EPA/SAB/80/002
Review of Inhalation Toxicology Research Programs
at EPA's
Health Effects Research Laboratories
Research Triangle Park and Cincinnati
November 25, 1980
Health Effects Research Review Subcommittee
Environmental Health Committee
Science Advisory Board
U.S. Environmental Protection Agency

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EPA NOTICE
This report has been written as part of the activities of
the Science Advisory Board, a public advisory group providing
extramural scientific information to the Administrator and
other officials of the Environmental Protection Agency. The
Board is structured to provide a balanced expert assessment of
the scientific matters related to problems facing the Agency.
This report has not been reviewed for approval by the Agency,
hence its contents do not necessarily represent the views and
policies- of the Environmental Protection Agency, nor does
mention of trade names or commericial products constitute
endorsement or recommendation for use.

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BACKGROUND
This review was requested by Mr. Costle, Administrator of
•EPA, as a follow-up to the Health Effects Research Review
conducted by* the Science Advisory Board (SAB) in 1978 in
response to a Congressional mandate. The Administrator accepted
the findings of that report and indicated his desire to have
continuing outside review of EPA's research programs and
projects as a factor in promoting the high quality of research
which is essential to development of sound regulations.
The Environmental Health Committee (EHAC) accepted this
responsibility on behalf of the Science Advisory Board. The
Committee made two suggestions to modify the procedures used in
the original Health Effects Research Review. The latter had
been a comprehensive and intensive review, as requested by the
Congress, and membership of the Review Group was determined
entirely by the SAB. The Committee suggested that EPA's
Laboratory Directors be consulted about the selection of program
areas for review and that Laboratory Directors be invited to
suggest candidates for Review Subcommittee membership, who would
be acceptable to the Laboratories. This procedure was followed.
Selected members of EHAC met with EPA representatives, in
July 1979 to discuss plans for the review. EPA representatives
were Drs. Gage, Hunt and Dowd from EPA headquarters and
Laboratory Directors Hueter and Garner. A general plan was
agreed upon, and Inhalation Toxicology was selected as an
appropriate first topic for review by a Subcommittee established
for the purpose of accomplishing this task (Appendix A).
More detailed plans were made in visits to the Health
Effects Research Laboratory in Research Triangle Park, N.C.
(HERL-RTP) in September 1979 and to HERL-Cincinnati in January
and February 1980. At HERL-RTP there was planning underway for
an Oxidants Workshop in January, and it was considered desirable
to postpone the SAB review until after the Workshop (March 20-
21, 1930 was later selected as a meeting date). At the Cincinnati
meeting, it was clear that larger issues were at stake than the
quality, relevance-, and general well-being of the Inhalation
Toxicology Program. Problems in planning and management
(related to Research Committee guidance and directives from ORD-
HQ) led to great uncertainty about whether there should continue
to be an "Inhalation Toxicology Program" at HEEL-Cincinnati. The
future of the program at Cincinnati and the integration of
inhalation toxicology between HERL-RTP and HERlr-Cincinnati thus
became a concern of the Subcommittee.

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The work of the Subcommittee was facilitated by attendance
of some of its members at the Symposium on Diesel Exhaust Health
Effects in December and the Oxidants Workshop in January. These
meetings included research reports by the Inhalation Toxicology
Laboratories at RTP and Cincinnati, respectively.
In further preparation for the formal visit on March 20-21,
1980, the Subcommittee asked both Laboratories to respond to a
questionnaire, which was designed to elicit a self-evaluation of
strengths, research productivity, and institutional obstacles to
optimal performance (Appendix B). There were twelve questions
divided among 1) work group organization, planning, performance
and restraints; 2) publication of research, including reports
in peer-reviewed journals; 3) unique capabilities; 4) institutional
mechanisms for planning, implementing, and reporting research;
and S) administrative problems.
The material available for review thus included responses
to the questionnaire (which were obtained from HSEL-Cineinnati
but not from HEBL-RTP); documentation of scientific credentials
and productivity (curricula vitae and publication lists); and
presentations at the March 20-21 meeting. Subsequent to the
meeting, the HERL-Cincinnati Laboratory submitted a proposal for
future facilities and inhalation toxicology research activities
of the Laboratory.

