**DEPARTMENT OF HEALTH AND HUMAN SERVICES**

**and**

**FOOD AND DRUG ADMINISTRATION**

**NATIONAL CENTER FOR TOXICOLOGICAL RESEARCH**

**convene the**

**[Ranch Hand Advisory Committee Meeting]{.smallcaps}**

***Rockville, Maryland***

***January 21, 2004***

**[Certified Verbatim Transcript]{.smallcaps}**

**TABLE OF CONTENTS**

[Page]{.underline}

Opening Session 1

Approval of Previous Meeting Minutes 6

Program Management Update 14

RHAC Membership 15

Vietnam Veterans Health Studies at the National Academies 25

Air Force Health Study Update 41

Serum Dioxin and Four Biochemical Parameters of Adipose Tissue 41

Cancer Prevalence in Comparisons 70

Cancer in Air Force Veterans of the Vietnam War 89

TCDD and Prostate Cancer in U.S. Air Force Veterans of the Vietnam War
98

Adjustments for Ethnicity and Cut Points 109

Dioxin and Memory Loss 121

Dioxin and Syndrome X 131

Protocol Completion 135

Public Comment Period 139

RHAC Business 139

# Closing Session 154 

**LIST OF PARTICIPANTS**

**[RHAC Members]{.underline}**

Dr. Robert Harrison, Chair

Dr. Paul Camacho

Dr. Michael Gough

Dr. Sanford Leffingwell

Dr. Kwame Osei

Dr. Michael Stoto

Dr. Ronald Trewyn

**[FDA/NCTR Representatives]{.underline}**

Dr. Leonard Schechtman

RHAC Executive Secretary

Ms. Kimberly Campbell

Committee Management Specialist

**[U.S. Air Force Representatives]{.underline}**

Col. Karen Fox, M.D.

Lt. Margaret Montgomery

Dr. Joel Michalek

Lt. Col. Julie Robinson

**[U.S. Air Force Contractors]{.underline}**

Mr. Manuel Blancas

UDTech

Dr. William Grubbs

Science Applications International Corporation

Dr. Judson Miner

Operational Technologies Corporation

Mr. William Murray

ANSER

Mr. Maurice Owens

Science Applications International Corporation

Dr. Marian Pavuk

SpecPro, Inc.

Ms. Meagan Yeager

Science Applications International Corporation

**[Guests]{.underline}**

Dr. David Butler

National Academy of Sciences

Dr. Ezdihar Hassoun

University of Toledo

Dr. David Johnson

Florida Department of Health

Ms. Pat Phibbs

Bureau of National Affairs

Ms. Elizabeth Skillen

Agency for Toxic Substances and Disease Registry

**DEPARTMENT OF HEALTH AND HUMAN SERVICES**

**FOOD AND DRUG ADMINISTRATION**

**NATIONAL CENTER FOR TOXICOLOGICAL RESEARCH**

**[Ranch Hand Advisory Committee Meeting]{.smallcaps}**

***January 21, 2004***

***Rockville, Maryland***

**[Certified Verbatim Transcript]{.underline}**

**\[CONVENE 8:14 A.M.\]**

**R. HARRISON:** Good morning, everyone. I'm Bob Harrison. Welcome to
the meeting of the Ranch Hand Advisory Committee. As usual, we'll start
off with introductions. And first of all, we'll go around the table and
then we'll start over on that end and just go down each row just
zigzagging back and forth. And I guess first, Joel will be first. So
Joel, why don't you introduce yourself?

**J. MICHALEK:** Joel Michalek, Principal Investigator of the Air Force
Health Study.

**L. SCHECHTMAN:** Excuse me. If everyone at the table would please use
the microphones; simply push the talk button so that your red light
lights up and then we --- everybody in the room will be able to hear
you. Thank you.

**J. MICHALEK:** All right. I'm Joel Michalek, Principal Investigator of
the Ranch Hand Study or the Air Force Health Study.

