UNITED STATES OF AMERICA PRIVATE

ENVIRONMENTAL PROTECTION AGENCY

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HSRB MEETING

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	WEDNESDAY, OCTOBER 18, 2006

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	ARLINGTON, VIRGINIA

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	This transcript was produced from an audio recording provided by SAIC.

                C-O-N-T-E-N-T-S

AGENDA ITEM	PAGE

Introduction and Identification of	3

 Board Members

Welcome	4

Opening Remarks	8

Meeting Administrative Procedures	11

Meeting Process	15

Update on EPA Follow-up of HSRB	19

  Recommendations

EPA Human Studies Research	25

  Review Official

CHROMIUM REPEAT OPEN APPLICATION TEST

HSRB Review of Science and Ethics Criteria	28

  For Completed Human Exposure Studies

Chromium Repeat Open Application Test	34

Public Comments	126

Board Discussion

Science and Ethics of IR3535 Insect	184

Repellent Product Efficacy Proposals

Ethics	257

Adjourn

	P-R-O-C-E-E-D-I-N-G-S

		DR. FISHER:  (In progress)  - were given, and we are thankful for
whoever put together those disks.  I think it was really great to be
able to read the material so well, and we really appreciate that.

		In addition, based on recommendations of the Board, as chair I had at
least three, maybe four - I can't remember at this point - but at least
three conference calls with EPA to plan this agenda, and I think we both
got a lot out of it.

		So I think this should be a very positive meeting, and we're very
grateful to EPA for being so responsive to our concerns, and also I hope
we've been responsive to learning about their responsibilities and what
they need to do.

		So with that, I'll start going around.  Dr. Krishnan, do you want to
just say your name and we'll start that way.

		DR. KRISHNAN: Kannan Krishnan from the University of Montreal.

		DR. MENIKOFF: Jerry Menikoff, University of Kansas.

		DR.  BELLINGER: David Bellinger, Harvard Medical School.

		MR. CHADWICK: Gary Chadwick, University of Rochester.

		DR. SHARP: Richard Sharp, Baylor College of Medicine.

		DR. PHILPOTT: Sean Philpott, Altamarks Biographics Institute
(phonetic).

		DR. CHAMBERS: Jan Chambers, Mississippi State University.

		DR. LEHMAN-MEKEEMAN: Lois Lehman-McKeeman, Bristol-Myers Squibb.

		DR. FENSKE: Richard Fenske, University of Washington.

		MS. FISH: Sue Fish, Boston University.

		DR. FISHER:  Okay, the next thing I'd like to do is introduce Kevin
Teichman who is the acting deputy assistant administrator for the
science, Office of Research and Development for EPA, and we're very
happy to have him here, and we'd like to hear from him.

	WELCOME

		DR. TEICHMAN: Thank you very much, Celia.

		First of all, good morning, and welcome to this meeting of the EPA
Human Studies Review Board.  It is my pleasure to be here.

		Celia has introduced who I am, the acting deputy assistant, if you can
imagine more qualifiers before a title let me know, the acting deputy
assistant administrator for science in the Office of Research and
Development.

		At the same time I am the acting chief scientist in the office of the
science adviser where organizationally the HSRB resides.

		Leaving the prepared remarks that Paul made for me for a moment, which
is always threatening, I am also replacing Bill Farland, who I believe
the committee knows very well, and misses almost as much as I do the
wise advice that Bill offered the agency for over 26 years.  Those are
very big shoes to fill even in this temporary capacity.

		I along with my partner here, Jim Jones, the director of the Office of
Pesticide Programs, appreciate all of the hard work that the committee
goes through to prepare for and participate in such meetings, and I
understand both the time requirement that is demanded of you, and all
the effort that goes into review the materials properly and sufficiently
beforehand to make sure the discussion here is as robust as can be, and
takes into account all of the other professional obligations on your
time, so we appreciate what you are able to give to us.

		We also appreciate the effort in preparing the Board reports, and in
fact the prompt nature in which this committee accomplishes that.  You
are to be commended.  Such reports are truly evident of all the
thoughtful work and expert advice that you put in on behalf of the
agency.

		I also want to welcome at this point Dr. Richard Sharp in particular,
who I think is also with me attending his very first such HSRB meeting,
so we will learn together how things proceed here.  So welcome.

		And for this particular meeting, I know, Madame Chairperson, we have
the Board reviewing both the completed and a proposed study involving
exposure of human subjects to a pesticide active ingredient.

		We will also be presenting for HSRB review the results of a completed
human toxicity study evaluating the allergic contact dermatitis response
of individuals with known sensitivity to hexavalent chromium, and
associated with repeated exposure to a wood treatment solution
containing this chemical.

		The Board will also be asked to review two revised research protocols
for the efficacy of new formulations for repellant IR-3535 against ticks
and mosquitoes.  And based on all of your recommendations and review of
completed and proposed human studies research, the agency will seek your
advice as well and draft EPA guidance to the public concerning
submission of proposed and completed human studies research for review
by the Board, so that your procedures will be very important to us as
well, how to do this.

		Finally, I understand the Board will be discussing - and I hope to
most certainly be back to this if at all possible - how the handling of
material claimed to be confidential business information will be handled
by the HSRB.

		This morning we will have the opportunity to introduce Dr. Warren Lux,
who is three people to my left.  Dr. Lux is the new human subjects
research review official within EPA.  His appointment to the office of
science adviser predates mine by about a week, so give him a little bit
of latitude as well in his new position.  But he will provide the high
level leadership and overall agency direction regarding our human
research ethics work that we do within the agency, certainly involved
with EPA or EPA-funded research.

		Lastly I wanted to thank everybody within EPA who has worked so hard,
particularly with Paul Lewis sitting to your right, for their work
preparing for the meeting.  I wish to welcome those members of the
public who are here to observe the operations of the Board.

		To conclude, the HSRB process is just one of the examples of the
agency supporting an open and transparent process that ensures sound
science informs its environmental decision making.

		That is what's critical here, and your Board is one of the most
instrumental examples of how we accomplish that.

		Thank you for participating at today's meeting, and I look forward to
a very successful meeting.

		Thank you very much, Dr. Fisher.

		DR. FISHER: Thank you very much, Dr. Teichman, and welcome.

		Mr. Jones.

	OPENING REMARKS

		MR. JONES: I'd like to add my good morning and welcome to the Board
members this morning.  It's a pleasure to have all of you back here in
Crystal City in the Potomac Yards facility.  We had a very interesting
summer in the pesticides program, largely - not largely, but in no small
part - due to the work of this Board in the spring and summer of this
year.  We were able to meet a major statutory deadline that Congress
gave to us about ten years ago, and I want to thank all of you for all
of that hard work.  It was really a busy spring for all of you as we had
four meetings in a very short period of time, and I know that that
stretched all of you, and it stretched all of us as well.

		I also am very cognizant of the last meeting which was a pretty bumpy
one, certainly for us in the pesticides program.  But I think as well,
the preparation for that was a little bumpy for all of you.

		I believe that we took the feedback that we got from the Board very
seriously, and Dr. Fisher, I appreciate your comments at the beginning,
which I assume are somewhat related to the responsiveness that we'd had
to the issues, the very relevant important issues that the Board raised
at the last meeting related to how we prepare for these meetings, so
that you can be best prepared, and hopefully we brought that to a better
place, and hopefully we've demonstrated our responsiveness around those
issues.

		So as issues arise, which they are bound to, in the course and life of
this Board, related to how we get ready so that you can get read,
please, we're all ears.  We want to know to the extent that we can make
your job easier.

		We also had challenges related to an issue we first brought to the
Board at the last meeting related to protocols.  It was kind of
interesting that we at EPA in the pesticides program had far fewer
issues around what we thought were the most controversial type of
studies - the intention dosing toxicity studies - procedurally those
went quite well.  When we got to the protocol it was a little bumpier.
Again we spent a lot of time over the summer trying to figure out with
Dr. Fisher how we could tee those issues up more effectively, and we're
back today with a protocol that you have seen earlier, and hopefully
we'll be in a much better place not only with that protocol but more
generically as it relates to protocols.

		And as Dr. Teichman mentioned a minute ago, we're going to be talking
today really for the first time as a Board about a tricky issue related
to confidential business information, and hopefully our dialogue today
will bring that to a place that will allow us to succeed with the
statutes that we have; will allow you to succeed in giving advice on
issues associated with studies where confidential business information
may be relevant.  And I'm confident we can bring that to a place that
allows for the process to work very effectively.

		So some interesting issues that we've got today, as Dr. Teichman.  And
I certainly won't go over reviewing that agenda with all of you.

		But again I really just wanted to say, hopefully we've been responsive
as it relates to many of the issues you raised at our fourth meeting
last summer, and that will lead to a more effective operation of this
Board which is really what's in our interest.

		Thank you.

		DR. FISHER: Thank you very much, Mr. Jones.

		Dr. Lewis.

	MEETING ADMINISTRATIVE PROCEDURES

		DR. LEWIS: Thank you, Dr. Fisher.

		I am Paul Lewis, and I serve as the designated federal officer to the
EPA Human Studies Review Board.

		I want to thank Dr. Fisher and members of the Board for attending this
meeting, and we appreciate the time and diligent work of Board members
preparing for this meeting, taking into account your busy schedules and
other professional obligations.

		And we also would like to welcome the public to observe this meeting,
and my EPA colleagues for all the hard work preparing for the meeting
and deliberations we'll be having in the next couple of days.

		I'd like to also thank Dr. Richard Sharp as a new member of the HSRB,
and I am looking forward to working with Dr. Sharp at the first analysis
of issues being brought before the Board today and in subsequent
meetings.

		By way of background the HSRB is a federal advisory committee that
provides advice, information and recommendation on issues related to the
scientific and ethical aspects of human subjects research.

		The HSRB only provides advice and recommendations to the EPA;
decision-making and implementation authority remains with the agency.

		As the designated federal officer at this meeting I serve as liaison
between the Board and the agency.  I am also responsible for ensuring
provisions of the Federal Advisory Committee Act, commonly known as
FACA, are met.  And these are to include that this committee has a
charter governed by uniform procedures.  The Board only provides advice
and is open for public viewing.

		HSRB meetings follow all FACA requirements.  These include open
meetings, timely public meetings in the Federal Register, and docket
availability via the ORD docket.  As a matter of fact many of our
documents are also available through the HSRB website.

		As the designated federal officer for the Board, a critical
responsibility is to work with appropriate agency officials to ensure
that all appropriate ethics regulations are satisfied.

		In that capacity Board members are briefed with provisions of federal
conflict of interest laws.

		In addition each participant has filed a standard government financial
disclosure report, and I along with our deputy ethics office, the EPA
Office of Science Adviser, in consultation with the Office of General
Counsel, have reviewed these reports to ensure all ethics requirements
are met.

		The Board reviewing challenging issues over the next several days, and
with a full agenda, and meeting times are approximate, thus may not keep
to exact times as noted due to Board discussions, deliberations, and
public comments.  We strive to ensure adequate time for agency
presentations, public comments to be presented, and Board deliberations.

		Board presenters, Board members, and public commenters, please
identify yourself and speak into the microphones provided.  The meeting
is being recorded, and copies of presentation materials and public
comments, written public comments, will be available at bureau
regulations dot gov.

		In terms of the public comment process, for members of the public
requesting time to make a public comment, your remarks are limited to
five minutes.

		For those that have not preregistered, please notify either myself or
another member of the HSRB staff that will be sitting outside a table
outside this room if you are interested in making a public comment.

		As I mentioned previously there is a public docket to this meeting,
and all background materials, questions posed to the Board by the
agency, and other relevant documents are available on the docket,
regulations dot gov.

		In addition several supporting materials are available on the HSRB
website, and our agenda actually lists the contact information for that
material.

		The Board will prepare a report from this meeting, a response to the
questions posed by the agency and their review of materials presented,
and their subsequent analysis.  And the agency anticipates announcing a
Board review and subsequent approval of its report from this meeting by
Federal Register notice later on.

		In closing I'd like to thank the Board for the meeting the next two
days, and I'm looking forward to both a challenging and interesting
discussion over the next several days.

		Thank you, Dr. Fisher.

		DR. FISHER: Thank you very much, Dr. Lewis, and also thank you for all
your hard work, and all our daily conversations and emails, and becoming
a member of the family it seems.  Everybody in my family knows, oh Paul
is on the phone.

		Okay before I continue, we have three additional Board members who
just came, so just - I won't ask you to identify yourself, but I will
identify Dr. William Brimijoin is here, Dr. Michael Lebowitz, and Dr.
Suzanne Fitzpatrick.  So we welcome you.

	MEETING PROCESS

		DR. FISHER: Okay, and I'm just going to review a little bit about our
process, and then we're going to move on.

