UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D,C. 20460
SSB-EC-87-G23
February 25, 1987
The Honorable Lee M. Thomas • OFFICE
Administrator THe *oM,
U. S. Environmental Protection Agency
401 M Street, S.W.
Washington, D.C. 20460
Dear Mr. Thomas:
As part of an ongoing series of researeh-in-progress reviews, the
Science Advisory Board has reviewed the Office of Research and
Development's Integrated Air Cancer Project.
The Integrated Air Cancer Project views air pollution from the
standpoint of the receptor and tries to address these issues: (1) what
components of polluted air pose the greatest potential cancer risk,
and what are the sources of those components; and (2) how are primary
emissions dispersed, transported and transformed in the atmosphere *•
and what are humans actually exposed to in the ambient envirorrosnt?
The Agency requested that the Science Advisory Board address
eight specific questions in three broad areas of strategy and approach,
relevance to risk assessment, and determination of health effects*
To address these questions, the Science Advisory Board forroed the
Integrated Air Cancer Project Research Review Subcommittee.
After reviewing a written description of the program and the
results of previous technical peer reviews, the Subcommittee heard
briefings on the program September 16 at the Health Effects Research
Laboratory in Research Triangle Park, North Carolina. The following
day, the Subcommittee asked additional questions of the researchers,
prepared a draft report, and provided an oral suroary of its findings
to the researchers and the laboratory management.
In general, the Subcommittee finds the Integrated Air Cancer
Project to be scientifically well-founded. The project represents
a logical and appropriately innovative approach that can achieve its
long-range goals of addressing these complex environmental health issues.
The project effectively exploits some of the research tools and
results developed in the past decade and presents an example of
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effective multi-laboratory research management within the Agency,
For the first tiros, the Agency is addressing the carcinogenic potency
of mixtures of materials in the air. IMs approach is a critical
step to characterizing the exposure of humans to a complex environment.
The attached report details the Subcommittee's findings. The
Subcommittee concludes that this project is well planned, organized and
executed. The project could be improved by considering three highlighted
recommendations- First, to obtain the greatest short-term benefit from
the work done In this program, the Subcommittee recommends that EPA give
increased attention to both data presentation and exploratory data analysis
used to discover new relationships or confirm certain hypotheses. Second,
the Subcommittee believes that chemical compound identification ought to
proceed more quickly. The importance of ecrapound identification to the
project's first objective of carcinogen designation merits additional
effort. Finally, the Subcommittee recotmends that an epidemiological
perspective could aid in developing the linK of the chemical studies to
cancer risk in human populations.
Through the efforts of the project's leaders, and the cooperation and
support of the laboratory directors, an extensive multi-laboratory team
has been asssembled which is actively and effectively working together
to accomplish the goals of this long-range and cccnplex project. Since
its inception, the project has been productive and h^s achieved important
new results* it premises to remain productive. The Subcommittee ccmpends
the project managers, the project task leaders, the researchers, the
laboratory directors, and the Agency for the success of this project to
date,
The Subcommittee strongly supports continuation of this project* This
recommendation is based on the scientific srerit of the work undertaken and
its potential use as a training ground for Agency scientists undertaking
multidisciplinary environmental research*
The Subcommittee appreciates the opportunity to conduct this review
and would be pleased to discuss it further with you. We would appreciate
a formal response to the conclusions and recommendations presented in
the report.
Sincerely,
George M. Hidy
Chair, Integrated Mr Cancer Project
Research Review Subcommittee
Science Advisory Board
Norton Nelson
Chair, Executive Committee
Science Advisory Board
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OF THE OFFICE OF RESEARCH AND DEVELOPMENT'S
INTEGRATED AIR CMCER PROJECT
REPORT OP .THE INTEGRATED AIR CMCER PROJECT
RESEARCH REVIEW SUBCOMMITTEE
SCIENCE ADVISOR* BOARD
February 198?
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U. S, EWWRONMENXM, PROTECTION AGENCY
NOTICE
This report has been written as a 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 natters related to problems facing the Agency* This
re|X»rt 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,
nor of other agencies in the Executive Branch of the Federal
government^ nor does mention of trade names or commercial products
constitute endorsement of recommendation for use.