**M. STOTO:** I'm Mike Stoto, a member of the Committee. I work at the
RAND Corporation.

**P. CAMACHO:** Paul --- I'm Paul Camacho, a member of the Committee.
I'm at UMS-Boston.

**L. SCHECHTMAN:** I'm Leonard Schechtman. I'm with FDA's National
Center for Toxicological Research, Associate Deputy Director of
Washington Operations and the Executive Secretary of the Ranch Hand
Advisory Committee.

**R. HARRISON:** I'm Robert Harrison. I'm Professor of Medicine
*Emeritus*, University of Rochester in Rochester, New York.

**M. GOUGH:** I'm Michael Gough. I'm a member of the Committee. I'm
retired from various places.

**S. LEFFINGWELL:** Sandy Leffingwell, physician, new kid on the block.

**N. RIVERA:** Use your mike, sir.

**S. LEFFINGWELL:** Sandy Leffingwell, a new kid on the block. I'm a
physician.

**J. ROBINSON:** I'm Julie Robinson. I'm the Branch Chief for the Air
Force Health Study.

**R. TREWYN:** Ron Trewyn, Kansas State University, a principal
troublemaker.

**K. OSEI:** Kwami Osei, Professor of Medicine, Director of Division of
Endocrinology at Ohio State --- Buckeyes.

**R. HARRISON:** Kwami, hit the button again and turn it off.

**L. SCHECHTMAN:** Okay. Just a little bit of housekeeping; there will
\...

**R. HARRISON:** Are we going to introduce the \...

**L. SCHECHTMAN:** Sorry?

**R. HARRISON:** Are we going to introduce the people in the audience?

**L. SCHECHTMAN:** Oh yes, let's finish the introductions.

**D. BUTLER:** My name is David Butler. I'm a Senior Program Officer in
the National Academy of Sciences, Institute of Medicine. I direct
environmental health studies, including studies related to the Air Force
Health Study.

**D. JOHNSON:** I'm Dave Johnson. I'm the Executive Medical Director for
the Division of Environmental Health at the Florida Department of
Health.

**R. HARRISON:** At what?

**D. JOHNSON:** Florida Department of Health.

**R. HARRISON:** Florida Department of Health. Thank you.

**K. FOX:** Colonel Karen Fox with the Air Force.

**J. MINER:** I'm Jay Miner, Operational Technologies contractor. I work
in Program Management for the Air Force. In my former life, I had
Colonel Robinson's job.

**E. HASSOUN:** Ezdihar Hassoun. I'm the Associate Professor of
Toxicology for the University of Toledo College of Pharmacy.

**M. PAVUK:** I'm Marian Pavuk; I'm with SpecPro. I work with Joel
Michalek on the Ranch Hand Study.

**R. HARRISON:** And we all know who you are.

**K. CAMPBELL:** I'm Kim Campbell. I'm the Management Specialist for the
Ranch Hand Advisory Committee.

**R. TREWYN:** That's who we make our complaints to.

**M. MONTGOMERY:** Lieutenant Margaret Montgomery. I'm the Operations
Manager for the Ranch Hand Study.

**M. BLANCAS:** Manny Blancas with UDTech. I'm a contractor working for
Program Management on the Ranch Hand Study.

**W. MURRAY:** Bill Murray. I'm with ANSER, representing the Air Force.

**E. SKILLEN:** I'm Elizabeth Skillen. I'm with HHS, home base ATSDR.

**R. HARRISON:** Let's go ahead to the rear --- right rear there.

**\[INAUDIBLE\]:** I'm a pharmacy student.

**\[INAUDIBLE\]:** I'm a pharmacy student.

**M. OWENS:** I'm Maurice Owens. I'm with Science Applications
International Corporation. I'm a Program Manager for the Ranch Hand
Study.

**W. GRUBBS:** I'm Bill Grubbs and I'm also with SAIC.

**M. YEAGER:** I'm Meghan Yeager. I'm also with SAIC.

**R. HARRISON:** Thank you very much.

**L. SCHECHTMAN:** Thank you all and welcome. A couple of things: we
have an attendance sheet, sign-up sheet for your --- to acknowledge your
presence that'll be --- that's being passed around the room. We would
like you to please fill out the information and sign that for us. Most
of you are used to seeing Barbara Jewell as part of these and every
meeting historically ever held relative to the Ranch Hand Group. Her
good fortune and our misfortune is that she has just retired and we will
surely and sorely miss her.

