Full Text ES-92-04

OZONE:  MECHANISMS OF ACTION

NIH GUIDE, Volume 21, Number 26, July 17, 1992

RFA:  ES-92-04

P.T. 34

Keywords: 
  Air Pollution 
  Toxicology 


National Institute of Environmental Health Sciences
National Heart, Lung, and Blood Institute

Application Receipt Date:  November 24, 1992

PURPOSE

The mission of the National Institute of Enviornmental Health Sciences
(NIEHS) is to provide scientific knowledge for the prevention and
amelioration of untoward health effects due to exposure to
environmental agents.  Under the Clean Air Act (CAA) Amendments of
1990, the NIEHS has been directed to conduct a program of basic
research related to the health effects of exposure to air pollution,
particularly ozone, and to assure that such programs do not conflict
with research undertaken by the Administrator of the Environmental
Protection Agency (EPA).  In addition, the National Heart, Lung, and
Blood Institute (NHLBI) has an interest in understanding the pathologic
and/or biologic changes resulting from inhalation of ozone.  To this
end, the NIEHS, NHLBI, and EPA participated in workshops convened for
the specific purpose of identifying and assigning priorities to key
research needs with an emphasis on the health effects and risks of
chronic ozone exposure and the mechanisms by which exposure to ozone
exacerbates or amplifies lung diseases.  In this context, chronic ozone
exposure is considered to be a condition or a set of conditions that
results in continuous exposure to ozone at or above current National
Ambient Air Quality Standards (NAAQS) levels for a relatively long
period of time, the intermittent exposure at these levels of ozone
repeatedly for a relatively long period of time, or some appropriate
combination of the continuous and intermittent exposure over a long
period of time.  The recommendations from the workshop were that
aggressive research programs should be encouraged and supported in the
following areas:  (a) biomarkers of exposure and effect, (b) mechanisms
of action, and (c) epidemiology.  To address the problems identified,
the NIEHS and the NHLBI solicit applications for studies related to the
mechanisms of the health effects and better understanding of the risks
associated with prolonged ozone exposure and the development of
biomarkers that can predict the effects.

HEALTHY PEOPLE 2000

The Public Health Service (PHS) is committed to achieving the health
promotion and disease prevention objectives of "Health People 2000," a
PHS-led national activity for setting priority areas.  This Request For
Application (RFA), Ozone:  Mechanisms of Action, is related to the
priority area of environmental health.  Potential applicants may obtain
a copy of "Healthy People 2000" (Full Report:  Stock No.
017-001-00474-0) or "Healthy People 2000" (Summary Report:  Stock No.
017-001-00473-1) through the Superintendent of Documents, Government
Printing Office, Washington DC  20402-9325 (telephone 202-783-3238).

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.
Applications from minority individuals and women are encouraged.

MECHANISM OF SUPPORT

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

This RFA is a one-time solicitation.  Future unsolicited competing
continuation applications will compete with all investigator-initiated
applications and be reviewed according to the customary peer review
procedures.

FUNDS AVAILABLE

The estimated funds (total costs) available for the first year of
support for the entire program is $1.8 million.  The expected of number
of awards is approximately nine; six to be funded by the NIEHS and
three by the NHLBI.

This level of support is dependent on the receipt of a sufficient
number of applications of high scientific merit. Although this program
is provided for in the financial plans of the NIEHS and the NHLBI,
awards pursuant to this RFA are contingent upon the availability of
funds for this purpose.  Support will not be provided under this RFA
for research activities focused exclusively on clinical trials or the
initiation of large scale epidemiology studies.

RESEARCH OBJECTIVES

Ozone is the major oxidant in photochemical smog.  The current ambient
air quality standard in the USA for ozone, established in 1978, is 0.12
ppm as a daily maximum with a one-hour averaging time, not to be
exceeded more than four times in three years. This standard was based
primarily on integration of scientific data available from controlled
animal exposure studies, human exposure studies, and epidemiological
studies which reported respiratory function impairment following
short-term ozone exposure (1,9,10).  However, in the ambient air in the
US, a one-hour ozone peak of 0.12 ppm is, on average, associated with
a maximum 8-hour average concentration of 0.10 ppm.  Recent 6.6 hour
EPA chamber studies of 0.08 - 0.12 ppm have reported progressive
decrement of lung function demonstrating that the effects of ozone on
lung function may be cumulative (6,7) at least over a single day's
exposure.