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TABLE OF CONTENTS
EASE
EXECUTIVE SUMMARY ... .,...,..., I
INTRODUCTION .».. .....*.......... 3
OVERVIEW .,»...,.... 3
General Garments .,.,,....»...,.,.,..»..,.,.... 3
Major Project Strengths .«*...*..»...».......*. 4
Major Project Weaknesses .,*...*. 5
ISSUES .,..,,...*. . 5
Strategy and Approach * 6
Relevance to Risk Assessment .,..,,...,...,... 7
Bioassay Methods and Other Health Encpoints .. 8
ADDITIONAL SUBCOMMITTEE COMMENTS 8
Clarification of Objectives .................. 8
Extension of the Program » ... 8
Miscellaneous Remarks ...*.........,..»....... 9
APPENDICES
1, Issues for Consideration
2. Subcommittee Foster
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EXECUTIVE!
The Subccwnrittee finds that the Integrated Air Cancer Project (IACP)
is a scientifically well-founded initiative that has effectively applied
current knowledge of field sampling, chemical analysis, source-receptor
linkage methods and rautagenic testing. It has also systematically addressed
the carcincgenicity of mixtures in ambient air. Four important achievements
have occurred in its early stages. These includes (a) developing methods
for sampling and testing organic mixtures for mutagenicity; (b) segregating
non-volatile and volatile organic fractions contributing to itutagenicity;
(c) demonstrating mutagenicity in organic products of atmospheric reactions?
and (d) applying receptor modeling to estimate source contributions to
airborne organic mutagens.
The Subcommittee attributes the early achievements of the IACP to
its leadership and the cooperation of participating staff. To date, the
leadership has successfully resolved the potential difficulties in merging
skills from four different laboratories,* and have produced a relatively
stable funding- base, and reinforced the need for cooperation at the staff
level,
The Subcommittee suggests that IACP can further its results by
aggressively conducting chemical analysis for wutagenic compound identi-
fication. The project should present the data in a uniform framework
applying statistical methods. The Subcommittee encourages exploratory
data analysis to seek important interrelationship;'; in the data set. The
project also would benefit by the participation oE an epidemiologist.
Through this interaction, the project can collaborate raore closely
with BPA's expanding risk assessment capability.
At the request of EPA, the subcommittee evaluated three groups of
eight specific issues. These include;
Strategy and Approach
1. What is the role of IACP in Clean Air Act (Section 112} strategy
development?
Subcommittee response; The results of the project will assist EPA
in addressing the nature, potency and origins of organic air toxi-
cants. It will also provide sampling test methods and guidance
on control priorities.
* These are the Air and Energy Research Laboratory (AERL) , the Atmospheric
Sciences Research Laboratory (ASRL) , the Environmental Monitoring Systems
Laboratory (EMSL), and the Health Effects Research Laboratory (HEKL).
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2. Does IACP provide a new means to understand the behavior of
airborne toxics?
Subcggnittee response.: By integrating chemical identifica-
tion, rnutagenic activity and source contributions, the IACP
will improve our understanding of the behavior of airborne
toxics.
3. Does IACP assist in developing risk assessment methods?
Subcgtpittee response: Although the project does not address risk
assessment ger se, IACP will stimulate methods development.
4. Should IACP address control technology?
Subccnmittee, response; It is premature to factor emission
controls Tnto the current research design.
Relevanceto Risk Assessment
1. Does IACP have a suitable approach for its goals?
Subccnroi ttee responsei The methods are carefully considered and
use accepted chemistry and bioassay measures. Hie risk evaluation
aspects could be improved by adding personal diaries to the Boise
study.
2. Should more emphasis be placed on personal or microenvirormental
monitoring?
Subccmrii ttee response: Incorporating personal monitoring should
be a low priority. The ambient and indoor neasureflients are
suitable for the present program.
Bioassay Methods_and .Health Endpoints
1. Are additional bioassays warranted?
Subcccmittee res_gpnsei Not at the present tiirte, because the
bioassays new in the program are practical and appropriately
selected.
