U.S. ENVIRONMENTAL PROTECTION AGENCY PRIVATE

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HUMAN STUDIES REVIEW BOARD (HSRB)

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PUBLIC MEETING

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WEDNESDAY,

OCTOBER 24, 2007

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	The meeting convened at 8:30 a.m. in the Conference Center at One
Potomac Yard, 2777 South Crystal Drive, Arlington, Virginia, Celia B.
Fisher, PhD, Chair, presiding.

HSRB MEMBERS PRESENT:

CELIA B. FISHER, PhD, Chair

STEPHEN BRIMIJOIN, PhD, Vice Chair

GARY L. CHADWICK, PharmD, MPH, CIP, Member

JANICE CHAMBERS, PhD, DABT, Member

SUSAN S. FISH, PharmD, MPH, Member

SUZANNE C. FITZPATRICK, PhD, DABT, Member

DALLAS E. JOHNSON, PhD, Member

KYUNGMANN KIM, PhD, CCRP, Member

KANNAN KRISHNAN, PhD, Member

MICHAEL D. LEBOWITZ, PhD, Member

LOIS D. LEHMAN-MCKEEMAN, PhD, Member

JERRY A. MENIKOFF, MD, Member

REBECCA PARKIN, PhD, MPH, Member

SEAN M. PHILPOTT, PhD, Member

RICHARD B. SHARP, PhD, Member

HSRB STAFF:

PAUL I. LEWIS, PhD, Designated Federal Officer

HSRB CONSULTANTS:

GERMAINE BUCK LOUIS, PhD, Division of

	Epidemiology, Statistics & Prevention

	Research, National Institute of Children

	& Human Development

P. BARRY RYAN, PhD, Department of

	Environmental and Occupational Health,

	Rollins School of Public Health, Emory

	University

EPA STAFF:

JOHN CARLEY, Office of Pesticide Programs

LARRY CUPITT, PhD, Office of Research and

	Development

DEBBIE EDWARDS, PhD, Director, Office of

	Pesticide Programs

	ROY FORTMANN, PhD, Office of Research

	and Development

	GEORGE GRAY, PhD, EPA Science Advisor

	WILLIAM JORDAN, Office of Pesticide

	Programs

	NANCY McCARROLL, Office of Pesticide

	Programs

	WARREN LUX, MD, Human Subjects Research

	Review Official, Office of the Science

	Advisor

PUBLIC COMMENT:

JUDITH HAUSWIRTH, PhD Keller & Heckman, LLP

DOUGLAS T. RICHARDS, American Pacific

	Corporation

	TABLE OF CONTENTS

Convene Meeting and Identification of

	Board Members, Celia Fisher, Ph.D.

	(HSRB Chair)	4

Welcome, George Gray, Ph.D. (EPA Science

	Advisory)	7

Opening Remarks, Debbie Edwards, Ph.D.

	(Director, Office of Pesticide

	Programs [OPP] EPA)	13

Meeting Administrative Procedures, Paul

	Lewis, Ph.D. (Designated Federal

	Officer [DFO], HSRB, OSA, EPA)	17

EPA Follow-up on HSRB Recommendations, Mr.

	William Jordan (OPP, EPA)	23

Scientific and Ethical Approaches for

	Observational Exposure Studies

	EPA Draft Document Scientific and

	Ethical Approaches for Observational

	Exposure Studies,

	Larry Cupitt, PhD,

	Office of Research and Development	40

Public Comments	64

Board Discussion	93

Science and Ethics of Sodium Azide Study	268

	Nancy McCarroll (OPP, EPA)

	John Carley (OPP, EPA)

Public Comments	310

Board Discussion	318

Adjournment

	P R O C E E D I N G S

	8:39 A.M.

		DR. FISHER:  Okay, so let's get started with our meeting today.  A
couple of our members are in transit, so I'm sure they'll be here any
minute.

		So why don't we go around.  I'm Dr. Celia Fisher, chair of the HSRB
and I think we'll go round, Steve, do you want to introduce yourself
first?

		DR. BRIMIJOIN:  I'm actually delighted to see that I am finally after
15 years of volunteer service for the US EPA, I am finally known by my
correct name.  Today, after 15 years, and I thank you, Paul, and whoever
else was involved in this, I'm Stephen Brimijoin.  I'm at the Mayo
Clinic in Pharmacology and I'm vice chair of this Board.

		DR. FISHER:  And I wanted to thank Steve for doing an excellent job,
from what I read in the transcripts, as well as from what everybody else
said in terms of leading the meeting last time.

		DR. PARKIN:  I'm Rebecca Parkin.  I'm a Professor of Environmental and
Occupational Health at the G.W. University School of Public Health and
Health Services.

		DR. FISH:  I'm Sue Fish from Boston University, Schools of Public
Health and Medicine.

		DR. CHADWICK:  Gary Chadwick from the University of Rochester.

		DR. BUCK LOUIS:  I'm Germaine Buck Louis.  I'm a reproductive and
cranial epidemiologist and Branch Chief of the Epidemiology Branch at
NICHD and currently acting director of FE Biostats and Prevention.

		DR. RYAN:  I'm Barry Ryan, I'm Professor of Exposure Assessment and
Environmental Chemistry, Rowland School of Public Health at Emory
University.

		DR. KRISHNAN:  Kannan Krishnan, toxicologist, Professor at University
of Montreal.

		DR. JOHNSON:  My name is Dallas Johnson.  I'm Professor Emeritus,
Kansas State University.  I'm a statistician.  I'm a Visiting Professor
at Texas A&M University this fall semester.

		DR. KIM:  My name is KyungMann Kim.  I hope it doesn't take 15 years
for people to pick up my first name.  I'm a statistician from the
University of Wisconsin at Madison.

		DR. LEBOWITZ:  I'm Michael Lebowitz, a retired Professor of Medicine,
Epidemiology, Bio Stat. and Environmental Health Sciences in Tucson,
Arizona.

		DR. CHAMBERS:  I'm Jan Chambers.  I'm Professor in the College of
Veterinary Medicine at City State University and I'm a pesticide
toxicologist.

		DR. SHARP:  I'm Richard Sharp.  I'm Director of Bioethics Research at
Cleveland Clinic.

		DR. PHILPOTT:  I'm Sean Philpott.  I'm Policy and Ethics Director for
an NGO here in Washington called PATH and in deference to poor Steve
there, what most people don't even realize is I actually do have two
names because my entire family calls me Jean-Michel.

		DR. FISHER:  And young man, I will stop calling you Kim, I promise.

		(Laughter.)

		I wanted to especially welcome Dallas and Rebecca to join us.  We're
looking forward to your contributions.

		Dr. Gray, would you like to make some remarks?

		DR. GRAY:  Well, sure.  I would like to extend my good morning and
welcome to everyone here.  We really do appreciate your being here
together with Debbie Edwards who is the Director of the Office of
Pesticide Programs.

		We, as we say every time, and I think Rebecca and Dallas, you'll find
out, we appreciate your hard work.  This is a very hard working board
and we appreciate the time and effort that you put into this, the
requirement of your thought and your effort and you all have day jobs
and other things to do and we appreciate very much your service to the
Agency.

		I also want to thank everyone in EPA who worked hard to get ready for
this meeting.  I think we'll find it to be both an interesting and I
hope a very productive meeting.  So I want to thank them for all of
their hard work.

		To go back, I do want to welcome our three new board members, only two
of which are with us today to our meeting.  You've already met Rebecca
Parkin and Dallas Johnson.  Our other new member is Dr. Ernest Prentice.
 Dr. Prentice isn't able to join us this week, but he will be

-- he's looking forward to being part of this Board and I think you'll
find him to be a terrific contributor and Rebecca and Dallas, we look
forward to the benefit of your expertise.  So thank you very much for
being willing to serve.

		I do also want to thank Dave Bellinger.  You know, he's had to resign
from the Board for a variety of just conflicting professional
commitments and just a lot of those calls on his time, but I want to
thank him for all of the effort that he put in.  He was an important
contributor and brought a very useful perspective to the Board.

		Now today does mark kind of a new milestone for the Board in the
roughly year and a half now that the Board has been working, almost all
of our effort has been on the review of these third party intentional
dosing exposures of non-pregnant, non-nursing people who are and these
are for submission to the Agency for use primarily in the pesticide
program.  Now today, we're going to be asking you to bring your
expertise and your knowledge and your perspective to a new topic, a
product prepared by the Agency's Office of Research and Development.
It's of particular interest to me.

		I think most of you know that in addition to being the Agency's
Science Advisor, I wear another hat in that I am the Assistant
Administrator for the Office of Research and Development.  So this has
been prepared in that group.  So this is our effort to develop a
framework, to develop procedures, to help with our investigators
thinking about, just thinking about ethical and scientific issues around
human observational studies.

		Unfortunately, I'm going to be in and out a little bit today, but this
is something that has the attention at the highest levels of ORD.
Sitting immediately behind me is Kevin Teichman.  He's our Acting Deputy
Assistant Administrator for Science.  He has been very involved in
watching this project, understanding this project and is taking a close
personal interest in it.

		So I am and Kevin is and in fact, all of the Office of Research and
Development are interested in your view of this topic and the thoughtful
advice that I know that you'll provide.  So I think it will be an
interesting new challenge for you and I really do appreciate your
willingness to take that on.

		This is a big thing for the Agency, to ensure that our observational
human exposure research continues to be done with both the most
up-to-date scientific and ethical standards.  And our National Exposure
Research Laboratory and in EPA speak, of course, we have an acronym and
we make it something you can say, so NERL is our group that both does a
lot of this work and is a leader for the -- really for the exposure
assessment community in these observational sorts of studies.  But what
we want to do is make sure that we have a document that looks at the
particular issues that EPA researchers need to consider as they plan and
as they implement these observational studies.  It's not meant to be an
official agency guidance document, but the idea is is that it's a
reference, it's a resource, it's something that people, that
investigators and scientists can look at to help understand the way in
which they can approach these observational studies which are an
important part of our exposure assessment portfolio.

		Of course, there will also be some of that regular business where
you'll be looking at some already proposed and some completed human
studies, and again, there we look forward to your thoughtful review.
This is an important part of helping to move things through to stay with
the particular framework that we've set for ourselves, for looking at
and using these sorts of studies and we appreciate your thought there.

		So Dr. Fisher, thank you for the opportunity to say a few words.
Again, my thanks to the Board, not only for your on-going service, but I
am especially interested in this topic that you'll be taking on today.
I look forward to your remarks and I want you to know that they'll be
considered very seriously by the Agency.  So thank you very much.

		DR. FISHER:  Thank you very much, Dr. Gray.

		Dr. Edwards, would you like to say something?

		DR. EDWARDS:   Just a few words, thank you, Dr. Fisher.

		I'd like to join Dr. Gray in welcoming the Board to EPA for this, what
is the eighth meeting of the Human Studies Review Board.  I was actually
very surprised to see that when I realized it was the eighth meeting.
It seems like just yesterday the Board formed and began its work, but a
lot of good work has been done over those past seven meetings which we
appreciate very much.

		For most of you, we welcome you back to this conference facility and
this Human Studies Review Board meeting.  It's our pleasure to host this
meeting here in our very own building.  Please let us know -- you see a
lot of EPA people around here, please let us know if there's anything we
can do at all to support you during the meeting.

		I especially want to welcome the new members also.  Dr. Prentice
couldn't make it today.  We're sorry about that, but I hope to be able
to meet him at the next meeting.

		We're looking forward to working with Dr. Parkin and Dr. Johnson.
Welcome, again, to the Board.  I think you'll enjoy it.  I hope you will
anyway, very interesting issues.

		Once again, we'll be presenting a variety of topics on which we're
seeking advice and Dr. Gray has just explained the research to do with
observational exposure on which we're seeking advice.  That will be very
important as well to the pesticide program, so we'll be looking forward
to that advice from you.

		We'll also be presenting, the pesticide program, new protocols and
completed studies.  You'll be looking at diverse types of human research
from field studies on insect repellents to a clinical study of a drug
from which we're deriving information on the potential toxicity of a
pesticide active ingredient.

		And finally, we're going to provide you with a progress report on our
work with the Exposure Task Forces.

		I want to thank all of you for the effort you give to helping us
address these scientific and ethical issues around the conduct and
evaluation of human research.  We appreciate the time you devote to this
important work.  It is very important to us.  It is very important to
the public at large, not only here in the meetings where you
participate, but also in all the preparation that you do and in the
drafting on the final reports outcomes of the meetings.

