United States Office of the Administrator EPA-SAB-CASAC-89-021
Environmental Protection Science A
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4 K\IA/ ? UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
\***^jf WASHINGTON, D.C, 20460
EPA-SAB-CASAC-89-021
June 15, 1989
OFFICE Of"
THE AQMINISTJS? A TO R
Honorable William Reilly
Administrator
U.S. Environmental Protection Agency
401 M Street, SW
Washington, DC 20460
Dear Mr. Reilly:
We are pleased to transmit via this letter the advice of the
plean Air Scientific Advisory Committee (CASAC) concerning its
.teview of the Agency's Clinical Research Plan. The Clinical Lab
Review Subcommittee of CASAC conducted this review on February 9r
1989 in chapel Hill, North Carolina* The process included a
review of the Agency briefing document, "Clinical Research Branch
- A Research Strategy for the Future", detailed presentations
from Laboratory personnel, and public dialogue. The full CASAC
has reviewed this effort and is pleased to endorse thes views of
its Subcommittee and adopt them as a CASAC report. A detailed
presentation of our views is contained in the attached report.
We appreciate the opportunity to present our advice
concerning this research effort and would appreciate receiving a
written response which addresses our recommendations.
Sincerely,
Mark J. utell, M.D.
Chairman, clinical Lab
Review Subcommittee
Roger 0. McClellan, D.V-H.
Chairman, Clean Air Scientific
Advisory Committee
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UNITED STATES ENVIRONMENTAL. PROTECTION AGENCY
WASHINGTON, D.C. 20460
June 21, 1989 OFFICE OF
THE ADMINISTRATOR
The Honorable William Reilly
Administrator
U.S. Environmental Protection Agency
401 M. Street, S,W.
Washington/ D.c. 20460
Dear Mr. Reilly;
The Environmental Effects, Transport and Fate Committee of
the Science Advisory Board has completed its review of the Risk
Assessment Forum's proposed Guidelines for Exposure-Related
Measurements. The review was conducted at the request of EPA's
Risk Assessment Forum, and was conducted on December 2, 1988, in
Washington, D.C.
The Subcommittee recognizes these proposed guidelines as a
logical complement to the previously issued Guidelines for
Estimating Exposures. The prior guidelines, published and
reviewed by the SAB in 1986, provide a framework for exposure
assessment that may be integrated with the current guidelines
'resulting in a useful tool for exposure assessors. The
Committee recommends that such integration take place with
careful attention to the necessary linkages between measurements
and modeling.
In addition to integration of the two sets of guidelines,
the Committee recommends some modifications, since the
guidelines address exposure assessment for human health effects,
this bias should be acknowledged. Alternatively, the guidelines,
which have generic elements that can be brought to bear on
effects to ecosystems, should be expanded to encompass exposure
assessments in an ecological context. The focus and intended
audience of the guidelines also need to be defined, and revisions
made accordingly. The Committee discussed quality assurance and
control stringency, the importance of exposure duration
considerations, and needs concerning development and analysis of
data, in addition, a recommendations was made to incorporate
demographics, population dynamics, and population activity
patterns into the process for assessing exposures. Finally, the
Committee requests that the guidelines be amended to include
references to other-bodies of work that contain useful
information on expowur&/£&sessment.
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Independent comments were received from two members of the
Indoor Air Quality and Total Human Exposure Committee, These
members reviewed the Exposure Measurement Guidelines and provided
a response. These independent comments are attached to the
report to provide further feedback and critiques of the
Guidelines.
The subcommittee appreciates the opportunity to conduct this
scientific review. We request that the Agency formally respond
to the scientific advice transmitted in the attached report.
Sincerely
Dr. Raymond Loehr, Chairman
Executive Committee
Science Advisory Board
rman*
Environmental Effects,
Transport and Fate
Committee
ENC
cc
Dorothy Fatten
Michael Callahan
Bill Wood
Peter Preuss
Donald Barnes
* Dr. Hartung served as Chairman until December 31, 1988. Dr.
Ken DicHson currently serves as Chairman of the Environmental
Effects, Transport and Fate Committee. Since this review was
initiated during Dr. Hartung'a tenure, his efforts have seen it
to completion.