A great deal of the past and current research on humans has focused on
respiratory functions, especially on the acute responses to short-term
exposures to ozone.  For the most part, research has been conducted on
healthy young subjects.  The lung function effects appear to be
dose-dependent where dose is a product of concentration, duration of
exposure, and lung ventilation.  Although the lung function effects
have been reasonably well described, the range of responses in both
healthy and asthmatic subjects has been wide, the reproducibility of
responses is not fully characterized and the mechanisms underlying the
dysfunctions are still unclear (4).  The data indicate that a response
to ozone is a complex process involving a wide range of physiological,
cellular and biochemical changes (11).  It is not known whether ozone
triggers the bronchoconstrictive response directly by altering the
irritability of the airway smooth muscle or indirectly by the
stimulation of receptors in the deep lung (5).  In addition, a recent
report indicates that, in the presence of ozone, the responsiveness of
the airways to other agents and allergens which triggers asthma may be
increased (8).

A case has been made for the possible relationship between
environmental ozone exposure and asthma-related hospital admissions.
Ambient ozone is suggested as the potential offender in the development
of increased airway reactivity which is manifested by an increase in
asthma-related hospital admissions (12).  Furthermore, very little is
known about the effects of ozone on subjects with chronic obstructive
pulmonary disease.  As a consequence, the human health effects
associated with acute and relatively short-term exposure to this
pollutant, particularly in sensitive population groups, remain
uncertain.  The human health effects of serial recurring acute
exposures to ozone are even less clear.

In animals, ozone exposure has been shown to affect the structure and
function of the respiratory tract in a variety of ways.  Acute and
subacute exposure studies have demonstrated changes in various
functional endpoints, including mucus secretions, inflammatory response
involving macrophage, as well as basic ventilatory mechanisms.  For
example, the effects of ozone on the mucociliary particle clearance in
rats and rabbits exposed to 0.1 - 1.2 ppm for 2-4 hours showed a
concentration- dependent trend of reduced clearance rate.  But contrary
to animal observations (2,3) which show retarded mucociliary clearance
in response to ozone exposure, humans studies with 0.2 and 0.4 ppm for
2 hours showed accelerated clearance (10).

Structural changes in the respiratory acinus also have been reported in
animal studies.  The similarity of responses in animals suggest similar
relationships between ozone exposure and respiratory responses in
humans, but there is no clear evidence for such a relationship.
Moreover, the human health significance of possible localized
structural changes and the role of transient functional, cellular, and
biochemical responses in the pathogenesis of lung disease as a
consequence of ozone exposure is also not clearly understood.
Furthermore, the limited evidence from animal studies that long-term
exposures to ozone at expected ambient concentrations can cause
substantial histological and related physiological abnormalities needs
to be explored in humans, as current information under these conditions
does not allow prediction of long-term and permanent health effects
resulting from chronic ozone exposure.

In summary, the combination of ozone concentration profiles, duration
of exposure and ventilation, and frequency of ozone exposure which
might bring about a change in human lung function is not well
understood.  The mechanisms responsible for the observed changes are
not clear.  The National Ambient Air Quality Standard for ozone is
based on a maximum one-hour average while it is well known that the
human population is often exposed to ozone levels exceeding this
standard for 6 to 11 hours repeatedly over a period of 1-4 days.  These
issues are important to public health and welfare, particularly to
children, the aging population and individuals with pre-existing
respiratory disease conditions.

Other

The goal of the NIEHS and NHLBI in this solicitation is to determine
the relationships and mechanisms of health effects in long-term
environmental exposures to ozone.  Basic research applications
utilizing animal, clinical and existing data from both epidemiological
studies and large-scale health and air monitoring records are
solicited.  This research may include studies to identify the
physiological effects of ozone exposure as well as studies to determine
the underlying cause for such effects.  Research toward understanding
the chronic and relative permanency of health effects resulting from
long-term and multiple exposure to ozone, the degree to which
biological function has been compromised as a consequence of exposure,
and the extent to which the health effects are physiologically and/or
pathologically progressive or regressive is specifically requested.  In
the evaluation of these effects, it is suggested that realistic levels
of exposure to ozone be utilized.  Although higher than normal ozone
levels may be appropriate for parts of a study, the relevance of study
objectives to human health will be used as review criterion for
funding.  In addition, encouragement is given to studies examining the
time-course and persistence of the effects, as well as individual
sensitivity and responsiveness, e.g. seasonal and age variations, as
well as pre-existing disease conditions.  The use of existing
information derived from epidemiological, human clinical and field
studies, and animal models is also appropriate.