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FINDINGS AND COMMENTS
Health Effects Research Laboratory-RTP
The Inhalation Toxicology Research Program was presented in
two parts, the animal toxicology studies at RTP, on March 20,
and the human studies conducted in the Chapel Hill facility, on
March 21. Although most of the presentations were very good to
excellent, the Subcommittee was very much concerned that the
animal studies group, which made its presentation on the first
day, was not present for the presentations of human research
programs on the second day, and those concerned with human
inhalation studies were not present for presentations of animal
inhalation studies on the first day- The two groups are very
much related, and it is essential that they be completely aware
of the work that each is doing. The Subcommittee urges the
Laboratory Director to institute mechanisms to promote this
exchange.
The program of the Clinical Studies group appears, finally,
to have gotten moving. The general direction seems appropriate;
however, it is uncertain, whether the group has the necessary
strength to generate its own research program. Additional staff
is needed to provide the critical mass necessary for development
of a program that generates its own momentum and research
direction. Although the program must always have a strong
regulatory orientation, the present program seems somewhat
stifled by excessive orientation to establishing exposure
response relationships. Possibly, the human studies program
could move toward a broader view of pulmonary disease produced
by inhaled materials if it would work more closely with the
animal toxicology program-
The staff of the clinical research group is not large
enough to make adequate use of the facilities available. The
present facilities would probably support a staff at least
twice, and perhaps three to four times, as large. In
considering size, it is appropriate to recognize that good
research requires not only the time to conduct experiments but
also time to conceptualise and plan, analyze, and write. The
loss of Dr. Joel Ginsberg, Health Scientist in the Human Studies
Division's Clinical Research Branch, will be a serious blow. The
roles of some supporting personnel (clinical chemistry and
immunology) are not clear and probably should be reduced in
favor of providing positions for personnel who can contribute
more directly to the program. Those services needed to document
the health of subjects could be readily purchased from the
University of North Carolina (02IC) Medical Center-. The

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understaffing of research physicians has been a continuing
problem and should be corrected. The option of placing the
facility substantially under the direction of the CTNC Medical
Center appears to warrant further serious consideration.
The Chapel Hill physical facilities for human inhalation
studies are unique, although they are becoming dated. The
result is a facility that may be one of the least cost-effective
to operate of any now in existence. Hie facility is over-
engineered, without updated computer units, and requires an
excessively large supporting staff. Because these facilities
are so expensive to operate, their use should be better
coordinated with the research at other facilities around the
country, and they should be used primarily for those purposes
for which they are uniquely suited and far which other less
expensive facilities cannot be used.
In general, the animal inhalation research at HERL-RTP is
of a high quality, the majority of the staff presented material
well and responded vigorously and knowledgeably to searching
questions by the Subcommittee. The modeling work presented by
Dr. Miller was excellent and at the forefront of such efforts in
the United States, and perhaps in the world. This work should
be encouraged and expanded. Description of the particulate
research program, however, demonstrated a lack of insight into
the properties of particulates- The decision to utilize a
coarse- and fine mode for evaluating particulates in air was
based as much upon the methods of formation of particulates in
the atmosphere as it was upon the mechanisms by which
particulates may cause effects on health following inhalation.
The Inhalation toxicology research in the pesieide area
lacks a sense of direction. The presentation was unclear.
Obviously, there is a history of uncertainty with this program;
a history our group was not briefed on. The Subcommittee cannot
be expected to understand all of the institutional history
associated with, the research program. Nevertheless, the
Subcommittee wishes to convey to the Laboratory Director that
this program cannot withstand even casual scrutiny by a visiting
group of peers. It would seem that it must be straightened out
or dropped.
A source of major concern was the tacit assumption conveyed
by the presentations that the best way to approach current SPA
Research Committee demands for health effects data is to develop
the broadest possible spectrum of screening tests. HERL-&TP
individuals have expended a considerable effort to bring these
tests to an efficient operating level, and they can undoubtedly