2. Should non-cancer endpoints be included?
Subcommittee response; Given the available resources, this
extension would" dilute the focus of the project: it is
not reconraended.
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The Subcommittee provides additional recommendations which include:
(15 in describing the project, the investigators should make it clear
that the project addresses only organics resulting from, incomplete fuel
combustion and not all airborne toxics? (2) the EPA/Chinese cooperative
study of airborne materials (Lung Cancer and Mr Pollution Study-Xuan
Wei County, Yunan Province, China) may well provide a valuable comparison
for the IACP findings; (These two programs should b= closely coordinated,}
(3) because the lACP's success will depend on long-term, sustained support
and funding, EPA should provide this support to ensure that it obtains
the full benefit from the work undertaken? and (4) the project has a
strong early record of achievement through management and staff focus on
its objectives and this focus should' be sustained—temptations to expand
or dilute the project with additional goals should be resisted at the
present time,
INTRODUCTION
At the request of the Office of Research and Development (ORD}» the
Science .Mvisory Board agreed to conduct a series of reviews on a number
of ongoing research programs within the Agency. Committees of recognized
experts have conducted the peer reviews of ongoing research progratns to
communicate to the Agency the progress being made in meeting research
needs pertinent to the development of regulations and policy. One of the
reviews requested for FY 1986"was a review of the Integrated Air Cancer
Project. ORD's requests to the Science Advisory Board are presented in
Appendix 1.
To conduct this review, the Science Advisory Board formed the Integrated
Mr Cancer Project Research Review Subcommittee, w^ich reviewed documents
describing the study, including the results of threo previous technical
peer reviews. The Subcommittee held a public nesting in Research Triangle
Park, North Carolina on September 16-17, 1986, and prepared a draft of
this report on-site. Subsequent revisions of the report were handled by
mail and telephone .conversations. The Executive Committee of the Science
Advisory Board reviewed and accepted the report.
The Subcommittee was chaired by Dr. George Hidy of the Desert Research
Institute and included two members of the technical peer review panel
which reviewed the program in its earlier stages. These members were
Dr. Joan Daisey of Lawrence Berkeley Laboratory (previously affiliated
with New York University) who chaired the technical peer review panel,
and Dr. Dennis Schuetzle of Ford Motor Company. The Subcommittee
(Appendix 2) represented a wide range of disciplines both in the health
and measurement areas.
OVERVIEW
General Cgnroents
The Subcommittee commends the efforts of the Integrated Air Cancer
Project and the team which has undertaken it. The project plan is both
scientifically well founded and appropriately innovative in applying
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current knowledge. The project is adequately funded in relation to EPA's
research priorities. The researchers are highly motivated, and realistic
about what their efforts will yield and logical in their approach to this
important environmental issue* The team is especially important to the
Agency because of its integrated interdisciplinary and multi-laboratory
nature and its coordinated approach to the investigation of a complex
problem. The management team should be commended and encouraged to
continue its efforts.
The Project made early and extensive use of a technical peer review
panel chaired by Dr. Joan Daisey. It is important to note that the 1ACP
addressed the recommendations of this earlier review panel and used the
panel as part of the planning effort. Indeed, the panel monitored the
progress of IACP in implementing its study design. The IACP research
team was responsive to the recommendations of the technial peer review
panel to iraprove the project,
Major Project Strengths
The major strengths include the following:
1. Strengthening the program by establishing a technical peer review
and advisory panel and being responsive to that panel's recatansndations.
The panel, which was established in 1984 and chaired by Dr. Joan Dasiey,
consisted of outside experts frcm each of the disciplines represented
in the project who were also experienced in interdisciplinary
environmental studies.
2, Focusing the program by setting achievable short-term objectives
which ace targeted to and compatible with its long-term goals.
3. Developing a cost-effective and efficient approach to characterize urban
air chemistry and to identify fractions and individual compounds with
high mutagenic activity that are good candidates for cancer testing
in animals*
&
4. Developing bioassay directed fractionation and compound identification
methods to identify iitiportant mutagens and characterize complex mixtures
of airborne organic substances.