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ABSTRACT
The Clinical Lab Review Subcommittee of the Clean Air
Scientific Advisory Committee (CASAC) reviewed the EPA's clinical
Research Branch (CRB) in order to provide the Agency with advice
concerning current and future directions in health research at the
EPA 'clinical facility. The Subcommittee concluded that the
Research Plan was being conducted in a professional and technically
adequate manner. The Subcommittee recommended that additional
professional support be provided to two of the three sections of
the Clinical Research Branch, and that the third section be
supported in its goal of increased involvement in field and
epidemiologic studies. The Subcommittee commented on the
proportion of effort devoted to specific pollutants, and advised
that a reduction in research on sulfur dioxide and carbon monoxide
was warranted along with a substantial increase in research on
acidic aerosols and a modest increase in research on nitrogen
dioxide. The Subcommittee strongly encouraged that research on
ozone clinical studies continue at the same level of effort for the
next 3-5 years, and was clearly concerned about the lack of proper
justification for the specific projects on indoor air and toxic
pollutants. Finally, the Subcommittee recommended that a standing,
external scientific review/advisory committee be established for
the research program.
KEY WORDS: clinical research; national ambient air quality
standards (NAAQS)
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NOTICE
This report has been written as part of the activities of the
Science Advisory Board, a public advisory group providing
extramural scientific information and advice to the Administrator
and other officials of the Environmental Protection Agency, The
Board is structured to provide a balanced expert assessment of
scientific Matters related to problems facing the Agency, This
report has not been reviewed for approval by the Agency; and,
hence, the contents of this report do not necessarily represent the
views and policies of the Environmental Protection Agency or other
agencies in the Federal Government, Mention of trade names or
commercial products does not constitute a recommendation for use.
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U.S. ENVIRONMENTAL PROTECTION AGENCY
• SCIENCE ADVISORY BOARD
CLEAN AIR SCIENTIFIC ADVISORY COMMITTEE
CLINICAL LAB REVIEW SUBCOMMITTEE
Chairman
Dr. Mark J. Utell, Professor of Medicine and Toxicology,
Co-*Director, Pulmonary Disease Unit, University of
Rochester School of Medicine, Rochester, New York
Members
Dr. Robert Drew, Director of Health and Environmental
Sciences Department, American Petroleum Institute,
Washington, D.C.
Dr, Robert FranR, Professor of Environmental Health
Sciences, The Johns Hopkins School of Hygiene and
Public Health, Baltimore, Maryland
Dr. Morton Lippmann, Professor, Institute of Environmental
Medicine, New York University Medical Center,
Tuxedo, New YorK
Dr, Ronald Wyzga, Electric power Research Institute,
Palo Alto, California
Science, Advisory Board Staff
Mr, A. Robert Flaak, Environmental Scientist and Executive
Secretary, Science Advisory Board, U.S. Environmental
Protection Agency, Washington, DC
Ms, Carolyn Osborne, staff Secretary, Science Advisory Board,
U.S. Environmental Protection Agency, Washington, DC
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U.S. ENVIRONMENTAL PROTECTION AGENCY
SCIENCE ADVISORY BOARD
CLEAN AIR SCIENTIFIC ADVISORY COMMITTEE
Chairman
Dr. Roger 0. McClellan, President, Chemical Industry Institute
of Toxicology, Research Triangle Park, North Carolina
Members '
Dr. Timothy Larson, Environmental Engineering and Science
Program, Department of Civil Engineering, University of
Washington, Seattle, Washington
Dr. Gilbert s* Omenn, Professor of Medicine and of Environmental
Health, Dean, school of Public Health and Community
Medicine, University of Washington, Seattle, Washington
Dr. Marc B* Schenker, Director, Occupational and Environmental
Health Unit, University of California, Davis, California
Dr. Mark J. utell, Professor of Medicine and Toxicology,
Co-Director, Pulmonary Disease Unit, University of Rochester
School of Medicine, Rochester, New York
Dr. Jerome J. Wesolowski, Chief, Air and industrial Hygiene
Laboratory, California Department of Health, Berkeley,
California
Bfe
Dr. George T. Wolff, Principal Scientist, General Motors
Research Labs, Environmental Science Department,
Warren, Michigan
Sc.lenc.je Advisory, Board, staff
Mr. A. Robert Plaak, Environmental Scientist and Executive
Secretary, Science Advisory Board, U.S. Environmental
Protection Agency, Washington, D.C.