		So basically I think Paul reminded you of what our responsibilities
are; that we take them very seriously; that we are here to comment on
the scientific and ethical aspects of research proposals as well as
completed research, and to make recommendations to EPA and help them
when they ask us on ways to strengthen their program.

		Our charter says that our objectives and the scope of the activities
is that we provide the advice, information, and recommendations on
issues related to scientific and ethical aspects of human subjects
research, and we see our major objective as to provide advise on
research proposals and protocols, reports of completed research with
human subjects, and how to strengthen EPA's programs.

		One of the tasks that we have taken on over the last number of
meetings is to help clarify and develop the criteria that the board uses
to evaluate science and ethics on different types of completed research
and protocols.  And we've done this so that we will have consistency and
fairness in the way that we approach each of the protocols as we move
on.

		And I think as we will see today, we greatly appreciate especially
what John Carley has done in terms of integration some of the ways we're
looking at information into guidance.

		The way - the board process for those who haven't been here before is
that Paul and I assign primary and secondary discussions for each of
these completed studies and protocols that the board receives.

		The way the process is is that EPA first makes the presentation on the
science and the ethics; the board then asks questions if the board has
questions about those.

		Then we have public comments, and we will ask, as Paul said, the
public comments are limited to five minutes, and then the board will ask
questions if questions arise from the public commenters.

		We then go on to the primary and secondary reviewers who provide their
initial review.  We discuss that, or ask questions, and then move on to
see if we have a conclusion of the board.

		And as it says up there, if we note that there are significant issues
that were not posed by EPA, we will also do that in our role as
advisers.

		In terms of the board process, the science evaluation always precedes
the ethics evaluation; the rationale behind that is that to be of
benefit a study must be scientifically valid, and in addition, in order
to understand the risks, which are a very important part of the
risk-benefit analysis, we need to understand the science.

		So that the risk-benefit analysis in ethics especially in studies that
are not in any way assumed to have direct benefits to the subject, the
weighing of risks to benefits depends on the societal benefit and
scientific validity of the study, and the risks obviously come from a
science evaluation of what risks are posed by different chemicals.

		So that's our process.  I'm now going to turn to Bill Jordan to give
us an update on HSRB recommendations.

		I believe we had an update last time.  And the update I think is
critically important, because it lets us know as a board what we are
doing that has been helpful, or perhaps unhelpful, to EPA, when we see
how our recommendations have been integrated into their decisions about
- and I think it's very educative for the public, but it's educative for
us as well.  Because we also want to ensure that our process is
something that is going to be useful in terms of our advice.

		So Mr. Jordan.

	UPDATE ON EPA FOLLOW-UP OF HSRB RECOMMENDATIONS

		MR. JORDAN: Thank you, Dr. Fisher.

		I'll say a few words about how much I have valued the opportunity to
work with Carl Lewis and you on preparation for this meeting, and thank
you for your significant investment of time and energy in helping us to
figure out how we can have the most effective meeting possible and deal
with important topics, and I'm looking forward to having a successful
meeting, so thank you.

		It was also to allow the presentation to get up on the screen.  And I
want to thank our colleagues in the health effects division who have
helped prepare the materials.  They deserve the credit to making sure
that we are ready, and you all have the materials you need to be ready.

		At the last meeting the board tackled four different topics, the first
of which was a completed intentional dosing study using the pesticide
active ingredient chloropicrin (phonetic).  And the board concluded that
that study of the acute inhalation toxicity of material provided a
useful scientific information for risk assessment, and met the
applicable ethical standard in EPA's regulation, and therefore, advised
that you thought we could use that in our risk assessments, which we are
doing; we are using the results to derive an acute reference dose that
will be the basis for a revised risk assessment that we expect to issue
later this fall.  And we will move ahead with chloropicrin through our
regulatory process, and look at it in conjunction with a number of other
pesticide active ingredients that are used as fumigants for soil pests
and other fumigant uses.

		The second topic that you gave us advice on was a set of guidelines,
testing guidelines, dealing with insect repellent efficacy.  These draft
guidelines were, the first time that we put them forward in this
version, this format for the board's review, and we asked a number of
questions about how the guidelines should be written.  And you gave us
very thoughtful and thorough answers to those questions, which we will
incorporate when we work on the next draft of the insect repellent
efficacy guidelines.

		Our intention, and most of our staff have been working on reviewing
protocols that have come into us, and we hope to benefit from the
discussion of the two IR-3535 protocols that are on the agenda later
today, and use that discussion along with what we heard from you in the
report about the guidelines to come up with another draft version of the
guidelines.

		As I mentioned, last meeting you also discussed the two protocols for
testing the insect repellent IR-3535 that were submitted by Dr. Scott
Carol (phonetic).  You concluded that both of the protocols as they came
before you needed revision in order to address both scientific and
ethical issues.

		The investigator, Dr. Carol, made extensive revisions to the proposed
protocols and we have been working with Dr. Carol, as you'll hear in
more detail, later today, to prepare a version of the protocols that we
think are scientifically sound, and meet applicable ethical standards,
and because we think they have improved substantially and are ready
again for review, we're bringing them back to the board for your further
consideration.

		The last topic that came before the board was a set of five proposed
protocols that were directed at measuring exposure to pesticides of
people who are engaged in various activities associated with the
mixing/loading application of pesticide products.

		These five protocols dealt with different scenarios for that - those
activities, and when the board looked at the materials before them, they
- you all said that they needed revision to address a range of
scientific and ethical issues.

		We had thought long and hard about that advice, and in particular the
scientific issues that you identified are similar to and overlap with
some of the issues that we've had as we worked with the whole area of
exposure evaluation and assessment.  And we are planning to take a
number of those scientific issues to a meeting of our FIFRA (phonetic)
scientific advisory panel in January of this year.  We will ask the
scientific advisory panel for advice on the science issues, and use
their advice, working with the agricultural handler exposure task force
to develop revised protocols that will, we hope, address the scientific
issues in a way that gives us higher confidence that materials, the data
produced by such research will be scientifically sound and useful to
answer the kinds of regulatory questions that we as an agency need to
address as we regulate pesticides.

		It's not exactly clear how all of that will play out, but our best
prediction is that the agricultural handler exposure task force will
work with us to have revised protocols available for submission in
either spring or summer of next year, so that they can go in the field
in the following year to actually execute the research.

		So that's where we stand on the four topics that were raised at the
last meeting.

		DR. FISHER: Thank you very much.

		I was wondering, Mr. Jordan, it might be helpful to have a public
clarification on the distinction between the roles of the scientific
advisory panel and the - and our board, because I think there had been
some statements concerning the need for consistency which may be in some
sense misinformed.  So it's my understanding that the SAT is going to be
looking at general issues, how best to perform certain types of
scientific studies, whereas the role of our board is to look at specific
protocols that are presented to us.

		In addition we are both independent boards that are not necessarily
there to - our mission is not to come out with the same recommendation.

		MR. JORDAN: Dr. Fisher, your summary of the roles of the HSRB and the
Scientific Advisory Panel is accurate and hits the points exactly.

		I'd like to elaborate on a couple of ideas.  One is that the law that
EPA uses to regulate pesticides, the Federal Insecticide, Fungicide and
Rodenticide Act, directs EPA to work with the FIFRA scientific advisory
panel as the main source of scientific advice on issues that arise in
the course of our regulatory program.

		So when we are issuing regulations or taking regulatory actions
involving cancellation or suspension, we are required to go to the
board.  And as a matter of practice, we have found that the board has
provided us very valuable advice over the years on a range of scientific
issues.

		So we have worked with the SAP to help sort out specific issues
relating to particular chemicals, and general issues relating to broad
scientific questions that arise in the course of our regulatory
activities.

		Some of the folks who are members of the HSRB have also actively
served on the SAP and Dr. Brimijoin, Dr. Chambers, Dr. Fenske, I may be
missing some others.  But Paul Lewis cut his teeth in the advisory
committee process, working with the SAP.  So there are a lot of folks
who are familiar with the SAP and bring insights to the HSRB about how
it operates.

		The HSRB, as you reviewed in your opening comments, has a very
specific charge, which includes not only consideration of ethical issues
but also scientific issues, because bad science is bad ethics.  And so
there is the possibility that there will be some subject matter that
overlaps between the SAP and the HSRB, in fact, we've already seen that
with regard to the review of the Nethercutt (phonetic) study that is
presented first to the SAP and then to this board.  It also came up in
connection with the insect repellent efficacy guidelines.

		But my hope and my expectation is that both boards, when they address
an issue, will look at the science, and if there is a course of sound
science that both boards have pointed to, and we are confident that the
focus, while slightly different - broader science issues in the SAP, and
specific protocols and studies here in the HSRB - that we will not have
either a lot of duplicative work or any conflicts between those two
bodies in terms of the kind of advice that we get.

		DR. FISHER: Okay, thank you very much.

		Dr. Lux, would you like to introduce yourself?

	EPA HUMAN STUDIES RESEARCH REVIEW OFFICIAL

		DR. LUX: Yes, thank you.  I guess we're going to go back to the
introduction mode for a moment.

		I'm newly arrived here by way - Paul asked me to say a few words about
who I am and where I came from, and I will try to do that very briefly.

		I am a neurologist.  My clinical focus over the years has been on the
treatment of persons with frontal lobe disorders, particularly traumatic
brain injury.  So people with cognitive and behavioral disorders,
particularly of the sort that involve their own self regulation,
cognitive and behavioral self regulation.

		My scholarly interest has been in understanding the cognitive
capacities that underlie human agency, and therefore, that underlie
effective execution of autonomy, of personal autonomy, and that's how I
got into bioethics, and then went on and had formal training in
bioethics as well as in clinical medicine.

		So that's where I come from, that's how I come to this position.

		Here as you all know the human research, human subjects research,
which which EPA is involved is really quite extensive, and it covers a
lot of different domains.  We are engaged in human subjects research in
house.  We conduct human subjects research at other institutions.  We
support and fund human subjects research by other institutions.  And we
utilize human subjects research, done by, supported by, funded by
others, in the regulatory process.

		And my task is to further develop the ethical infrastructure revealing
that whole array of things.  And in that regard my office is in the
office of science adviser specifically so that it does have a reach
across all of the different activities of the agency.

		Your role as I understand it is to review these third party studies.
Your role by law is to review - you are required to review these third
party studies.  But your charter is much broader, and allows you to
review studies across the various domains in which the EPA is involved.

		And as we further develop the infrastructure for that, I expect from
time to time to come to you to seek your advice on some of those studies
as well, and I will very much appreciate having it, and I look forward
to working with you on it.

		DR. FISHER: Thank you very much.  We look forward to it as well.

		Okay, I guess we're now going to turn to the chromium repeat open
applications test, and before we do, I'm going to make a presentation,
so continuing my presentation.

	HSRB REVIEW OF SCIENCE AND ETHICS CRITERIA FOR

	COMPLETED HUMAN EXPOSURE STUDIES

		DR. FISHER: As I mentioned before, the board has developed criteria
that we use to apply to different types of studies, and I think it's
always helpful if we review what those criteria are prior to our
discussions.

		Okay, so the first question that we ask is, we look at the scientific
aspects of research.  Did the research - the broad and general issues
are whether or not the research, design and implementation meet
scientific standards, and whether the data generated by the protocol
have useful implications for the agency's weight of the evidence
determination, or when applicable, other aspects of the risk assessment.

		In terms of specific criteria that we have come up with and have been
put in our public report, and I think one of the reasons that I'm also
presenting this, and I think that EPA has done a great job of picking up
on this, is that these criteria I think will be helpful later on to
investigators when they submit protocols or previous studies; that it's
always helpful to let the board know how these criteria were met,
because this is what we're going to be looking at.

		So is a valid scientific question addressed by the study, whether the
purpose was clearly defined; whether there are specific objectives and
hypotheses; can the study as described achieve these objectives, and
test the hypothesis.

		Next slide.  We also look at population characteristics; where or not
there is a justification for the selection of the specific target
population; whether or not the sample size is appropriate, and how that
number was derived; can the findings of the study be generalized beyond
the study sample, and was that the purpose of the study?  Are the
participants representative of the population of concern?

		Are the inclusion and exclusion criteria appropriate both from a
scientific and an ethical perspective, and whether the sample is a
vulnerable group.

		We also look at the procedures.  What is the basis for the proposed
dose levels and formulations in the study?  Will the measurements be
accurate and reliable?  Are the measurements appropriate to the question
being asked?  Are adequate quality assurance procedures described?  And
can the data be statistically analyzed.

		We also look at the social value as well as participant risks.  As I
mentioned before, the risk-benefit is a balance that we need to look at
from an ethics perspective.  Part of that value is going to be whether
or not there is existing data adequate to answer the scientific
question, because remember, our responsibility is to judge whether or
not it's ethical to pose any risks to a human subject based on the
benefits of the scientific question.

