BERYLLIUM-INDUCED DISEASES

Release Date:  March 18, 1999

PA NUMBER:  PA-99-075

P.T.

National Institute of Environmental Health Sciences
National Heart, Lung and Blood Institute
National Institute of Occupational Safety and Health
Department of Energy

PURPOSE

The purpose of this initiative is to encourage the support of scientific projects
designed to understand the cellular and molecular events that underlie the
transition from antigen sensitization to beryllium to chronic beryllium disease
in order to improve identification of markers of disease initiation and
progression for early therapeutic intervention and effective environmental
control strategies.  The mission of the National Institute of Environmental
Health Sciences (NIEHS) is to reduce the burden of human illness and dysfunction
from environmental exposures to chemical agents by understanding the interactions
between environmental exposures, individual susceptibility and time. Research
supported by the National Heart, Lung and Blood Institute (NHLBI) includes
scientific investigations on the cause of lung diseases and on their prevention,
diagnosis, and treatment with a focus on understanding the structure and function
of the respiratory system, increasing fundamental knowledge of mechanisms
associated with specific pulmonary disorders such as granulomatus diseases, and
applying new findings to evolving treatment strategies for patients.  The mission
of the National Institute of Occupational Safety and Health (NIOSH) is to
identify and prevent causes of work related diseases and injuries and the
potential hazards of new work technologies from chemicals, machinery and
hazardous working conditions.  The mission of the Department of Energy (DOE)
includes supporting research on health risks associated with defense and non-
defense applications of nuclear energy, which have led to occupational exposures
to beryllium at many DOE facilities.  Metals are unique among pollutants that
cause adverse health effects among humans in that they occur naturally and are
ubiquitous in the environment.  Exposure to beryllium can occur when it is mined,
processed or converted into metals, alloys and chemicals.  The U.S. is the
leading producer and consumer of beryllium and its alloys.  Although beryllium
is a naturally occurring substance, the major source of its emission into the
environment is the combustion of fossil fuels, primarily coal, which releases
beryllium-containing particulates and fly ash into the atmosphere.  The chemical
form of beryllium is an important factor in its bioavailability and toxicology. 
Acute beryllium disease is caused by relatively water-soluble compounds of
beryllium; chronic beryllium disease is caused by metal and relatively insoluble
compounds of beryllium.  Bioaccumulation of beryllium in the food chain is
considered to be insignificant.

Chronic beryllium disease (CBD) is an occupationally acquired lung disease
similar clinically to other granulomatous diseases, such as sarcoidosis,
schistosomiasis and tuberculosis.  The disease process begins as a sensitizing
cell-mediated immune response to beryllium antigen which develops into a
noncaseating granuloma.  The most significant exposure to beryllium occurs in the
occupational setting.  Workers potentially exposed are those engaged in primary
production, metal machining and reclaiming scrap alloys.

Although acute beryllium disease occurs rarely today, chronic beryllium disease
(CBD, or berylliosis) continues to occur in industries where beryllium and its
alloys are smelted, fabricated and machined.  Acute beryllium disease acts as a
direct chemical irritant causing a non-specific inflammatory reaction.  Chronic
beryllium disease is typically a progressive pulmonary granulomatosis.  A small
percentage of exposed persons (1-6%) develop beryllium hypersensitivity and
chronic disease with attack rates up to 16% in selected worker populations with
higher exposures.

Beryllium exposure occurs primarily by inhalation and contact through broken
skin.  Inhaled beryllium is solubilized in the lungs and distributed primarily
to bone, liver and kidneys.  Most beryllium is excreted in the urine, the
pulmonary half-life ranges from several weeks to six months; however, relatively
insoluble chemical forms of beryllium may be retained for years.  In chronic
disease, the alveoli contain small interstitial granulomata which resemble those
seen in sarcoidosis.  As the disease progresses, the granulomas become organized
and eventually form small, fibrous nodules, and there is progressive impairment
of pulmonary function.

Recent immunologic evidence suggests that the key pathogenic event in CBD is a
cell-mediated hypersensitivity reaction to beryllium bound to tissue proteins. 
Following inhalation of beryllium, large numbers of CD+4 lymphocytes accumulate
in the lungs and elevated helper/suppressor T-cell ratios in the pulmonary
lymphocyte population has been found.  These helper T-cells demonstrate a marked
proliferative response on exposure to beryllium. The lymphocyte proliferation
response is the basis for the current screening test, the blood Lymphocyte
Proliferation Test (LPT), to detect beryllium hypersensitivity.