Ms
. Carolyn Qsborne, Staff Secretary, Science Advisory Board,
U.S. Environmental Protection Agency, Washington, DC
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TABLE OF CONTENTS
1,0 EXECUTIVE SUMMARY 1
2.0 INTRODUCTION AND BACKGROUND ......... 2
3.0 CLINICAL RESEARCH BRANCH * .... 3
4.0 RESTRUCTURING OF THE CLINICAL
RESEARCH BRANCH ,........'•,.,.. 5
4.l Human Dosimetry Section ..«...., 5
4.2 Cell and Molecular Biology Section . „ 6
4,3 Physiology Section ..... 7
5,0 RISK ASSESSMENT AND THE CLINICAL
RESEARCH BRANCH .............. 8
6.0 PROGRAMMATIC EMPHASIS FOR THE CLINICAL
RESEARCH BRANCH 9
7.0 PEER-REVIEW IN THE CLINICAL REVIEW BRANCH •. , 11
8.0 RECOMMENDATIONS ......... . 11
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1.0 EXECUTIVE SUMMARY
In February 1988, the Office of Research, and Development (ORD)
requested that the Clean Air Scientific Advisory Committee (CASAC)
establish a peer-review subcommittee to review the strategy and
philosophy guiding the research program at the Clinical Research
Branch (CRB) of the Health Effects Research Laboratory (H1RL). The
CRB conducts studies -into the effects of environmental pollutants
on human health. As a result of restructuring within the HERL, the
CRB is now a component of a new division, the Human studies
Division. The CRB includes three sections, i.e., Physiology, Human
Dosimetry, and Cell and Molecular Biology,
At a public meeting held on February 9, 1989 in Chapel Hill,
North Carolina, the Subcommittee concluded that the restructuring
of the HIRL represents a significant and appropriate regrouping,
providing good opportunities for programmatic growth. It
recommended that additional professional support be provided to
both the Human Dosimetry Section and Cell and Molecular Biology
Section in order to support these new and highly productive
programs. In addition, it recommended that full support be given
to the Physiology Section's goal of increasing its involvement in
field and epidemiologic studies. The Subcommittee called attention
to the past productive exchange between the clinical Research
Branch and the personnel involved in other aspects of inhalation
toxicology and pulmonary biology within HERL. The subcommittee
cautioned the Agency to nurture this collaboration and avoid having
it inadvertently diminished in any way by the recent
reorganization»
At the meeting, the Agency projected that the overall CRB
program level of effort would remain relatively constant over the
next five years and that the proportions of the effort devoted to
specific pollutants and programs would shift. Reduced activities
with ozone, sulfur dioxide and carbon monoxide are anticipated
while increased activities in nitrogen dioxide, acid aerosols,
indoor air, toxic pollutants, and biomarkers are likely. There
was a clear Subcommittee consensus that reduction in research on
sulfur dioxide and carbon monoxide was warranted as well as a
substantial increase in research on acidic aerosols and a modest
increase in research on nitrogen dioxide. However, the
Subcommittee strongly encouraged that the present level of
commitment: to clinical studies of the effects of ozone, alone
and/or in combination with other pollutants, be maintained during
the next, 3-8 years. There was a clear concern about proper
justification for the specific projects on indoor aiar and toxic
pollutants. It was recommended that any projected clinical studies
in these areas be better justified and both scientific and
programmatic issues be subjected to external review before any
strong commitments are made.
