicity
10
10
10
10
Page 39 of 50
Beryllium Toxicity
Contact dermatitis.
Ulcerative granulomas.
Emphysema.
Interstitial pneumonitis.
Hypersensitivity.
Page 40 of 50
Beryllium Toxicity
Pneumococcal immunization.
Influenza immunization.
Corticosteroid therapy.
Excision of beryllium-contaminated cutaneous sites.
Page 41 of 50
Beryllium Toxicity
Relevant
Content
Question
Clinical assessment
8
Page 42 of 50
Beryllium Toxicity
Clinical assessment
11
Clinical assessment
12
Identify other tests that can assist with diagnosis of beryllium related
diseases
Identify the primary drug for treatment of chronic beryllium disease (CBD)
Page 43 of 50
Beryllium Toxicity
Literature Cited
References
Page 44 of 50
Beryllium Toxicity
Glazer CS, Newman LS. 2003. Chronic beryllium disease: dont miss the
diagnosis. J Respir Dis 24(8):35763.
Glazer CS, Newman LS. 2004. Occupational interstitial lung disease. Clin
Chest Med 25(3):46778.
Gordon T, Bowser D. 2003. Beryllium: genotoxicity and carcinogenicity.
Mutat Res 533(1-2):99105.
Grimaudo NJ. 2001. Biocompatibility of nickel and cobalt dental alloys.
Gen Dent 49(5):498503.
Henneberger PK, Cumro D, Deubner DD, Kent MS, McCawley M, Kreiss K.
2001. Beryllium sensitization and disease among long-term and shortterm workers in a beryllium ceramics plant. Int Arch Occup Environ Health
74(3):16776.
Henneberger PK, Goe SK, Miller WE, Doney B, Groce DW. 2004.
Industries in the United States with airborne beryllium exposure and
estimates of the number of current workers potentially exposed. J Occup
Environ Hyg 1:64859.
(IARC) International Agency for Research on Cancer. 2001. Overall
evaluations of carcinogenicity to humans. International Agency for the
Research on Cancer. Available at:
http://monographs.iarc.fr/ENG/Classification/crthgr01.php (updated 2001
December 18; cited 2007).
(IARC) International Agency for Research on Cancer. 1993. Beryllium and
beryllium compounds (Group 1). Vol. 58. Lyon, France: World Health
Organization. p. 41.
IRIS Integrated Risk Information System. 2002. Beryllium and
compounds. Integrated Risk Information System. Available at:
http://www.epa.gov/iris/subst/0012.htm (updated 2002 March 11; cited
2007).
Judd NL, Griffith WC, Takaro T, Faustman EM. 2003. A model for
optimization of biomarker testing frequency to minimize disease and cost:
example of beryllium sensitization testing. Risk Anal 23(6):121120.
Kelleher PC, Martyny JW, Mroz MM, Maier LA, Ruttenber AJ, Young DA, et
al. 2001. Beryllium particulate exposure and disease relations in a
beryllium machining plant. J Occup Environ Med 43(3):23849.
Kim Y. 2004. Acute beryllium disease in metal workers. Eur Respir J.
24:149S.
Kolanz ME, Madl AK, Kelsh MA, Kent MS, Kalmes RM, Paustenbach DJ.
2001. A comparison and critique of historical and current exposure
assessment methods for beryllium: implications for evaluating risk of
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103.
McCanlies EC, Kreiss K, Andrew M, Weston A. 2003. HLA-DP1 and
chronic beryllium disease: a HuGE review. American Journal of
Epidemiology 157:388-398.
McCanlies EC, Schuler CR, Kreiss K, Frye BL, Ensey JS, Weston A. 2007.
TNF-alpha polymorphisms in chronic beryllium disease and beryllium
sensitization. Journal of Occupational & Environmental Medicine. 49:446452.
Meyer KC. 1994. Beryllium and lung disease. Chest. 106:942-946.
Middleton DC. 1998. Chronic beryllium disease: uncommon disease, less
common diagnosis. Environ Health Perspect 106(12):7657.
Milovanova TN, Popma SH, Cherian S, Moore JS, Rossman MD. 2004.
Flow cytometric test for beryllium sensitivity. Cytometry B-Clin Cytom
60(1):2330.