		Finally, I also want to thank Dr. Paul Lewis.  Paul, there he is, and
Crystal Rogers Jenkins.  They've done a huge amount of work in handling
all the administrative details of the meeting and also in helping my
staff prepare for our part of the meeting.

		So there is a lot of work ahead and I don't want to delay you any
further from getting into the agenda, but just to reiterate my thanks
for your participation today.  Thank you.

		DR. FISHER:  Thank you, Dr. Edwards, and I did want to mention that
this time around we've really, based on the recommendations of the
Board, established a work group that works with us for agendas.  And
Bill Jordan, as always, has been especially helpful and responsive in
terms of those work groups and I think that it's been very helpful in
terms of being able to identify consultants, identify how we would best
address the kind of issues that Dr. Gray has been talking about as well
as the issues that you have.  So I think it's working very well and I
did want to thank Mr. Jordan for his great work.

		Dr. Lewis?

		DR. LEWIS:  Thank you, Dr. Fisher, and I want to thank you first for
serving as chair for this week's meeting and also members of the Board
for attending.  Also, I would like to echo what we've heard from Dr.
Gray and Dr. Edwards welcoming our new members to this Advisory
Committee, Dr. Parkin and Dr. Johnson.

		The Agency appreciates the time and diligent work of Board Members in
preparing for this meeting, taking into account your busy schedules and
other professional obligations.  And I also want to thank the public for
being here today observing this meeting and for my EPA colleagues for
all their hard work preparing for the challenging topics that we have
ahead.

		As the Designated Federal Officer for this meeting, I serve as a
liaison between the Board and the Agency and I am also responsible for
insuring provisions of the Federal Advisory Committee Act are met.  And
HSRB meetings are subject to all Federal Advisory Committee Act
requirements.  As a Designated Federal Officer for the Board, a critical
responsibility is to work with appropriate agency officials to ensure
that all necessary ethics regulations are satisfied.

		In that capacity, Board Members and consultants, and I'll touch upon
that in a moment, are briefed with provisions of the federal conflict of
interest laws.  In addition, each participant has filed a Standard
Government Financial Disclosure Report and I, along with our Deputy
Ethics Officer for the EPA Office Science Advisor and in consultation
with the Office of General Counsel, have reviewed these reports to
ensure all ethics requirements are met.

		The Board will be reviewing challenging issues over the next several
days and we have a full agenda from today until Friday and meeting times
are approximate.  Thus, we may not keep to exact times as noted due to
Board discussions and public comments.  We strive to ensure adequate
time for Agency presentations, public comments presented, and for Board
deliberations.

		For Board Members, presenters, consultants, and public commenters, we
would appreciate you speaking into the microphone since this meeting is
being recorded.  In addition, copies of meeting materials and public
comments will be available on regulations.gov, the Agency website for
all materials associated with this meeting.

		For members of the public requesting time to make a comment, I must
remind you that your remarks are limited to five minutes.  And for those
that have not pre-registered, have not contacted me previously, please
notify myself during a break or during lunch if you would like to make a
public comment in the course of the discussion.

		As I mentioned, there is a public docket for this meeting and all
background materials, questions posed to the Board, and all reference
materials are available in the ORD docket via regulations.gov, and the
agenda outside this meeting lists the contact information for Board
documents.

		For members of the press who have questions about this week's meeting,
please contact me during the break or during lunch and I will direct you
to the appropriate person to address any questions that you may have.

		I want to spend a moment talking about consultants for today's and
tomorrow's meeting.  We have several consultants joining the Board.  As
an example for observational discussion this morning and afternoon, I
would like to welcome Dr. Ryan and Dr. Buck, who will be serving as the
consultants in associate discussions for our meeting.

		As consultants to the Board, they are being asked to provide
specialized information or assistance to the Board concerning specific
topic or topics for review.  Consultants are not considered members of
the Board, and do not participate in the Board's decision making
process, but I want to again welcome them and I'm looking forward to the
help they can provide the Board in terms of the advice that we are
seeking for today.

		As per the Federal Advisory Committee Act, minutes of this meeting are
prepared.  The minutes will be a description of matters discussed and
the conclusions reached by the Board.  As the Designated Federal
Officer, I have prepared such minutes and they are certified by the
chair, Dr. Fisher, within 90 days of our meeting.  They'll be available
on both the Human Studies Review Board website and on regulations.gov.

		The Board will also prepare a report as a response to the charged
questions that are listed on the agenda over the course of the three-day
meeting.  The Agency anticipates announcing Board review and subsequent
approval of this report via Federal Register notice.  We anticipate that
some time later on this year and when the draft report and the final
report is made available, will be available both on the regulations.gov
website and the HSRB website.

		I'd like to close by thanking the Board for its participation and for
again my colleagues for helping us in terms of preparing for discussion.
 I'm looking forward to a very interesting and enlightened discussion
over the next several days.

		Dr. Fisher?

		DR. FISHER:  Thank you, Dr. Lewis.

		Mr. Jordan, would you like to give us a summary?

		MR. JORDAN:  Certainly, thank you, Dr. Fisher, and I also want to
welcome everybody to the Human Studies Review Board.  It's become a
tradition and I think a very good one for someone from EPA to provide a
report back on what EPA has done with regard to the topics that were
considered at the previous meeting.  In that way, the Board Members know
how EPA responds to the advice that we have gotten and what actions we
are taking as a consequence.

		At the June meeting, there were five broad topics:  two insect
repellant protocols, one from the Carrol-Loye Biological Research
facility.  One from ICR in Baltimore.  There were also two completed,
actually more than two, a completed toxicity study on acrolein and
several clinical studies on 4 amino-pyridine.  And finally, we spent a
lot of time on a range of science and ethics issues related to handler
research, handler exposure research protocols that were proposed by the
task forces.  I'll be talking a little bit about each of those very
briefly.

		For the Carrol-Loye protocol LNX-001, the Board concurred with EPA's
conclusion that the studies were scientifically sound.  The protocol on
scientifically sound to be used to assess the repellant efficacy of the
tested products and concurred with EPA's conclusions that the studies
would meet applicable standards of the human studies regulation.

		We have heard from Dr. Carroll that he has not initiated this
research.  We expect he will conduct the research and submit a report to
us and based on that we would proceed to review the study report.

		The second protocol that the Board looked at was from Insect Control
Research.  The Board recommended several changes to the protocol for
both scientific and ethical reasons.  One of them was to use the first
confirmed landing with an intent to bite as evidence of failure of
efficacy.  The Board recommended performing serology testing on
aspirated mosquitos providing an explanation for the statistical
analysis plan and adding a dosimetry study.  The Board's conclusion was
that if appropriately revised, the protocol should produce
scientifically reliable data.  The Board also concurred with EPA's
assessment that the submitted protocol would not meet applicable
requirements and recommended changes that would make it compliant with
our human studies regulations.

		Following the Board's review, ICR undertook to revise the protocol and
submitted it to EPA.  We looked at that and determined that further
revisions were necessary to address the recommendations that the Board
had made and our own assessment as well.  And after reviewing our
comments, ICR informed us that the sponsor decided not to pursue the
research.  So we do not anticipate that the proposed research will be
conducted and as far as we're concerned that's sort of represents an end
of that one.

		We presented to the Board a completed inhalation toxicity study on
acrolein, a study that we found in the public literature.  And the Board
reviewed it with us and concluded that the study was sufficiently sound
from a scientific perspective to be used to estimate a safe level of
acute inhalation exposure to acrolein.

		There were a number of limitations on the study in terms of how much
we understood about it.  It was a very old study and fortunately Dr.
Lebowitz was familiar with the facility and was able to provide some
additional background information, but there was still quite a gap in
the information about the study.  There were some aspects of the
reported research that were troubling to people.

		The majority of the Board, however, concluded that there was not clear
and convincing evidence that this study was fundamentally unethical or
significantly deficient relative to the ethical standards prevailing
when the study was conducted.

		So based on that advice and consistent with our own view of the same
nature, we have relied on the results of the Weber-Tschopp inhalation
toxicity study as the basis for estimating a safe level of acute
inhalation exposure to acrolein and use that as a point of departure for
our regulatory decision making.

		Then we presented a series of several clinical studies on 4
amino-pyridine and these studies were conducted to evaluate the
effectiveness of the compound as a pharmaceutical.  The Board concluded
that the clinical studies taken together were sufficiently sound from a
scientific perspective to be used to derive a point of departure for
estimating risk to humans.

		The Board also concurred with EPA's conclusion that there was not
clear and convincing evidence that the studies were fundamentally
unethical or sufficiently deficient with respect to the ethical
standards prevailing when the studies were conducted.  And as you might
expect, EPA has relied on the results of these three studies to evaluate
the potential human risk of 4 amino-pyridine.

		As you remember, we spent a lot of time in the last meeting on a
series of scientific and ethical issues related to the proposed handler
exposure research.  The Board's report, draft report, goes into
considerable detail about those issues.  At the risk of not doing
justice to the depth and content of the report, I'm going to attempt to
summarize the highlights of the Board's discussion.  I recognize that it
is still in draft and tell you a little bit about where I think we are
headed with regard to those particular issues.

		In general, the Board concluded that the government documents provided
by the task forces adequately addressed the potential risks and benefits
of the proposed research and agreed with EPA that as the particular
protocols were developed for specific scenarios, there would be a need
to particularize those discussions, those general discussions of risk
and benefits to make them appropriate for the specific exposure
scenarios.  And the Board, I'm sorry, the task forces understand that
responsibility and when they proceed with protocols, I'm confident that
they will do that.

		The second area that the Board discussed was the need for data on the
efficiency of residue removal procedures.  As you may remember, the
studies are conducted with passive dosimetry and in order to collect
information on the residues on the parts of the body that are not
covered by the passive dosimeters, the investigators proposed to do hand
washes and to wipe the subject's face and neck and measure the residues
in the wipes and washes.

		Not all of the residues are successfully removed through those
procedures and to the extent that that is true, there is potential for
underestimating potential exposure.  What EPA will do and we've
communicated this to the task forces is that we will review the results
from these procedures on a study-by-study basis to determine the need
for data on the efficiency of the residue removal procedures and the
need for possible correction of exposure estimates.

		If the hand washes and face and neck wipes are a relatively small
component or contributor of the overall exposure, we think that the need
for corrections and testing the efficiency would be much smaller and so
that's the reason that we will wait until we see the results of the
particular studies.

		There was also a discussion by the Board of whether to include
concurrent biomonitoring to complement the information gained from the
passive dosimetry measurements and the Board agreed with the EPA's
conclusions that routinely including concurrent biomonitoring was not
necessary.  Of course, on a case-by-case basis we will always have the
option to look at that and recommend that and so in the context of
particular protocols, it may be possible to revisit this issue but we
think in general that it is going to be a very unusual circumstance.

		The task forces provided their standard operating procedures that
would be relatively consistent across all of the different scenarios,
thanks to standard operating procedures to ensure data quality.  The
Board's review of those SOPs found them to be reasonably complete.
There were recommendations to add a couple of additional SOPs to address
data quality, sample integrity, compliance with the standard operating
procedures.  And it's our understanding, the task forces expect to add
such SOPs.

		Okay, the next topic is one relating to both statistics and the kinds
of data that would be collected, specifically, whether or not the task
force research should collect data from repeated measurements on
different days of the same subject in order to be able to characterize
within worker variability.  The purpose, as indicated in the Board's
recommendation that EPA collects such data, is to allow the Agency to be
able to estimate what was called a usual exposure at the high end of the
distribution of individual exposures.

		And by usual exposure, we understood that the HSRB means the
distribution of the means of workers multi-day exposures across the
handler population.  Some workers may be characteristically much more
careful in the way that they perform a particular handler activity.
Other workers may be somewhat sloppier and so if you looked at those
workers day after day after day, you would find that they have, when
they're doing the same activity, they'd have differences in their
average over several days.

		We agree with the understanding and agree with the Board's conclusion
that measures, repeated measures would be necessary in order to
characterize within worker variability and therefore would be necessary
to be able to characterize the distribution of usual exposures.  EPA,
however, has decided that we don't need such information to assess the
risks associated with multi-day exposures.  We will use data collected
on individuals, multiple different individuals, to characterize the
distribution across individuals and use values from that distribution in
our estimates and multi-day exposures.  And so we're not going to ask
the task forces to collect repeated measurements.