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Finally, the Subcommittee recommended that a standing
external, scientific review/advisory committee be established for
the research program of the CRB, .This review process could not
only help strengthen the research program but also provide support
to a long-term research strategy*
2.0 INTRODUCTION AND BACKGROUND
In February 1988, the Director of the Office of Health
Research (ORE.) , with concurrence from the Assistant Administrator
for the Office of Research and Development (ORD), requested that
the Science Advisory Board (SAB) review EPA's clinical Research
Branch (CRB). The purpose of the review was to obtain commentary
and advice from the SAB on current and future directions in health
research at the EPA clinical research facility. The review panel,
constituted as a Subcommittee of the Clean Air Scientific Advisory
Committee (CASAC) , was advised that this was not a "scientific
program review" in the traditional peer review sense, but rather
an examination of the overall strategy and philosophy guiding all
aspects of the clinical research program
The Clinical Research Branch conducts studies into the effects
of environmental pollutants on human health. The CRB, situated in
the Health Affairs area on the campus of the University of North
Carolina (UNC) at Chapel Hill, is a research laboratory of the EPA
within the Human Studies Division (HSD) of the Health Effects
Research Laboratory (HERL), The research environment and
activities of the CRB are unique. Five human exposure chambers are
operated by the CRB. Volunteer subjects are exposed to
environmental pollutants, and the acute responses during and
following the exposures are measured using techniques drawn froa
a variety of disciplines, including cardiopulmoiwry physiology,
immunology, biochemistry, cell biology, molecular biology, and the
physical sciences. The UNC center for Environmental Medicine and
Lung Biology (CEMLB) developed under a cooperative agreement with
EPA, has been closely involved with CRB in this research to the
mutual benefit of the Agency and the University, In addition to
the research collaboration, the University provides access to the
Committee for the Protection of. the Rights of Human Subjects as
well as to large numbers of volunteers, both healthy and those
considered to be potentially at increased risk* These include
children recruited from the UNC Frank Porter Graham Center for
Child Development. The scientific investigative team, including
EPA investigators from both the CRB and other HERL units, together
with collaborating investigators, have had a profound impact on the
regulatory and risk assessment process in EPA related to criteria
air pollutants.
The Subcommittee was provided with a briefing document
entitled "Clinical Research Branch — A Research Strategy for the
Future". The Subcommittee was requested to examine the conceptual
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framework for this strategy and to consider the mix of ongoing and
planned research. Specifically, it was to focus on- the six
questions presented below:
1. Is the present balance of scientific expertise in the
Clinical Research Branch appropriate and sufficient?
2. Does the current program take adequate advantage of the
wide range of skills and expertise within the Health Effects
Research Laboratory?
3. Is the clinical research program addressing the most
appropriate health issues facing the Agency?
4. Is it appropriate and plausible to begin placing less
emphasis on National Ambient Air Quality Standard (NAAQS)
pollutants and more on other pollutants, such as volatile organic
compounds?
5. Is there a potential role for clinical research in
answering the health questions associated with biotechnology?
6. Are there additional environmental health g^iestions which
the clinical research program should address over the nexrt 5-10
years?
3.0 CLINICAL RESEARCH BRANCH
The briefing document (with four appendices) provided to the
Subcommittee prior to the meeting included a description of the
CRB and how it fits into the newly reorganized Health Effects
Research Laboratory* The CRB is comprised of three sections, Human
Dosimetry, Cell and Molecular Biology, and Physiology. It was
apparent that many research projects are multidisciplinary, using
expertise from all three sections. A broad spectrum of expertise
is available in the CRB, and this is supplemented by faculty from
the UNC campus via"-' the cooperative agreement. The appendices
consisted of laboratory organization charts, a summary of the major
research accomplishments, a list of publications, and the
curriculum vita© of the Principal Investigators.
Decisions as to specific pollutants of interest, protocol
design, endpoints, and other features of the studies are made
primarily by the Laboratory Director, Division Director, Branch
chief, and Section Chiefs. These individuals must be Jcnowledgeable
in the relevant sciences as well as in the Agency's mission and
programmatic needs. Investigators within the CRB present their
scientific results at national and international meetings and often
at CASAC meetings; in addition, they maintain close ties with the
Agency's program offices.
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The Clinical Research Branch provides data that can be used
directly for regulatory and risk assessment activities. The testing
capabilities of the CRB assess the biologic response to inhaled
pollutants and evaluate the health significance of the observed
response. The investigators develop exposure-response
relationships in a variety of population segments. In addition,
they work closely with animal toxicologists to facilitate better
extrapolation across time and species. Mechanistic studies have
been an essential part of this extrapolation process.
The briefing document also examined the approaches to human
research, including both in vitro and in vivo exposure techniques,
combinations of pollutants, and a variety of testing methods. The
identification of sensitive individuals and populations such as
asthmatics and perhaps even immunocompromised individuals is
essential in developing accurate risk characterization.
Epidemiology should continue to play a key role in identifying
environmental hazards*
Because exposure to many pollutants of concern may span years
or decades, it is often necessary to predict the consequences of
long term, low-level exposures in humans. Since it is not feasible
(or ethical) to expose humans over long periods of time,
extrapolation of testing results from acute exposure may, in
conjunction with results from animal and epidemiological studies,
be relied upon to make these predictions. Considerable emphasis
has been given to extrapolation development in the CRB.