Examples of areas that would be considered appropriate for
investigation under this RFA include:

o  Is there a threshold for permanent damage by ozone exposure (i.e.,
biomarkers of responses associated with irreversible physiologic
dysfunction associated with exposure)?

o  What is the mechanism of action of ozone (i.e., the role of
receptors, mediators, etc.)?

o  What is the sequence of pathophysiological reactions that occur in
lung tissue in response to the inhalation of ozone i.e., the primary
and secondary chemical reaction products, their loci, and the
mechanisms and nature of their toxic effects.

o  What is the relative health impact of different patterns of ozone
exposure (i.e., mixture, frequency and duration of exposure)?

o  What are the temporal mechanisms of the progression of health
effects due to ozone exposure and are they reversible (i.e., the time
course of development and recovery processes of injury due to exposure
and the effects of ozone on the natural aging process in the lung)?

o  How are genetic factors and existing pulmonary diseases related to
the mechanism of response to ozone (i.e., identification of genetic and
disease elements which influence the control of and susceptibility to
ozone exposure)?

o  What is the mechanistic basis for the impact of other stimuli on
ozone sensitivity (i.e., the synergistic and antagonistic effect of
ozone exposure singly and in combination with other environmental
agents such as acid and particulate matter on pulmonary and
non-pulmonary homeostatic control mechanisms)?

STUDY POPULATIONS

SPECIAL INSTRUCTIONS TO APPLICANTS REGARDING IMPLEMENTATION OF NIH
POLICIES CONCERNING INCLUSION OF WOMEN AND MINORITIES IN CLINICAL
RESEARCH STUDY POPULATIONS

NIH and ADAMHA policy is that applicants for NIH/ADAMHA clinical
research grants and cooperative agreements will be required to include
minorities and women in study populations so that research findings can
be of benefit to all persons at risk of the disease, disorder or
condition under study; special emphasis should be placed on the need
for inclusion of minorities and women in studies of diseases, disorders
and conditions which disproportionately affect them.  This policy is
intended to apply to males and females of all ages.  If women or
minorities are excluded or inadequately represented in clinical
research, particularly in proposed population-based studies, a clear
compelling rationale should be provided.

The composition of the proposed study population must be described in
terms of gender and racial/ethnic group, together with a rationale for
its choice.  In addition, general and racial/ethnic issues should be
addressed in developing a research design and sample size appropriate
for the scientific objectives of the study.  This information should be
included in the form PHS 398 in Sections 1-4 of the Research Plan and
summarized in Section 5, Human Subjects.

Applicants are urged to assess carefully the feasibility of including
the broadest possible representation of minority groups.  However, NIH
recognizes that it may not be feasible or appropriate in all research
projects to include representation of the full array of United States
racial/ethnic minority populations (i.e., Native Americans (including
American Indians or Alaskan Natives), Asian/Pacific Islanders, Blacks,
Hispanics).

The rationale for studies on single minority population groups should
be provided.

For the purpose of this policy, clinical research includes human
biomedical and behavioral studies of etiology, epidemiology, prevention
(and prevention strategies), diagnosis, or treatment of diseases,
disorders or conditions, including but not limited to clinical trials.

The usual NIH policies concerning research on human subjects also
apply.  Basic research or clinical studies in which human tissues
cannot be identified or linked to individuals are excluded.  However,
every effort should be made to include human tissues from women and
racial/ethnic minorities when it is important to apply the results of
the study broadly, and this should be addressed by applicants.

For foreign awards, the policy on inclusion of women applies fully;
since the definition of minority differs in other countries, the
applicant must discuss the relevance of research involving foreign
population groups to the United States' populations, including
minorities.

If the required information is not contained within the application,
the application will be returned.