Replacing Barbara is our new Management Specialist who just introduced
herself; that\'s Kim Campbell. So you will see her name coming through
on lots and lots of e-mail messages that are both informative and are
designed to hound you so that you can get back to us the information
that we need from each and every one of you on a regular basis. So we
welcome Kim to this effort and we know that although no one could ever
fill Barbara Jewell\'s shoes, Kim will do us good service and she will
be an excellent, excellent replacement. Go ahead.

**R. HARRISON:** I'd like to make one suggestion, alteration to the
agenda. As some of you may have noticed in your e-mail, the National
Academy of Sciences has been asked to look into the --- certain issues
concerning the Ranch Hand Study. And Dr. Butler, who introduced himself
earlier, is here to discuss the status of that request and the status of
the National Academy of Sciences decision-making process. And I thought
that it would be better to put him before Joel begins his report. And if
it's agreeable to the Committee, we'll let Mr. Ogershok do the Program
Management update and then immediately after that, ask Dr. Butler to
give his presentation. Okay? So for right now then, Mr. Ogershok.

**M. STOTO:** Are we going to do the minutes?

**R. HARRISON:** What?

**M. STOTO:** Are we going to discuss the minutes?

**R. HARRISON:** Sorry. Hold on just a minute, Jay. Mike has caught me
in another procedural issue.

**J. MINER:** Mine is going to be really short.

**L. SCHECHTMAN:** Okay. Just to inform the Committee, the meeting
minutes of November of last year that were reviewed, edited and
ultimately have been approved by Dr. Harrison by his signature had gone
through the Committee; changes and edits were recommended. Those minutes
were taken back with the recommendations by Dr. Harrison, updated, and
signed off and approved --- just to let you know that that took place;
that was the November 2001 meeting minutes. Now as far as the meeting
minutes from the previous meeting, those have been circulated.

**M. STOTO:** Is it really --- is it really 2001 or is it 2002?

**L. SCHECHTMAN:** 2002, sorry.

**M. STOTO:** Okay.

**L. SCHECHTMAN:** The --- well, wait a second.

**M. STOTO:** It says "2001\" in the draft meeting of March 2003.

**L. SCHECHTMAN:** We will confirm that. We'll confirm that. I'm pretty
sure since it was the end of the 2001 year.

**M. STOTO:** Okay.

**L. SCHECHTMAN:** I think that\'s correct actually --- 2001. Yeah.

**R. HARRISON:** I think we had a fallow year there.

**L. SCHECHTMAN:** And then we had the March 2003 meeting. Those minutes
were generated, circulated to the Ranch Hand Committee members for their
comments, edits and suggestions. And we're at a point now where we're
welcoming that input and seeking approval for those minutes.

**R. HARRISON:** Any other questions, Mike?

**M. STOTO:** Yeah. I mean, I tried to look through those minutes for
the March 2003 meeting and found them very difficult to understand. And
because so much time has passed since the meeting, I found them
difficult to correct. I mean, at one point it quotes me saying something
that doesn't make any sense. And I suppose it's possible I did say
something that didn't make any sense, but it's more likely that the
minutes didn't reflect what I said and I can\'t remember what I said.

So I guess rather than talk about this particular draft, I'd like to
raise the issue of how can we do a better job of getting these minutes
done accurate? And I think that one thing is that we need to do them on
a more timely basis because I really can\'t do my job as a Committee
member of correcting these minutes because ten months have passed and I
--- and my memory is not that good. So I think that one thing I\'d like
to discuss is try to find a way that we can get something to look at in
a more timely way. I'm not sure.

**R. HARRISON:** And I think the start to the answer to that would be
the explanation for the time interval between the meeting and getting
the draft minutes to us. Len, can you \...