5. &pprcpriate selection of practical mutagenic and carcinogenic assays*
6. Developing unique and innovative methodology to detect vapor phase
rnutagens in primary emissions and their demonstration in laboratory
experiments.
7. Identifying mutagens and potential carcinogens originating from atmospheric
transformations of primary source materials.
8. Making an innovative use of receptor modeling to understand the
contribution of sources of mutagenic compounds in the ambient air.
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9. Establishing an effective and committed interdisciplinary research
team supported by four laboratory directors who have marshalled
sufficient resources to implement IACP.
Major_Project_ Weaknesses
1, Data Analysis
The IACP, at this stage of development, would benefit ftrcm increased
attention to an in-depth analysis of data, particularly in exposure
assessment. The Subcommittee perceived an uneven application of
statistical methods to the data representation in the poster presentations
and in scrae of the briefings. "Level A" statistics, the basic statistical
representation, should be uniformly applied and cccqplete for the data.
Application of "Level B" statistics, or exploratory data analysis, is
presently needed. Both elements of this analysis would profit from
having someone with oversight responsibility for data analysis. Such
oversight in data management and analysis would ensure that the data
set is treated statistically in an uniform manner. Exploratory analysis
would be used to discover new relationships or confirm certain hypotheses
in this large data base -that way not be apparent from simpler analyses.
Successful completion of "Level B" could require one or two individuals
who could work full time on data analysis. The perspective on the IACP
results as a whole should profit from this approach.
2, Comgound^Identi£ication
Carcinogen compound identification merit'? increased attention.
This area is proceeding more slowly than warranted when compared to its
importance to the fulfilling the lACP's first objective. This component
is essential to addressing the objectives of the study.
^* E^idemiological Input
The involvement of an epidemiologist with the IACP, without converting
the project into an epidemiological study per se, would be advantageous
because of the additional perspective the epidemiologist and the IACP
will provide each other for risk assessment, and the identification of
possible opportunities for related studies*
ISSUES
the Agency submitted three groups of issues for the Subccmmittee's
evaluation* These included the project's overall strategy and approach,
its relevance to risk assessment, and bioassay methods and other health
endpoints.
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Strategy and Approach
1 . ifoat pole could this research program play _in developing the _strjategjLes
and data necessary for understanding, prioritizing, and regulating pollutants
and sources which constitute the roost^jserious. risk under the Clean Air
Act (e.g. f Section 112)?
Fran the regulatory point of view, the IACP makes three significant
contributions. First, the IACP improves EPA's understanding of sources
of airborne mutagens; the contribution of atmospheric trans format ions to
the presence of mutagens in ambient air; complex organic mixtures in the
atnesphere? and human exposure to and risk from these mixtures. These
improvements should lead the Agency to develop a broader perspective on air
toxics and different approaches to regulate toxic air pollutants.
Second, the IACP determines the relative contribution of semi-volatile
and particulate material to the total burden of mutagenic material in
ambient air. Finally, the IACP provides a basis for standardizing
methods that define exposure and those inputs to risk analysis which the
Agency needs to recognize.
2 * Do the strategy and approach taken^by^this^ project_ provide a new
avenue to understanding part -of the air toxics
Yes, While several approaches (source characterization, source
apportionment) used in this study are not new in r.hemselves, the
integration of these techniques with mutagenic assessment is unique.
the method yields results on the primary sources of ambient airborne
mutajens, the identification of compounds accountable for this mutagenic
activity, and the importance of atmospheric conversion to the presence
of mutagens. The project is unique in its approach to addressing exposure
to complex organic mixtures. However, the IACP should be careful in
describing its efforts to clarify that its scope is limited to organic
products of incomplete combustion and does not include airborne carcinogens,
such as asbestos, heavy metals and radon.
3. Does this project represent _a useful step_ forward^ in developing methods
and data^for J:he risk^assesstnenjc of complex mixtures?
Yes. The study provides an important way to address human exposure
to airborne organic species and provides an approach to generating inputs
for risk assessment. The IACP wisely has not attempted to address new
methods for risk assessment, per se. The IACP should serve as a catalyst
for such efforts. Three areas where the IACP might Inspire creative
related or complementary work are adding an epidemiological perspective
to assist in relating to human risk, personal monitoring to develop an
exposure estimate, and clinical studies of the effects of respiratory
irritants,
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4» Should ve<_£»&_ considering aresearch conjKaient which would address
the__ef facts _of emerging, .control, technologies, _e.