HEALTHY PEOPLE 2000

The Public Health Service (PHS) is committed to achieving the health promotion
and disease prevention objectives of "Healthy People 2000," a PHS-led national
activity for setting priority areas.  This Program Announcement (PA), Beryllium-
Induced Diseases, is related to one or more of the priority areas.  Potential
applicants may obtain a copy of "Healthy People 2000" at
http://www.crisny.org/health/us/health7.html.

ELIGIBILITY REQUIREMENTS

Applications may be submitted by domestic and foreign, for-profit and non-profit
organizations, public and private, such as universities, colleges, hospitals,
laboratories, units of State and local governments, and eligible agencies of the
Federal government.  Racial/ethnic minority individuals, women, and persons with
disabilities are encouraged to apply as Principal Investigators.

MECHANISM OF SUPPORT

This PA will use the National Institutes of Health (NIH) research project grant
(R01) award mechanism.  Responsibility for the planning, direction, and execution
of the proposed project will be solely that of the applicant.  The total project
period for an application submitted in response to this PA may not exceed five
years.

RESEARCH OBJECTIVES

The goal of this proposed research initiative is to encourage and support studies
which will advance our understanding of the mechanisms of chronic beryllium
disease.  Current knowledge, as well as areas where new information is needed,
was reviewed in a  conference on beryllium-related diseases sponsored by the
NIEHS in Research Triangle Park, North Carolina, (Environmental Health
Perspectives, 104:935-1000, 1996) and a recent workshop at NIEHS in May, 1998. 
The participating institutes and agencies are interested in supporting research
in (but not limited to) the following areas:

1.  Genetic Basis of Beryllium Sensitivity and Development of CBD

Information is needed regarding the genetic basis for the disease to:

o  identify the specific site(s) in the genetic material (genome DNA) responsible
for the susceptibility to CBD especially the major histocompatibility complex
(MHC) locus thought to be responsible for the class II - restricted lymphocytes
that accumulate in CBD,

o  develop tests capable of identifying individuals in the population who have
a genetic susceptibility to beryllium sensitivity, and

o  determine the mechanisms by which beryllium may interact at specific gene loci
and alter the regulation of gene expression.

2.  Inflammation and Granuloma Formation

Beryllium not only has antigen-specific effects, but also acts in non-specific
inflammatory ways to promote the cellular events leading to granuloma formation. 
Emerging science suggests that beryllium induces changes in lung permeability,
production of proinflammatory cytokines and growth factors that lead to
fibroblast granuloma formation and maintenance.  Studies of beryllium related
inflammatory events, plus antigen-specific events in CBD and beryllium
sensitization and mechanisms leading to the maintenance of fibrotic and
granulomatous response in CBD will be considered responsive to this program
announcement.

3.  Development of in Vitro and in Vivo Models of Beryllium Sensitivity

These should include, but not be restricted to:

o  in vitro and in vivo models of beryllium sensitivity to investigate the
phenotypic and genetic properties of sensitized cells and the molecular events
involved in  the pathogenesis of CBD,

o  an appropriate animal model designed to implement basic research programs to
address fundamental dose-response, exposure assessment and risk assessment
issues, that are not possible or convenient to obtain in any other way, and

o  in vitro models useful to characterize sensitive sites or receptors in
cultures of mononuclear cells, such as identification of sites sensitized by
elemental beryllium on cultured macrophages, and transfection of exogenous DNA
on clones of sensitized cells.

4.  Biomarkers of Beryllium Sensitivity and Progression of CBD

Biomarkers are needed for recognition of exposure, detection of sensitivity, 
assessing prognosis and the likelihood of progression to more advanced and
fibrotic outcomes, and markers of response to therapy.

5.  Methods of Prevention

There is a need to:

o  identify industrial hygiene and medical surveillance programs to prevent CBD,

o  develop exposure assessment methods to include measurement of the inhaled dose
of beryllium, particle size characteristics, solubility and other chemical
characteristics that confer risk of beryllium sensitization of disease,

o  assess the effectiveness of medical surveillance tools and development of
innovative surveillance algorithms for the appropriate detection and management
of people with beryllium sensitization or CBD,

o  use in vitro and preclinical studies to ultimately contribute to the
development of novel approaches to CBD treatment through regulation of beryllium
inflammatory and antigenic events, and

o  determine the rate of progression from beryllium sensitization to CBD, and to
identify host and environmental factors that contribute to risk of disease
progression.

INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS

It is the policy of the NIH that women and members of minority groups and their
subpopulations must be included in all NIH supported biomedical and behavioral
research projects involving human subjects, unless a clear and compelling
rationale and justification is provided that inclusion is inappropriate with
respect to the health of the subjects or the purpose of the research. This policy
results from the NIH Revitalization Act of 1993 (Section 492B of Public Law
103-43.

All investigators proposing research involving human subjects should read the
"NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical
Research," which was published in the Federal Register of March 28, 1994 (FR 59
14508-14513) and in the NIH Guide for Grants and Contracts, Vol. 23, No. 11,
March 18, 1994, available on the web at: 
http://grants.nih.gov/grants/guide/notice-files/not94-100.html.

INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS

It is the policy of NIH that children (i.e., individuals under the age of 21)
must be included in all human subjects research, conducted or supported by the
NIH, unless there are scientific and ethical reasons not to include them. This
policy applies to all initial (Type 1) applications submitted for receipt dates
after October 1, 1998.

All investigators proposing research involving human subjects should read the
"NIH Policy and Guidelines" on the Inclusion of Children as Participants in
Research Involving Human Subjects that was published in the NIH Guide for Grants
and Contracts, March 6, 1998, and is available at the following URL address: 
http://www.nih.gov/grants/guide/notice-files/not98-024.html

Investigators also may obtain copies of these policies from the program staff
listed under INQUIRIES.  Program staff may also provide additional relevant
information concerning the policy.

APPLICATION PROCEDURES

Applications are to be submitted on the grant application form PHS 398 (rev.
4/98) and will be accepted at the standard application receipt dates indicated
in the application kit.  These forms are available at most institutional offices
of sponsored research and from the Division of Extramural Outreach and
Information Resources, National Institutes of Health, 6701 Rockledge Drive, MSC
7910, Bethesda, MD 20892-7910, telephone 301/435-0714, email: 
GrantsInfo@nih.gov.  Application kits are also available at:
http://www.nih.gov/grants/forms.htm

Applicants planning to submit an investigator-initiated new (type 1), competing
continuation (type 2), competing supplement, or any amended/revised version of
the preceding grant application types requesting $500,000 or more in direct costs
for any year are advised to contact the Institute or Center (IC) program staff
before submitting the application, i.e., as plans for the study are being
developed.  The applicant must obtain agreement from the IC staff that the IC
will accept the application for consideration for award.  Finally, the applicant
must identify, in a cover letter sent with the application, the staff member and
Institute or Center who agreed to accept assignment of the application.  Refer
to the NIH Guide for Grants and Contracts, March 20, 1998 at
http://www.nih.gov/grants/guide/notice-files/not98-030.html.

The title and number of the program announcement must be typed on line 2 of the
face page of the application form, and the YES box must be marked.

Submit a signed, typewritten original of the application, including the
Checklist, and three signed, photocopies, in one package to:

CENTER FOR SCIENTIFIC REVIEW
NATIONAL INSTITUTES OF HEALTH
6701 ROCKLEDGE DRIVE, ROOM 1040, MSC 7710
BETHESDA, MD 20892-7710
BETHESDA, MD 20817 (for express/courier service)

REVIEW CONSIDERATIONS

Applications will be assigned on the basis of established PHS referral
guidelines.  An appropriate scientific review group convened in accordance with
the standard NIH peer review procedures will evaluate applications for scientific
and technical merit.  As part of the initial merit review, all applications will
receive a written critique and undergo a process in which only those applications
deemed to have the highest scientific merit, generally the top half of
applications under review, will be discussed, assigned a priority score, and
receive a second level review by the appropriate national advisory council or
board.

Review Criteria

The goals of NIH-supported research are to advance our understanding of
biological systems, improve the control of disease, and enhance health. In the
written comments reviewers will be asked to discuss the following aspects of the
application in order to judge the likelihood that the proposed research will have
a substantial impact on the pursuit of these goals. Each of these criteria will
be addressed and considered in assigning the overall score, weighting them as
appropriate for each application. Note that the application does not need to be
strong in all categories to be judged likely to have major scientific impact and
thus deserve a high priority score. For example, an investigator may propose to
carry out important work that by its nature is not innovative but is essential
to move a field forward.