**L. SCHECHTMAN:** Well, there was turnover in our office and the people
who are responsible for the minutes early on have since left Committee
activities. So we were doing what we could to get those minutes
generated as quickly as we could --- unfortunately not quick enough ---
prior to this particular meeting. What we were left with was working
from the verbatim transcript of the previous meeting and any information
that appears in the current minutes were generated from the verbatim
transcript as it was written into the transcript per the discussion
around the table.

Any inaccuracies in those minutes may or may not be attributable to the
content of the verbatim transcript. And we would be willing to sit down
with any individuals, any members of the Committee who had problems,
such as those described by Dr. Stoto, and go over those matters along
with the public record, the verbatim transcript, and make sure that
despite the fact that the verbatim transcript may not have given or ---
the minutes may not have transmitted the information accurately as to
what the thoughts were of the speaker that the verbatim transcript was,
as I said, what was used as the basis for the minutes so that we can
make those corrections.

**R. HARRISON:** I guess, so essentially what you're saying is that this
was an unusual delay? But I wonder if you could give us an estimate of
when we --- for instance, when will we see the minutes? When will you
all see the minutes for this meeting? And because what you're kind of
saying that whoever did the minutes wasn\'t there and so the --- to make
any kind of judgment about the verbatim transcript. The other question I
wondered is, is the --- are the --- are parts of the minutes key to
parts of the verbatim transcript?

So if Mike has a question about something that he purportedly said, he
shouldn't have to go through reams of pages of transcript to get to it.
He ought to know that it's on page 123 at least. So those would be the
two questions I would have. What do you --- what is the time interval
going to be and is there a way to key the minutes to the transcript so
that --- so that when a question arises, the Committee member can get
directly to that point?

**L. SCHECHTMAN:** Okay. I guess what I can do is answer the questions
in reverse order. We can work with the transcriber to see if indeed
there is a way to do what you request about keying the minutes to the
verbatim transcript; that's never been done in the past. We would look
into that possibility. But as far as the minutes as they are generated
in the order in which the information appears in the minutes, that is
the exact sequence of events that are transcribed in the verbatim
transcript. So that even if we weren't able to tie it page by page to
the minutes, which I think is probably highly unlikely, that we could go
back in order with the verbatim transcript and the minutes side by side
and be able to hone in on a given area of the verbatim transcript to
match it against the minutes.

**M. STOTO:** I think we should separate two issues: one is how to fix
the minutes for the March 2003 meeting versus how to improve the process
so that we're not in this situation in the future. I mean, I --- one of
--- one of the things that I don't like about the way --- about this
form of minutes is that it is chronological. And it really doesn't do a
good job of describing what happened at the meeting to say "and then we
broke for lunch" or "and then somebody came in and did this" in the
middle of a scientific discussion, although that may be the way it
transpired.

I mean, I would like to see minutes that summarize the essence of what
happened at the meeting and are not just a condensed version of the
transcription, which I think that this is now. So I think that I would
like --- obviously, this is open for discussion --- but I personally
would like to see minutes that were more oriented, organized by subject,
and key decisions and so on rather than a summary of the --- second
thing, I think that this is --- it's really important to get these
minutes right.

And it probably is worth an investment of someone like a writer with a
background in science who can listen to the discussion, prepare a draft
on a timely basis; someone, you know, whose job it is to do that and to
get that draft back to the Committee and to the Ranch Hand staff in a
timely basis so that corrections can be made while everyone remembers
what was --- what the issues were.

**R. HARRISON:** Okay. Any other comments? Mike?

**M. GOUGH:** Well, I want to echo what Mike just said because we've had
this discussion about minutes before. And the difficulty of waiting so
long is that people\'s memories fade and people\'s memories fade about
different things. So then instead of getting five, or six or seven
people agreeing on what was said, we often get one person who remembers
it --- saying what was said. Now when I do that, it's perfectly right.
But I mean, I think everybody does it as honestly as they can. But I
agree, it's got to be done more timely and also the structure of the
minutes is just really clumsy.