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BioassayMethods and Other Health Sndpoints
I, Since bioassay techniques are assumed to be imperfect predictors
of huroan carcinogens, does the SAB feel that addiAtonal bioassays should
be included at this time?
For the purposes of the IACP, the staff have selected the best
available practical methods. The Subccitmittee does not recommend inhalation
testing at this stage because of the large expense and high uncertainties
associated with interpretation. Possibly at a later stage in the project,
data will be sufficient to support the design of inhalation studies*
2, • EPA's air toxics health researchprogram does address non-cancer
healtheffects. However?, these studies aregenerally oriented toward
specif ic coitpciinds of concern rather than complex mixtures of ambient
air. Should healthjandgoints other than cancer be staudiegr_as_j>art of
the IACP?
No, because such expansion will dilute the project's current
direction, given the available resources. As the IACP progresses in
identifying various gaseous and particulate components in wood stove
effluents and its atmospheric transformations, other EPA research groups
can review these chemicals and determine whether any of them pose non-
cancerous respiratory disease hazards. The IACP should not alter its
focus to include non-cancer endpoints.
ADDITIONAL SUBCOMMITTEE COMMENTS
Clarification of Objectives
The IACP should edit its written materials and provide status
summaries to clarify its objectives and the reasons for selecting a
particular subset of activities. In particular, it should emphasize
that the IACP is addressing organic products of incomplete combustion
and not the full range of air carcinogens that would Include such
pollutants as asbestos and radon. Such materials should directly state
that risk assessment is not a major objective of the IACP. The Subcommittee
considered whether the term cancer in the JACP's title could be misleading
given the fact that most assays concern routagenicity. It concluded that
the title is appropriate, since ultimately the long-term goal of this
project is to assess human exposure to carcinogens.
Extension of theProgram
The meteorological measurements could be improved at Boise by including
observations of the vertical temperature structure and acoustic sounder
recordings, as well as appropriate measures of solar radiation.
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SPA might have a research management analyst examine this program,
not to change,.it, but instead to study its success. The results of this
analysis ^ten could be applied to other opportunities for collaborative
work at EPA and possibly other government research programs.
Miscellaneous Remarks
Other miscellaneous points related to the study include the
following:
The China study (Lung Cancer and Air Pollution Study-Xuan Wei
County, Yunan Province, China) is an important related study, and
the IACP management team should ensure that they are aware of its
progress and results.
Because of the respect which the Subcommittee has for this project
and the Subcannit tee's concern for its future, the following three points
are being repeated.
1, the I&CP is a long-term project requiring long-term support. The
Subcommittee strongly reccnroends that EPA provide the stable, long-term
support needed to complete its program.
2. The 1ACP is a training ground for Agency scientists to learn to
think more broadly and is, therefore, of great importance to EPA beyond
the immediate utility of the research results.
3. The IACP needs to be vigilant if it is to maintain its focus over the
length of this study. The techniques developed and peripheral results
are interesting and valuable in themselves. However, if they are
overemphasized within IACP resources, the project may be diluted and
may not productively address its long-term goals.
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APPENDIX 1
ISSUES FOR CONSIDEfiATION
The Office of Research and Development has described the Integrated
Air Cancer Project (IACP) as a long-range interdisciplinary research
program planned to identify principal airborne carcinogens, their sources,
and to improve EPA's ability to assess human exposure and risk from these
carcinogens. To accomplish these goals, an interdisciplinary team of
scientists from four Agency research laboratories has designed a stepwise
program of laboratory and field studies with short-tern objectives that
contribute to the long-range project goals.
The Office of Research and Development referred the following issues to
the Science Mvisory Board:
1* Air toxics are increasingly important to the Agency fron the perspectives
of source characterisation, monitoring and modeling of exposure and
health effects. In addition, complex mixtures in urban air have posed
particularly difficult problems for the Agency,
A. what role could this research program play in developing
the strategies and data necessary for understanding,
prioritizing, and regulating pollutants and sources which
constitute the most serious risk under the Clean Air Act
(e.g., Section 112)?