(1) Significance: Does this study address an important problem? If the aims of
the application are achieved, how will scientific knowledge be advanced? What
will be the effect of these studies on the concepts or methods that drive this
field?

(2) Approach: Are the conceptual framework, design, methods, and analyses
adequately developed, well-integrated, and appropriate to the aims of the
project? Does the applicant acknowledge potential problem areas and consider
alternative tactics?

(3) Innovation: Does the project employ novel concepts, approaches or method? Are
the aims original and innovative? Does the project challenge existing paradigms
or develop new methodologies or technologies?

(4) Investigator: Is the investigator appropriately trained and well suited to
carry out this work? Is the work proposed appropriate to the experience level of
the principal investigator and other researchers (if any)?

(5) Environment: Does the scientific environment in which the work will be done
contribute to the probability of success? Do the proposed experiments take
advantage of unique features of the scientific environment or employ useful
collaborative arrangements? Is there evidence of institutional support?

In addition to the above criteria, in accordance with NIH policy, all
applications will also be reviewed with respect to the following:

o The adequacy of plans to include both genders, minorities and their subgroups,
and children as appropriate for the scientific goals of the research. Plans for
the recruitment and retention of subjects will also be evaluated.

o The reasonableness of the proposed budget and duration in relation to the
proposed research.

o The adequacy of the proposed protection for humans, animals or the environment,
to the extent they may be adversely affected by the project proposed in the
application.

AWARD CRITERIA

Applications will compete for available funds with all other approved
applications.  The following will be considered in making funding decisions;
quality of the proposed project as determined by peer review availability of
funds, and institutional program priority.

INQUIRIES

Inquiries concerning this Program Announcement are encouraged. The opportunity
to clarify any issues or questions from potential applicants is welcome.

Direct inquiries regarding programmatic issues to:

Dr. George Malindzak
Organs and Systems Toxicology Branch
National Institute of Environmental Health Sciences
P.O. Box 12233, MD EC-23
111 T. W. Alexander Drive, East Campus, Rm. 3415
Research Triangle Park, NC  27709
Telephone:  (919) 541-3289
FAX:  (919) 541-5064
Email:  malindzak@niehs.nih.gov

Robert Musson, Ph.D.
Division of Lung Biology and Disease Program
National Heart, Lung and Blood Institute
6701 Rockledge Drive, Room 10108, MSC 7952
Bethesda, MD  20892-7952
Telephone: (301) 435-0222
FAX:  (301) 480-3557
Email:  mussonr@gwgate.nhlbi.nih.gov

Roy M. Fleming, Sc.D.
National Institute for Occupational Safety and Health
Center for Disease Control and Prevention
1600 Clifton Road, NE
Building 1, Room 3053, MS-D30
Atlanta, GA  30333
Telephone:  (404) 639-3343
FAX:  (404) 639-4616
Email:  rmf2@cdc.gov

Paul J. Seligman, M.D., M.P.H.
Deputy Assistant Secretary
Office of Health Studies
Department of Energy
19901 Germantown Road
Germantown, MD  20874
Telephone:  (301) 903-5926
FAX:  (301) 903-3445
Email:  paul.seligman@eh.doe.gov

Direct inquiries regarding fiscal matters to:

Mr. David Mineo
Division of Extramural Research and Training
National Institute of Environmental Health Sciences
P.O. Box 12233, MD EC-22
111 T. W. Alexander Drive, East Campus
Research Triangle Park, NC 27709
Telephone: (919) 541-1373
Fax: (919) 541-2860
Email: mineo@niehs.nih.gov

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance No.
93.113, 93.854 and 93.242.  Awards are made under authorization of the Public
Health Service Act, Title IV, Part A (Public Law 78-410, as amended by Public Law
99-158, 42 USC 241 and 285) and administered under PHS grants policies and
Federal Regulations 42 CFR 52 and 45 CFR Part 74. This program is not subject to
the intergovernmental review requirements of Executive Order 12372 or Health
Systems Agency review.

The PHS strongly encourages all grant recipients to provide a smoke-free
workplace and promote the non-use of all tobacco products. In addition, Public
Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain
facilities (or in some cases, any portion of a facility) in which regular or
routine education, library, day care, health care, or early childhood development
services are provided to children. This is consistent with the PHS mission to
protect and advance the physical and mental health of the American people.


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