The briefing document concluded with a preview of emerging
issues and research priorities. New issues included indoor air
pollutants, air toxics, development of new techniques, biomarkers,
and biotechnology. All of these issues may experience growth in
the CRB in the next 5-10 years.
*%
Members of the Subcommittee agreed that missing both from the
briefing document and subsequent presentations was a discussion of
the expected legislative and regulatory pressures on the Agency
over the next few years. The Subcommittee found itself in the
uncomfortable position of having to provide opinion on the
worthiness of a research plan without being provided the driving
forces behind the plan. For example, if the Agency believes that
regulatory needs will require substantially more information on
the health effects of indoor air, then it makes sense to consider
an expanded research program in that area. The development of a
research plan guided in part by administrative needs and
scientific issues is a laudable goal. The Subcommittee strongly
recommended continuing efforts to further define and develop a
research strategy which logically evolves from Agency needs and key
research questions, other SAB efforts, such as the recent report
on Future Risk:, discuss this further.
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4.0 RESTRUCTURING OF THE CLINICAL RESEARCH BRANCH
The Clinical Research Branch is now a component of a new
division within HERL, the Human Studies Division (HSD), The
HSD's other branch. Epidemiology, represents a regrouping and
programmatic expansion of field and population data base studies
within HERL. While a review of current and future directions in
health research within the Epidemiology Branch is beyond the scope
of the charge to this subcommittee, the plans and opportunities for
closer research ties between the two branches warrant our comment,
especially as they may influence the research activities within the
CRB.
The new organizational structure has considerable merit
insofar as it encourages and facilitates closer ties between the
two groups studying the human health effects of exposures to
environmental chemicals. Some of the new and sensitive assays
developed in the laboratory can be used, in field studies. Field
demonstrations of the efficacy and power of these new assays and
biomarkers of exposure could provide powerful resources to the
emerging subspecialty of environmental epidemiology. The CRB's
research program will also benefit from the participation of its
scientists in field studies in terms of their broadened
appreciation of "real-world" exposures and responses, and of
desirable modifications of laboratory protocols and apparatus for
their effective utilization in the field.
The new organization has the potential significant risk of
diminishing the currently productive interchange and collaboration
between CRB staff and pulmonary toxicology staff at Research
Triangle Park also wording on dosimetry and extrapolation modeling.
The separation of these' two branches of the former Inhalation
Toxicology Division of HERL should not, and may not, diminish such
collaboration, but the possibility exists and warrants a continued
-concern by the Directors of the two Divisions and of HERL managers.
The restructuring within the CRB into three sections, i.e.,
physiology, cell and molecular biology, and human dosimetry also
represents a significant and highly appropriate regrouping,
providing good opportunities for programmatic growth and
significant enhancement of CRB contributions to HERL, to the field,
to public health protection, and to peer recognition. The
Subcommittee's specific comments on current and future directions
within each of the three sections follow.
4,1 Human Dosimetry Section
This Section, headed by Dr. Timothy Gerrity, is the newest
independent entity in the CRB. It provides a means for significant
advances in the CHB's developing programs in human dosimetry and
extrapolation modeling. Dr. Gerrity has the background,
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perspectives, and skills needed" to direct and lead an expanded
research Program in this very important area, and the leadership
of the OHR, HERL, and HSO should make every possible effort to
provide the staff and resources he will need to accomplish the
rather ambitious plans outlined at the CRB program review.
Dr. Gerrity described plans to introduce or expand laboratory
capabilities for radioisotope clearance studies of lung
permeability and particle clearance; dosimetry and metabolic
studies of the nonradioactive 18o isotope as a tracer of gases such
as ozone, nitrogen oxides, and sulfur oxides? aerosol bolus
dispersion as a test of small airways size and function? 3-D NMR
imaging of airways? dual-laser aerosol photometry for volatile
aerosols? and magnetopneumography for studying retention of
ferrimagnetie tracer particles. Each of these techniques is
complex and far from routine, and each has considerable utility
and merit for CSB research. Dr. Gerrity himself is familiar with
their essential features and could certainly see to their effective
implementation if he were supervising the use of only one or two
of them. However, he clearly needs additional professional
staffing to integrate all or most of these into the Section and
Branch research projects in a timely and efficient manner.