		Are new studies involving human subjects necessary to answer the
question?  What are the potential benefits of the study?  What is the
likelihood that the benefits would be realized?  What are the risks of a
serious or irreversible, and is there a plan allocating individuals to
treatment if in fact there is a negative reaction to the experimental
treatment?

		Next.  Then I think it's appropriate for the chromium study, which is
a human dosing study, that we go over what the board developed as
criteria for human dosing.  Next slide.

		Some of this overlaps with our general criteria.  Is the scientific
question worthwhile?  Are human subjects necessary?  Is potential risk
serious or irreversible.

		We look at the dose selection.  Is it sufficient to test the question?
 I think it was the board's conclusion that in most instances a single
dose is not sufficient to answer a question.  And is the dose selection
based on appropriate data, and is that data provided, preclinical,
previous studies, et cetera.  Next slide.

		End point selection is something we also look at.  Is it consistent
with the aim of the study?  Is it appropriate to answer the question
about human responses, sensitivity, accuracy, validity, replicability.

		Is the end point measured accurately and reliably with good quality
assurance?

		As we talked about in the general criteria are the characteristics of
the population generalizable to the question that EPA has asked, whether
or not the data is reasonable to address, and are there appropriate
inclusion/exclusion criteria.

		Next slide.  We look at the method, once again, whether the sample
size is sufficient.  Is the selection of control and experimental groups
appropriate?  Is the staging of dose intervals, dose amounts, and the
type of exposures sufficient to answer the question?  Is there quality
assurance for observations, instruments, and data?

		We also look at the statistical analyses, in particular whether or not
the data can be analyzed, and is the statistical method appropriate to
answer the question.

		Then we also looked at single dose level studies.  So we can move on.
If the chromium is not daily dose, right?  Okay, so let's move on.

		Now we'll get to the ethics evaluation.  Of course in any already
completed study we ask whether or not the study failed to fully meet
specific ethical standards prevalent at the time the research was
conducted.  Examples are FIFRA, Declaration of Helsinki, the 1991 Common
Rule, and for those studies that were conducted and completed after
April 7th, it would be the EPA Common Rule.

		Okay, if the study did not fully meet ethical standards prevalent at
the time, then we ask whether or not the conduct of the study was
fundamentally unethical; whether there is clear and convincing evidence
that the research was intended to seriously harm participants, or failed
to obtain informed consent.

		And whether or not the conduct of the study was significantly
deficient relative to the ethical standards prevailing at the time.  Is
there clear and convincing evidence that the deficiencies identified
could have resulted in serious harm based on knowledge available at the
time the study was conducted or the information provided to participants
could seriously impair informed consent.

		Additional ethical criteria that we are using in order to make these
determinations: are risks justified by those benefits, I've spoken about
that before.  Are risks necessarily and sufficiently minimized?  Are the
subjects equitably selected?  Are there sufficient safeguards against
coercion?  Are there procedures for ensuring subject safety including
adequate monitoring?  And has the PI provided sufficient and appropriate
documentation of the IRB review.

		Next slide.  We also look carefully at the informed consent, whether
or not there has been documentation that consent has been obtained,
whether the consent included appropriate information of the identity of
the pesticide and mode of action, whether there was an adequate
discussion of risk, alternatives to research participation must be
included; whether there is clear information about participation and
compensation, if relevant; whether there was a clear statement of who is
financially responsible for study-related injury; and whether there was
clear communication of a voluntary nature of participation and how one
can withdraw from the study.

		And I think that's all for the chromium.

		Okay, so now we are going to turn to Dr. Liccione - is that how you
pronounce your name?  Liccione, I'm sorry - and Mr. Carley are going to
give us an EPA overview of this study.

	CHROMIUM REPEAT OPEN APPLICATION TEST

		DR. LICCIONE: I would begin by thanking the board for their time and
consideration.

		The topic I will be talking about today concerns dermal sensitization
testing of chromium in a human study.

		Next slide.  The following outline of the topics that are going to be
presented.

		First, we're going to give you a brief introduction on allergic
contact dermatitis and what it means, and then some information on
regulatory framework and a little about the science background.

		Then we'll talk about the previous science advisory panel and human
studies review board, review of chromium, and then finally we will focus
on the topic today, the Procter (phonetic), which is the human study for
evaluation.

		Next slide.  And this slide defines more specifically the form of
chromium that will be our focus, and that is, chromium in treated wood.
Hexavalent chromium is a component of a pesticide product for use as a
wood preservative.  And in the particular form that was studied in the
Procter study is called acid copper chromate, which is a mixture of
copper oxide and chromium trioxide.  It also is known by the common name
Copper Shield.

		And the agency has concerns that the general public may experience
dermal exposure to chromium remaining on wood treated with ACC.  And
there is also concern for potential to cause allergic contact
dermatitis, which I will sometimes refer to as ACD, which is known to be
a sensitive dermal endpoint associated with sensitizers such as
chromium.

		Next slide.  What kind of information can be derived from dermal
sensitization testing?  The agency perspective is that information
derived from tests for skin sensitization serves to identify the
possible hazard to a population repeatedly exposed to a pest substance.

		Next slide.  What do we mean by treated article as it pertains to a
pesticide?  A treated article is a registered pesticide that is
incorporated into an article to protect the integrity of the article or
substance itself.  Treated articles such as treated wood do not bear
pesticide labels nor other information to inform the public about any
potential hazards including dermal sensitization.

		Next slide.  Okay, what is ACD?  It is in short a delayed
hypersensitivity reaction that can be characterized by two phases: an
induction phase which involves exposure of sufficient magnitude or
duration to activate the specific immune mechanisms resulting in the
acquisition of sensitization.

		The second phase is often called the elicitation or challenge state,
whereby response is induced in sensitized individuals upon exposure to
the allergen produced by the relevant route.

		Next slide.  When talking about dermal sensitization testing it is
very important to consider irritation responses which may be difficult
at times to distinguish from ACD.  There are some similarities, but
there are very important differences.  With irritation you may get a
little edema, but most often you find edema, especially associated with
other signs, with ACD.  Paradema (phonetic) may be present in both
situations.  Itching which is not on the slide may also be present,
although it tends to be more homogeneous with ACD.

		In regard to a reaction time, in general for irritation, tendency for
a more immediate response, but note that sometimes there is a cumulative
irritant effect.

		Reaction time with ACD generally requires some time, usually 24 to 72
hours.  And with irritation you can get a response on the first
exposure, whereas with ACD you generally don't see a response after one
exposure.

		A particularly big difference is that ACD is an immunological process
that involves memory stages by key lift sites (phonetic), whereas
irritation does not.

		Next slide.  Other important points to consider about ACD is that it
is recognized as a threshold phenomena.  Thresholds are largely
determined by the potency of the allergen, and the induction and
elicitation thresholds can vary among individuals.

		An important point to consider is that induction thresholds are
considered to be higher than what is seen with the elicitation stage.

		Those response relationships have been documented for both of these
phases.

		Next slide.  Other important points: induction may occur after a
single exposure to a large area of skin, or as a consequence of repeated
skin exposures.

		Some data also suggest that a sensitizing potential may increase with
the repeated exposures.

		Next slide.  As I have mentioned, chromium and the dermal
sensitization issues associated with chromium exposure have previously
went both to the science advisory panel and also to the Human Studies
Review Board.

		In May of 2004 the scientific issues in terms of developing the
foundation of a scientifically sound approach to quantitative risk
assessment of dermal sensitization for pesticide chemicals was presented
to the science advisory panel.

		These included chemicals incorporated in other materials, in other
words, the treated articles.  And hexavalent chromium was presented as a
case study.

		Next slide.  The board took a look.  The panel actually looked at all
the available data, the animal data, largely the local lymph node assay
immunopatch test data were considered.

		And the science advisory panel noted numerous limitations of the use
of the animal data, and the deficiencies in many of the human studies.

		Next slide.  However, the science advisory panel did identify one
particular human study as the best available, and this is the Nethercutt
study.  And the panel identified the critical dose from this study to be
89 nanograms per square centimeter.  And this represents what is called
a MET 10 percent, or the 10 percent minimum elicitation threshold.

		This value was considered a conservative level largely because it
involved occluded patch testing, for 48 hours, which tends to both
maximize absorption and make the skin more reactive.

		The panel however recommended that an open application test with
repeated daily exposures would be more appropriate for risk assessment
purposes when dealing with treated articles.  And this is often called
the repeated open application test as one good example of the kind of
protocol that the SAP was envisioning.

		Next slide.  Just to talk a little bit about the Nethercutt study.  As
I mentioned it was also reviewed by the HSRB not too long ago, in May
2006.  And the board concluded that the study was sufficiently sound to
be used to estimate a safe level of dermal exposure to chromium.

		The board also concluded that the study was properly designed; that it
was well conducted; and it employed an appropriate scientific and
clinical methods to determine MET for dermal sensitization.

		The final conclusion, and an important one, was that the HSRB
concluded that the MET 10 percent was a reasonable point of departure to
be used in terms of risk assessment.

		Next slide.  I'd like now to turn our attention to the main focus of
today, and that is the Procter study that deals with the human testing
of chromium.

		Next slide.  As I mentioned the science advisory panel recommended a
repeated open application test, and that's what ROAT stands for,
sometimes I will refer to it as the ROAT protocol or ROAT study.

		And the purpose of the study was to develop a 10 percent MET level for
chromium STP within ACC wood treatment solution.

		They also looked at both potassium dichromate.  However, I want to
mention that our concern here today is with ACC, not in particular
potassium dichromate, so I will not be talking too much about potassium
dichromate.  And utilizing this ROAT protocol.

		For ACC the specific purpose then was to determine a safe level of
repeated dermal exposure.  Our focus as I mentioned will be ACC today,
and in this study, 148 possible volunteers were contacted; 88 were found
to be eligible for this study; ultimately a total chromium sensitized
population of 60 actually took part in the study, consisting of both men
and women; there were 10 control participants, all female; and all 60
chromium sensitized study participants were actually confirmed to be
chromium sensitive, based on a patch test single exposure, and that was
performed by the sponsoring clinic.

		Next slide.  They included both inclusion and exclusion criteria, and
I think the exclusion criteria show the importance.  Any persons taking
immunosuppressive or steroidal medications was not included.  Any
current exposure to chromium or copper in the workplace in home, anyone
presenting with symptoms of active dermatitis, fissures or lesions of
the skin were precluded.  Any serious systemic disease or medical
condition; pregnancy or anyone attempting pregnancy; current breast
feeding; any illicit drug or alcohol use; and anyone that was planning
to leave the area for two days or more.

		Written consent was provided to participate in this study.  Medical
and occupational history questionnaires were filled out.  Information on
dermatitis was available for all subjects.  Next slide.

		The concentrations that were selected for the ROAT study were doses,
including a control that consisted of a copy chlorate solution.  The low
dose was 90, then there was a 250, 750, and then the high dose was the
2,500 nanograms per square centimeter.  And to note the importance that
the dulse (phonetic) metric that is applicable for these kinds of
studies and consistent with dermatological researchers considers the
best is the mass per unit area.

		The lowest concentration that was selected, the 90, represented the 10
percent MET value from the Nethercutt study.

		According to the study authors, the highest concentration was
considered an extreme upper bound in terms of exposure to chromium six
from exposure to ACC-treated wood.

		Next slide.  Patients were exposed to chromium in brief, and at the
same time, on different arms, to either the ACC or the potassium
dichromium.  High concentrations - the four concentrations in the
controls were applied in the 10 microliter volume to five one-square
centimeter areas on their right forearm utilizing this transparent tape,
and the diagrams and description of the methodology was very carefully
portrayed in the document.

		The concentrations for the potassium dichlorate were done on the left,
whereas the ACC was treated on the flexor area of the right forearm.

		Exposure then was for six hours per day for a 10-day application with
a weekend period off.

		Next slide.  Okay, the grading of the allergic and irritant responses
was performed by Dr. Joseph Fowler (phonetic), and I just want to
comment briefly about Dr. Fowler's credentials.  He is a very
experienced dermatologist, with considerable expertise with chromium
dermal sensitization.

		He was the principal investigator and the diagnosing physician for
this study.  So that was his role.  He's licensed to practice in
Kentucky and in Indiana.  He is the current president of the North
American Contact Dermatitis Group.  I will be referring to this group as
the NACDG.

		He was the past president of the American Contact Dermatitis Society.
The study was actually conducted in his private practice at the
Louisville, Kentucky clinic, and study participants were largely
recruited from the patient population from his private practice.

		All skin responses were graded for the usual responses: eridemia
(phonetic), vesicular germination (phonetic), papule scaling, itching,
according to the following scale.

		So the scale here I won't review and go into all of this, but this
just shows you that it was clearly defined what criteria are used in it.
 And a very important point is that the criteria that were utilized is
very similar to the criteria that physicians used in the NACDG.

		Next slide.  The test sites were examined daily for the presence of
any irritant and/or allergic responses.  If the response was just to be
allergic, the dose was discontinued only for that dose causing the
allergic dermatitis response.