		The next topic was actually a very broad one involving the task
forces' proposed approaches to recruiting and enrolling subjects.  We
had recommended some improvements in the way that that be done, but
basically thought the approach sounded as though it was compliant with
the investigators' responsibilities under the Human Studies regulations.
 The Board generally agreed, made a few other recommendations for
improvements and we will work with the task forces to address those
recommendations and we're optimistic that they will be addressed to the
satisfaction of both EPA and the Board.

		And then the last topic that I want to mention, but not discuss in any
great detail is the task forces' proposals to use a purposive diversity
sampling strategy.  The Board reviewed that and recommended that
sampling strategies that included more elements of randomization be
considered.  That is a specific agenda item that appears later in the
meeting and so I'll go into that in more depth when it appears on the
agenda.

		So thanks.

		DR. FISHER:  Thank you very much, Bill.  And I think we all appreciate
it's been so helpful to get this kind of summary to inform us as to how
well we're doing in terms of advising you and covering those issues.

		Are there any questions or comments from the Board?

		DR. JOHNSON:  I have a question.

		DR. FISHER:  Sure.

		DR. JOHNSON:  I've come across this term several times before in
reading some of the materials and I don't quite understand what it
means.  So if you'd explain what we mean by a point of departure?  Thank
you.

		MR. JORDAN:  Sure.  To answer your question, I'll need to describe
fairly briefly the approach that EPA uses to assess the risk of
pesticides.

		The way that the Agency does that is to identify the types of hazards,
the types of adverse effects that a pesticide may have.  For the vast
majority of pesticides, the largest type of data that most of the data
come from animal toxicity studies.  And we identify out of all of the
different types of toxicity studies, the first effect that would occur
as a consequence of exposure.  And so by determining that effect and the
dose level at which it occurs, we are then confident that if that effect
never occurs, none of the other adverse effects observed in many of the
toxicity studies would occur either.

		That dose level is referred to as a point of departure.  And the way
that we endeavor to make certain that nobody ever experiences that
effect is that we apply uncertainty factors to that point of departure.
Usually, when we're dealing with animal toxicity data, we apply an
uncertainty factor of 10x to take into account the possibility that
animals, that humans may be more sensitive to the adverse effect than
animals are.  And then we apply an additional uncertainty factor of 10x
to ensure that we're protecting the most sensitive subpopulation within
the broader human population and then we apply an additional 10x
uncertainty factor to account for the possibility that we may have
uncertainties with regard to the sensitivity of children or our
understanding of the exposure profile.

		And so in some cases we are therefore wanting to make sure that no
human -- that human beings are not getting exposed to a level greater
than one thousandth of the toxicity value associated with the first
toxic endpoint.  And we refer to that toxic endpoint as the point of
departure.

		When we're dealing with human data, it operates essentially the same
way, but we don't use typically the uncertainty factor for the
extrapolation from animal toxicity to human toxicity.

		DR. FISHER:  Thank you very much, Bill.  As usual, your explanations
are always phrased in a way that everybody can understand and I'm sure
the rest of the Board is happy to be reminded of what these mean.

		I think now we're going to turn to Dr. Cupitt and Dr. Fortmann.

		Dr. Gray, once again, I think the Board is very appreciative of this
opportunity not only to comment, but to learn.  I think that one of the
reasons the Board was so eager to look at this document was that it is
related to the kinds of decisions that we have to make in terms of
recommendations and we have learned a lot just from reading the
document.

		And I also know that Dr. Cupitt and Dr. Fortmann worked really hard to
get the document in shape for this meeting and not only is it so well
written, but it's beautiful.  So I want to thank you, again, for that
and we're looking forward to your comments.

		Dr. Gray?

		DR. GRAY:  I just want to say that I really do think that this is a
great opportunity.  Part of what made us work very hard and have this
push was that we thought this Board was the perfect group to bring this
document to because of the mix of expertise and the ability to look at
both the scientific and ethical approaches here.

		So it did put us under a bit of a time squeeze and it was an awful lot
of work that was done by Larry and Roy and other folks at NERL and we
appreciate that.  And we also appreciate your willingness to take on
something a little new, a little different and we're really looking
forward to your advice.

		DR. FISHER:  Thank you.  So I don't know who's speaking first.  Okay,
Dr. Cupitt.

		DR. CUPITT:  Hi.  I'm Larry Cupitt.  It's pronounced a lot like the
little boy with the bow and arrow.  We just changed the spelling on the
end.  And if you want to call me Stupid Cupitt, it's okay, I'll answer.

		(Laughter.)

		I'm here with Roy Fortmann, and we're from the National Exposure
Research Laboratory and ORD, as Dr. Gray had explained.  And again, I'd
like to express my thanks to the Board for taking the time to look at
this document and to advise us because we take seriously both the
scientific and ethical standards that we need to live up to as we do
this and we think that the work that we do is critically important to
the Agency, as it proceeds.

		And part of that is defined here where we've got this picture and
identification of what the Agency's mission is, to protect human health
and the environment.  And the Agency in many cases adopts a risk
assessment/risk management paradigm for addressing and understanding the
challenges that may provide risks to human health and the environment.
And exposure is critically important to both the risk assessment
paradigm and the risk management paradigm, because understanding the
distribution of the chemicals throughout the environment and
understanding how people come into contact with those is critically
important for the Agency in doing its job to protect human health and
the environment.  So we think that our role is really important.

		The document itself, we put it together to serve as a resource
principally for our own researchers and for ourselves in the National
Exposure Research Laboratory.  We wanted to look at what the standards
were today in terms of the scientific and ethical issues that we had to
consider in designing and implementing observational studies.  And we
wanted to provide both a resource for people to read and references so
that our scientists could go get more information as they tried to put
together a study design and a human subjects protocol so that we could
ensure that not only was the science of the highest quality, but that we
understood what the ethical standards were that were dealing with
because we go into people's private homes and those kinds of things and
we have real ethical issues that we have to understand and adapt to and
deal with and we wanted to make sure that those ethical standards were
upheld at the highest possible level.  So that's the purpose for this
document.

		Why did we want to do it?  Well, frankly, we take this seriously.
I've been involved personally with human subjects research now since
basically the rules first came out and we take seriously the issue of
making sure that we safeguard the privacy, the integrity, just we do
honor to those people who join us in this research, because they're
really volunteers to participate in this research with us and we really
want to make sure that we respect them in a way that is appropriate.

		But the other reason why we are motivated to do this, I've already
sort of talked about and that is exposure science can make a difference.
 We have listed here and you saw in the document some cases where
understanding people's exposure has come out with agency actions or
actions in other agencies that really can make a difference in
protecting human health and the environment.

		I wanted to talk a little bit about some of the fundamental concepts.
We define exposure as the contact of a chemical or a pollutant or some
kind of thing, but I'm going to use the word chemical here just as a
symbolic term for any kind of pollutant that we might be dealing with.
The contact of an individual with that chemical through the air that we
breathe or the food or the things that we rub up against or the water
that we drink, and understanding and characterizing that exposure means
that we have to do two things.  We have to understand and characterize
the distribution of that chemical throughout the environment, especially
where people are likely to come into contact with it.

		And then we have to understand the activities that people undertake
that bring them into contact with those chemicals in the environment, so
that putting that together we can understand what that exposure is.  And
understanding this is both critical for assessing the risk.  Dr. Jordan
just talked about how there was a factor of ten that was added for some
uncertainty associated with exposure.

		But it is also critically important to the Agency as they undertake
the risk management aspects of their role, because it is oftentimes
through changing the source of that chemical, that pollutant, or
changing the way that people come into contact with it that the Agency
actually reduces exposure and thereby reduces risk.

		In the National Exposure Research Laboratory, we collect data through
exposure studies that are observational.  So what are observational
human exposure studies?  Studies in which we observe and measure
people's contact with chemicals, the chemicals that are already present
in their environment, and the study is undertaken under real world
conditions.  We go into people's homes and their offices.  We follow
them in their cars or the school bus as the child goes to school and
outdoors as they walk to school or do things and play in their yards as
they undertake their normal day to day activities.

		So I've already  mentioned that we characterize both the distribution
of the chemicals in the environment and the people's activities.  The
kinds of samples that we collect are shown here on this slide.  Now we
won't collect every one of these samples in every study necessarily.  It
sort of depends on what the objective of the study is.  But, you know,
it is not unusual, for example, with air samples to collect -- am I
doing it the wrong way?  That way?  There it is.

		To collect outdoor samples, either at a central site or even in a
person's backyard, to collect samples indoors with things or to put
samplers on people so that they can actually then go about their daily
activities and we get some idea of what they encountered as they went
through their daily activities.  We collect samples of food, water, and
beverages.  We'll do hand wipes and surface residue transfer studies.
We'll collect dust, soil, biological or urine samples so that we can
understand both the distribution of the chemicals throughout the
environment, the chemicals in contact with the individuals, and we also
collect data on what the people are doing --  no, you went too far,
okay, thank you -- including time activity information, personal
activities, what kind of products they use, what kind of foods they eat,
and what things are present in their house.

		For example, do they open their windows a lot so there is a lot of air
exchange if we're interested in air pollution impacts on individuals.
These describe what we do for characterizing the environment or in
people's homes and offices, etcetera, and what they do.  But I thought
one thing that, we put together basically a video for an internal use of
on what we kind of do.  It's basically a visual tour of one of our
divisions and I have spliced parts of that together to show you, to give
you a little more explanation of what we do in an observational exposure
study.

		And there are two scientists here --

		(Video presentation begins.)

		DR. TULLVE:  "The role of our research program is to understand what
chemicals people come into contact with, at what levels, what the
sources of those chemicals are, and where and when, how often, and why
they come into contact with those chemicals in the every day
environment."

		DR. WILLIAMS:  "One of my jobs is to collect information that helps
the US EPA collect the necessary data to protect Americans.  This can be
very difficult work.  We require a multitude of talents.  We use teams
to go around with talented exposure scientists, physical scientists,
statisticians, modelers, and data specialists.  Our instrumental
monitoring capabilities enable us to detect and analyze environmental
pollutants at very low concentrations.

		How do we accomplish our mission?  We identify human populations
living in original or refined exposure assessment for airborne
pollutants.  We go to where these people and investigate how they live
their lives.  The second involves developing the data collection tools
needed to better define human exposures.  This may require the
development of novel, low burden, passive monitors, surveying
instruments that collect time and activity information or sophisticated
source of portion and statistical analysis procedures.

		Lastly, we perform grid studies by developing the necessary human
subjects protocols, the information collection requests, and peer review
study design to ensure the general precepts will be useful to the Agency
and to the scientific community at large for monitoring personal
exposures, residential indoor, residential outdoor, community-based
measures.  This represents a unique situation for NERL can develop the
tools and approaches to help communities and regions better understand
the usefulness of using data for central community monitors to assess
human health risks by being able to collect data where individuals live,
understand where they go and what they do and be able to determine the
impact of their exposure sources, how people live their lives.  We have
a unique ability to put together the puzzle."

		DR. TULLVE:  "To do this, we study the locations where people spend
significant amounts of time and for children, this includes their homes,
daycare centers or schools.  We collect the best sampling using a wet
and wipe.  We collect it from different locations on the floor, on
surfaces, and toys, and any other location that the child may come in
contact with.  Or we would use the HDS3 to collect dust samples or in
some instances we would actually collect the dust sample by asking the
care giver to provide us with the vacuum cleaner bag.  In addition to
the environmental samples that we collect while in the home, we also
collect personal samples.

		The personal samples include a cotton garment, so that we can estimate
the amount of chemical and dust that ends up on the child's skin during
normal play behavior.  We also collect a duplicate diet plate.  This
allows us to investigate the amount of chemical that a child may ingest
from what the child eats during the day.

		The last type of sample we collect is from the child himself.  We
collect a urine sample and of course, we need to know what the child has
been doing during the time that we're collecting these samples and we
collect this information in a time activity diary.  We use all of this
information, provide data to support our clients, to fill existing data
gaps for exposure and risk assessments for children, identify new and
emerging chemicals of interest, refine our methods, provide inputs to
the exposure end dose finals and develop future research directions for
new and emerging exposure issues."

		(End of video presentation.)

		DR. CUPITT:  I just wanted to mention that you were going to see two
principal investigators from the NERL laboratory, Dr. Nicole Tullve was
the female, and she just last week was co-chair of the International
Society for Exposure Analysis that was held in RTP in Durham.  And Mr.
Ron Williams was the second PI.  He's been with us for quite a while and
they're very much involved in observational exposure studies.

		Now having talked a little bit about what we in the NERL actually do
in observational exposure studies, I wanted to turn my attention to the
document itself that we're asking for your comments on and your review.