Mller-Quernheim J, Kienast K, Held M, Pfeifer S, Costabel U. 1999.
Treatment of chronic sarcoidosis with an azathioprine/prednisolone
regimen. Eur Respir J 14:111722.
Mller-Quernheim J. Chronic beryllium disease. In: Orphanet
encyclopedia. Available at: http://www.orpha.net/data/patho/GB/ukCBD.pdf. (updated 2005 November; cited 2007
(NTP) National Toxicology Program. 1999. Report on Carcinogens
Background Document for Beryllium and Beryllium Compounds. Meeting
of the NTP Board of Scientific Counselors. Report on Carcinogens
Subcommittee. U.S. Department of Health and Human Services, Public
Health Service, National Toxicology Program, Research Triangle Park, NC.
(NTP) National Toxicology Program. 2002. Beryllium and beryllium
compounds. Vol. 10. Report on carcinogens: carcinogen profiles. Research
Triangle Park, North Carolina: National Toxicology Program.
Newman LS, Kreiss K. 1992. Nonoccupational beryllium disease
masquerading as sarcoidosis: identification by blood lymphocyte
proliferative response to beryllium. American Review of Respiratory
Disease. 145:1212-1214.
Newman LS, Lloyd J, Daniloff E. 1996. The natural history of beryllium
sensitization and chronic beryllium disease. Environ Health Perspect
104(Suppl 5):93743.
Newman LS, Maier L. 2001. Beryllium. In: Clinical environmental health
and toxic exposures. Sullivan J, Krieger G, editors. 2nd ed. Philadelphia:
Williams & Wilkins. p. 91926.
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Newman LS, Maier LA, Martyny JW, Mroz MM, VanDyke MV, Sackett HS.
2005. Letter to the editor: Beryllium workers' health risks. J Occup
Environ Hyg 2(6): D 4850.
Newman LS, Mroz MM, Balkissoon R, Maier LA. 2005. Beryllium
sensitization progresses to chronic beryllium disease: a longitudinal study
of disease risk. Am J Respir Crit Care Med 171:5460.
Newman LS, Mroz MM, Maier LA, Daniloff EM, Balkissoon R. 2001. Efficacy
of serial medical surveillance for chronic beryllium disease in a beryllium
machining plant. J Occup Environ Med 43(3):2317.
Newman LS. 1998. Metals that cause sarcoidosis. Semin Respir Infect
13:21220.
Newman LS. 1996. Significance of the blood beryllium lymphocyte
proliferation test. Environ Health Perspect 104(Suppl 5):9536.
Pappas GP, Newman LS. 1993. Early pulmonary physiologic abnormalities
in beryllium disease. Am Rev Respir Dis 148:6616.
Paustenbach DJ, Madl AK, Greene JF. 2001. Identifying an appropriate
occupational exposure limit (OEL) for beryllium: data gaps and current
research initiatives. Appl Occup Environ Hyg 16(5):52738.
Pott GB, Palmer BE, Sullivan AK, Silviera L, Maier LA, Newman LS, Kotzin
BL, Fontenot AP. 2005. Frequency of beryllium-specific, TH1-type
cytokine-expressing CD4+ T cells in patients with beryllium-induced
disease. J Allergy Clin Immunol 115(5):103642.
Richeldi L. Sorrentino R. Saltini C. 1993. HLA-DP1 glutamate 69: a
genetic marker of beryllium disease. Science. 262:242-244, .
Richeldi L, Kreiss K, Mroz MM, Zhen B, Tartoni P, Saltini C. 1997.
Interaction of genetic and exposure factors in the prevalence of
berylliosis. American Journal of Industrial Medicine. 32:337-340.
Rossman MD, Stubbs J, Lee CW, Argyris E, Magira E, Monos D. 2002.
Human leukocyte antigen Class II amino acid epitopes: susceptibility and
progression markers for beryllium hypersensitivity. American Journal of
Respiratory & Critical Care Medicine. 165:788-794.
Rossman MD. 2001. Chronic beryllium disease: a hypersensitivity
disorder. Appl Occup Environ Hyg 16(5):6158.
Rossman MD. 1996. Chronic beryllium disease: diagnosis and
management. Environ Health Perspect 104(Suppl 5):9457.