**R. HARRISON:** Anyone else? Yes?

**S. LEFFINGWELL:** Leffingwell. Is it reasonable to assume that we're
supplied the transcripts and the minutes in an electronic format as well
as paper?

**R. HARRISON:** That's very unreasonable to assume.

**S. LEFFINGWELL:** Oh dear. Okay. If we had the electronic version of
the verbatim transcript, then we can search on key terms and find things
like Dr. Stoto referred to more easily.

**R. HARRISON:** There are a number of programs that allow you to search
by key word that would take the thousands of words that we're going to
generate today and make any particular sequence of three or four of them
findable. So \...

**M. STOTO:** Well, we could \...

**R. HARRISON:** I\'m sorry, Mike. I interrupted Paul and he was going
to say something next.

**P. CAMACHO:** It was just about the technology. It's the --- do we
have the voice technology that can just make text out it? I doubt it; I
don't think we have that.

**R. HARRISON:** I know for sure that's not feasible. Mike?

**M. STOTO:** I don't think it's a technology issue. I mean, honest. I
mean, in fact, we did get the draft minutes by e-mail and I don't know
whether it's Word or pdf. But that\'s easy enough to do and, you know,
you can search there.

**P. CAMACHO:** It doesn't sound easy.

**M. STOTO:** And I would search for "Stoto" to see what was attributed
to me. But I think that the fundamental thing is that the person who
drafts the minutes needs to understand more about what the issues are.

**P. CAMACHO:** Yeah.

**M. STOTO:** And that\'s not going to happen by fancy text \...

**P. CAMACHO:** Well, this \...

**M. STOTO:** \... transcribing and so on.

**P. CAMACHO:** But this way --- but this way you have both. If you get
a --- if we get a --- if you had a technology transfer, then you
wouldn't have an abbreviated version and you wouldn't be going through
\...

**R. HARRISON:** Let me --- but I think the point \...

**M. STOTO:** I mean, I don't --- I want an abbreviated version; I don't
want a transcript. I want something that's --- you know, minutes are
supposed to summarize the key points, not everything that was said.

**R. HARRISON:** The point though, Mike, that I think you're implying
but not saying is that the problem here is a matter of resources; that
instead of a sort of unknowledgeable person transcribing this --- not
transcribing it, but converting it in the minutes --- that the Committee
leadership needs to invest in a little more money and get a little more
pop for the --- for its nickel.

**M. STOTO:** Yes.

**R. HARRISON:** Okay. Anyone else on the subject of minutes?

**L. SCHECHTMAN:** Okay. As far as some of the information that was
exchanged just now, we did hire a new transcriber. I don't know that you
introduced yourself?

**N. RIVERA:** No.

**L. SCHECHTMAN:** Would you, please?

**N. RIVERA:** Sorry. I'm Nadine Rivera. And Dr. Stoto, I am a
writer/editor, a scientific writer/editor, so I know exactly what you're
talking about.

**L. SCHECHTMAN:** And which is \...

**R. HARRISON:** Can you --- can you --- can you tell us exactly where
you live because Mike was \...

**L. SCHECHTMAN:** \... which is exactly the reason why we hired Nadine
to do this job because of her background as a scientific writer as well
as a transcriber so that we would hopefully, and having predicted your
comments, we'll be able to fulfill those requests.

**M. STOTO:** Okay. Thank you.

**R. HARRISON:** Dr. Stoto is beaming, which means all is well and we
can proceed with --- and I could tell when he started walking up that
this wasn't Mr. Ogershok who was going to do this management thing. Go
ahead, Jay.

**J. MINER:** Mr. Ogershok was not able to be here at the meeting and
--- but does send his greetings. The Human Assistance Program Office
pretty much --- on Program Management, there's not a whole lot going on
right now with contractual actions. I think the only one that we have
pending of interest is an action to put a contract out to UC-Davis to
continue some adipose tissue studies and glucose transport mechanisms.
We did receive our budget authority and unlike some of the rest of the
federal government, we're not under a continuing resolution, so that's a
good thing.