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apply then routinely. It was not clear from the presentations
that many of the individuals understood the limitations and
strengths of these tests. Reorientation of objectives is needed
to assure that staff are applying scientific judgment, are aware
of the previous literature, and can restrict testing to those
studies where there is a high probability of yielding results
appropriate to the hypothesis under test. The cardiopulmonary
test battery program may serve as an example for this needed
reorientation. Under this program, a battery of tests was
developed and described, including EKG, arterial blood pressure,
venous blood pressure, cardiac output, blood gases, blood
chemistry, body weight, wet and dry heart weight, and histology.
Thera was no evidence that any thought had been given to
specific circumstances or purposes for which each of the tests
was to be utilized. Rather, it was asserted in a general way
that this assortment of tests had been developed "in order to
respond adequately to various Research Committee needs."
The staff of the animal studies group is very competent in
the areas of toxicity of ozone, N0T, and S0X. They have
broadened their outlook in recent years and show promise of
developing into a broad-based, first class inhalation toxicology
group. To reach this goal it is critical that the group be
increased in size and develop capabilities relating to the
toxicity of particles. It is also important that the group
include several comparative pathologists who are knowledgeable
and interested in both classical and quantitative morphological
pathology. This should help the group to continue developing
its competence in studying the late effects of inhaled
materials. The professional development of the individuals in
the group is at an important juncture. Most of the individuals
in the group probably could benefit from further substantial
"bench-type" research; however, they are becoming increasingly
committed to Involvement in administering contracts and grants
and providing in-house consultation. This problem could be
remedied by increasing the size of the group and by spreading
the "non-research" workload. Recognizing the Agency's continued
responsibilities to consider the health effects of airborne
materials, increased staff in this area appears not only
warranted but imperative.
The animal toxicology program is moving, appropriately, to a
broader base. Not many years ago, the program was tied to the
use of a few test procedures, especially the bacterial clearance
systems, developed to a large extent by Coffin and Gardner. The
efforts in the areas of pulmonary function evaluation and
comparative pulmonary dosimetry (i.e. , Dr. Miller's work) are
positive steps in the right direction. It is especially

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important that the program increase its efforts with inhaled
particles, recognizing the extent to which many airborne
environmental pollutants exist as particles. It is also
critical that the program progress from its present strong
orientation toward effects that occur during or shortly after
exposure to an orientation toward late occurring functional and
carcinogenic effects following chronic exposure.
In both the Clinical Studies and Animal Toxicology
Programs, there appears to be an excessive orientation toward
developing and using batteries of tests without giving adequate
consideration to how and for what materials the tests will be
used. A more thoughtful and selective approach is in order.
The diversification of the Animal Inhalation Toxicology
Program into new areas, such as the pesticides and hazardous
materials areas, should be encouraged. However, it is clear
that such programs must be more carefully planned and initiated
than was evident. It is especially necessary that a more
integrated approach be taken considering the interrelationships
between source exposure -* intake -» fate within the body
health effects.
The animal exposure facilities at RTF are primarily useful
for work with low toxicity gases and vapors. They are
marginally adequate for use with low toxicity particles and aria
not suitable for use with high toxicity or carcinogenic
materials, fith the exception of the walk-in exposure rooms, it
is the Subcommittee's view that the facilities are not
appropriate for conducting long-term exposure studies.
Health Effects Research Laboratory-Cincinnati
The two visits to the Cincinnati laboratory and attendance
at the December Symposium on Health Effects of Diesel amissions
gave the Subcommittee a good mix of informal discussions and
formal presentations that provided a good overview of the
current inhalation toxicology program. These were complemented
by a brief and thoughful narrative presentation that was highly
responsive to the questions provided in writing.
The program at HERL-Cincinnati has been, in essence, totally
oriented toward the study of automotive emissions. In this area
they have made some notable contributions, although the
productivity of. the group has declined in recent years. This
decline can be traced, to a large degree, to uncertainties about
the future of the program- and inappropriate and excessive
program direction from EPA Headquarters. Headquarters