		We began drafting this in 2005 even, I think maybe, but certainly in
2006 with a series of stakeholder conversations, talking to people in
EPA program offices, talking to people in the regions and a variety of
other interested parties about what might go into such a document and
how we might use it as the Exposure Research Laboratory.

		In November, late November of last year, we convened an expert panel
to have a workshop to explore the issues that needed to be in such a
document and that expert panel advised us in terms of what the content
should include and address and those kinds of issues that we ought to do
it and a little bit of the structure in terms of what, how we ought to
go about devising this document.

		Based on that, we first prepared a draft of the document in six, seven
chapters.  Depends on whether you count the introduction or not, that
kind of stuff.  And it underwent internal review within EPA.  We sent it
out to people in the regions.  We sent it to program office people and
to scientists in ORD.

		Based on their comment that internal document was revised into this
external review draft and we are now at the next two bullets, here
asking for your review and your input and comment, but the document has
also been put out for public comment.  There's a docket and it will be
open until November 19, 2007 so we're also seeking public comment on
this document.

		Our hope is to take your comments and advice and the input from the
public and to revise this document to publish it as a final document for
RPIs to use so that we can move forward looking at conducting
observational human exposure studies in the future.

		So the charge, you got three charge questions and let me first say the
first question talks in specifics about ethical considerations.  We were
not excluding science in doing that.  We adhere to the concept that bad
science is unethical and therefore this ethical consideration, does each
section identify the major areas and issues were ethical considerations,
and obviously that overlaps with the scientific considerations too that
need to be addressed.

		We also asked the second charge question, are there additional
sources, have we missed anything?  Are there additional sources of
information that should be considered for inclusion in the sections.

		And then finally, can we improve how it's presented and do it clearly
so that our scientists can benefit from this.  So these were what we
were specifically trying to understand, basically.  Did we get it all in
there?  Did we get the right references?  And did we do it sufficiently
well, that it will be useful.

		The next slide goes through briefly the organization of the document.
The first section is the introduction, purpose and scope.  It talks a
little bit about what observational human exposure studies are and talks
about the ethical issues underlying observational human exposure
studies.  It sets out the purpose and what we're going to do for the
rest of the document.

		It's in section two where we begin to get into the meat of this and
here we talk about elements to be considered in study conceptualization
and planning, how we put this thing together, how we decide whether or
not it warrants moving forward with an observational human exposure
study.  What we have to do in terms of that problem conceptualization,
how we go through the planning to put together both a scientific study
design which also then is a major component in the IRB review or the
human subjects protocol, how we put these things together jointly so
that they can be reviewed both for scientific quality and for the
ethical standards which in this case is through an IRB.

		I wanted to note also that at the end of that all of this is still
subject to the Agency's human subjects research review official, Warren
Lux, Dr. Lux, has the last word in terms of making sure that all of this
is appropriate before we can ever move forward.  And then we talk about
how we need to put together an organization, a procedure for
implementing and monitoring the study as it proceeds and how we move
forward from there.

		So that's what's in Chapter 2.

		Section three talks about ensuring protection of vulnerable groups and
who is a vulnerable group, basically looking at a number of the human
subjects rules and other considerations, justifying -- how you might
justify when you want to involve or exclude vulnerable groups; the
issues in the human subjects rules of minimal risk and vulnerable risks;
and then finally specifically talking about children, women, and other
potential vulnerable groups in this section.

		Section four deals with privacy and confidentiality in particular.
There are real privacy issues.  We invade people's privacy in essence.
We go into their homes and as a result, this is really critically
important to us in conducting these studies, in making sure that we --
they have volunteered to let us go into their homes.  So it's not an
unwarranted or an unacceptable or invasion of privacy, but it is one
nonetheless.  It's their exercising their will to allow us into that
private space, but we have to take that seriously.  And the issues of
confidentiality that derive from that, how we honor their privacy by
keeping things confidential in terms of information about them or even
that they're participating whenever that's possible is really a concern
to us.

		But then there are also these observations, things that will come
along where we may be obligated by law to report certain things that we
would observe and we have to be very clear in terms of dealing with
these individuals about making explicit those things that we can be
confidential about and those things that we cannot, and that gets
discussed in here.

		And of course, there are third party issues.  I mean, if we're going
into people's apartments and it's the landlord who is spraying with
pesticides or doing something else and we are observing that, our
observations may have an impact on that third party and we have to
understand those too.  So section four in this document goes into all of
those kinds of issues.

		Section five talks about basically creating an appropriate
relationship between the participant and the researcher and how to
actually respect them appropriately.  Here we've included discussions on
informed consent and the three pillars of informed consent:
information, comprehension, and a voluntary participation and there's a
long discussion in section four about all of this and about how you do
it through communication that is both, it's two-way communication.  It's
both giving out information but it's also listening so that you can
understand what their concerns are and that kind of stuff.  So informed
consent is not a document.  It is a process.  We need to get beyond just
looking are the pages correct, but are we doing this in a way that
respects our participants appropriately.

		We get into the issue of payments.  Now payments clearly in the
literature has been very controversial.  We try to quote and show both
sides in the document and to discuss this in terms of where the latest
thinking is and where the advice might be.  And then, of course, we talk
about research rights, grievance, supportive environment, recruitment
strategies, those kinds of things.

		But it is all really fundamentally built on this issue of
communications and doing the communications well.  In section six, we
then extend it from the participant to the community and to the
stakeholders.  There's a good bit of discussion here on community, who
is the community.  How do you get somebody who is actually a
representative of the community as a whole to participate with you to
help you understand the community concerns.  Building relationships and
trust, the use of community advisory boards, etcetera.

		I'll be blunt.  We talk a lot about community.  We don't talk a whole
lot about stakeholders and frankly, some advice and input on
stakeholders here would be very useful to us in this section.  But
again, it's built on this issue of communication.

		And finally, chapter seven, section seven, rather, talks about
communication.  But it talks about it mostly from the researcher
perspective and we recognize this.  We've already talked about building
these relationships with this bi-directional communication.

		Here we're talking about as a researcher, what kind of approaches do
you need to do, what do you need to think through  because it is
actually intended here for our researchers to use.  What do you have to
work through in developing a communications strategy and an
implementation plan?  What kind of educational materials, what are
really effective for use in such a study?  And so that's where the
document ends.  It ends with section seven.

		In summary, we think observational human exposure studies are
important because they collect real world information that determines
what chemicals people are coming into contact with, what the
concentration of those chemicals is, what the most important sources,
pathways, routes of exposure might be, and when, where, how often, and
why people come into contact with those chemicals.

		We think that's important for the agency in doing its job.  We think
that, we take seriously as managers and as scientists the protection of
our research participants.  Without them, we couldn't do our job and we
want to respect them appropriately.  So we want to live up not only to
the regulatory requirements, but also the spirit of the ethical
standards that motivate those ethical requirements.

		And I look forward to your comments and questions and observations and
your input to help us make that document one that really will be worth
while for our scientists as they try to plan and move forward on
conducting and implementing, designing and implementing observational
human exposure studies.  Thank you.

		DR. FISHER:  Thank you very much, Dr. Cupitt.

		Were you going to say anything?  Did you have a presentation, Dr.
Fortmann?

		DR. FORTMANN:  No, Larry has done an excellent job on presenting.

		DR. FISHER:  Okay, very good.  Then I think we'll go to Board
discussion and we'll do so within -- we've divided up the different
sections with lead discussants and secondary, so I think that's the way
to proceed.

		I'm sorry, are there any clarifying questions?  And then I'm going to
ask for public comment, sorry.

		DR. LEBOWITZ:  Mike Lebowitz here.  In the over 40 years I've been
working first with NAPCA and then EPA and seeing how this information is
used within the Agency and the different centers within ORD and also in
the different offices as I worked with different AAs and so forth, I am
constantly struck by the -- as it were the overlap of interest and the
importance of the use of this information in setting policy and setting
rules, regs, guidelines, using the information even to establish
international guidelines which in representing the Agency
internationally and so forth in developing some of the same principles
elsewhere.

		The thing that strikes me is that the -- that I'd like to have
clarified is in fact, how we clearly separate observation from other
activities in which we may engage.  Now it's very easy for me to do so
when I did animal tox.  It was obviously intentional when I did
controlled human exposure studies, inside and outside the Agency.  It
was very clear.

		What we observe outside though and how we observe it and what the
participants go through the in process is really, has always been a
serious issue from the scientific standpoint as well as the ethical
standpoint.  And I think that -- I mean I'd like some clarification, if
I might on that, because I view most of what is done within the Agency
prior to risk assessment and risk management suggestions is
observational in that it's only when we put people or animals in
chambers, as it were, that it's intentional.  And I wondered if you
could spend a little bit more time, Larry, in clarifying that from an
Agency standpoint?

		DR. CUPITT:  Well, I would first begin by quoting Bill Jordan who took
the lead at writing the human subjects regulations, the new ones that
were added recently for the Agency where the definitions involving
observational studies show up.  And that is there's a definition
basically in the law, 26406, I think, that talks about what intentional
exposure is.  And then it says everything else is observational. And so
if it doesn't fall in that, it is observational, by EPA and its
regulations.

		Now that decision, frankly, is not mine.  It's not the researchers.
It is indeed that of Dr. Warren Lux.  And so I would have to defer to
him in regard to that, but that's all I would really say at this point.
Maybe ask Bill Jordan and Dr. Lux to comment.

		DR. LUX:  Sure, I'd like to say a couple of things.  First of all, I
think it's important that the Board distinguishes between the regulatory
definition of observational exposure studies and your intuition on what
it means to observe somebody in the natural environment.  And your
intuition about that is closer to what NERL is trying to do here.  And
all of those studies also meet the regulatory definition of
observational studies.

		But the regulatory definition was designed and here I will defer to
Bill, but my understanding is that the regulatory definition was
designed specifically to identify what it meant to be an intentional
exposure study so that other things then would fall under this broader
rubric of observational, including all of those things that NERL does
that are intuitively observational, plus other kinds of studies in which
there are interactions and interventions with individuals but those
interactions and interventions, although they might go beyond what's
intuitively observational, are not intentional exposure.

		Intentional exposure in the regulations is the introduction of a
substance, any substance into the research by the research and it
involves the study of that substance.  So that all kinds of studies in
which we are studying and which the Agency is studying ambient
exposures, exposures that would normally occur, but they are controlling
that exposure and introducing it at that mean ambient level, that's an
intentional exposure study.

		If the Agency does not do that, or if the researcher does not do that,
does not introduce the substance, does not control the introduction of
the substance into the research, then it involves, then it meets the
regulatory definition of observational.

		Bill, would you like to expand a bit?

		MR. JORDAN:  I'll try.  I'll certainly talk a little bit.  The
definition that appears in various places, it's in a couple of locations
in the regulations says research involving intentional exposure of a
human subject means a study of a substance which Warren focused on in
which the exposure to the substance experienced by the subject
participating in the study would not have occurred but for the subject's
participation in the study.

		So if you do an observational research and wipe people's hands with an
alcohol-water mixture, they're being exposed to an alcohol-water
mixture, that's intentional exposure to the alcohol-water mixture, but
that's not the substance being studied.  So that fact doesn't -- that
kind of exposure does not make an observational study an intentional
dosing study.  I think that's the point that Warren was focusing on.
It's only if the substance being studied is where the focus ought to be.

		The second piece of that definition that I would like to talk a moment
about is the last part, the test that says the exposure would not have
occurred but for the subject's participation in the study.  So that's
phrasing that's intended to be fairly expansive in our thinking at EPA.

		The idea here is that if the researcher determines that the subject is
going to be exposed in Dr. Lebowitz' example, clearly, if the
researcher/investigator says to the subject you go sit in that air
chamber and we'll pump some particulate matter into the chamber and
you'll breathe it, that's exposure.  Or the insect repellant studies
where we have -- researchers proposing to apply a test material to the
subject's skin.  That's also a study that's an intentional exposure.  So
too skin absorption, metabolism studies where the researcher applies a
known amount of material to the subject skin.  What gets trickier are
the kinds of studies that we're hearing about in the handler exposure
area.  And what EPA will do when we look at a protocol is ask ourselves
has the subject made all of the decisions about exposure, all of the
decisions that would influence or determine what exposure he or she
would get.  If the answer to that question is effectively  yes, and if
those decisions are not influenced or directed by the researcher, then
it's an observational study.

		But when we're seeing, as we do in the handler exposure studies for
very good scientific reasons, that the researchers are scripting the
behavior, saying you will apply this amount of pesticide or you'll mop
the floor with this particular chemical, then it is an intentional
dosing study.