And as far as contract deliverables for our current contract, Science
Applications International Corporation is doing a great job: delivering
chapters on time; obtaining Air Force comments; incorporating, resolving
and then getting the draft chapters back out to us. And then hopefully,
that process will then flow to you. You will receive initial draft
chapters, Air Force comments, comments as resolved, and then the final
draft chapter, which Lieutenant Colonel Robinson will be sending to the
Committee for distribution. Other than that, that's it.

**N. RIVERA:** What's your name, sir?

**J. MINER:** Miner, M-I-N-E-R; first name Judson.

**R. HARRISON:** Thank you very much, Jay. Len has just thought of
something else that he needs to tell us about before Dr. Butler gives
his talk.

**L. SCHECHTMAN:** Okay. Actually, we may need the extra few minutes
because one of the agenda items was a committee management report by
myself. And I wanted to give the Committee an update on just what had
transpired between oh, the fall of 2003 and the current situation in
terms of Committee member appointments. And some of this information I'd
like to read into the record just so that everyone will be aware as to
the steps that took place both from our end and the feedback we got back
from the Department of Health and Human Services.

So in October of 2003 --- October 14^th^ --- we sent a waiver request to
the Office of the Secretary of HHS requesting a special exception to
Department policy on Committee reappointment. And it read, "This is to
request a special, but essential exception to Department policy limiting
the term of service of advisory committee members. The committee in
question is the Advisory Committee on Special Studies Relating to the
Possible Long-Term Health Effects of Phenoxy Herbicides and
Contaminants, a/k/a the Ranch Hand Advisory Committee, which has been
operating since 1981.

The Committee advises the Secretary and the Assistant Secretary for
Health concerning its oversight of the conduct of the Ranch Hand Study
by the Air Force and other studies in which the Secretary or the
Assistant Secretary of Health believes involvement by the Committee is
desirable. When the original charter was established on January 19^th^,
1981, the function statement specifically stated that 'members shall be
invited to serve for the duration of the Committee.' Thus, granting an
exception to allow members of the Ranch Hand Committee to continue to
serve clearly meets the intent of this element of the original Ranch
Hand Committee charter under which the Committee was established.

This Ranch Hand Study is currently scheduled to conclude on September
30^th^, 2006. The fifth and final round of physical examinations of the
study participants has just been completed and the medical data are now
being compiled. A review of those study results by the Ranch Hand
Committee is currently scheduled to begin in March of 2004. Initially,
there will be six chapters plus a glossary that will be ready for review
at that time. An additional twelve chapters plus a discussion of future
directions are currently projected to be completed by September 2004.

The draft final Ranch Hand Study report is also projected to be
completed in the last quarter of fiscal year 2004. These will all
subsequently be reviewed by the Ranch Hand Committee over the following
one to two years. Since the Ranch Hand Study itself is anticipated to
conclude September 30^th^, 2006, the Ranch Hand Advisory Committee
activities are expected to conclude by the end of 2006. Despite the fact
that the study is reaching completion, the Ranch Hand Advisory Committee
is faced with the possibility of having to replace four existing
Committee members.

Of the nine positions constituting the Ranch Hand Advisory Committee,
one former vacancy has been filled and two are in the process of being
filled. As new members, none will have previously participated in a
Ranch Hand Committee meeting, four in the Ranch Hand Study review
process. Five of the remaining seven experienced Ranch Hand Advisory
Committee members are to be rotated off the Committee in accordance with
current Departmental policies unless the necessary exceptions can be
imposed.

Thus, of the total of nine members of the Ranch Hand Advisory Committee,
seven of them, 80 percent, would be new replacements charged with the
responsibility of seeing the study through to its completion.
Considering the expertise and long-standing involvement of the current
Ranch Hand Advisory Committee members with the Ranch Hand study itself,
the study participants and the study director, and their familiarity
with the biological specimens, types of data generated, medical
histories, data interpretation, reporting process, *et cetera*,
replacement of existing Committee members with new individuals
unfamiliar with the majority of these elements would only serve to
impose an extreme hardship on the work of the current Ranch Hand
Advisory Committee members and disrupt the efficiency of the Ranch Hand
Advisory Committee activities.