		In contract, if the response was irritantcy, or if it was of uncertain
designation, doses was continued, and there was further monitoring for
morphology, change in severity, and the persistency of the effect to try
to determine the classification.

		Next slide.  The ROAT results were treated in two different
categories, and were modeled with respect to the calculation of the MET
. One was to consider only allergic responses, and this is what is
referred to as scenario one in the study.  The assumption behind this is
that participants who had allergic responses to lower doses were also
considered to be allergic to all higher doses, and this actually did
occur in at least one participant.

		The other scenario that was modeled and interpreted for results is
allergic plus irritant responses.  The assumption for this scenario two
is that once again participants who had allergic responses to the lower
doses were also considered allergic to all the other doses, higher
doses.

		And all irritant responses were assumed to be allergic responses, with
the exception that when only itching was reported without any visual
signs such as erythema (phonetic), papule formation, the observation was
not considered either an irritant or an allergic response.

		Now both scenario results were also normalized to the chromium
sensitized U.S. population.  Based on what is known about the population
in the NAGDC database, and utilizing the more current evaluations for
1998 to 2002.

		This was based on the observation of the disproportionate number of
the most severe respondents in the current ROAT study.  The
normalization briefly was done by comparing the number of participants
who had a plus one, a plus two, or a plus three patch test reaction to
the proportion of individuals with these exact patch test grades in the
NACDG database of the patch test grade, for all individuals that were
actually patch tested by those physicians from those years.

		The data from the patch test normalized population then were used for
estimating the MET percent values that would be representative of
general chromium sensitized populations in the United States.

		And the next slide shows you the results, the METs were actually
determined by benchmark dose modeling that the agency currently uses, so
what you are seeing there is the BMD 10, and for the scenario one,
remember this is just the allergic scenario, and the value was 270
nanograms per centimeter squared, about three times higher than the
Nethercutt MET percent.

		So for scenario one, after going through the normalization procedure,
we did a higher MET 10 percent value, which would - as one would expect
- after renormalization.

		For scenario two, once again, scenario two is both allergic and
irritant responses combined, and the soon to be allergic.  We get a
lower MET value, and we get roughly about where Nethercutt comes in.
And then the normalized one is also higher.

		The next slide shows the lower confidence limits, in other words, the
BNB 10 percent lower, about 95 percent confidence limits, for each of
the scenarios.  So that is from our own - they utilized our benchmark
dose methodology.

		Okay, next slide.  The study has many strengths.  Both males and
females were represented in the study.  And they had a large population
of sensitized individuals which in terms of statistical power it's one
of the better studies that you see in terms of dermal sensitization
designs.

		The study participants were blinded to the control and test solutions,
and good experimental design to establish both responsive relationship
for elicitation.  And the study utilized good criteria that was
consistent with the NACDG database.  The methodology was clearly
explained, and there was verification of dose delivery.

		And repeated dermal exposure is more realistic for risk assessment.
So those are the strengths.

		Next slide.  We didn't find any apparent weaknesses with the study.

		Next slide.  We conclude, the agency concludes, that this study, the
Procter human study, contains information sufficient for assessing human
risk from potential repeated human exposure to chromium as it exists in
treated wood as an ACC solution.

		Next slide.  The scientific considerations for the board today is one
to recognize that the agency identified this study on chromium, a human
study, who had documented, previously documented sensitivity to
chromium, and one that utilized a ROAT protocol as recommended by the
science advisory panel.

		The study was conducted to identify a level of chromium exposure below
dermal exposure would not appear to elicit an ACD response using the
wood treated solution ACC.

		Please comment on whether the Procter study is sufficiently sound from
a scientific perspective to be used, for use for quantitative dermal
exposure for exposure to ACC treated wood.

		Thank you.

		DR. FISHER: Thank you.  Now before we hear about the effects, I think
we'll have some questions about the science.

		I have a question, an incredibly naive question, but I'm trying to
figure out what a dermal patch has to do with touching wood.

		DR. LICCIONE: Okay, the patch does not have anything to do with
contact with the wood.  The patch test here was utilized to confirm
previous sensitivity.

		In the protocol, the ROAT protocol itself is not an occlusion.  It is
a transparent tape that allows you to delivery carefully to the same
area.  But it is open, open so it was typical exposure.

		DR. FISHER: Right, I understand that, but I guess the perspective of
one of our criteria is the value of the study, and the proposed value of
the study is that treated wood public bystanders putting their hand on
the wood may in fact have some contact with it.

		So I'm just wondering, it would seem to me that the compound itself in
terms of how it might get to the skin, the mix with the wood, would have
some  implications.  So I'm just trying to figure out, what is the great
benefit of the data produced here to answer the question about whether
or not the public is safe.

		DR. LICCIONE: Right.  By using the repeated open application, which is
not a patch test, allows you to deliver the stuff on contact.  So if you
are sitting on a deck and you put your arm, you can get exposed.

		This is the best way to do this, to repeat an open application, where
you allow delivery to an open system, and allows you to look at
different doses at the same time.

		DR. FISHER: Once again my question is, whether or not in the real
application of it, the fact that it's in the wood itself, that's my
question, and how this is generalized to coming through the wood.

		DR. LICCIONE: Okay.  The chromium as they explained it in the
background document, chromium six, there is a fixation process that
generally takes place in about two weeks.  So anyone coming into contact
with it before it finally sixes could actually be exposed to chromium
solution.

		The doses that were selected to identify, one was the upper bound,
2,500 based on some exposure information that they discuss.  So that
would be the worst case scenario.  So say there is wood in the factory,
and it's shipped out before it has any time to begin to fixate, that
would be an upper bound.  Lower bound was to the 95th Nethercutt,
because they wanted to try the minimal one, and Nethercutt had addressed
issues of what happens if you are exposed, even with the patch, to some
MET level over great areas.

		So in that compass the 90 was a good reasonable cutoff.  So in terms
of exposure it's realistic in the sense that if someone - if a factory
sent this out before it actually got fixed, we could get exposure.  And
the good thing is that allows you to do a more realistic kind of
exposure where it's opening where it could allow - where it dries
normally, and also, realistic washing.

		DR. FISHER: Thank you.  Other questions?  Yes, Dr. Chadwick, and then
Dr.  Fitzpatrick.

		DR. CHADWICK:   On slide 22, the last report, you talk about
normalization because of a disproportionate number of high responders.
And the normalization as I understand it then results in a higher --

		DR. LICCIONE: Right.

		DR. CHADWICK:  - than you would get without normalization.  So my
question is twofold.  One, why did they have such high responders?  And
why did they feel it important to normalize as opposed to just use the
raw data?

		DR. LICCIONE: Okay, good questions.  Those are questions that we
ourselves considered.

		DR. CHADWICK: I appreciate the judgment.

		DR. LICCIONE: Yes.  One of the reasons, one of the feedback on the
normalization procedure, okay, what could account for what happened in
this study?  Why was there a disproportionately large response to the
plus two or plus three responding?

		What may have happened is that they selected the population.  A large
number of them were the plus ones in the original population, the 100.
If you take a look at the 88, a good number of them, I think the
percentage is down here so that you can - that I can explain it a little
better - about 70 percent of them turned out to be negative.  And of
those were actually weak sensitizers to begin with.

		The reason maybe that - because it's an immunological process, one,
over time these weak sensitizers lost their sensitivity.  So that's one
factor.

		The other factor is that these weak sensitizers were identified by
patch tests to begin with.  There were some false positives that could
happen, so I think what these weak sensitizers were, their response can
be interpreted as an HCP (phonetic).

		So I think that could happen.  That's what they do discuss about some
of the factors.  But the factor that appears to trump for them is loss
of sensitivity, given that those - a number of them were already weak
sensitizers.

		And it's also concordance.  The patch attempts, though they were more
strongly reacted, tend to act more strongly than the ROAT.  You see the
one individual participant number 70 that reacted, the only one that
actually showing the severe -- the most serious response to the ROAT,
the plus three with only one individual.  Most of the other individuals
were ones and twos, more twos - there was only one weak sensitizer that
actually reacted with a ROAT score of one, not a patch, I'm now talking
about the ROAT of one plus.  And that was only to a high dose, to the
highest dose.  So there are some dose response relationship.

		And we'd like comments on the normalization.  That's the rationale
that appears, that I think is - immune responses can change with time,
in that most of your initial population that was identified as negative
had actually lost some sensitivity.

		DR. FISHER: Dr. Chadwick, do you want to continue?

		DR. CHADWICK: So the normalization was done after the data was
collected?		DR. LICCIONE: That's right.

		DR. CHADWICK: Part of the original study, they collected some higher
numbers and higher reactions than -

		DR. LICCIONE: Exactly.  They amended the protocol.  What they noticed
was that, well, how do you interpret this study when you have so many
more?  And they went back to NACDG database and they saw both they were
proportionally responding to the plus three is significantly different.
And just to show you the numbers here, somewhere here.

		Yeah, the NACDG database for a patch test greater than plus three, we
are talking about seven point seven percent, virtually you had 27
percent seen in this study.  So the attempt was to normalize it,
basically what they used was a simple proportionate analysis.  You have
an extreme random population in here, and that in itself is part of - a
very extensive population to begin with.  Then we get some information
about distribution.

		I never see normalization done with dermal sensitization.  I've seen
it without the biological end point.  I'm sure you've all seen this.
And Nethercutt didn't do it because I think no one actually went back
and obtained the data to do that.  Something where exactly will be
what's considered the upper bound, but there is an argument for the
normalization.  We are dealing with a very small population, based on
the heterogeneity within the database.

		And I think - I gave it some thought.  One of the issues that I was
concerned with was how representative of the exposures of the people
that we had.  Because if you look at it, there was variance in exposure
to cement.  There's exposure to leather.  There's exposure to cosmetics.
 There are some unknowns.  So in the real chromium sensitive population,
you'd think they'd look at a cross-section.

		So I think that was what they were attempting to do.  They tried to
make it more meaningful to the overall general population of chromium
sensitized.

		DR. FISHER: Okay, Dr. Fitzpatrick, then Lois and then Camden and then
--

		(CD Change)

		- skin tight, that is always a variable of fact.  But we don't see any
- once again another COT (phonetic) actually looked at some of those
issues and did not report that any major differences.

		I mean if somebody - great lengths were done to preclude anybody with
any damaged skin or anything like that.

		DR. FISHER: Suzanne, please.

		DR. FITZPATRICK: Did he determine what the most sensitive skin type
was?

		DR. LICCIONE: No.  What they did was, they took the chromium sensitive
population known and they actually then just took what population
existed and precluded anyone that might have had anything that have
affected it.

		But yes, everyone within this room would - somehow they're going to
absorb an allergen, and the biggest difference is your immunological
response to that is going to vary a lot.

		DR. FISHER: Lois.

		DR. LEHMAN-McKEEMAN: I have two somewhat related questions.

		You note early in your presentation that irritation is not an
immunological reaction.

		DR. LICCIONE: That's correct.

		DR. LEHMAN-McKEEMAN: And yet in making the final evaluation of these
data the irritation is actually included with the allergic reaction in
one of the scenarios.

		So the question I have, is that scientifically legitimate to do?

		DR. LICCIONE: The - oh, I'm sorry, finish your question.

		DR. LEHMAN-McKEEMAN: Well, you can go ahead.

		DR. LICCIONE: Okay.  Usually, as I mentioned right from the beginning
irritation and ACD is sometimes very difficult to tell.  This requires
judgment from an experienced dermatologist, Dr. Joseph Hollerez
(phonetic).  I believe what they did here in this study was to consider
worst case scenarios.  So you went ahead and assumed that all these
irritants were fine.  Obviously they are not.  There's very clear cases
that there's irritantcy responses that were not ACD.  There were some
questionable ones, but what they did - I think they were trying to
present a worst case scenario.

		DR. LEHMAN-McKEEMAN: Well, just in looking at the tables themselves,
many of the subjects who presented with irritation in fact presented on
day one.

		DR. LICCIONE: Right.

		DR. LEHMAN-McKEEMAN: And so that kind of argues against that really
being allergy.  But at the same time I have to wonder - and this is the
second part of my question - if you have this background of what appears
to be a relatively high incidence of irritation, potentially that can
skew the immunological reaction somewhat if you are exposing the skin
perhaps a little differently.

		And the major point of my question is this, if that's the case, is
that potentially related to the product itself that's being tested?  And
if it is, is the evaluation and comparison to this historical database
actually a relevant thing to do?  Because you really have an apple and
an orange here that you are trying to compare.

		DR. LICCIONE: Okay, let me go back.

		Chromium is both an irritant and an allergic contact dermatitis
response.  You typically see this with any allergen.  So when you do
these studies you are going to see irritantcy.   Sometimes just
irritantcy alone.  There were five individuals that didn't have it.