Furthermore, it is not clear that all of these new technologies
should be pursued simultaneously. It would be desirable to seelc
external peer review to establish priorities for the methods
development and applications.
In addition to the introduction and incorporation of these
complex and powerful measurement methodologies into CRB research,
the Human Dosimetry Section clearly needs to pursue its research
on dosimetry and extrapolation modeling. Here again, Dr. Gerrity
has an excellent background as a researcher himself and can readily
provide input and leadership in this research. However, as in the
case of the application of the state-of-the art measurement
methodologies, the rate of progress will be limited by his time
commitment and access to additional resources. He will need and
should have at least one more professional staff member with
appropriate background and/or training in such modeling.
4.2 Cell and Molecular Biology Section
The Section on Cell and Molecular Biology, headed by Dr.
Hillel Koran, involves a relatively young program with
responsibility to investigate the effects of pollutants on human
pulmonary inflammatory, immunological and systemic responses.
Human cells and fluids are obtained from the lungs and airways fay
bronchoalveolar lavage (BAL) and/or nasal lavage, or from
peripheral blood, and can be analyzed by state-of-the-art
immunological, biochemical, and molecular biological techniques.
Studies are conducted with human materials collected following In
vivo exposure or materials collected from unexposed subjects can
be exposed to pollutant materials in vitro. In addition, in vivo
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and .in vitro exposures can be combined. Dr. Koren is highly
qualified to head up this basic science program in the CRB and is
ably assisted by Dr. Robert Devlin, a molecular biologist. Despite
its short existence, the productivity of this section has been
substantial. The Subcommittee was impressed particularly by the
leadership role this laboratory has played in its research on
biomarkers in BAL of humans exposed to ozone.
Dr. Koren described plans to continue ifl vivo studies with
ozone, nitrogen dioxide and pollutant mixtures; to introduce in
vitro studies with air toxics and hazardous waste products; to
develop new molecular techniques including assays for messenger
RNA, 2-D protein gel electrophoresis, and human lung cell cultures
to increase sensitivity for detecting pollutant effects; and to
enhance extrapolation between species using 18o isotope studies.
The Subcommittee is highly supportive of continuing in vivo studies
in humans with criteria air pollutants, including ozone and
nitrogen dioxide. Likewise, the efforts to introduce new molecular
biology methodologies is a logical progression of current
activities. The efforts to pursue extrapolation from animal to man
is one that extends across all three sections of the CRB. The
subcommittee was far less certain as to the merits of the in vitro
studies with air toxics and indoor air pollutants. Furthermore,
it is not clear which studies should be undertaken and how they
will increase our understanding of adverse health effects. It
would be desirable to seek external peer review to establish
priority regarding the relative merits of in vitro studies with
oxidants, air toxics, fibers, hazardous waste incineration
effluents or pesticides. As with the Human Dosimetry Section, the
Subcommittee advocated increased staffing of this section.
4.3 Physiology Section
Physiology is the largest and, operationally, the oldest
section within CRB. Dr. Donald Horstman presently heads a group
of six professionals and two technicians. As with the other
Sections in the CRB, the research program has focused principally
on acute responses to criteria pollutants. Ozone has received the
greatest attention followed by carbon monoxide and sulfur dioxide.
The variety of assays utilized in these studies, and the range of
information gathered, has expanded notably in recent years. In
great measure, this reflects collaboration with other Sections in
the CRB as well as collaboration across branches of HERL and with
the staff of CEMLB. For example, ongoing studies on ozone are
examining possible inter-relationships among changes in pulmonary
function, airway reactivity, membrane permeability and, in
association with Dr, Keren's Section, both cells and mediators
lavaged from peripheral lung. In a joint effort with Dr. Gerrity,
the aerosol bolus technique is being established to assess changes
in small airway function associated with these exposures.
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The Physiology Section merits praise for high, levels of
productivity and scientific caliber, and for the relevance of its
work to regulatory needs. The recent series of studies clearly
demonstrating the cumulative effects of ozone on the' lung during
a single 6 3/4-hour exposure is lilcely to have profound influence
on the experimental design of future studies and to carry important
implications for regulatory policy.
In future chamber studies, one goal is to place increased
emphasis on what Dr. Horstman termed "real world conditions". This
will include studies of interactions between pollutants, between
pollutants and environmental variables (temperature, relative
humidity), and of the consequence of varying tne pattern of
exposure for a specified .inhaled dose.