As stated previously, it is also noteworthy that the function statement
of the original Ranch Hand Advisory Committee charter states 'members
shall be invited to serve for the duration of the Committee.' Thus,
maintaining the existing membership of the Ranch Hand Advisory Committee
in accordance with the language of its original charter is in compliance
with that Committee charter. Obviously, the removal of the existing
knowledgeable and experienced Ranch Hand Committee members whose terms
are about to expire at a point in time when the study is coming to an
end would introduce an avoidable burden on the activities and
productivity of the Ranch Hand Advisory Committee.

In fact, the entire life span of the Ranch Hand Study has led up to this
culmination point for the final analysis of study results. It is for
these reasons that it will be of critical importance to maintain the
current makeup of the Ranch Hand Advisory Committee. Retention of the
existing knowledge and experience of the present Ranch Hand Advisory
Committee members who have followed the study and analyzed the data over
the years would preserve the continuity of the Committee efforts and
thereby avoid any retardation or interruption of the Ranch Hand Advisory
Committee productivity.

With the present Ranch Hand Advisory Committee members, it would take
new inexperienced replacements the remaining years of the study to
achieve a comparable level of familiarity with the medical data and
Committee processes in order to provide the necessary expertise so
essential to the completion of the Ranch Hand Study analysis. It is even
conceivable that were 80 percent --- that is, seven of nine of the
existing membership of the Ranch Hand Advisory Committee --- to be
replaced at this time, the work of the Committee may not be completed by
the time the study concludes and resources are no longer available.

In view of these factors, the National Center for Toxicological Research
wishes to reappoint" and we listed Drs. Camacho, Osei, Sills, Gough and
Harrison. "Reappointment of these members would require a waiver from
Department policies which prohibit service of more than four continuous
years on an advisory committee without a one-year break in service. We
are requesting that they be reappointed for an additional two-year term,
which will take them through the end of the study. The additional
service would commence February 1^st^, 2004 and end on January 31, 2006.

All of these members have expressed a willingness to continue their
service on the Committee. In addition" --- there is no addition. Sorry.
And that was signed by the Director of the National Center for
Toxicological Research as generated by our Washington Office. So that
letter to the Office of the Secretary went out on the 14^th^ of October
2003 as I mentioned. On the 20^th^ of that month, we received word that
permission to revert back to the original charter and to put the
language in the original charter that states that members may remain
with the Committee until the termination of 2006 had been approved.

Two days later, October 22^nd^, we received word from the Department
that they would not change the charter. As such, we were forced to go
with the language in the original charter and nominations were forwarded
to HHS on November 20^th^ after all attempts had failed in obtaining the
waiver approval. I then sent an e-mail dated November 19^th^ to all of
the standing Committee members, which I won't take the time to read into
the record unless I'm requested to do so, informing all of the members
of the Ranch Hand Advisory Committee as to the state of affairs and who
--- and those members who would no longer be allowed to serve on the
Committee as a result of the Department's rules and their unwillingness
to accept the waiver request. Are there any questions? Yes?

**M. STOTO:** Did they formally turn the waiver request down or did they
just not respond? Sorry.

**L. SCHECHTMAN:** No, it was a formal rejection of the waiver.

**R. TREWYN:** I thought when you were describing it though, you said
that the --- that you were --- then had to go with the original language
and the original language was the term. And I assume it meant that it
was the existing regulations that you had to go with.

**L. SCHECHTMAN:** I'm sorry; that's correct.

**R. HARRISON:** So are we here or not here?

**R. TREWYN:** You're not here.

**R. HARRISON:** We're not here; this is it. Okay. Free at last, free at
last, thank God Almighty.

**L. SCHECHTMAN:** Basically what it boils down to, if I can just for
purposes of clarification, Dr. Harrison and Dr. Gough, who have served
on this Committee forever essentially \...