B, Do the ^tra^eciy^nd^approacji taken by this project
provide a new avenue to "understanding part of the air
toxics problem?
C. Does this project represent a useful step forward in
developing methods and data for the risk assessment of
ecraplex mixtures?
D. Should we,- be considering a research ccraponent that
would address the effects of eirerging control technologies t
e.g., catalysts on wood stoves and diesels, on the
emissions from sources?
2. The Agency's risk assessment process requires information from research
in a number of areas, such as source characterization, transport and
fate, exposure assessment, dose estimation, arid health assessment.
Exposure assessment has been considered an important component of the
IACP program. Intensive chemical and bioassay characterization of specific
microenvironments, however, is planned to precede the development of
personal ronitors for specific pollutants identified as either tracer
chemicals or important carcinogens. At this stage of the project,
extensive personal monitoring or large exposure monitoring surveys
do not appear to be the appropriate approach to meeting the initial
project goals.
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Append ix I
Continued
A. Does the SAB agree with this strategy and approach to
exposure assessment or do you consider a change in emphasis
important to the accomplishment of the project goals?
B. In particular, what emphasis should be placed on personal
exposure monitoring, raieroenvironraental monitoring
(e.g», indoor) and ambient monitoring at this stage and
in future stages of the IAGP?
3. The IACP has used short-term nutagenesis and animal cancer
bipasgays as the most reasonable indicators of human cancer.
A. Since bioassay techniques are iinperfect predictors
of human carcinogens, does the SAB feel that additional
bioassays should be included at this time?
B. EPA's air toxics health research program does address
non-cancer health effects. However, these studies are
generally oriented toward specific compounds of concern
rather than complex mixtures of ambient air. Should
health endpoints other than cancer be studied as part
of the IACP?
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APPENDIX 2
U.S. ENVIRONMENTAL PROTECTION AGENCY
SCIENCE ADVISORY BQABD
INTEGRATED AIR CANCER PROJECT RESEARCH REVIEW SUBCOMMITTEE
Chairman
Dr. George M* Hidy, President, Desert Research Institute,
Pest Office Box 60220, Reno, Nevada 89506
Members
Dr. Joan Daisey, Indoor Environment Program, 90-3058,
Lawrence Berkeley Laboratory, Berkeley, California 94720
Dr. Phil Enterline, Director of the Center for Environmental
Epidemiology, Department of Biostatistics, Rocm A-410, Graduate
School of Public Health, 130 Desoto Street, University of
Pittsburgh, Pittsburgh, Pennsylvania 15261
Dr. Timothy Larson, Environmental Engineering and Science Program,
Department of Civil Engineering, FX-1Q, University of Washington
Seattle, Washington 98195
Dr. Paul Nettesheia, National Institute of Environmental Health
Sciences, MD-D2-01, Post Office Sox 12233, Research Triangle
Park, North Carolina 27707
Dr. Paul Lioy, Director, Exposure Measurement and Assessment
Division, UMDW-Robert Wood Johnson Medical School, Department of
Environmental Coramunity Medicine, 675 Hoes Lane, Piscataway,
New Jersey 08854-5635
Dr. Michael Shelby, National Institute of Environmental Health
Sciences, MD-E4-Q3, Post Office Box 12233, Research Triangle
Park, North Carolina 27707
Dr. Dennis Sehuetzle, Principle Research Scientist and Manager,
Chemical Analysis Research Department, Scientific Research Labs
- 83061, Ford Motor Company, Box 2053, Dearborn, Michigan 48121
ExecutiveSecretary
Kathleen W. Conway, Deputy Director, Science Advisory Board
U.S. Environmental Protection Agency, 401 M Street, S,W.,
A1Q1H?, Washington, D,C. 20460
Sta_ffj5ecretary
Dorothy M. Clark, Secretary, Science Advisory Board, U.S. Environmental
Protection Agency, 401 M Street, S.W,, A1Q1-F, Washington, D,C. 20460
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