Peer reviewers will address specifically whether the research plan in
the application conforms to these policies.  If the representation of
women or minorities in a study design is inadequate to answer the
scientific question(s) addressed and the justification for the selected
study population is inadequate, it will be considered a scientific
weakness or deficiency in the study design and will be reflected in
assigning the priority score to the application.

All applications for clinical research submitted to NIH are required to
address these policies.  NIH funding components will not award grants
or cooperative agreements that do not comply with these policies.

APPLICATIONS PROCEDURES

The research grant application form PHS 398 (rev. 9/91) is to be used
in applying for these grants.  These forms are available at most
institutional business offices from the Office of Grants Inquiries,
Division of Research Grants, National Institutes of Health, 5333
Westbard Avenue, Room 449, Bethesda, MD  20892, telephone (301)
496-7441.

The RFA label available in the PHS 398 application form must be affixed
to the bottom of the face page of the application.  Failure to use this
label could result in delayed processing of the application such that
it may not reach the review committee in time for review.  In addition,
the RFA title and number must be typed on line 2a 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:

Division of Research Grants
National Institutes of Health
Westwood Building, Room 240
Bethesda, MD  20892**

At the time of submission, two additional copies of the application
must also be sent to:

Mr. David L. Mineo
Grants Management Officer
Grants Management Branch
Division of Extramural Research and Training
National Institute of Environmental Health Sciences
104 T.W. Alexander Drive
P.O. Box 12233
Research Triangle Park, NC  27709
Telephone:  (919) 541-1373

Copies of applications will be sent to the Grants Management Officer,
NHLBI.

Applications must be received by November 24, 1992.  If an application
is received after that date, it will be returned to the applicant
without review.  The Division of Research Grants (DRG) will not accept
any application in response to this announcement that is essentially
the same as one currently pending initial review, unless the applicant
withdraws the pending application.  The DRG will not accept any
application that is essentially the same as one already reviewed.  This
does not preclude the submission of substantial revisions of
applications already reviewed, but such applications must include an
introduction
addressing the previous critique.

REVIEW CONSIDERATIONS

Upon receipt, applications will be reviewed by NIH staff for
completeness and responsiveness.  Incomplete applications will be
returned to the applicant without further consideration.  If the
application is not responsive to the RFA, NIEHS or NHLBI staff will
contact the applicant to determine whether to return the application to
the applicant or submit it for review in competition with unsolicited
applications at the next review cycle.  Those applications that are
complete and responsive will be evaluated in accordance with the
criteria stated below for scientific/technical merit by an appropriate
peer review group convened by the NIEHS and NHLBI.  The second level of
review will be provided by the National Advisory Environmental Health
Sciences Council or the National Heart, Lung, and Blood Advisory
Council.

Review criteria for RFAs are generally the same as those for
unsolicited research grant applications.

o  scientific, technical, or medical significance and originality of
proposed research;

o  appropriateness and adequacy of the experimental approach and
methodology proposed to carry out the research;

o  qualifications and research experience of the Principal Investigator
and staff, particularly, but not exclusively, in the area of the
proposed research;

o  availability of resources necessary to perform the research;

o  appropriateness of the proposed budget and duration in relation to
the proposed research;

An additional criterion for this RFA is:

o  the liklihood that this research will achieve a better understanding
of the mechanisms of chronic and permanency of health effects resulting
from long-term and multiple exposure to ozone, the degree to which
biological function has been compromised as a consequence of exposure,
and the extent to which health effects are progressive or regressive.

Applications will, be assigned according to extant PHS Referral
Guidelines.  For developing programs that deal with clinical
populations, applicants may wish to consider utilization of General
Clinical Research Center (GCRC) facilities.  More information on the
GCRC program is available from Dr. Judith Vaitukaitis at the National
Center for Research Resources, telephone (301) 496-6595.

AWARD CRITERIA

The anticipated date of award is July 1, 1993.

Applications will compete for available funds with all other approved
applications assigned to that ICD.  The following will be considered
making funding decisions:

o  Quality of the proposed project as determined by peer review

o  Availability of funds

o  Program balance among research areas of the announcement.

INQUIRIES

Written and telephone inquiries concerning this RFA are encouraged.
The opportunity to clarify any issues or questions from potential
applicants is welcome.