		DR. FISHER:  Can I just ask a question about that?

		I think the blurry area which is, of course, the most interesting, I
thought it was really very informative to say that the subject makes
decisions about the exposure, where in the ag. handler I can see that in
some sense it's not occurring.  They're employees.  They're not making
that decision.

		How have you interpreted, if you have, these kinds of home
observations where a researcher may give a particular product or
formulation that's approved by EPA to a family who uses that type of
product, but then the family is told use it as you would use it.  So
that's kind of like on the border of your -- and I'm just wondering if
that's come up, if that's something that needs greater discussion at
some point.  This may not be the point, but I think that's that blurry
area that people are wondering about.

		MR. JORDAN:  I think that we have not done that.  Let me confirm that.

		DR. FORTMANN:  Right, point of clarification.  In the observational
studies that we do that EPA does, we do not ask anyone to use any
particular product.  We definitely do not provide any type of products
or make any suggestions of products that people would use in these
studies.  And that's why when we were preparing the presentation, we
wanted to make very clear what our observational studies are and that is
as people go about their normal activities in their normal environments,
we do not make any attempt to change the participants' behavior or the
participants' environment in the studies that we do.

		And this particular document is limited to the observational studies
that NERL does.  At ISEA last week I think some of the people in this
room were at the session that we had on ethical issues, and we made very
clear that observational -- this document does not address, for example,
intervention studies.  It strictly addresses observational studies.  So
no, we do not.

		DR. FISHER:  That's very helpful.  Thank you.

		Warren, did you want to say something?

		DR. LUX:  Sure.  Were I to see a study in which we gave a family a
substance to use, I would regard that on the basis of Bill's prior
discussion as an intentional exposure study, not an observational study,
because the researcher would be introducing into the research a
substance that otherwise would not have been there.

		With regard -- just one other slightly, somewhat related observation
for you, there are intervention studies where we alter exposures without
introducing substances.  For example, the placement of certain types of
filters in rooms to reduce exposure to certain kinds of air pollutants.
Those sorts of studies I also would regard as observational studies.
They do not entail the introduction of a substance into the research,
although the substance under study is reduced by the intervention.

		DR. FISHER:  Thank you.  These are very helpful.

		Dr. Fish, and then Dr. Krishnan.

		DR. FISH:  After this very elaborate discussion, I think my question
is going to be a five word answer or so.

		In my many years of teaching research design courses, I've never heard
the term "scoping", in your planning and scoping.  Dr. Cupitt, could you
explain what scoping is, different from planning?  Differentiate those
two?

		DR. CUPITT:  I'm going to defer to Roy.  Those were his words?

		DR. FORTMANN:  And those are words that are commonly used in our
planning process.  The scoping involves the size of the study, the --
it's very integrated into the planning process.

		DR. FISH:  So is it differentiated in -- how is scoping different from
planning, I guess -- or are they redundant terms?

		DR. FORTMANN:  Scoping would be -- to look at -- they're complementary
terms, I guess.

		DR. FISHER:  Let me just try -- I mean my understanding of scoping is
that you have a research plan, but you have to scope out what the
practical environment -- what's the practical issues within the
environment that you need to study?  What is the house like?  What can
be done?

		So you might have a generalized plan, but until you go in and actually
know what's going on, you can't really finish your design.  Is that --

		DR. FORTMANN:  It really is conceptualization of a study that's needed
based on the research questions.  Scoping is the next step in terms of
addressing how you might address those research questions and the
planning would be the more detailed design of the study.  And Mike may
be able to help me out here.

		DR. LEBOWITZ:  Yes, I would add to that, the conceptualization is
extremely important.  Conceptualization of specific environments,
environmental concerns, even community concerns.  Prior to focusing down
on the goals, objectives of the research, and then that may lead to a
planning situation and then in which scoping becomes a practical aspect
of the planning.  But then there's also the scoping of what you do with
the data or the results once collected in terms of communication, in
terms of use by other members of the Agency or other groups in the
Agency or the -- or the scientific community in general.

		Sometimes that kind of scoping about other intra-agency interests may
also influence what is scoped out before the goals and objectives are
set out because there are overlapping interests of the different centers
and also in the different offices, so the Office of Water might say we
have a specific interest and so we understand if you're going to do
these kinds of studies looking at water, this might help our mission as
well within the office.  I've seen that both prior to, a priori and a
posteriori, where we helped scope out for some of the offices where they
might use information collected by NERL.

		DR. FISHER:  Thank you, Mike.

		Dr. Krishnan?

		DR. KRISHNAN:  My question relates to the intentional versus
observational studies.  The discussion has been useful, but I have a
clarifying question in that regard.

		The focus has been very much on the exposure, when you define or when
you look at the observational versus intentional studies.  How about the
subject manipulation in those studies?  For example, when we think of
biomonitoring studies?  I mean particularly blood sampling, those are
done for good reasons, but the blood sampling, for example, when it's
done -- well, it's an invasive procedure essentially.  To me,
non-invasive measurements in people as they go about their normal
activities is observational, but if it's invasive sampling, do you
consider that observational or intentional?  To me, it's not just the
exposure that defines, but also any manipulation of the subject.

		If the blood is obtained from a blood bank as they do a normal
activity of giving blood and then if you look at the concentration of
chemicals, that to me is observational, but if a sampling is actually
done in people using invasive procedure, that shouldn't be a part of the
observation.  That's what I'm thinking.  I want to get some
clarification from both of you.

		DR. LUX:  This is why I suggested that you try to separate the idea of
what is intuitively observational from the idea of what's observational
under the regulatory definition, because what you cite with invasive
procedures which is not intuitively observational, nonetheless will meet
the regulatory definition of observational, so long as you're not
creating an exposure to a substance that would not otherwise have
occurred and in which that substance is under study.

		So that the simple incorporation of invasive procedures does not
necessarily in and of itself get it out of the observational camp.

		DR. FISHER:  I wanted to say that my understanding of this has evolved
and I really think that Dr. Lux has put it in a way that I think that
we've been struggling with, that it may be that observational is not the
same as naturalistic in the sense that you do absolutely nothing.  All
you do is observe.  And I think what Dr. Lux is trying to say and what
I'm beginning to understand is that we have to avoid conflating
experimental control procedures or data collection procedures from
whether or not a particular chemical has been introduced into the
environment.

		So the regulations speak to whether or not that chemical has been
introduced by the researcher.  The regulations do not speak to whether
or not other experimental measures like urine collection or blood
collections are or are not observational.  That's part of the research
methodology, but it doesn't have to do with the introduction of the
chemical.

		And I think, you know, I think we've been maybe everybody has been
somewhat confused, but I think little by little it's coming together as
where those distinctions lie, and what becomes so important is what is
or is not permitted to be done under regulations if, in fact, it's an
intentional exposure and we have to be very careful that we are clear
that you can do certain things to measure exposure and also I think we
have to become clear that an observational study as I think this
document is pointing out, is not waiving ethical issues.  You still have
to make sure that the risks involved in terms of data collection, urine,
blood use, putting on these outfits that may have heat exposure, but
which doesn't increase your exposure to the chemical itself, you still
need to evaluate the risks and benefits of that, but it doesn't come
under the definition of intentional.

		DR. LUX:  I think Dr. Fisher is precisely correct about that and
that's the way we would look at it.  I would add with regard -- you
asked about manipulating the chemical versus manipulating the behavior
of the person and you can manipulate the behavior of the person in such
a way as to produce an intentional exposure as well, so we would take
that into account.  As Bill Jordan pointed out, the definition was
broadly set, so that if you manipulate the behavior of an individual
such that they would be exposed to a pesticide that they wouldn't
otherwise have been exposed to, even though you didn't introduce the
pesticide yourself in, that would still meet the definition of
intentional exposure research under the regulations.

		DR. FISHER:  And I have one more question.  Because you gave an
interesting example, Warren, with respect to let's say you put in
various types of filters in various homes.  So basically what you're
doing is you may be testing it, but you may be reducing exposure.

Right?

		DR. LUX:  Correct.

		DR. FISHER:  And so I think what you were saying is is that a
reduction of exposure would not fall under intentional exposure, if in
fact, the chemical itself wasn't introduced, but the exposure may be
reduced by some kind of experimental manipulation that that also would
not be considered intentional exposure?

		DR. LUX:  Right, that's the way I would interpret it.  That one
requires some interpretation, but I think if you're mitigating an
exposure, that one would keep that in the category of observational.

		As Bill is pointing out, mitigating an exposure that would otherwise
have occurred.  We're not introducing the exposure that we're mitigating
and I think that indeed is a very important point.

		Most of those studies though actually that I've seen in my year here
that have come across my desk have not been human studies anyway because
the data are being acquired about the air and there are no data being
acquired from the humans anyway.  But in any event, were one to acquire
some collateral data from the humans, I think it is likely that such a
study would be regarded as observational.

		DR. FISHER:  Two things.  One I wanted to make clear that some of our
interest is also in terms of how we will be evaluating some third party
research that comes.  So some of our questions are not addressed to the
kinds of research that EPA may not be doing.

		My final question has to do with clinical trials.  And if, in fact, a
substance is introduced for a clinical trial purpose, but also has
information that could be used as we've seen in some of the studies that
we've looked at, is that intentional exposure or because the purpose was
not to measure the compound from an EPA perspective, it is or is not or
has that not been decided yet?  Because I saw in the minutes from the
meeting, Warren, that you mentioned something about how it was not.  But
I didn't know if that was circumscribed to a particular type of
intervention study.

		DR. LUX:  The regulation as I read it, does not distinguish among
different types of substances.  It does not distinguish among toxic
substances in different substances or therapeutic substances.  So if
we're introducing any substance then it is an intentional exposure
study, as I read the regulation.

		That can lead to what I think may have been some unintended
consequences with regard to what is and isn't permitted and that what is
going to be done about that going forward is under study.

		DR. FISHER:  So for example, if there's been a clinical trial with
children for a particular substance that was used for medical purpose at
this point it's unclear whether EPA could ever use that data, is that
the case?

		DR. LUX:  Correct.

		DR. FISHER:  Are there other questions?

		Yes, Suzanne.

		DR. FITZPATRICK:  Yes, I just have a simple question.  I was wondering
how many of these studies you run every year and how you set your
priorities?  And on top of that, if you -- I noticed you could do a
CREDA or something with an outside stakeholder, how do you make sure
that they don't prejudice the results or you know, if they have a vested
interest in the outcome of the results to make sure that's, at least it
doesn't have the appearance of a conflict?

		DR. CUPITT:  The number of studies we conduct is actually very small.
Oftentimes, we'll conduct a number of very small studies looking at a
methodology to see if a methodology would work.  If we then translate
that into a very large study that happens very rarely because it takes,
for example, in the study that's going right now which is in Detroit,
looking at air exposures of adults, we've had three years of sampling.
And after you do three years of sampling, you need the time to make sure
you've got all the data analysis done.  So it happens very rarely.
Unless we're doing small-scale studies to look at a sampling protocol,
one way to figure out how that -- how either the chemical is distributed
throughout the environment or how people's activities bring them into
contact with that.  Those we would -- we haven't done any children's
studies now for the last few years, but we might do one a year or maybe
one every two years, something like that.  The number of studies is
actually very small, simply because of the logistics of getting into it
and defining it.

		We tried to discuss in Section 2 how we set those priorities.  And
historically, one of the things that we did was we brought together
outside panels of peer reviewers to talk, for example, about if we
looked at children's exposure what are the various pathways and what do
we already know -- we went to people within the Agency and experts
outside, what -- where do we think that the weaknesses are, what are the
weaknesses, and how would we go about looking at each of those kinds of
components?  And based on that, based on the availability of the funding
and on the needs of the program offices within EPA, we set some
priorities in terms of what we would do and we actually set about doing
a series of studies to address those weaknesses.  That was going to be
culminated then in a larger study involving putting all of those
protocols and what we learned together to try to test it then on a
larger sample size.

		DR. FITZPATRICK:  Do you have -- does EPA have the ability to require
sponsors to do these kinds of studies if you're concerned about a
compound?

		DR. CUPITT:  ORD generally doesn't get into that, but Bill can speak
about other parts of the Agency which do have regulatory authority
associated with that.

		MR. JORDAN:  EPA's pesticide office is unusual in that we do have the
authority to require pesticide companies to generate data necessary to
support the continued registration of a pesticide.  When it comes to
other regulatory programs in the EPA, the authority is not as strong.
Air pollutants, water pollutants do not have the authority that we have
for pesticides.  For industrial chemicals, there is such authority, but
it can only be invoked through the use of a fairly cumbersome process
and is fairly infrequently used.