		There's also cases where you are only going to see ACD.  Then there
are going to be cases where you get both.  You will typically, if you
follow some of these, you will get irritantcy at a lower dose than you
get the ACD.  This is typically what you are going to find.

		You will find that in the NACDG database as well.  And the population
there would have the same kind of typical thing that you would expect.

		The other thing is true as you point out irritation did occur in some
cases day one.  But in other cases it didn't appear until much later;
great variability.

		The other thing to keep in mind is that irritation was in all cases
plus one low grade thing.  There was no evidence of any serious
cumulative irritant response which I was concerned about that would in
fact, absorption or interpretation.

		So I think the study is good in that sense.  Because if you do a study
with cosmetics, you are going to run into the same problem.  That's why
I initially talked about irritation, because it is a problem with these
kinds of studies.  You have to be clear on the criteria, but it is not
an immunological process.  So it's only one plus two response, but that
only lasted I think one day.

		So I don't think that the irritantcy responses confound the
interpretation.

		As I mentioned, I think what they were trying to do here is say, even
if you are assumed all these irritantcy responses, this is the worst
case scenario, you come back down to what Nethercutt got, an NEM percent
of 90.  And that's a more unrealistic kind of exposure.

		Not that irritation is not an important input.  It certainly is.   And
you know the agency does look at irritation, and it is part of the
product.

		I don't think that there is an apple and orange difference between the
database.  The database out there are going to respond in the same way.
If you took those individuals they are also going to respond in the same
way.

		And just some of these individuals are actually part of that database.
 They have been tested by some of these physicians too.  So you are
going to - and like any other study you can only get so many people who
are going to want to do this type of study.  I just recently got over
poison ivy, and apparently it's just like chromium, never want to do it
again.

		DR. FISHER: Dr. Krishnan.

		DR. KRISHNAN: As I was looking at the protocol I was struck by the
fact that the pH of the solution was seven and the potassium dichromate
study was more acidic, or rather five, in case of the copper seal
solution, I can assume why, but I just would appreciate any
clarification that you may have.

		DR. LICCIONE: Why the difference?  Well, I think potassium dichromate
tends to be more acidic.  But we're not concerned with the potassium
dichromate for this particular study, for our purposes for regulating
for ACC.

		The potassium dichromate was intended for the use for a soil criteria
cleanup criteria.  And so we didn't really spend much time on potassium
dichromate.

		But I think part of the problem with potassium dichromate that was
noticed by dermatologists is that it is - tends to be more acidic.  And
then also the solution was causing more irritation and they had to
actually go back and drop the dose.  Nethercutt actually discusses some
of these early pitfalls.

		DR. KRISHNAN: In trying to understand the comparison with the
historical clinical database, I was wondering whether it would be
investigator related, you know, the difference in rating could be
investigator related.

		So my question, in order to be able to understand that, is whether Dr.
 Fowler's data are also part of the database, which I presume, but I'm
just asking.  And number two, whether the plus three grading in that
database also reflects some of the chromium studies.

		DR. LICCIONE: Okay, the first question was the criteria.  As I
mentioned earlier, that's one of the first things we checked was the
criteria that was being used by Fowler was the same as the NACDG
database, and the answer is, yes, it is.

		Did they contain some of the individuals in the chromium study?  That
offhand I do not know.  It's very likely that that population was part
of that, because that is the known population of database.  But to what
extent I don't know.

		What was the one other question you had?  Okay.

		DR. FISHER: Micah.

		DR. LEBOWITZ: Thanks.  I'd like some clarification first of some of
your definitions, when you are differentiating irritation and allergic
contact dermatitis.

		I assume this is not an official NACDG definition or delineation
between the two.  And also of course there are delayed effects of
irritants that aren't immediate, and immediate - there are some
allergens even for contact dermatitis that also have an immediate
hypersensitivity response.

		DR. LICCIONE: Right, the excited - you're talking about the excited
skin syndrome.

		DR. LEBOWITZ: Right, and I'm assuming this differentiation you are
placing here is more for the elucidation of the committee, and not
anything official that we should be terribly concerned about as an
agency definition.

		DR. LICCIONE: Right.  That's correct.

		DR. LEBOWITZ: And in fact, I was curious, we talked earlier about
potential - not likely, but potential differences between HSRB and SAPs,
but there is - the SAP I don't know how seriously it considered the
NACDG criteria or protocols in coming up with its recommendations, but -
and I don't know how much the NACDG people were involved in the SAP, but
it seems to me that there always is a potential for scientific and
medical confusion when you have different groups coming up with
different criteria and protocols.  And I don't know how to resolve that.
 I don't know if the SAP or the agency addressed that question.

		But it's sort of important to me in terms of how these studies are
examined and defined.  Do you know anything about that?

		DR. LICCIONE: I don't know offhand if the SAP got into the - I wasn't
around - I wasn't at the agency then.  When I read the former SAP
report, I didn't see whether they actually considered the NACDG.  But I
do want to say that the NACDG is considered a very solid thing with
dermatologists, because it's not only chromium that they deal with; they
deal with many things.  So they have considered the good diagnostic
procedure; that I can say, when it comes to diagnostic and clinical and
medical, Dr. Fell (phonetic) himself is - conducts more patch tests than
anyone in this country.  And I don't know if the SAP has gotten into it.

		But if you look at many of these protocols on irritation, and I know
that the SAP for example brought up some - that was a contentious issue
with the Hansen study, the study that the board also commented on, where
one of the problems was that they used a little bit different criteria.

		But I think that from the dermatological societies out there, that
this database has very good -

		DR. LEBOWITZ: I mean the reason I asked, I've been involved in the
NACDG stuff over the years, and so I was sort of peripherally - it's not
my main area - but I'm always - and I'm involved in a lot of
standardization.

		So it's possible or conceivable that the SAP was influenced very much
by the case study, in this case, the hexavalent chromium, in making its
decisions as to what to recommend.  And that may or may not be the same
if it looked at other causes of allergic contact dermatitis.

		I had some specific questions about the study as well.  It concerned
me that those who were initially considered controls, who happened to
react to the patch test, were then thrown in with the -

		DR. LICCIONE: Those two individuals.  I wondered what happened there
too.  I'm not sure how that could - I'm not sure how that was - they
somehow must have developed sensitivity to chromium somehow, and a
likely source could be cosmetics.

		DR. LEBOWITZ: But not to be excluded seemed to be a concern.  I don't
know if it would change the data.

		DR. LICCIONE: Oh, you mean the individuals that were -

		DR. LEBOWITZ: Yeah, in the original patch testing.

		DR. LICCIONE: The ones that were negative and excluded?

		DR. LEBOWITZ: The controls that were positive -

		DR. LICCIONE: Oh, right, the two that were positive -

		DR. LEBOWITZ:  - were changed.

		DR. LICCIONE:  - were actually included in the -

		DR. LEBOWITZ: Yeah, I don't think they should have been.  But that's
another point.

		Do you happen to know, I didn't read the full study or have time to
ask the individual reviewers, but the time between the patch testing for
inclusion and the ROAT exposure study, was it at least two weeks in
between that?

		DR. LICCIONE: Yes.  I think they were defining day one, the first
three days were dedicated to the patch, and then the 48 hours after the
patch, and then they started.  That's why when you see the report, it's
a little confusing.  Sometimes they say visit 11 or day 15.

		DR. LEBOWITZ: That concerned me a bit too in terms of immune response,
because there is a tendency for an inclusion method to actually elicit a
 longer term response that might have affected the results of the ROAT
testing.

		DR. LICCIONE: Well, I do know that others generally do that.
Nethercutt did that.  You check the sensitivity to see -

		DR. LEBOWITZ: Oh, yes, but then you usually wait long enough for the
immune response to calm down before you start testing with multiple
doses.

		And that's the reason I asked.

		The issue of - which you didn't bring up in your slide but it's very
important - is there was a two centimeter interval between each of the
five different doses on each of the arms.

		And I think that's fairly standard.  However, when you have very large
doses, you know, close to doses that are not large, then you may have a
bleed out effect, which I don't know if that's anything.

		DR. LICCIONE: Okay, they weren't too careful to avoid what you had
said about the hyperexcitability, the excited skin syndrome.

		DR. LEBOWITZ: Yeah, when you have two large doses together.  But one
large dose can affect -

		DR. LICCIONE: Well, there is no evidence of that.  If you look at
grading up and down in terms of, they actually didn't find evidence that
that happened.

		Also, Dr. Mydvack (phonetic), who is -

		DR. LEBOWITZ: Yeah, I worked with him.

		DR. LICCIONE:  - okay, who has done mechanism - assisted in the design
of this protocol.

		DR. LEBOWITZ: Yeah, I didn't see that; thanks.

		And finally, two questions, three.  Model versus actual, we've talked
about.  Normalization, I don't know if the NACDG distribution is
Gaussian that they call it normalization.  It may be also very skewed.

		And I think what you - what the term here is really that they have
tried to make the population response in this study similar to what the
response may be in a general U.S. population.

		DR. LICCIONE: Correct, that is correct.  That was the attempt.

		DR. LEBOWITZ: Okay, so that helps me understand it.

		Now, the MET 10 percent is a good point of departure.  But they really
don't determine a NOWA (phonetic) here do they?

		DR. LICCIONE: That's correct.  It is not NOWA.  The idea, Nethercutt
explains what the MET 10 percent means.  You are looking at a 10 percent
response level, but given that the population, the prevalence of
chromium sensitization is so low, less than one percent; there are
different values that go around, but it's very low; dermatologists who
work with chromium consider that to be protective of 99.9 percent of the
general chromium sensitized population.

		DR. LEBOWITZ: And finally, thank you both for your presentation, and
your clear response to the questions.

		DR. LICCIONE: Great, thanks for the questions.  That helps us very
much.

		DR. FISHER: John, I had a question, then Rich, and then Rich.

		Okay, my question has to do with, remember quality assurance is one of
our criteria, and going by the last conversation that had been brought
up by our members in terms of when it's no longer irritation and it
becomes the allergic reaction.

		Was Dr. Feller the only person who was evaluating this transition?

		DR. LICCIONE: He was the diagnosing physician.

		DR. FISHER: So he's the investigator, the diagnosing physician.  Was
there any independent evaluation of when the difference between
irritation and allergy took place?  I mean is he the only person
evaluating everything?

		DR. LICCIONE: Yes.

		DR. FISHER: So he's running the study, hypothesized what the results
were going to be, what's involved in selecting the doses, and is also
the only person who is measuring the responses and making distinctions
between irritation and allergen and also deciding whether or not
somebody should withdraw from the study; all him?

		DR. LICCIONE: That's my understanding.  He is the principal
investigator and the diagnoses.

		DR. SHARP: Thank you, Dr. Liccione.  A few questions.

		I have the dubious distinction of being the primary responder here.

		Just to follow up on what Dr. Fisher said, because that kind of
surprised me.  You are referring to Dr. Fowler as the principal
investigator.  I thought he was the clinical actor in this, but I
thought this study was run by Exponent (phonetic).

		DR. LICCIONE: The study - yeah, was managed by and run by Exponent,
but they also defined him as a principal investigator.  It's just
clearly spelled out as principal investigator.

		DR. SHARP: That's not the title.

		DR. LICCIONE: It doesn't say it on the front page, but if you look at
the back pages there are statements about the role.

		VOICE: 119.

		DR. SHARP: I assume that Exponent wrote the protocol then.

		DR. LICCIONE: Yes, that's what I assume too.  But they actually
conducted, did the study.  They didn't - Fowler did do the recruiting.

		DR. SHARP: No, I guess my point is, that as a research study, it's my
impression that Dr. Fowler is an experienced clinician, but he's not -
well, he may be a well published researcher as well, I don't know.  Is
he?

		DR. LICCIONE: Yes.  Very well -

		DR. SHARP: So you consider that he designed this study, not Exponent;
they just assisted him?

		DR. LICCIONE: No, I think Exponent may have done the design of the
study from what my understanding of Exponent's role.  But he did have
some capacity as a principal investigator, which means he had some input
into the design of the study.

		DR. SHARP: Okay, thank you.

		You made a statement a little while ago, which I just wanted to double
check on.  You stated that the control group was not treated with Copper
Shield?

		DR. LICCIONE: No, they were.  It was with a copper solution.  Because
the ACC also contains a copper, so they weren't exposed to chromium -

		DR. SHARP: Pardon me?

		DR. LICCIONE: They were exposed to copper chloride.

		DR. SHARP: No, Copper Shield is the formulation that includes chromium
and copper.

		DR. LICCIONE: right.

		DR. SHARP: They were exposed to it; correct?

		DR. LICCIONE: Not to Copper Shield.

		DR. SHARP: Well, you might want to double check that, because they are
listed in the table of results as having been treated with all the doses
of Copper Shield.

		DR. LICCIONE: Right, right.  There was also I think some there, like a
vehicle control, copper -

		DR. SHARP: Well, there was a zero.