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involvement, and especially Research Committee involvement, has
extended well beyond problem identification into raicr©management
of the research effort. This, coupled with an excessively
short-term orientation imposed by Headquarters, has had a
devastating effect upon the program. It is tragic that the
group was not allowed to start lifespan, multiple exposure level
studies with irradiated and non-irradiated diesel exhaust in the
fall of 1978. Instead, the research effort was forced into a
time schedule dictated by the anticipated date of issuance of
standards. The result was an inadequate research effort. It is
ironic that a portion of the data used by the Administrator in
issuing an interim standard for diesel exhaust particle
emissions was developed from a study (influence of diesel
exhaust on clearance) that was, mildly put, not encouraged.
The Inhalation toxicology facilities of HSEL-Cincinnati
fall into two broad categories: (1) those uniquely suited for
work with automotive emissions (Center Hill) and (2) general use
chambers suitable for use with low toxicity, non-carcinogenic
materials. The Center Hill facilities are unique in that the
capability exists for photoirradiation of automotive exhaust, a
capability that does not exist, to the Subcommittee's knowledge,
anywhere else in the United States. The other chamber's
capability is of limited usefulness because it is restricted to
low toxicity, noncarcinogenic materials.
The present staff involved with inhalation toxicology
studies at HEEL-Cincinnati falls into two broad groups:
(1) those involved with generation and monitoring of automotive
emissions and (2) pathobiologists.
The first group is quite strong; however, their orientation
is rather narrow, and it is doubtful that their capabilities
could be readily applied to work other than with automotive
emissions- The pathobiology group is in need of strengthening
if the Program is to continue. This group appears to have
tackled work, with automotive emissions in a reasonably competent
manner but has failed to conceptualize other problems (and
related approaches) in a very convincing way. Taken as a group,
the number of individuals involved in inhalation toxicology
studies appears marginally to approach a critical mass. If the
group is to continue, it would be appropriate to analyze
critically the composition of the group and sake selections,
deletions, and additions to strengthen their collective
capabilities..
After a series of discussions, initiated at the January
meeting in Cincinnati, Dr. Yilma Sunt asked the Laboratory to

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develop a long-term research plan (three to five years). This
plan was prepared in May 1980 and was made available to the
Subcommittee in June. Since there has been no meeting of the
Subcommittee since then, only individual comments are available.
There was general endorsement of the proposal, except for the
recommendation that diesel particulates be considered as a model
aerosol. Diesel particulates are too atypical in physical and
chemical properties to be considered a model aerosol for urban
atmospheres.

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SUMMARY OF RECOMMENDATIONS
1.	The development of a long-term orientation toward
inhalation toxicology problems should be encouraged, recognizing
more adequately than in the past the extent to which air
pollutants will be of concern to EPA for the foreseeable future.
This includes better integrated research planning and retention
of inhalation toxicology capabilities at HERL-Cincinnati. The
result would be to increase EPA's ability to assess health
effects of inhaled particles, a complex and long-term problem.
2.	Increased collaboration and interaction between the
Human Studies and Animal Toxicology groups at HERL-RTP and the
Inhalation Toxicology groups at RTP and at HEBL-Cincinnati
should be encouraged. These laboratory groups should be
perceived and dealt with as complementary rather than as
competitive.
3.	The role of Headquarters staff should be critically
evaluated, especially the roles of program office staff and
research committees in determining research approaches. There
should be greater emphasis on problem identification by the
Washington staff, with the details of research protocols and the
conduct of research left to the field research staff. A review
is in order because the present approach is having a profound
effect on EPA research, essentially negative in terms of both
morale and research content.
4.	Avenues should be pursued by which to create a more
effective personnel management system, placing primary
responsibility at the laboratory level for management and
assignment of research personnel. Identifying personnel slots
by specific pieces of authorising legislation and carrying
this identification down to the laboratory level seriously
impairs the effective management of research personnel. Changes
in enabling legislation may be required.
5.	A better balance should be developed between orientation
of research toward meeting specific regulatory deadlines and
letting the research needs determine the schedule required to
carry out the program.
6.	The utility of batteries of tests should be critically
reviewed, and; there should be more selectivity in developing
test procedures, carefully matching the test to specific needs
and questions.