		DR. CUPITT:  And ORD has no regulatory authority.

		DR. FISHER:  Michael?

		DR. LEBOWITZ:  Yes, I would like to expand that though in terms of the
Agency as a whole.  I mean within ORD the centers work together so we're
sponsored by and serve actually, in fact, as is often utilized and
there's some interaction with NERL, with HERL, etcetera, so that there
are other observational studies going on, funded in a different
mechanism of a second party.  This document doesn't speak to second
party or a third party research, but at the same time that information
corrected through ORD as used by the offices for regulatory purposes and
in fact, Clean Air Science Advisory Committee is part of ORD, but in
fact, is recommending through both Office of Air and most importantly
through the ORD AA to the Administrator of EPA in terms of the Clean Air
Act as an example and similar things happen with water, etcetera.

		So the Agency -- there's actually a lot more interaction within the
Agency in which NERL participates and its research is used as well by
the other offices within EPA to help it in its regulatory policies.

		Is that a fair statement, Larry?

		DR. CUPITT:  We certainly do collaborate with other academics and
people who have received grants.  We have done that historically.

		Mike, I did want to make one minor correction.  We do indeed intend to
use this document for second party research that we sponsor as NERL
because our PIs will use this as an internal resource, whether they are
conducting the work themselves or whether they are overseeing work or
collaborating with work that we in NERL have indeed sponsored.  So it is
for the NERL scientists and PIs to use to make sure that the work that
we might sponsor through a contractor.  For example, if we need to go
and do a lot of field sampling in some specific location, we may not
have the travel funds or the ability to get people out there to do the
field sampling.  We have to hire a contractor to do that.  That work,
under our guidance would still meet all of the requirements that we have
to meet and this would still be a useful tool for those PIs who are
involved in that research.

		DR. FISHER:  Thank you.  Are there any other Board comments?

		Are there any public comments?  Excuse me?

		Okay, we're going to -- the Board comments, if it's on the particular
sections, we'll do after the break.  But if it's about this general
discussion, then we're having additional Board comments now, but we are
going to have a long time after.

		Steve, did you want to comment or you can wait?  Okay.

		Anybody else?  I am assuming there are no public comments.  And please
remember that if there are public comments at other points, to come and
tell Paul about that so that we can put on the docket.

		Okay, so we're going to take a break.  We're a little early which is
great, so let's come back at 10:30 and that will give us 15 minutes.
Okay?  Thank you.

		(Off the record.)

		DR. FISHER:  Larry I think had a couple of slides.  He was trying to
save us some time, but I think they would be helpful to us.  And so he
is going to present them.

		DR. CUPITT:  Okay.  Could you go to slide 20 in my presentation,
please?  I wanted to take an attempt at talking about the difference
between scoping and planning ever so briefly.  Scoping is basically
looking at what the big objectives are.

		For example, this shows our modeling schematic for how we might choose
which pathway would be important for exposure.  We might want to as
scoping look at all of the pathways and determine which one do we have
the least information about or the greatest uncertainty, which one could
have the greatest impact.

		These were hidden slides.  They are not in your copies.  I'm sorry.
Basically the scoping would be deciding which of these things we would
want to choose to do.  And the planning would be deciding how we would
want to go about doing it.

		Now, if you could go to the next slide, 21, this actually is so that
you can read the definition that Bill Jordan read from earlier in terms
of what the regulations actually say involving intentional exposure and
basically that these sections say that everything else is observational.

		And Bill had made the point about the various components of that.  I
just thought for those people who understand things visually you might
want to be able to read it yourselves.

		DR. FISHER:  Thank you very much.

		I think a question that came up, I know Michael asked this question.
There were two sentences I think that we used.  One is up there, which
is the introduction of a substance that would not have occurred.  And
the other is introduction of a substance into the research by the
researcher.

		And so I want to clarify if, in fact, it's a product that might have
been used or formulation that might have been used anyway by the
subject, but it is provided by the researcher.

		Is that intentional if, in fact, the subject has the right to use it
in any way they -- you know, is asked to use it in any way they would
use it normally?

		DR. LUX:  If we have asked them to use it as a condition of the
research, then I would regard it as meeting this definition of
intentional exposure.

		DR. FISHER:  Okay.  And I have one other question that some of the
Board members have been asking.  If a third party conducts an
observational study to which -- and I think as we have been talking
about and, as the document that Larry and Roy have prepared beautifully
points out, you still have to evaluate the ethics and the risks and the
benefits of observational study, according to the regulations, the third
party does not have to submit that a priori, right, in terms of its
plan, as it does for intentional exposure?  It has to submit it, and
then the Board makes some recommendations?

		However, is there an ethical review when third party observational
study is submitted or in the future if it's planned to EPA to which it
may or may not accept the data based upon failure of ethical procedures?

		DR. LUX:  Bill can answer how OPP reviews it in terms of EPA's
internal review, but all such research is also required to undergo
external IRB review as well.

		Bill?

		MR. JORDAN:  Yes.  EPA's Pesticide Office will review any results of
observational research conducted by a third party that is submitting
under the pesticide laws for an ethics --

		DR. FISHER:  For ethics.  And so even if the data is good, might the
data not be used if, in fact, the research was not conducted in
conformity, even if it was IRB-approved but not conducted in conformity
with ethical standards and let's say 45 CFR 46, which are related, like
under A?

		MR. JORDAN:  It's a possibility.  We haven't had that situation arise
yet.

		DR. FISHER:  Okay.  So now we're going to begin with the Board
discussion of the document itself.  And I'll start with Steve, who is
the lead discussant.  We are going to start with section 1.  So, Steve?

		VICE CHAIR BRIMIJOIN:  Thanks, Celia.

		So I think this part, at least my part of this discussion, will be
brief so we can get to the meatier sections of the document.

		But I'll just start out by saying that this is possibly the single
best written, most gracefully and clearly written federal document I
have encountered.  That doesn't mean it's perfect.

		(Laughter.)

		VICE CHAIR BRIMIJOIN:  But I really can see that a great deal of
effort must have gone into the writing and the editing of this document.

		The introduction of this document is organized in a straightforward
fashion.  And I think it does what an introduction is supposed to do.
It clearly points the way toward the specific sections that are going to
follow and gives an outline of the approach that will be taken in each
section.

		It begins itself with scoping.  And, actually, I think we have
probably heard enough about this, but scoping I think is best regarded
as a jargon term.  And I think one possible tweaking for the document
would be to spend a sentence defining that a little bit more clearly for
especially those investigators outside of NERL who may be a little
confused.

		It turns to the issue of what -- well, it defines the scope of this
document as pertaining specifically to observational exposure studies,
not intentional dosing.  And it makes a start at defining observational
exposure.

		I think the sense maybe all of us have from the discussion that
preceded the break is that it is still not a matter of crystal clarity
in the average person's mind, even the average Board member, or hadn't
been up to this point precisely what is meant by this.

		And I think a good start has been made here.  I think it would improve
matters if this went a little bit further.  It has become clear.  I
think Dr. Lux has done really an excellent job of separating these
concepts of sort of ordinary language usage of observational and
regulatory language usage.  And it has become clear that observational
does not necessarily mean benign.  That is, of course, why there are
ethical issues involved in observational studies.  And an observational
study might be carried out by someone who was doing what they always do
with things they always do.  And at the end of the study, they had
volunteered to give up a kidney.  Obviously there would be intense
ethical issues associated and can be.

		So I suggest two things.  One is just a little bit more, maybe a
paragraph, following up on Dr. Lux's analysis to define the issue.  And
then it might be a text box with some examples because it does come down
to examples.

		For example, we know that with the ag handlers task force, that that
is going to be treated as an intentional exposure, even though "these
guys are doing their normal jobs," but it is intentional because we are
scripting their activities.  We are asking them to do things that they
may do sometimes but not specifically today.  And they may wind up using
similar but not the same chemicals that they would have otherwise used.

		So I think it would be helpful again, especially as this document is
made available to third party PIs, who are looking for some background
to have that kind of explanation and to give them guidance.

		So I understand this document makes very clear that it is not a
guidance document.  A guidance document is a coercive document.  This is
the document that actually will offer guidance.

		And I am not suggesting that it should be stated in those terms, but
that is the way I understand it.  It is to be helpful, much as I heard
yesterday coming down to Metro, instead of telling people, "Stand to the
right in the escalators," I heard a voice coming over the PA saying, "If
you're new to the Metro, you'll notice that most people will stand to
the right on the escalator."  That's the kind of guidance we need.

		So those are really the essence.  That's all I have to say about the
introduction.

		DR. FISHER:  Thank you, Steve.

		I wanted to point out in New York, the instructions are
"Jurah-jurah-jurah" on the Metro.

		(Laughter.)

		DR. FISHER:  Gary?

		MEMBER CHADWICK:  I agree that this is one of the best written
government documents I have seen in a long time, although that is,
admittedly, a low bar.

		(Laughter.)

		MEMBER CHADWICK:  I do think this is good.  This is really good.  I
was very pleased in reading through this.

		I guess just a couple of general comments that I would make, sort of
in line with what Steve was saying.  I think it does provide a solid and
succinct description of the content and also some background information
for the document.

		I think, as I was reading through the document, not so much in this
section but throughout the document, references are made to
publications.  And it basically says, "Go take a look."  And I think
there could be some more attempt at summarizing what the key points are
and why people should go take a look in this section at table 1-4 that
actually does that pretty well for this particular section.  But I found
that lacking in other sections, that sort of approach.

		So I would commend you for use in this particular section and suggest
that it really would strengthen the document, particularly as you have
said that you wanted it to not only be a stand-alone document but even
the sections itself to be stand-alone to take that opportunity to really
make it so that once I have read a section, I am pretty well-grounded in
what at least I should know, not necessarily -- and I agree with the
approach taken that you are not answering the questions, you're not
telling exactly what needs to be done.  But at least you're saying,
"Think about these things.  These are the things you need to think
about."  So I would make that comment.

		I do think that the document itself addresses the major areas and
concerns and so forth.  I think there was a comment made earlier about
-- actually, I think it was your lead-off comment about the fact that
you're not ignoring the science in this document.  But I think to some
extent you are.

		And it might be useful at least to make some acknowledgement of how
science and ethics fit in, again not necessarily to talk about all of
the different study designs and scientific principles and that sort of
thing, but I think there is an assumption that particularly those around
this table and perhaps the writers as well have made about how science
and ethics interplay that I think is not necessarily clear, particularly
to new researchers in a field, how it works and how good science and
good ethics feed each other.

		One of the things that I noticed throughout this document is there are
references -- and I'll probably make a comment in another section later
-- there are references that are more I think appropriate to a
journal-style document, rather than this non-guidance guidance document
-- I'm not sure how I would characterize this -- that basically
summarizes what was found, as opposed to taking ownership of the
decisions.

		An example that I found in this particular section was on page 10,
lines 1 through 3, talks about how the document is limited to
observational studies, but it basically says the panel recommended that
it be, rather than saying based on a panel recommendation, we have
limited, so just a little difference in flavor.

		Again, I think this is an extremely well-written document.  I think
this has the opportunity or the potential to be one of the most
important documents since the IRB guide book that came out over 15 years
ago.  So I am really, really excited about this.

		So I'm done.

		DR. FISHER:  Any other Board comments about section 1?  Rebecca?

		MEMBER PARKIN:  One thing I noticed as early as this section that
comes up throughout the document, I'm not quite sure where we bring up
those things that are over-arching, but this is one that struck me here
in this section -- and it also struck me in the slide presentation --
was that the abstract talks about, for example, that you're going to be
addressing chemicals and other stressors, but many times the document
flips back and only focuses on chemicals.  In fact, I didn't even find
any example other than a chemical example in the entire document.  So it
leaves the reader with the impression that you don't really mean it
except for chemicals.

		I did notice that on your slide, you did add radon as an example.  So
I am sure you have them, but a reader comes away with a sense of, well,
they really only care about chemicals.  And I think it is important that
the language and the examples reflect that throughout the entire report.

		DR. FISHER:  Thank you.

		MEMBER KRISHNAN:  Celia?

		DR. FISHER:  Yes, Kannan?

		MEMBER KRISHNAN:  I just want to reemphasize the importance of
expanding on the observational studies themselves.  The definition right
now, they just got both of them.