		DR. LICCIONE: Zero, that's right.

		DR. SHARP: Everyone got the zero, but the controls got all the doses.

		DR. LICCIONE: Right.  I'm going to say it as the vehicle controls.

		DR. SHARP: Yes, I agree.  There was - I realize what you are saying
now.  Okay.

		Do you know of what the - the dose, or the loads, as they correctly
state in the study, of chromium six during the rote studies are very
well defined and nicely documented, do you know what the chromium load
was on the skin during the patch test?

		DR. LICCIONE: All he said was, in the confirmatory patch test -

		DR. SHARP: The initial patch test, yeah.

		DR. LICCIONE: The confirmatory patch test, all they said was, they
didn't give them much detail, they just said point two five percent
potassium dichromate was actually used.  And we're assuming, because
they used Finn chambers, at most 10 - 20 microliters, but they didn't
come out and say that.  But I don't think that's that important an
issue.  That part was just to verify sensitivity.

		DR. SHARP: Well, it's just a question, I'm trying to understand this.
Do we know what the load on the skin was during the patch testing?  We
don't, is that the case?

		DR. LICCIONE: Not exactly.  They didn't say the exact volume.  They
just said point two five percent.

		DR. PHILPOTT: If I may interrupt, Richard, this is Sean Philpott, we
know from the Nethercutt study, and reviewing the literature for that,
that it's considerably higher, it's about twofold higher than the
highest dose that they are using.  It's 4.4 migs per square centimeter.

		DR. LICCIONE: Not migs, micrograms.  But note that Nethercutt used a
little bit of a different thing.  He used the true test patches with the
gel.  This study they used the Finn chambers, so roughly maybe 10
microliters, 20 microliter capacity, they just didn't spell that out,
but the purpose of that was just to confirm sensitivity.

		The most concern that we had with loading of course comes in the main
study, the ROAT study.

		DR. SHARP: But I'm asking about the patch test.  And so what I'm
gathering from Dr. Philpott's comment is that the patch test load was
higher than any of the ROATs.

		DR. LICCIONE: But not only that, it's included so it's kept on.  So
all those other factors -

		DR. SHARP: Okay.  And then in reference to the NACDG database, do you
know if the same load was used for all the patch testing in that
database?

		DR. LICCIONE: I don't know.  They didn't give details.

		DR. SHARP: Did you explore that at all?

		DR. LICCIONE: No.

		DR. SHARP: Do you have the database?

		DR. LICCIONE: No.  I think it - I'm not sure how accessible it is.  We
haven't looked into that.  We wanted to see comments from the board on
the normalization.

		DR. SHARP: We don't know how many cases are in the database?

		DR. LICCIONE: Oh, yes we do, we know there is a total of - for those
years there were 495 individuals.

		Now how they exactly patched, all we do know, one of the important
things that was clear is that they used the same criteria.

		But we don't suspect that it would make that big of a difference,
because once again as Nerthercutt showed, it's mass per unit area.

		DR. SHARP: Well, that's what I was asking about, did they use the same
load?  Did they use the same mass per unit area consistently across all
the NACDG members?  I know they all used the same chamber, and they used
a certain SOP, but I wasn't sure about that load which was my question.

		DR. LICCIONE: Right.  I don't know, and in fact, I'm not even sure if
it changed over time, when they changed procedure.

		DR. SHARP: You don't know that one?  Okay.

		The - I have just a couple of more questions, honest - Dr. Fitzpatrick
raised the issue of the gender discrepancy between the treatment or
sensitized and control groups.  I guess all of us are kind of surprised
that when you have the ability to select a control group, and you have a
mixture of males and females, I don't know of any investigator who would
then purposely choose all females, all of one gender, for a study of
this kind.

		Do you have any explanation for that?

		DR. LICCIONE: They don't offer any explanation.  I wonder too why the
total population ultimately ended up in just 10 controls that were
female.  I guess sometimes in these studies it's hard to find
recruitment.  But I don't know why they ended up.  At least Nethercutt
has looked at sex of dermal sensitization with chromium, doesn't find a
gender difference.

		DR. SHARP: Well, I don't know, this is just an observation that I made
which I haven't quite digested yet, but that's what we're here for to
try to figure this out, the one plus responders in this study were 30
percent male and 70 percent female.  So a lot of the females were - 23
out of the 33 females were one plus, and 13 of them were two and three,
where there were more males.  I don't know quite what to make of that.

		DR. LICCIONE: That's because of the population that's available rather
than how much was actually -

		DR. SHARP: No, I'm just saying proportionally there were more females
in the lower - this is for the patch testing with the potassium
dichromate prior to the ROAT study, if you look at the percent or the
proportion of the one plus response, it's 30 percent male and 70 percent
female.  If you look at the proportion of those who responded at either
two plus or three plus, it's essentially 50-50, 50 percent male - 52
percent male, 48 percent female.

		And so - and then you have a control group that is all female.  So I'm
trying to figure out from a study design point of view what the
implications of that might be.

		Did your group discuss that at all?

		DR. LICCIONE: Well, we, in looking at Nethercutt and others that
address gender issues, and we don't think that there is a gender issue.

		DR. SHARP: Well, there appears to be from this data.  That's what I'm
pointing out.  Maybe we will hear more from that later.

		DR. CHADWICK: Can I follow up on that question?  This is Gary
Chadwick.  Do we know if the controls were all part of the dermatology
associates lab?

		DR. LICCIONE: Yes, they were.

		DR. CHADWICK: So all the controls were employees of Dr. Fowler?

		DR. LICCIONE: Yes.

		DR. FISHER: Employees were patients?

		DR. LICCIONE: They were 10 employees; one was a former employee, and
another was a doctor.  But most of them were employees, though.

		DR. FISHER: Dr. Sharp, were you finished, or do you have another
question?

		DR. SHARP: I do have one more question.

		Was the - in this subjects or the participants in the study were
blinded to the dosing levels at the particular skin areas which is
important in terms of something like, say, itching; but the evaluator -
most of the evaluation was done by visual observation of Dr. Fowler - he
was not blinded to -

		DR. LICCIONE: That's correct.

		DR. SHARP:  - he knew who all the controls were, of course, since they
worked for him.

		DR. LICCIONE: That's true.

		DR. SHARP: And he knew who all the patients were, because they're his
patients.  And he also knew where the high dose was, where the medium
dose was, where the zero dose was.

		I mean this is perhaps just the nature of the study, but did you
discuss that in your group?

		DR. LICCIONE: Yes, we wondered - I looked everywhere to see if there
was a double-blind blinded study, that it in fact was double-blinded.
But we couldn't find any evidence that it was double blinded.  So we
assume it wasn't double blinded.

		But when you typically see studies done like this, you oftentimes
don't find studies that are double blinded in these dermatology type
studies.

		DR. SHARP: Okay.

		DR. LICCIONE: It would have been a great strength if it was included
as a double blind.  It would have been nice.

		DR. SHARP: And the one other thing that I noticed, and I wanted to get
whether you all discussed this or not, is if you look at the irritant
response data, you find that for Copper Shield, 13 out of the 60
sensitized individuals had an irritant - were classified as having an
irritant rather than an allergic response; but zero out of the 10
controls.

		DR. LICCIONE: Okay, I just wanted to clarify, the 13 out of the - that
doesn't mean they didn't have ACD at higher doses.

		DR. SHARP: They may have had -

		DR. LICCIONE: Only five individuals did not have - only five
individuals had only truly only  irritantcy.

		DR. SHARP: So there were 13 people who had - who were discussed in the
section of the report that discusses the irritant response.

		DR. LICCIONE: That's correct.

		DR. SHARP: They go through and discuss each person.  Now I'm not
saying they didn't.  Some of them, yes, may have had allergic response
as well.  But I'm just saying that there were 13 of the participants out
of the sensitized group where it was determined that what was being seen
on the skin was irritation rather than allergic response.

		But out of the control group there were no irritant events whatsoever.
 Does that strike you as unusual?

		DR. LICCIONE: I don't have an obvious explanation for why the controls
didn't show the irritantcy response.

		DR. SHARP: Because if it really is just an irritantcy response, are
sensitized groups more susceptible to irritant response?

		DR. LICCIONE: Apparently in this case that may have been the result.
When you see other studies you tend to see irritantcy in the controls as
well.

		DR. SHARP: Okay, thanks.

		DR. FISHER: Were you following up, Sean?

		DR. PHILPOTT: Yeah, I was going to follow up.  There was a question I
was going to ask, which is that if you actually ignore in the irritantcy
tables, if you ignore itching which is obviously very, very subjective,
but you look solely at other physical signs, what I find particularly
interesting is that many people who had ACD also exhibited irritantcy at
the next lower dose, and often very late in the study, suggesting as Dr.
Lehman-McKeeman has pointed out that it may be irritantcy, it may not.

		And I think it was Suzanne who pointed out that irritantcy, can lead
to immunologic changes that could drive you one way or the other.

		DR. LICCIONE: And I think that's why they went ahead and modeled that
response concluding both with that assumption.  Because when you
followed it out, it was interesting, because always when an individual
had both ACD and the irritantcy, it was always the irritantcy coming at
a lower dose.  And a lot of them when you tracked it, it was like, well,
it becomes difficult, but especially at the plus one grade, to say is
this truly irritantcy or is it truly - I actually looked at some of the
pictures, and it's sometimes difficult to tell.  And it's a problem that
all dermatologists face when they do these kind of studies.

		DR. FISHER: Dr. Sharp, and then Dr. Philpott.

		DR. SHARP: Just a few shorter clarificational questions.  I wanted to
come back to this issue of whether the controls were actually exposed to
chromium.  You really need to know that answer, actually, because that
is a very basic issue.

		DR. LICCIONE: Yes, everyone was exposed to the Copper Shield, but the
vehicle control was like a copper vehicle control.

		DR. SHARP: My reading of protocol was similar to Richard's as well.

		DR. LICCIONE: I was confusing to what he was referring to as controls.
 Because he mentioned copper, and I thought he was talking about the
vehicle.

		DR. SHARP: At the amount, and given the extent of the duration of
their exposure, would that level of exposure to chromium be associated
with a potential to become sensitized to chromium?

		DR. LICCIONE: Oh, whether - okay.  As I mentioned earlier, the dulse
usually - well, at the higher dulses there is always that possibility.
The  dulse for the sensitization is considered to be much higher than
for elicitation.  But here there were some high end exposures that you
are referring to, the 2,500.  Your question is, could an individual
conceivably - like for example the controls.  That is a good question.
I can't answer that offhand.

		DR. SHARP: A related question to that.  Are there other examples of
exposures, something like beryllium, where patch testing itself had been
associated with sensitization responses.  That indicates that with
regard to the patch test that was done here that that exposure to
chromium could actually have caused sensitization.

		DR. LICCIONE: No, these were already known to be chromium sensitized.

		DR. SHARP: Again, I'm thinking specifically of the controls.

		DR. LICCIONE: Oh, of the controls.

		DR. SHARP: Could the patch testing itself at that level have actually
been a potential cause of sensitization in the controls?

		DR. LICCIONE: Nethercutt mentions - refers to that.  And other
dermatologists have pointed out that possible risk.  And that presumably
is theoretical possible in a high dulse.  And at the two five, whether
that happened or not, they just didn't follow up.

		DR. SHARP: So and then related to this, not knowing much -

		DR. FISHER: Could you bring that mike a little closer?

		DR. SHARP: Sorry.  Also fighting something coming from Houston to D.C.

		DR. FISHER: Oh, sorry.

		DR. SHARP: Related to this last question on this front is that not
knowing anything about this population, for people who are chromium
sensitized, are they at increased risk fo developing any other T-cell
mediated diseases or anything of that sort?

		DR. LICCIONE: Okay, not necessarily.  If you are sensitized to a
certain agent, does that suppose you could be sensitized to another
agent, you are saying?

		DR. SHARP: I'm wondering in general if people who are chromium
sensitized, are they at increased risk of developing any other type of
immunological -

		DR. LICCIONE: Not that the literature has borne out, that anyone has -
like poison ivy incident that I had doesn't mean I'm going to be
predisposed.  It means that I reacted to the allergen, that specific
allergen, in a certain way that my immune system is going to respond
particularly to that.

		DR. FISHER: Dr. Philpott.

		DR. PHILPOTT: I'm hopefully the last question, I guess.  And actually
it's more just returning to what Dr. Lebowitz raised, which is a
question that was of concern to me, which is about the duration of time
between the patch test and the conduct of the ROAT studies.

		It was my reading of the protocol actually that there was at least
apparently a two-week period, based on the time frame that they were
proposing their tentative schedule had patch testing in August with the
first round of ROAT the following month, and then two subsequent rounds
in later months as well, which would suggest that there was sufficient
time between patch testing and ROAT to allow the immune response to
decay.  The difference between the visit and the day numbers relates to
the fact that dermatologists work Monday through Friday.  So one was
Monday -

		DR. LICCIONE: Yeah, that was confusing.