Saltini C, Amicosante M. 2001. Beryllium disease. Am J Med Sci 321(1):
8998.
Page 48 of 50
Beryllium Toxicity
Saltini C, Richeldi L, Losi M, Amicosante M, Voorter C. van den BergLoonen E, Dweik RA, Wiedemann HP, Deubner DC, Tinelli C. 2001. Major
histocompatibility locus genetic markers of beryllium sensitization and
disease. European Respiratory Journal. 18:677-684.
Sanderson WT, Ward EM, Steenland K, Petersen MR. 2001. National
Institute for Occupational Safety and Health. Lung cancer case-control
study of beryllium workers. Am J Ind Med 39(2):13344.
Sato H, Silveira L, Fingerlin T, Dockstader K, Gillespie M, Lagan AL,
Lympany P, Sawyer RT, du Bois RM, Welsh KI, Maier LA. 2007. TNF
polymorphism and bronchoalveolar lavage cell TNF-alpha levels in chronic
beryllium disease and beryllium sensitization. Journal of Allergy & Clinical
Immunology. 119:687-696.
Sawyer RT, Maier LA, Kittle LA, Newman LS. 2002. Chronic beryllium
disease: a model interaction between innate and acquired immunity. Int
Immunopharmacol 2(23):24961.
Sood A, Beckett WS, Cullen MR. 2004. Variable response to long-term
corticosteroid therapy in chronic beryllium disease. Chest 126:20007.
Stange AW, Furman FJ, Hilmas DE. 2004. The beryllium lymphocyte
proliferation test: relevant issues in beryllium health surveillance. Am J
Indust Med 46:45362.
Steenland K, Ward E. 1991. Lung cancer incidence among patients with
beryllium disease: a cohort mortality study. J Natl Cancer Inst
83(19):13805.
Stefaniak AB, Hoover MD, Day GA, et al. 2004. Characterization of
physicochemical properties of beryllium aerosols associated with
prevalence of chronic beryllium disease. J Environ Monit 6(6):52332.
Stonehouse AJ, Zenczak S. 1991. Properties, production processes, and
applications. In: Rossman MD, Preuss O, Powers MB, eds. Beryllium:
biomedical and environmental aspects. Baltimore: Williams and Wilkins,
pp. 276 655.
Taylor TP, Ding M, Ehler DS, Foreman TM, Kaszuba JP, Sauer NN. 2003.
Beryllium in the environment: a review. J Environ Sci Health A Tox Hazard
Subst Environ Eng 38(2):43969.
Tinkle SS, Antonini JM, Rich BA, Roberts JR, Salmen R, DePree K, et al.
2003. Skin as a route of exposure and sensitization in chronic beryllium
disease. Environ Health Perspect 111(9):12028.
Tinkle SS, Kittle LA, Newman LS. 1999. Partial IL-10 inhibition of the cellmediated immune response in chronic beryllium disease. J Immunol
163(5):274753.
Page 49 of 50
Beryllium Toxicity
Verma DK, Ritchie AC, Shaw ML. 2003. Measurement of beryllium in lung
tissue of a chronic beryllium disease case and cases with sarcoidosis.
Occup Med (London) 53(3):2237.
Wambach PF, Tuggle RM. 2000. Development of an eight-hour
occupational exposure limit for beryllium. Appl Occup Environ Hyg
15(7):5817.
Wang Z, White PS, Petrovic M, Tatum OL, Newman LS, Maier LA, Marrone
BL. 1999. Differential susceptibilities to chronic beryllium disease
contributed by different Glu69 HLA-DP1 and -DPA1 alleles. Journal of
Immunology. 163:1647-1653.
Wang Z, Farris GM, Newman LS, Shou Y, Maier LA, Smith HN, Marrone
BL. 2001. Beryllium sensitivity is linked to HLA-DP genotype. Toxicology.
165:27-38.
Weston A, Snyder J, McCanlies EC, Schuler CR, Andrew ME, Kreiss K,
Demchuk E. 2005. Immunogenetic factors in beryllium sensitization and
chronic beryllium disease. Mutation Research. 592:68-78.
Willis HH, Florig HK. 2002. Potential exposures and risks from berylliumcontaining products. Risk Anal 22(5):101933.
Page 50 of 50