Direct inquiries regarding programmatic issues to:

George S. Malindzak, Jr., Ph.D.
Program Administrator
Scientific Programs Branch
Division of Extramural Research and Training
National Institute of Environmental Health Sciences
P.O. Box 12233
Research Triangle Park, NC  27709
Telephone:  (919) 541-3289

or

James P. Kiley, Ph.D.
Chief, Airways Diseases Branch
Division of Lung Diseases
National Heart, Lung, and Blood Institute
Westwood Building, Room 6A15
Bethesda, MD  20892
Telephone:  (301) 496-7332

Direct inquiries regarding fiscal matters to:

Mr. David L. Mineo
Grants Management Officer
Grants Management Branch
Division of Extramural Research and Training
National Institute of Environmental Health Sciences
P.O. Box 12233
Research Triangle Park, NC  27709
Telephone:  (919) 541-1373

or

Ms. Tanya McCoy
Grants Management Officer
Grants Management Branch
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
Westwood Building, Room 4A17
Bethesda, MD  20892
Telephone:  (301) 496-4970

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance
Nos. 93.113 and 93.115.  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, 43 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.

REFERENCE

1.  DeLucia, A.J., Adams, W.C. (1977):  Effects of ozone inhalation
during exercise on pulmonary function and blood chemistry.  J. Appl.
Physiol. 43: 75-81.
2.  Kenoyer, J.L., Phalen, R.F., Davis, J.R. (1981):  Particle
clearance from the respiratory tract as a test of toxicity.  Effect of
ozone on short and long term clearance.  Exp. Lung Res. 2:  111-120.
3.  Schelesinger, R.B., Driscoll, K.E. (1987):  Mucociliary clearance
from the lungs of rabbits following single and intermittent doses of
ozone. J. Toxicol. Environ. Health 20: 125-134.
4.  Koenig, J.O., Convery, D.S., Morgan, M.S. (1985):  Acute effects of
0.12 ppm ozone or 0.12 ppm nitrogen dioxide on pulmonary function in
healthy and adult adolescents.  Am. Rev. Resp. Dis. 19:  329-31.
5.  Hazucha, M.J., Bates, D.V. and Bromberg, P.A. (1989): Mechanisms of
action of ozone in the human lung. J. Appl. Physiol. 69: 1535-44.
6.  Horstman, D.H., Folinsbee, L.H., Ives, P.J., Addul-Salaam, S.,
McDonnell, W.F. (1990):  Ozone concentration and pulmonary response
relationships for 6.6 hour exposures with five hours of moderate
exercise to 0.08, 0.10 and 0.12 ppm.  Am. Rev. Respir. Dis. 172:
1158-63.
7.  Devlin, R.V., McDonnell, W.F., Mann, R., Becker, S., House, D.E.
Schreinemacher, D. and Koren, H.S. (1991):  Exposure of human to
ambient levels of ozone for 6.6 hours causes cellular and biochemical
changes in the lung.  Am. J. Respir Cell Mol. Bio. 4:  72-81.
8.  Molfino, N.A., Wright, S.C., Katz, I, Tarlo, S., Silverman, F.
McClean, P.A., Szalaki, J.P., Raizenne, M., Slutsky, A.S., Zamel, N.
(1991):  Effect of low concentrations of ozone on inhaled allergen
responses in asthmatic subjects.  Lancet 338: 199-302.
9.  EPA OAQPS Staff Paper:  Review of the National Ambient Air Quality
Standards for Ozone - Assessment of Scientific an Technical
Information.  US  EPA, June 1989.
10.  Air Quality Criteria for Ozone and other Photochemical Oxidants.
Volume 4 and 5.  US EPA, August 1986. EPA 600/8-84/020eF.
11.  Koren, H.S., Devlin, R.B., Graham, D.E., Mann, R., McGee, M.E.,
Horstman, D.H., Kozumbo, W.J., Becker, S., House, D.E., McDonnell, W.F.
and Bromberg, P.A. (1989):  Ozone-induces inflammation in the lower
airways of human subjects.  Am.  Rev. Respir. Dis. 139:407-415.
12.  Bates, D.V., (1991) Unanswered questions about asthma. Health and
Environment Digest, Vol 5 (10) 1-2.

.

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