		DR. PHILPOTT: But that would be day eight.

		DR. LICCIONE: That was confusing.  Well, that's good to know.

		DR. FISHER: Kannan.

		DR. KRISHNAN: Just wanted to see whether any effort was made to pull
the new data with the historical data before doing a normalization.  I
didn't see any effort of that.

		DR. LICCIONE: The effort on the part of the study authors?

		DR. KRISHNAN: As they do the normalization, has been done based just
on the - for example, the three plus grade occurrence in the historical
data only.   But was there any effort to pull the newer data with that
historical data?

		DR. LICCIONE: Older data?

		DR. KRISHNAN: And then attempt normalization.

		DR. LICCIONE: Well, the normalization they clearly see was for that
time period, 1998 to 2002.  More recent, over time some of those
individuals would lose sensitivity or change; others would be included.

		So that was the most recent data, historical control data that is
available.  Because historical control can change over time.

		DR. KRISHNAN: The one from the present said it wasn't pulled before
attempting a normalization.  That could change your proportion of
people, responders and so on.

		DR. LICCIONE: No, they did pool it, they were just trying to do a
proportionate analysis saying, okay.

		DR. KRISHNAN: By keeping them separate?

		DR. LICCIONE: Okay, I didn't understand what you were asking.

		DR. KRISHNAN: That's what I wanted to make sure.

		DR. LICCIONE: Okay, yes, that is correct.

		DR. KRISHNAN: In terms of blending, it seems to me that it was someone
other than Dr. Fowler who applied the solutions essentially.

		DR. LICCIONE: Right, the conduct of the study.

		DR. KRISHNAN: But it was the same location in all the patients, so
that wasn't randomized or anything.

		DR. LICCIONE: That was carefully done with markings to minimize any of
that kind of variability.

		DR. FISHER: Yes, I had a comment and a question.  One question is,
when was the last subject run in this study?  Because I know there is
some confusion about IRB approving something in August, 2006.

		When was the last subject run?

		DR. LICCIONE: I know - I'm not sure what you mean by run.  There were
three rounds.

		DR. FISHER: I guess my question is, was it after April, 2006?

		VOICE: I'll speak about that when I talk about the applicable
standard.  But when the last subject was run is not relevant to the
applicability of the standards.

		DR. FISHER: Okay, I see.

		VOICE: It's when the first subject was enrolled that we use as the
definition of initiation.  So that determines what the standards are.

		But I'll go over that in a little more detail in my presentation.

		DR. FISHER: Thank you.

		My only comment is thank you so much for all this effort.

		DR. LICCIONE: Oh, thank you.  These are very good questions you raise
that help us.

		DR. FISHER: But I do have a recommendation for next meeting.  And that
recommendation would be that in your presentation you cited no
weaknesses.  But you obviously say weaknesses with respect to a single
gender control; the fact that the study wasn't blinded.

		DR. LICCIONE: We just didn't know how significant they were.

		DR. FISHER: No, no -

		(CD Change)

		MR. CARLEY: - the longest citation that we have used in any - on any
of the studies that we brought to you.  And doing it once was long;
doing it three times would have made it utterly illegible.

		So the second and third submission are just cited by MRID on this
slide.

		The summary here is about what we have to deal with; it's not really
about the study itself, which John Liccione just summarized very well.
The original submission, 46884001, is the primary report of the
scientific results of the red study for chrome -6 as Copper Shield, as
ACC, as the wood preservative.

		This one came in in mid-July just a couple of weeks after your last
meeting, and we did a check on it for completeness, and discovered that
most of the materials required by the rule of Section 1303 were not
present, so we notified the registrants and they submitted the second
volume, 46922901, and then later in the summer questions arose about the
fact that they had described a study in which there were concurrent
application of two materials to the two arms of the same subjects, and
we had only half the results so we went back and we asked them for the
other results, to which they appended a duplicate copy of the material
about the ethical conduct with an identical in all respect except a
couple of page numbers.  So that's what we had to start with.

		And this is interesting.  This is a transitional artifact having to do
with the effective date of the rule.  The point that Dr. Fisher was
alluding to with her question earlier.

		This study was initiated before the effective date of the rule, last
April.  In fact it was initiated in mid-2005 when they enrolled the
first subject.  Therefore it was not subject to the requirement for
prior review of the protocol under 261125.  But the submission occurred
after the effective date of the rule, and the submission therefor was
subject to the requirement to document ethical conduct that's contained
in 261303.

		In terms of the scope of those requirements they're almost identical.
1303 requires one additional thing which is the actual consent materials
that were used but without the names of any of the subjects.  But the
scope that it would have come in with the protocol is the scope that was
required at the time of the court submission by 1303.

		This is one of rather few studies that you are ever going to see that
look like this, that were initiated shortly before the rule; submitted
after; and therefore have this big slug of documentation ex post.

		But we have to consider this as a completed study, as an old study if
you will in terms of its ethical acceptance criteria.  It's subject to
the criteria at 261704 for prerule studies reviewed as completed
studies.

		I mentioned that we did a completeness check when we got the first
submission.  It didn't address most of the requirements of 261303.  We
reported the deficiencies to the registrant in mid-August, and they then
resubmitted the supplement in late August, and the additional material
concerning the results of the sodium dichromate study in early December.

		Because this is a completed study, and because it is one subject to
the 1704 criteria for acceptance, I have used the same review framework
that I used for the other completed study subject to the same criteria
that we've discussed at earlier meetings.

		So this is the summary presentation of the manual framework with the
familiar seven topics beginning with value to society.

		This study is designed to determine the allergic response or the
threshold of allergic response of chrome-sensitized subjects after
repeated open applications of Copper Shield and potassium dichromate.

		Let me just mention that in my view the ethics of this needs to
consider both the Copper Shield and the copper dichromate as part of a
single study.  I didn't make the distinction that John Liccione did
between the ACC data and the copper dichromate data.

		The intent is to support more accurate assessment of exposure and risk
from chrome six when that exposure results from the use of ACC as a wood
preservative.  And in the case of the potassium dichromate from
contaminated soil, it was funded by Porous Products Research Laboratory,
which is the registrant of Copper Shield.

		I defer to John's excellent review on the questions of scientific
validity.

		Subject selection is very interesting.  All of the subjects had some
prior relationship with Dr. Fowler.  Most of them were his former
patients, and that raises some concerns; not necessarily disqualifying
concerns, but it means that special care needs to be taken to ensure
that the subjects understand that they are not in a doctor-patient
relationship; they're in an investigator-subject relationship.

		And so generally speaking that was handled pretty well.  Although all
of the subjects were former patients of Dr. Fowler and had been
identified, the pool fo candidates was identified from an analysis of
his patient records, all of the recruiting was handled for example not
by employees of Dr. Fowler's office, but by employees of the contractor
Exponent who did the work.

		And they clarified the changing role of Dr. Fowler with respect to
each subject, and I thought that was handled reasonably well.

		DR. FISHER: John, can I just break in for a minute and ask with
respect to HIPPA laws, how did he get the names of who his patients were
to the recruiters?

		MR. CARLEY: I don't think that was reported.  If it was, I don't
recall seeing it.

		DR. FISHER: It says that initially a research assistant contacted
these people to see if they wanted to participate.  Would that have been
someone in his office then?

		MR. CARLEY: The research assistant who contacted people was an
employee of Exponent.  Not an employee of Dr. Fowler.

		Okay, going back up, not done yet.  All of the control subject, as we
were discussing a few minutes ago, the untreated controls were employees
or near employees.  As Dr. Sharp pointed out, one was a former employee,
and another was a relative.

		And at the direction of the IRP all of those people signed a special
noncoercion statement in addition to the informed consent that all of
the other subjects signed that crossed their heart and said they weren't
being pressured to do this in any way.

		There was also a third component referred to in the protocol of April
2005.  That protocol was submitted to EPA for its review informally as
well as being submitted to the IRB.  And both in our comments on the
protocol and in the IRB's first round of comments on the protocol we
noticed that there was reference to a preliminary methods testing phase
using employees of Exponent, and there was no discussion in that
discussion of any IRB oversight or informed consent.

		The - to the best of my knowledge there has been no response to EPA's
comments on this subject.  The response to the IRB was, oh don't worry
about that; that's not part of the protocol that we're asking you to
review.  And the matter was dropped.

		Next subject is the risk-benefit thing which I've subdivided.  Several
specific steps, good steps, were taken to minimize the risk.  The total
dose for chrome six was kept to a level that was well under the RFD.
Only small areas of skin were treated.  Treatment was stopped at any
dose level that caused a response; but interestingly, only at that dose
level, and not necessarily at higher dose levels, something which I
don't fully understand.

		There was medical oversight throughout the process.

		The benefits that were characterized in the study: first, they
accurately stated that there were no direct benefits to the subjects.
They anticipated as one of the benefits an improved risk assessment.
And they asserted that the other benefit from the ACC aspect of the
study was potential wider use of ACC wood preservatives, and that this
was a societal benefit because the environmental consequences of the use
of ACC wood preservatives were more benign than the consequences of the
use of alternative wood preservatives.

		The ratio of risks to benefits was addressed in the report in this
quotation.  Given that the health risks to and response burden on the
study participants is minimized by the design of the studies, and that
volunteers are paid for their participation, the anticipated benefits to
society will outweigh the risk to study participants.

		Which brings up the question of compensation.  The - someone who
participated in all sessions and showed up for all of them would have
been paid $1,215, and I don't know exactly what to compare that to.
This was a nonresident study.  They went in; they got their daily dose;
and then half a day later they washed up and so forth.

		But my sense is that that compensation may have been high enough to
influence subjects' decisions to participate.

		There was -

		DR. FISHER: Do you know for the employees, do they get that on top of
being paid?

		MR. CARLEY: That was my understanding.  That was my interpretation of
what I read in the study.  I think the untreated controls were asked to
get hit on the arm with five drops of water in exchange for which they
got an extra $1,200.

		DR. FISHER: John, Richard just made a point.  I think we need to be
careful that the controls were treated; they're not untreated.  They're
treated -

		mR. CARLEY: Right, the unsensitized controls.  Sorry.

		DR. FISHER: Consistent with your point that those - whatever those two
things, the Copper Shield and the potassium dichromate both need to be
looked at.

		MR. CARLEY: Yes, my mistake, thank you.

		The study was reviewed by an independent ethics review board, Shulman
(phonetic) Associates of Cincinnati.  And the record submitted suggested
that the IRB did a pretty good job.  They reviewed; they conditionally
approved; they revised; they approved; and then they monitored the
study.

		The documentation of the IRB approvals is weak.  I say that because
what happened apparently is that the stamped, approved documents from
the IRB were retyped for inclusion in the study report, and in the
supplemental materials documenting ethical conduct.

		I went back and picked my way through the correspondence with the IRB
that was also provided in the supplement, and I satisfied myself that
the retyped consent materials and information for subjects in the study
report was indeed consistent with what - substantively consistent with
what the IRB approved.

		But I was troubled that they didn't follow the more common practice of
submitting stamped approved materials.  Compliance asserted with many
standards, including the common rule, the Declaration of Helsinki, the
Nuremberg Code, the recommendations of the NAS committee, the Belmont
report, and FDA's regulations.

		FDA's regulations were there because the IRB which apparently does
most of its work on the drug side, sent in reaction to the submittal
some model language that referred to appropriate regulations with a
request that the investigators adapt this appropriately to this
particular study.  That language was adopted, rather than adapted,
without any change and without making an adjustment.

		The intention was never to send this to FDA.  The intention was always
that this would be a study for EPA.  But they included whole paragraphs
without fixing it.

		On informed consent, all the subjects provided signed consent.  The
process is described in considerable detail, and the process by the way
is something on which EPA had commented at some length when we saw the
proposed protocol in April of 2005.

		The process was conducted by the Exponent staff, not the employees of
Dr. Fowler, who was of course known to the subjects as their
dermatologist, and whose staff they had worked with before.

		And I note in my review that the process showed some confusion about
what constitutes consent and when it was obtained.

		And specifically they talk about individuals who while they verbally
agree to participate, end quote, identified in the course of the very
telephone conduct, after a very brief discussion of unscripted, quote,
information regarding study objectives and protocol and the potential
hazards of thermal testing with chromate compounds, end quote.

		I repeat, that conversation if it was scripted, we don't have the
script.  This agreement, i.e. verbally agree to participate, is
subsequently characterized, as quote, verbally agreeing to potentially
participate, end quote.

		Then in their first office visit, potential participants as they were
called then are informed in more detail, and have an opportunity to ask
more questions.  And then participants, end quote, are given a copy of
the informed consent form to consider as they decide whether they want
to participate.

		And then they sign the primary consent form and supplemental forms as
appropriate.