		The chapter starts out with the common or lay term definition of, you
know, the measures in people as they do their daily activities.  And
then the regulation-related definition is subsequent.

		In the bottom here is a note that I think would be better if you can
really take it up into the main text and capture some of the discussions
we have had.  I think that would be very useful, particularly because in
the first page around line 34-35, where it says that the observational
studies do not involve any manipulation of a person's behavior, I think
based on what we heard, somehow the invasive sampling, for example,
which, in part, depending on how broadly we interpret that would be
considered as an intentional study but does not go along with the
description here, like the scripted exposure, invasive sampling, and
things like that.

		I think we just have to be bold and say some of those things.  And it
makes a lot of sense, essentially capture several of our own comments as
well as Dr. Lux.

		DR. FISHER:  Thank you.

		Okay.  So we will go to section 2.  And, Susan, you will begin that?

		MEMBER FISH:  Thanks, Celia.

		I would like to also reiterate the comments that have been made by
Gary and Steve that this is quite a remarkable document.  And since I
teach many classes, courses, on designing research in humans, I looked
at this section and thought, "Oh, this will be one that my students will
have to read."  I mean, I think it is just a remarkable document.

		So to begin section 2, which is really the scoping and planning or
conceptualizing and planning of the study -- I think "conceptualizing"
might be a better term than "scoping" because I do realize that it is
jargon.  But if this is meant to be an internal document and that is a
term that is used here, then I don't feel strongly about that.

		My first concern had to do with what is in figure 2-1, which is
separating the study design document from the human subjects protocol
document.

		Now, in the text, you explained that these are integrated or
overlapping documents.  My concern with having two documents is that
this is a setup for inconsistencies.  And it seems that throughout the
rest of the document, you say, "Science and ethics are interrelated."
But to have two separate documents is of great concern to me.

		It might be that the study design document is part the human subjects
protocol, but I caution you about having two different descriptions
because it is a setup for inconsistencies if that makes sense.  And that
may be what you were intending along the way.

		The next item is in the text book 2-1, the elements to be considered
in justifying a study.  I would like to suggest that the third bullet
down, a discussion of why human participants are required in the study
should include a discussion of alternative designs or models that had
been considered to help justify the use of humans in this particular way
that is being proposed.

		Section 2.2.1, which is entitled "Innovative Study Designs," I think
this section either needs to be retitled or the content needs to be
redesigned because I think the section to me doesn't speak to innovative
study designs but, rather, speaks to adding direct benefit for
participants into a research protocol, where the direct benefits are
being added just for the benefit, not affecting the research protocol;
for example, providing educational material to the participants.

		I think that is a noble cause, and I think that is a good step, but I
am not sure that I would entitle that "Innovative Study Designs."  I was
thinking more of Bayesian designs or along that line.  So it either
needs to be retitled or rewritten.

		Section 2.2.4 talks about conflict of interest, a subject near and
dear to my heart.  There is a statement that says there are many sources
of conflicts of interest, but those related to project funding -- that's
on lines 7 and 8, I believe -- or most likely to occur.

		Now, I'm not familiar necessarily with the kinds of research and
funding that this document is intended to apply to, but in my experience
in an academic setting, it's not that conflicts of interest related to
project funding are not the most common to occur but are the easiest to
identify and that the conflicts of interest that are non-financial that
have to do with personal promotion and willing the Nobel Prize and those
kinds of things are actually probably more common but much more
difficult to identify and to manage, reduce, or eliminate.

		Text box 2.3, "Elements to be Included in a Study Design."  I would
just like to expand on a few of these.  One, about halfway down that
bulleted list, one of the items is "Environmental conditions, factors,
or endpoints to be measured, including sampling and analysis
approaches."  I wanted to just suggest that you include something about
precision and accuracy in that description.

		And in the next bullet down, the "Survey Design and Questionnaires and
Other Survey Instruments," I think I would suggest you include whether
or not those instruments are validated instruments or new instruments
that need to be validated.

		In addition, around items in this text box, I'm sorry.  I don't have
the -- I didn't do this homework because I read the article on the way
down yesterday on the plane, but in last week's Public Library of
Science Medicine, October 16th -- I think that was last week -- there
are two articles relating to strengthening the reporting of
observational studies in epidemiology listing items that should be
included in a report of epidemiologic studies, meaning observational
studies.

		I think some of the tables in these two articles -- and I can give you
the references -- may be helpful to you and certainly should be
referenced.  I understand it's last week's article.  And you may not
have read it yet.  I read it yesterday.  So I will give that to you.

		<IP_ADDRESS>.  Standing in for Alicia, the point on sample size
determination, I applaud you tremendously for having a section on sample
size determination.

		And I think it's wonderful.  I just take exception to one of the
sentences.  And that is that the author that you cite, Dr. Lenth, notes
that there is a surprisingly small amount of literature on sample size
determinations.

		And I defer to my statistician colleagues, but I don't find that to be
true.  I think there's a tremendous amount of literature on sample size
determinations.  So that's probably a small point, but I felt like I
needed to say that just for Alicia, who is not here.

		Text box 2.5, which is the potential topics for the human subjects
research protocol.  And I think you did a great job describing that each
IRB has its own form and its own requirements and all of that.  And I
think that what you have listed here is really along the lines of best
practices, well beyond what any single IRB might require.  So I think
it's really quite wonderful.  there are just a few small points on this.

		In number 22, you discuss adverse events.  And in the absence of Dr.
Prentice, whom some of you don't know but some of us do know, if he were
here, he would say that the terms should be changed to "unanticipated
problems affecting subjects and others" because, in fact, that is the
language in the regulations.  And it is broader than adverse events.

		So if, for example, a laptop were to be stolen and it contained
subject identifiers, that might be an unanticipated problem affecting
subjects or others.

		Number 34 on this list is that the human research protocol, human
subjects research protocol, should include all foreseen uses of personal
data or biological materials.  And I just would urge you to consider
whether or not future unforeseen uses might be included in a discussion
of potential unforeseen uses or unplanned at this time uses that are not
planned yet.  You know what I mean.

		And then number 42 on that list is procedures for dealing with
falsification of data.  I think one of the other pieces of that concept
is procedures for preventing the falsification of data, which would be
as important as dealing with it once it has occurred.

		And I believe that's everything.  Those are all the small points that
I had.  Again, it's a fabulous document.  And I found a few typos.  And
I will give those to you just because they pop out at me.  It's a
character flaw I have.  But thank you for drafting this document.

		DR. FISHER:  Thank you, Sue.

		Mike?

		MEMBER LEBOWITZ:  I'm going to take a parallel that is a somewhat
different tact on this.  Now, I will say that this section is very
strong, especially in its consideration of the overall conceptualization
of steady planning, especially the ethical component often
insufficiently conceptualized by the scientists in the initial approach.
 And the planning and scoping include both, as does the review process.
And that strong emphasis is beneficial.

		The major areas of deficiency given the purpose of the document is in
the paucity of information, materials, and references regarding the
purpose, design, and conduct of exposure studies.

		Even the initial paragraphs place more emphasis on the ethical issues,
which are covered extensively elsewhere, than on the scientific ones.
And I think there should be more of a balance.

		There is an interesting aspect of review as well, where the ethics
reviewers have the assignment also to be reviewers of the science
component and vice versa, and that this may pose specific problems of
expertise.

		There is little explanation or coverage of exposure study designs and
methods, as I mentioned.  And specifically there are different
attributes.  Sufficient examples are not provided in references to such
discussions as well as to such studies are inadequate.

		And there are excellent sources of materials to guide researchers,
starting with EPA documents; for example, actual examples and references
to TEAM, PTEAM, ENHEXAS, the pesticide studies, et cetera.

		There are also excellent NRC, NAS, and also WHO documents that could
be utiliized.  There are many lessons learned from such that could be
culled to provide research.  I use the term "guidance" here, realizing
it's not a guidance document but still appropriate.

		Some of the sources include the NAS 1991 report on human exposure
assessment for airborne pollutants, the WHO EHC series, including number
27 on guidelines on studies in environmental epidemiology, and the WHO,
Euro, and ECEU documents on exposure assessment from the ECEHes and the
EU labs, detailed comments.  There are still contradictions, actually
starting in section 1.1 as to whether epi studies are included or not.
That is easy to clarify.

		Section 2.1.1 doesn't define types of study problems.  It questions
scientifically and doesn't provide the specific EPA or other references
where such can be found.  Likewise, 2.1.2 doesn't provide any basis or
criteria for justification of the science component or, again, specific
references, only provides the ethical component.

		2.2 doesn't outline the steps in planning the study scientifically or
where that information can be found.  2.2.1 has only one sentence about
the scientific aspects and, again, doesn't really discuss innovative
scientific aspects.

		Text box 2.3 is the closest this section comes to delineating the
components of the study that are relevant also to its planning.  Section
2.3 doesn't provide some of the more important specifics of the scope
and technical approaches or again provide the specific EPA or other
references where such can be found.

		2.3.1 doesn't include all the important and appropriate questions
regarding scientific feasibility.  It is one bullet that doesn't even
include questions about the feasibility of measurement methods.  <IP_ADDRESS>
is an insufficient discussion of sample size, as mentioned.

		And I must say given all the textbooks which talk about include some
specific survey statistical textbooks -- and there are plenty of such
references.  Also the issue of design factors can be found elsewhere
that isn't mentioned here.  And one can see Clickner's book or other
books on the topic.

		Then discussion of expected refusals and losses that need to be taken
into account isn't mentioned.  Issues of intra and inter-participant and
observer variability aren't discussed.

		The subsections also include monitoring of observer errors and biases,
participant reporting biases and reliability, inappropriate as well as
inadequate selection criteria, et cetera, or references were that can be
found.

		In response to the charges, to me this section appears to have
identified the major areas and issues where ethical considerations
should be addressed in the stated conceptualization.

		There are many additional sources of information, as I mentioned, that
should be considered for inclusion.  And that was part of our charge to
mention that.  And I've given some examples.  In addition, the current
section 2 is insufficient from a scientific standpoint as a resource of
information that researchers should have and address in designing
implementation of observational exposure studies, that the information
appears adequate.

		I would like to emphasize, too, that there are, in fact, specific
examples that can be included, not just referenced to them but specific
examples of NERL studies, like the pesticide exposure studies that I
think would be very useful to researchers, even within NERL, since not
all of them have the historical knowledge or perspective to appreciate
how neuroscientists and consultants have addressed those problems
previously.

		And there are also methods of measurement that are appropriate to
discuss in that regard.  I understand from one of the EPA NCEA people,
Mike Dellarco, that there are even new patch methods that have looked at
passive dosimetry for dermal exposure as an example, which is very
important, I think, in general discussion, showing that, in fact,
exposure assessment continues to be expanded and developed.

		So none of these comments are critical as much of what is put in the
document as much as what has been left out in my perspective, but, then,
as you know, I have a very specific scientific perspective on the
issues.  And so I think you will take it with that framework in mind and
understand that I am not trying to be too critical.

		As I say, I think the charges are answered by saying you have done a
great job.  It just means that you can have more to benefit your own
researchers and second party researchers.

		Thanks.

		DR. FISHER:  Thank you, Michael.

		Dallas?

		MEMBER JOHNSON:  Thank you.

		My comments will probably fall a little bit on the line of Mike's in
not that what is there, anything that is wrong with what is there, but
what still seems to be missing from my point of view.

		And, as a statistician, worrying about getting samples that represent
the population that you are trying to make an inference to, there's
nothing in this section that I expected to see in terms of talking about
selection of participants and/or selection of sampling units that you're
going to measure.

		And so I thought, well, maybe I just missed it.  So the nice thing
about having a .pdf document, you can do a search for words.  And so I
searched for the word "random" to start with and found that the word
occurred twice:  once on page 73 in section 6.2, where the word was
randomized; and then the word "random" also occurred in section 7.3.  So
then I looked for sample.  And sample actually occurred in the same two
locations.  So I'm assuming that it was used with the word "random."

		I think that the document needs to say something about what are the
ethical ways in which you select participants, that we stated that bad
science is unethical.  And I think in science, one of the main criteria
is to make sure that the participants that you are observing are
representative of the population that you want to make an inference to.

		So that's my main point, I guess, and I hope that you can address it
as you do a revision of what is there or maybe you don't intend it to be
there.  But it just seems like it's missing, that it should be there.

		DR. FISHER:  Thank you.

		Suzanne?

		MEMBER FITZPATRICK:  Addressing the science, I'm assuming that NERL
has other guidance on how to set up these kind of studies, like the how
tos and stuff.