A second complementary goal of the Physiology Section is to
increase its involvement in field and epidemiologic studies. In
part, this goal is reflected in Dr. William McDonnell's candidacy
for a Ph.D. in epidemiology (to complement his M.D, and, M.P.H.) at
UNC and Dr. Horstman»s personal inclination to move toward direct
participation in such studies. While the Subcommittee was not
charged with reviewing the Ipidemiological Branch and its programs,
we support enthusiastically the Physiology Section's goal — and
by extension, the CRB goal — of greater involvement in field and
epidemiological studies.
5.0 RISK ASSESSMENT AND THE CLINICAL RESEARCH BRANCH
The Agency is relying increasingly on risk assessment methods
for decision making. This increased role for risk assessment will
have significant consequences for the clinical Research Branch
which has already provided the Agency with valuable risk assessment
input. Nonetheless, these increased demands on the CRBf in the
presence of limited resources, can create tensions,
The first step of risk assessment is hazard identification,
the objective of which is to indicate the existence of a health
concern for the pollutant studied. This step often uses High
exposure conditions and sensitive subgroups to detect evidence of
toxicity. The second step of risJc assessment collects data needed
to estimate the dose-response relationship for the groups studied,
For several pollutants, little work has been done to characterize
the general shape of the dose-response curve, and the optimal
dosing regimen that would be dependent upon the shape of this
curve. In general, when quantal dose-response models are to be
estimated, dose levels should be considered which give rise to a
range of responsesi this consideration is unnecessary for the
hazard identification step of risk assessment.
The ultimate objective of the risk assessment process is to
estimate the health risk of a given population and is carried out
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in the risk characterization step. This step requires a thorough
characterisation of the object population and the development of
methods to extrapolate results from the study population to the
object population. This could require the development of
dose-response curves for several elements (subpopulations) of the
object population. If risk assessment is to provide a framework
for future research, these multifarious data needs must be
recognized.
Risk assessment requires several extrapolation efforts, animal
results to humans,- high to low-dose response; acute response to
chronic response; .in vitro to in vivo response; and the
relationship between observed biological responses and human
disease. These extrapolation issues are not unique to the CRB.
It is important that strong links be built between this Branch and
other parts of the Agency which address the same issues. These
efforts should be linked to an Agency-wide effort to address these
extrapolation problems (see letter of SAB Extrapolation Models
Subcommittee to the SPA Administrator, May 26, 1987}. There are,
however, specific elements of the clinical research program which
are Jcey for extrapolation issues with ozone. Hunan dosimetry work
which complements similar animal dosimetry work is necessary to
allow eventual extrapolation from animal data.
Similarly, efforts that allow interpretation of observed
biological responses so that they can be factored into risk
assessment are to be applauded. Many of the biological responses
observed in clinical study research require difficult judgments
about medical significance. It is important to develop as much
information as possible to aid this judgment. Complementary
chronic animal and epidemiology studies can be designed to help
interpret the clinical response data. Another approach is to
compare the responses observed in experiments to underlying
variability. The Clinical Research Branch is encouraged to develop
a data base to allow .estimates of this variability, An
understanding of the magnitude of changes that occur independent
of environmental insults can help place the biological response in
perspective.
6.0 PROGRAMMATIC EMPHASIS FOR THE CLINICAL RESEARCH BRANCH
Dr. John o'Neil, Chief of the CRB, projected that the overall
CRB program level of effort would remain relatively constant over
the next five years and that the proportions of that effort
devoted to specific pollutants and programs would shift. He
projected reduced activities for ozone, sulfur dioxide, and carbon
monoxide research and increased activities in nitrogen dioxide,
acid aerosols, indoor air, toxic pollutants, biomarkers, and
possibly pollutants associated with alternative fuel systems.
There was a Subcommittee consensus that program efforts
should shift in relation to program needs and the completion of
9
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high priority ongoing projects. There was, however, some serious
concern about the decision process used, and the rationale for,
some of the projected shifts, especially in light of the current
skill mix of the staff and of the prospects for productive research
in some of the areas projected to receive additional efforts.
Furthermore, the selection of research areas in the bar chart
presented by Dr. Q'Neil leaves out important areas of CRB research,
such as studies of mixtures, methods development, dosimetry and
extrapolation modeling. The EPA Staff agreed that a graphic
depicting these issues would be helpful.