		I found no evidence that there were any study-related procedures other
than the administration of questionnaires that were conducted before
obtaining a proper written consent to the full IC material.

		But the description I found both confusing and troubling because of
this ambiguity about what the status of people was, when they had been
contacted but not yet informed beyond the barest minimum.

		I don't - candidates would be a better term than participants, for
example.

		Subject privacy was maintained.  Subjects were free to withdraw.
However, if they withdrew they were entitled for payment for all of the
days they had done, but no payments were made until the end of the
study, and the reason offered was to ensure regular attendance and
completion of the study, which is clearly an attempt to bound the
freedom of the subjects to withdraw.

		In terms of prevailing standards, this was conducted in the U.S. in
2005, a reporting phase until 2006.  Plainly the common rule in FIFRA
12A2P are appropriate standards, and as I mentioned before 40 CFR 261303
requires at the time of submission documentation of the ethical conduct
of the study.

		I want to mention at this point two errors in my review of September
12th on page five.  The citation in the first paragraph of that review
should be to 261704 rather than 1705 as the standard for approval.  The
quotation is correct, but the citation is wrong.  The passage I quoted
is 1704 but I called it 1705.

		And then I also quote text from 1703, which does not reflect the
amended language that took effect on August 22nd, which adds nursing
women to the list of specially vulnerable groups, data concerning which
we can't rely on.

		Neither of those errors or the corrections has any effect on the
substance of the review.

		I noticed in general that compliance with the requirements of the
common rule was pretty good.  But while this is a noteworthy potential
ethical deficiency, we don't have evidence to resolve it, but the
preliminary testing does not appear to have involved IRB oversight.  It
may not have involved informed consent.  In any event it was described
as something involving employees of the organization.

		And so the issues of oversight and consent would have been subtle.
And that may be a problem, but it is one for which we don't have much or
any real evidence.

		So in summary, there are some gaps in the documentation of the ethical
conduct.  I would characterize them as minor gaps.  Certainly we have
far more information about the ethical conduct of this study than we do
about the conduct of some of the earlier studies that you have reviewed.
 And gaps themselves don't amount to clear and convincing evidence which
you need according to the regulatory standard.

		I found no evidence that the research was fundamentally unethical;
261703 does not prohibit us to rely on it; all of the subjects were at
least 18; and those potential subjects who were pregnant, trying to get
pregnant or nursing were excluded.  And there is as I mentioned a
possible deficiency in the preliminary study but in my judgment this
didn't rise to the level of clear and convincing evidence that the
conduct was significantly deficient, relative to prevailing ethical
standards.

		Which brings us to the charged questions which are the usual ones for
studies considered under the standard of 261704.

		Is there clear and convincing evidence that this study was
fundamentally unethical or that it was significantly deficient relative
to the ethical standards prevailing at the time?

		Thank you.

		DR. FISHER: Thank you, John.

		Are there any questions?  Dr. Fitzpatrick, then Jerry then - Michael,
did you raise your hand?  No, okay.

		DR. FITZPATRICK: Just a quick question.  Does it bother you that the
IRB stamp doesn't have an expiration date on it?

		MR. CARLEY: Didn't notice it.

		Something else that - no, no, no, I'm getting confused, there is a
different IRB.

		DR. FITZPATRICK: The stamp - well both of those studies, the stamp
only has the approval date but doesn't have the expiration date on it.
And you are assuming they approved it for a year but you don't really
know.

		MR. CARLEY: I didn't notice it, but I did notice that they were on top
of the periodic reporting thing, and everything was done finely.  In the
event looking at this ex post, I don't think there was any substantive
problem resulting from that.  They plainly stayed in touch and continued
to monitor the conduct of the study.

		DR. FISHER: Jerry?

		DR. MENIKOFF: I have a general question about benefits, and in
particular, the value of research to society.  And this may be partly
due to the strange status of the study, being that it is sort of a
pre-existing study.

		But in your review of this study, and you have actually said a little
more in your discussion, you note that they are trying to find out more
details about this compound and the risks.  But in the other  studies
we're dealing with later today you more explicitly, for example in the
insect repellent studies, you go into more discussion of alternative
products, and the possible benefit to society for having this as an
alternative product.

		In this study you said less about that.  And I guess I'm just, in
terms of educating myself, was that partly due to the procedural status
of this study, or more generally in terms of EPA's evaluation of the
benefits and looking at this benefit, the consequences of the study.

		Do you more routinely, for example, look at this compound - and this
is getting partly at the comment that one of the public commentators
will make - do you look at the issues relating to what other compounds
do people use to serve the same purpose and factor that into the benefit
analysis or the value to society analysis?

		Is that clear enough?

		MR. CARLEY: Well, I'll try to respond to the two or three separate
questions that I thought you asked, and if I don't hit the mark I'll try
again.

		What I think you were getting at with your use of the procedural thing
is the distinction between review of completed studies and review of
protocols.

		In the case of this study the question of whether it should have been
conducted is the only relevant one, that we are faced with the
existential phenomenon; it was conducted; it is before us.

		So in that sense I didn't spend a lot of time on scratching my head,
would I have recommended doing it differently if I had reviewed this
before the fact.

		In fact I did see it before the fact, and recommended quite a few
changes.  But I didn't spend a lot of time on that.

		DR. MENIKOFF: Let me just - I guess my main point is in terms of the
value of the research to society, it seems like at least in this case
you said less in terms of, we're trying to get a more accurate judgment
of the risks that this compound causes, and not get back to the broader
issue of, there are other compounds out there, the issue has been
raised, and we'll see shortly, that other compounds are just a lot less
risky, to what extent does the existence of riskier compounds out there
that our society uses to achieve the same purpose, do you view that in
general as always a part of your analysis of value of research to
society?

		MR. CARLEY: In general I think the answer is now.  Bill, step in and
help me with this if you like, but give me a chance to screw up first.

		There is a provision in FIFRA that talks about criteria for
registration, and basically say that essentiality cannot be made a
requirement.  So we are as an organization in the habit of looking at
the case pretty much in itself.

		In the case of looking at particular studies or study proposals, there
are practical limitations on the extent of the comparison.  When we look
at the questions that we developed for protocols including some of the
questions that you all specifically recommended at your last meeting,
some of these questions will come up, the basic idea being what's the
hole in the fabric that will be filled if this study goes forward?  How
will it fit into context?

		And that's I think the generic form of the question you're asking.
But I think probably at least up until this point we have not thought in
terms of considering alternative pesticides to this one as a directly
relevant factor in assessing a particular study.

		DR. MENIKOFF: Partly I guess it was just in terms of consistency with,
when we get for example to the insect repellents, it was specifically
raised that the public, there's a hole out there, and this product will
fill that need.  It sounds like you're basically telling me that in
general your jurisdiction, under your rules you're allowed to do, is
similar to the FDA in that once for example - but the FDA analogy is
that the FDA doesn't figure out whether this is a particularly good
drug, but rather that it's safe and effective, and then it's up to the
public to decide whether or not it wants to buy it.

		MR. CARLEY: That's a rough analogy.  It's a pretty good one.  And I
think it's extremely important, although you kind of rode over it, to
make the distinction between discussions that occur before the study has
been conducted, and the kind of discussion we are in now about this
study which is after it is done.

		MR. JORDAN: This is Bill Jordan.  If I could add a couple of words.  I
want to underscore the last point that John made.

		It seems to me that the inquiry for studies that were initiated and
completed and were not subject to the prior protocol reviews presents a
different situation from ones where we're looking at the protocol and
trying to decide whether or not among other things it's ethical to go
forward with this study, the benefits of the information to be gained by
the study will contribute enough to justify the risks that the subjects
will encounter.

		So John's choice not to dwell particularly on the justification value
of the information to - in how that sorted out, and would you do the
study if you were looking at it afresh seems to me to make a lot of
sense.

		When we get to protocols, we do actually have that choice in front of
us as an agency, and you as a board will have an opportunity to advise
on that.  But it seems to me that the question of how to weigh the risks
and benefits, the benefits of the information against the risks to the
subjects, when you move beyond simply the value of the information is
going to get tricky.  Pesticides have all sorts of risks.  They have
affects on people who may be handling them; they may be residues in
food; they may also affect wildlife; they may also have benefits
compared to other products.

		So trying to figure out whether approving the registration of a new
product based on the results of a human study is an overall benefit for
society is a dicey subject, and it's hard to make those comparisons
particularly at the early developmental stages where people are just
beginning to start the human studies and we may not have a full
understanding of the picture of effects on wildlife, or how effective it
is compared to another product and so on and so forth.

		So I think we'll all have to feel our way forward as we look at
protocols in this area, and trying to sort through this one in
particular will be one of the harder challenges.

		DR. FISHER: Ken?

		DR. KRISHNAN: The Copper Shield in itself is presented as an
alternative to the wood preservatives currently in use, based on the
lowest copper content among the preservatives.  So I don't know if that
helps or addresses any of your concerns, Jay.  Copper being hazardous to
some of the environmental components like the fish and other wildlife,
so there is an interest in having preservatives that lower copper
content.  That is more of a justification that's -

		mR. CARLEY: Let me add a point about that.  The benefits that were -
that the IRB and that we would have considered had this come to us
before the fact have to do with the benefits of the information expected
to be gained from the research, and this comparative copper load in the
environment as a consequence of a speculative significant change in the
usage patterns, the quantitative usage patterns of different wood
preservatives, is getting pretty far downstream.

		Using the specifics of this case, I would be inclined to give very,
very little weight to that argument that a major growth in the sponsor's
sales would represent some increment of environmental improvement and a
social benefit that should be attributed to the conduct of this study.

		I think that is far fetched, whatever the superlative form of that
adjective is.

		DR. FISHER: John, I had some comments and then some questions.

		One is, I think we had mentioned, and it should be underscored, at a
previous meeting, that compensation can't be included as a benefit.

		So I would like - it's probably good for you to note that as your
review goes on.  But I want to affirm that again, because we have said
that.  And this is a previous protocol obviously, but this for future
protocols that can't be done.

		MR. CARLEY: I call your particular attention to the quotation marks at
the beginning and end of the text in the bullet under risk-benefit
ratios.

		DR. FISHER: Exactly.

		My second comment is in some sense a little bit of a follow up with
respect to also including in benefits, right, that the ACC may then be
used in other - one of the benefits was that it could be used in other
products?  If you go back to -

		mR. CARLEY: Not so much in other products, but just at higher levels.
I don't mean higher concentrations; I mean more broadly, more widely.

		The argument is - quotation marks, or whatever paraphrase marks look
like - the argument is that this study would justify approval of this
product for uses which if they grew to sufficient prevalence would
result in a decrement in the environmental load from the use of wood
preservatives in America or something.

		DR. FISHER: I'm interested in its use in the informed consent.  And
given these are employees, to say that there is going to be greater use
of a product produced by a company in some sense has a certain amount of
meaning within an informed consent that could in some sense whether
they're signing a coercion note or not, be saying that this is an
important study for the company; you need to be involved in.  So it's
just something to think about.

		MR. CARLEY: Remember that there are a few arms lengths involved.  The
employees of Dr. Fowler were fairly far removed from it as far as the
products research laboratory, and from Exponent, who was the contractor
that brokered the study.

		They wouldn't be - I don't see an issue there.

		DR. FISHER: All right, great.

		Then I just want you to - if we look at the risk they describe in the
informed consent, so - and who knows which document this is.  It looks
like it's on page 179.

		But it says the study is being performed to determine whether you have
a response such as redness, itching or swelling at the site of
application of any of the test materials.

		The it says, you might develop a rash on your back, and then it says,
if a topical steroid is provided, the study doctor will discuss the
risks of the medication with you.

		Now given that it would be anticipated that some people are going to
experience this, I'm wondering, then that becomes a risk of
participation in the research if in fact you are going to get these
topical steroids, no?

		VOICE: Well, if I can answer that, one of the questions that I had
was, were the individuals that did develop ACD, were they provided a
topical steroid.  It was unclear.  And use of a topical steroid was an
exclusion criteria.  So I was interpreting it as they weren't treated.
But it was unclear.

		And I was hoping that you guys may have more insight to that.  At this
point I would assume that the topical steroid is treatment post
withdrawal from the study.

		DR. LICCIONE: That is correct.

		VOICE: That you've gotten your reaction, you've taken your
measurement, and you still have skin sloughing off, and we probably
ought to do something about that.

		DR. FISHER: Right.  But I guess my question is, whether or not if in
fact risks are associated with the treatment you are going to get, if
there is an experimental reaction that needs treatment, is it
appropriate to say, we'll let you know what the risks are of that
treatment if it happens to you but not part of being informed of the
risks that potentially could happen to you as a legitimate potential
risk of being in the study.  I guess that's my question?

		DR. PHILPOTT:  Excuse me, I'd say that the answer is no, because at
that point you are moving off of research into clinical care, and