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7.	Integrated approaches to studying airborne materials
should be encouraged, carefully considering the relationships
between source, exposure, intake, fate within the body, and
health effects.
8.	There should be a strengthening of EPA's capabilities
for evaluating late occurring functional and carcinogenic
effects of chronic exposure to airborne materials.
9.	An increase in staffing, especially additional research
physicians, for the Clinical Studies group or, alternatively, a
shifting of major responsibility for the program to the
University of North Carolina is needed.
10.	The strong input to development of criteria documents and
management of extramural research should continue. However,
there must be more adequate recognition by all concerned of the
time demands of the effort and its impact on the contributing
staff. Clearly, there is need to increase the size of the staff
to do this important work well.

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ADjjeodix: A
SCIENCE ADVISORY BOARD
HEALTH EFFECTS RESEARCH REVIEW SUBCOMMITTEE
Chairman;
Dr. James L. Whittenberger, Professor of Physiology, James
Stevens Simmons Professor of Public Health, School of Public
Health, Harvard University, 665 Huntington Avenue, Boston,
Massachusetts 02115
Members:
Dr. Morton Corn, Professor and Division Head, Environmental
Health Engineering, School of Hygiene and Public Health, Johns
Hopkins University, 615 N. Wolfe Street, Baltimore, Maryland
21205
Dr. Roger 0. McClellan, Director of Inhalation Toxicology-
Research Institute, Lovelace Foundation, P.O. Box 5890,
Albuquerque, New Mexico 87115
Dr. Sheldon D. Murphy, Professor of Toxicology, Department of
Pharmacology, University of Texas Medical School at Houston,
P. 0. Sox 20708, Houston, Texas 77025
Dr. Hioraas H. shepard, Professor of Pediatrics, Head, Center
Laboratory for Human Embryology, University of Washington
School of Medicine, Seattle, Washington 98195
SAB. Staff Officer;
Mr. Ernst Linde, Scientist Administrator, Science Advisory
Board A—101, U.S. Environmental Protection Agency, Washington,
D.C. 20460 Phone: (202) 472-9444

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Acp©x3ix B
SCIENCE ADVISORY BOARD
HEALTH EFFECTS RESEARCH REVIEW SUBCOMMITTEE
SAB Review of ORD* s Inhalation Toxicology Program
Questions for SPA Staff
Work Groups
1.	Describe the rationale^ s) for the organization of work
groups in the laboratory and the major long term and short term
questions addressed by the groups.
2.	Describe how the questions addressed by the work groups
relate to EPA concerns, in either a general or program specific
way.
3.	Describe major accomplishments of the work groups during
the past three years.
4.	Describe major setbacks or restraints encountered by the
work groups during the past three years.
Publications
5.	Provide a list of. projects pursued in your laboratory
during the past three years and publications reporting
scientific or technical outputs of these projects. Indicate
year project started and year of publication. Include papers
submitted for publication.
Unique Research Capabilities
6.	Describe any research capabilities in your organization
which you believe to be unique or rare in the U.S. How are
these capabilities being utilized?

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Institutional Mechanisms
7.	Describe institutional mechanisms now in place which help
planning, implementing or reporting research. Are there
additional mechanisms which you would recommend?
8.	Describe institutional mechanisms which help to improve the
scientific/technical capability of your laboratory group. Can
you suggest mechanisms not now utilized?
9.	Describe ongoing mechanisms which you now utilize
to interact with (a) CRD headquarters, {b) other EPA
scientific/technical staff and with (c) non-EPA scientific
and technical staff.
On items 1 to 9 above include comments on recent
changes, i.e.., changes which occurred in the past six months.
Staffing and Other Administrative Matters
10.	Provide a list of projects and associated staffs and
budgets for the current year.
11.	Provide a list of position vacancies for the current year.
Superimpose on this list your estimate of needs to pursue
projects in a satisfactory or outstanding manner.
12.	Provide a list showing the contracts, grants, and
cooperative agreements which individual staff scientists oversee
and their budgets. Indicate whether funding decision was made
by OHO headquarters or by laboratory.
Other Topics
Discuss additional topics which you consider important and
relevant to this review (e.g. adequacy of facilities, growing
demands on personnel, new grants procedures).

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