		So it might be that's why it wasn't included in this, you know, type
of guidance.  I don't know.

		DR. CUPITT:  We have a great deal of expertise in terms of doing that.

		MEMBER FITZPATRICK:  Yes.

		DR. CUPITT:  And clearly our focus was on those areas that, frankly,
we have not had so much expertise on.  I appreciate the comments.

		MEMBER FITZPATRICK:  Yes.

		DR. CUPITT:  And you are quite right.  Those are important things that
are missing.  And we will have to address them in the revision.  So
thank you.

		MEMBER FITZPATRICK:  I mean, I have thought more you could just
reference the other documents than adding it to this one because then
it's going to be even like twice as big.

		So if you already have guidance, you probably have SOPs on how you set
up all of these, just referencing them, rather than putting them.  At
least in my opinion, this might help because if this is twice as big,
you run the risk of no one reading the whole thing.

		So the other thing I had just a quick note, Susan had talked about
putting in that there might be some unforeseen uses of data that people
might consent them to.  Our lawyers have told us that under HIPAA, you
can't do that.  I'm just wondering what people think about it.

		We're not allowed to do that anymore.  We can't put that in that your
data might be used for some unforeseen uses.  That might be just our
lawyer's interpretation or something.

		DR. FISHER:  But that's only for -- it has to be identified as PHI.

		MEMBER FITZPATRICK:  Right.

		MEMBER FISH:  And it's also a HIPAA-covered entity.  And I suspect
these researchers are not HIPAA-covered entities.

		MEMBER FITZPATRICK:  Well, we're not either.  So I'm just saying that
we're not a covered entity either, but that's just something I'm
throwing out.

		The only other thing I am concerned with, Warren, your role as the
final arbitrator of it, I am wondering if they bring you in at the
concept area, too, because otherwise they have gone through all of this
work and then you'd say no.  Then you're going to look like everyone is
going to be mad at you.

		You know, so I'm wondering if they do some kind of concept review with
you to decide whether you are going to agree to the concept of what they
are doing.

		DR. LUX:  There's not a formal mechanism that's been set up for that.
Yet, my office as a full-time office is very new to the agency.  And
these are the kinds of things that are under evolution.

		I have an open phone line.  And so they do talk to me frequently.

		MEMBER FITZPATRICK:  We do that at FDA.  If someone is going out, we
have a concept review before to make sure that we agree with it
ethically.  And then it comes back for a more formal review.

		DR. FISHER:  Thank you, Suzanne.

		Are there any other comments about section 2?  Yes?  Okay.  Sure.  Dr.
Kim and then Steve.

		MEMBER KIM:  Thank you.

		I just want to follow up on earlier comments made by Dr. Johnson and
Dr. Lebowitz.  I did the same kind of exercise that Dr. Johnson
mentioned in terms of looking at the .pdf file search capabilities.

		I mean, I consider these observational studies essentially survey
sampling.  And I looked for a reference to a survey sampling.  I
couldn't find a single one.  So I suspect that there wasn't really a
sort of connection in terms of the methodological issues.

		And also the reference to the sample size calculation is not the type
of sample size calculation that you would like to do for a survey type
of study.  And I think the closest thing that I can think of is the type
of studies that National Center for Health Statistics does all the time.

		And I found a reference to the NHANES survey that is the only
reference to the survey sampling mentioned in this entire document.  So
I think there is something missing here that I think needs to be
included to make this really useful documentation.

		DR. FISHER:  Thank you, Steve.

		VICE CHAIR BRIMIJOIN:  I just wanted to go back to Sue Fish's one
small comment about replacing adverse events with unanticipated
problems.

		What would you think, Sue, about adverse events or other unanticipated
problems?  Adverse events stands out.  It leaps to mind what you're
talking about.  The other unanticipated problems is a very nebulous
category.

		MEMBER FISH:  Steve, I think that that's a wonderful suggestion.  The
research, ethics in research regulatory world, has moved away from
adverse events and more toward unanticipated problems, which confuses
researchers.  And so I think your suggestion, in fact, is a fabulous
one.

		MEMBER CHADWICK:  However, on point, you wouldn't really expect a lot
of adverse events in this type of research.  And, again, this document
is discussing observational research, not clinical trials.  And,
therefore, I think unanticipated problems in this is actually more
descriptive of what we are asking about, rather than adverse events.

		DR. FISHER:  Well, let me ask you a question.  Maybe this is covered
later on in monitoring and communication, but in observational studies
-- and I'm not sure this would come under either adverse or
unanticipated, but what if you find in a child's urine sample an
unanticipated high concentration of toxic substance that you had not
anticipated or may not be in all the subjects?  What would that be?
Okay.  A health alert.  Right.

		In other words, those are things that may happen.  And whether or not
that is adverse or unanticipated is probably a good example to put that
in.  And it's probably tied to the communication issues with
participants, as it is when you look at a DSMB.

		Is that going to be discussed later on, later on in another section,
right?

		DR. CUPITT:  It is somewhat discussed later on, but it probably needs
to be discussed again in talking about the 2.7, "Establishing Criteria
and Standards for Monitoring Scientific and Ethical Issues During a
Study."

		What you are talking about is something that perhaps we didn't
anticipate reasonably, but there needs to be a process in place by which
when that shows up we have a process to go through to establish what we
will do.

		DR. FISHER:  Yes, Rich?

		MEMBER SHARP:  So on that point, I would be disinclined to regard that
as an adverse event, first of all, because I think it is predictable and
so forth and the sort of thing that we just need to have in place a plan
for addressing that should it come up.  But that is not to deny that
there wouldn't be other types of adverse events that really could come
into play in purely observational studies.

		So, for example, if you go into the home and start asking personal
questions, somebody in that home finds that very objectionable and
attacks a study coordinator or something like that.  Clearly that's the
sort of thing that would be considered an adverse event, reportable
event, and so forth.

		And so, even though there may not be any intervention, the mere
presence in the home could be associated with some very unusual adverse
events.

		DR. FORTMANN:  Let me just add that section 7.8 is reporting
unanticipated results or observations.  And that specifically addresses
if you identify an elevated concentration and procedures for determining
what would be action levels or triggers for reporting back to
participants about unanticipated results.

		In other parts of the document, we talk about how to address
collateral observations and reporting of hazards in the home that aren't
part of the study.

		It is in different parts of the section in different sections.  And
one of the difficulties, obviously, with the document is there are a lot
of issues that cut across the different sections.  And, to the extent
possible, we have tried to link those sections, but we may not have
accomplished that in all cases.

		DR. FISHER:  I just want clarity.  It says here aren't there adverse
events and unanticipated adverse events in regulation?  So there could
be an anticipated adverse event.  I just wanted to clarify that so that
there are really three categories:  anticipated adverse events,
unanticipated, and then those unanticipated events, so just to clarify.

		What I thought right now is maybe we are going on to ensuring
protection of vulnerable groups.  So usually I summarize what we have
been talking about and then just get discussions.

		So I thought stopping here for at least what I have heard from
sections 1 and 2 would probably be helpful so we don't have to go back
and remember what we are talking about.

		So everybody said this is a fantastic document.  And I think the real
contribution, as you may see, is that a lot of what Board members are
responding to is not simply how it is going to be used internally but
the educated value it will play externally.  So we thank you for that.
And also please understand that some of our comments are really directed
at that.

		So I think we have been talking about and something that really
defines what scoping is would be helpful.  And obviously you have a
slide.  So you can certainly do that.

		I think the other suggestions, some of them had to do with increasing
the clarity of what observational studies are under regulatory.  I mean,
that was really I think important for us and maybe for other people in
terms of distinguishing between the regulatory language of observational
versus what Warren called kind of the intuitive notion and distinctions
between invasive measurement procedures that still under regulations are
still observational studies because they did not include any intentional
exposure to the substance itself and highlighting which -- I mean, the
whole point of your document highlights it, but it may need to be
highlighted that observational studies do not mean no risk, no ethical
evaluation.  And that's the point, obviously the whole point, of the
document.  But it's probably important to underscore, especially for
those reading it who are not in EPA and people that had asked for
examples.

		I agree that bulleted summaries or something like that for each
chapter, some of what you have done in other chapters, but just say,
"This is what the chapter said.  And these are the highlights" would be
very, very useful.

		Then there were clarifying statements regarding scientific validity
and ethics.  And I think it was pointed out section 2, box 2-1, you
know, maybe reflecting on whether or not having two different boxes are
in some sense undermining your own argument or whether there is a way to
link those boxes, also that there were just some minor language issues
in terms of that not just panel-recommended but that based on the panel
recommendations, you have included some things, then the issue of
providing other examples of stressors that are not just isolated to
chemical components and also maybe a statement or a limited discussion
on whether or not epidemiologic studies are included in this type of
research.  I assume they're not if they're survey research, but I have
no idea.

		Yes?

		DR. CUPITT:  Did you want me to respond?

		DR. FISHER:  Sure.

		DR. CUPITT:  No, we're not planning to include epidemiological
research in terms of what we are discussing.  But we do learn from the
ethical issues that arise in epidemiological studies.

		DR. FISHER:  So maybe just a point of clarification there.

		DR. CUPITT:  And we learn from the science that arises in
epidemiological studies.

		DR. FISHER:  With respect to section 2, I guess the broad opinion that
is being expressed by the Board is that ethics is not tangential to
science and science is not tangential to ethics.

		And, although Larry, in your presentation, you made that especially
clear, I think the Board is kind of resonating to the fact that people
outside of EPA or maybe even some of your own investigators may not be
as clear to them.

		And so to kind of in some sense articulate that and what the criteria
for science is, you know, I'm sure we all agree with Suzanne that you
don't want to double the document and have a methodological design
document, but I think the Board is expressing that more is needed,
especially in the areas where we have seen weaknesses in terms of the
validity.

		As you said, there is no scientific validity.  I mean, there is no
ethical value if there is not scientific validity.  And sample size has
been an issue, sample selection, population representativeness.

		These are issues that we have seen quite frequently.  And so this is
why we're presenting them.  And if that is a window as to where some
investigators are confused, then, you know, maybe it's helpful for you
to put that kind of information in.

		Also, people were talking about perhaps to underscore the purpose and
value and scope of observational studies.  These are all things I'm sure
you take for granted.  And so it's just that outside reviewer is saying,
"Gee, I'd like to learn more about that."

		And examples of more studies that are conducted I think people are
saying that examples are always helpful.  Then also in box 2-1, if there
could be a little more articulation about justifying the use of human
participants and the notion that it should be articulated in terms of
why alternative populations or models do not provide the kind of
scientific information that is necessary but some kind of comment about
alternatives.

		There was also a comment about maybe changing the terminology from
innovative design to those areas where you're putting in benefits to
subject.

		And I had a question for the ethicists.  When you put in at the end of
a study, for example, something that is educative or you do it because
you want to benefit the participant, is that considered part of the
risk-benefit analysis?

		MEMBER CHADWICK:  Yes.

		DR. FISHER:  Okay.  Just wanted to clarify that.  Okay.

		MEMBER FISH:  It wouldn't be happening if it weren't for the study.
So I think it is a benefit of participating in the study.

		DR. FISHER:  So when you are weighing the risks, you can weigh it
against that educative value?

		MEMBER FISH:  I think so.

		MEMBER PHILPOTT:  Well, to give you an example in the research that I
frequently examine and oversee in HIV prevention and specific
interventions and knowledge about false HIV modes of transmission are
considered an educative benefit to the study participants.  And what we
found is that their rates of infection, even in control groups, is much
lower than the community at large.

		DR. FISHER:  Yes, Michael?

		MEMBER LEBOWITZ:  The other benefit might be highlighted in the
communication section but referenced here.  And that is the benefit of
providing the individual and their community knowledge about their
exposures and the risks, either not associated with it or associated
with it as well as, where appropriate, means of risk management or
mediation of exposures to minimize risk.  And I have always thought of
that as a benefit to the participant.

		DR. FISHER:  Okay.  The other points that were made were in terms of
maybe providing some other examples of the more non-obvious examples of
conflicts of interest.

		And then I think we discussed the adverse events.  And obviously, as
you were saying, it is going to be it is in section 7.8.  And I'm just
wondering if in chapter 2 this is the place to relate it to science
because one of the issues really is in terms of if you are going to need
to identify a particular toxicity level as an adverse event.  Well, the
science has to in some sense inform that.  So I think this is where you
could reference 7.8 but also link it to the value of the science.

		And then there is the issue of the unforeseen uses of biological
material.  Now, that maybe goes maybe more in the informed consent kind