With respect to the projections as stated, the Subcommittee
views the proposed reduction in commitment to ozone research with
concern. Ozone is highly reactive and injurious to the lungs in
experimental studies at realistic concentrations. Huge numbers of
people are exposed to Multiple exceedances of the current national
ambient air quality standards (KAAQS) for ozone each year and
troubling questions about the possible relationship between the
acute effects of ozone and chronic, irreversible lung damage remain
unresolved. The Subcommittee also calls attention to tlie
remarkable progress made by CRB scientists on ozone research in
recent years. We believe that they are now crossing the threshold
from ozone exposure-response characterizations to more fundamental
and mechanistic understandings. They should clearly proceed on the
highly productive research lines now underway. Furthermore, these
studies are highly liJcely to lead to effective research focused on
the chronic health effects of ozone, an issue which should be, and
is likely to be a high priority research area for EPA in the next
five years.
While m reduction in clinical studies involving ozone in
purified air may well be warranted, we recommend that serious
consideration be given to including ozone in any projected study
of the effects of pollutant mixtures. One reason is that ozone is
almost always present in ambient pollutant mixtures. A second is
that synergism in mixtures generally requires that at least one
component of the mixture be highly biologically active by itself.
Ozone is clearly a good model toxicant in this regard. Finally,
there is evidence from animal toxicology that ozone potentiates
responses to both nitrogen dioxide and acidic aerosols, two of the
pollutant classes slated for additional research.
Thar* was a clear Subcommittee consensus that reductions in
research on sulfur dioxide and carbon monoxide were warranted as
well as a substantial increase in research, 'on acidic aerosols and
a modest increase in research on nitrogen dioxide. On the other
hand, there was a clear concern about whether the projected
increases in research on indoor air and toxic pollutants were
adequately justified. The Subcommittee views with reservation the
apparent commitment to research on issues such as the SicJc Building
Syndrome (SBS) and Environmental Tobacco Smoke (BTS). Our concern
was in regard to the opportunities for productive clinical research
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in these areas, and not with regard to HERL's overall need to
support health research on these classes of pollutants. We
strongly recommend that any projected clinical studies in these
areas be better justified and that the study design and protocols
be carefully peer-reviewed before any resource commitments are
made. We are also concerned that the staff's background and skill
mix, while highly suitable for clinical studies on irritant air
pollutants, may not be suitable for research activities on organic
solvents and other 'constituents of indoor air mixtures at low
concentrations, SIS and ETS are complex challenging issues, but
it is not clear whether the CRB has sufficient experience and
judgment born of experience to move ahead in this field in the near
future.
7,0 PEER-REVIEW IN THE CLINICAL RESEARCH BRANCH
The Clinical Research Branch has achieved national leadership
in the past few years in health-related scientific research on
criteria pollutants. The accumulated experience, knowledge and
judgment appear to have earned for the staff a considerable degree
of independence in the establishment of priorities in design of
experimental research. Nonetheless, a number of the individual
projects, and in particular the overall direction of the research
program would likely benefit from periodic scientific peer review.
This is particularly true with regard to emerging issues about
which the staff may be less confident. Several models of effective
scientific advisory councils exist, including that of the National
Institutes of Health, to assist HERt in designing one to meet the
needs of CRB. A standing advisory/review group of scientists
convening on a regular basis would provide continuity and
familiarity with the issues. This review process could not only
help strengthen the research program, but also., reduce the frequency
and time required for other aj, hoc reviews to which CRB is subject
from time to time. Such a formal process might also provide
support for the continuation of -,- ongoing programs in the face of
external pressure to shift directions depending on the popular
issue of the period.
8.0 RECOMMENDATIONS
a. Additional professional support should be provided to both
the Human Doslmetry Section and Cell and Molecular Biology section
in order to support the ambitious, novel, and highly productive
programs in these Sections.
b. Full support should be given to the Physiology Section's
goal of increasing its involvement in field and epidemiologic
studies *
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c. The present level of commitment to clinical studies of the
effects of ozone, alone or in combination with other pollutants,
should be maintained during the next 3-5 years.
d. Current plans to initiate research on indoor air pollution
and hazardous air pollutants should be subject to both external
scientific and programmatic review, to determine their
appropriateness and priority levels,
e, A standing external, scientific review/advisory committee
should be established for the research program of the CRB«,
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