**M. GOUGH:** No, I had a break.

**L. SCHECHTMAN:** You did? You had one break? And the duration of your
service, as I recall, was about twelve years? I'm sorry.

**M. GOUGH:** Ten years and six months.

**L. SCHECHTMAN:** Ten years and six months --- I stand corrected. And
Dr. Harrison's term of service was fourteen years and four months with
no break in service. Okay. So because of their extended service, despite
the quality of their service, the Department decided that they had
served the purposes of the Ranch Hand Advisory Committee for as long as
they possibly could be allowed to.

**M. STOTO:** And there were --- and there were others though that you
mentioned.

**L. SCHECHTMAN:** Right. Everyone else \...

**M. STOTO:** Everyone else was reappointed?

**L. SCHECHTMAN:** \... was reappointed because the duration of their
service hadn't exceeded the approvable limit by the Department.

**R. TREWYN:** So was the limits placed by the Department --- I'm just
curious --- were those just sort of ignored over the years? I mean,
obviously for fourteen years-four months, ten years-six months, that\'s
a fairly long period of time.

**L. SCHECHTMAN:** No, they were not ignored. Requests were put in to
have them --- their memberships renewed. Those were approved over the
years and it just reached a point in time where they said "enough"
unfortunately.

**R. HARRISON:** So we're --- so we're finished then. Well, this is ---
this is basically just an informational item just telling you what's
happened. I don't think that there's any reason to spend a lot of time
on it. I have a plane to catch in just about an hour. Do you have
something else to say?

**P. CAMACHO:** Well, now it's on? Well, doesn't this --- how do we ---
who's taking your place in a bottom line?

**L. SCHECHTMAN:** Okay. That was taken care of by the Department. Dr.
Stoto was requested because his long-standing --- but not quite as long
as them and experience on the Committee --- he was requested to serve as
the new chair of the Committee and he has accepted that position.

**M. STOTO:** Thank you. Has it been approved by the Secretary yet or
\...

**L. SCHECHTMAN:** To the best of my knowledge, it has.

**M. STOTO:** Oh, okay.

**L. SCHECHTMAN:** If it hasn't, we\'ll let you know.

**M. STOTO:** Okay. Well, thank you. I didn't know that and I want to
just, at this point, make sure we give tribute to the two members who
are --- who are leaving now for their service.

**L. SCHECHTMAN:** Absolutely; I agree. Dr. Harrison will serve on
today's --- at today's meeting as will Dr. Gough as a member and as
chair: Dr. Harrison as chair and Dr. Gough as member of the Committee.
Their terms don't expire until the end of the month, which is why we ---
one of the primary reasons for having this meeting prior to their
leaving, departing from the Committee because we indeed wanted to give
him --- give them the recognition that they so truly deserve for all of
their efforts over the years.

I will say this: we will thank you both verbally at this time. We've
been pressing the Department for letters of recognition and plaques for
each of you for your service; we know those will come. But sometimes
things, as you know in the government, do lag behind the desired
schedule. So verbally though, we want to thank the both of you for
exceptional efforts on the Ranch Hand Advisory Committee. Your terms of
office, despite the length of office, were efforts that the Committee
could not have done without.

And I know I speak for the rest of the members of the Committee as well
as the rest of the individuals who participate in our meetings in
acknowledging your valuable input, your efforts, and the time and energy
that you've invested in the Ranch Hand Advisory Committee over the
years. And I would welcome anyone around the table to offer any comments
in addition to those at this time.

**R. TREWYN:** Wing of the building going to be named after them or
something here? Let's make this appropriate, folks.

**R. HARRISON:** Well, I would just first of all like to --- like to say
that, and I think that most of you all know this, that Mike Stoto came
to this Committee after serving on --- in the National Academy of
Sciences and brings a store of knowledge about this area that I suspect
rivals anyone in this room. So it's --- number one, it's comfortable to
--- comforting to see him become chair and particularly because I would
also like to say that as someone who views most things governmental and
the Armed Forces with a high degree of cynicism, that I've been
impressed over the years that I've served on this Committee about the
concern that the Ranch Hand Study personnel have had on the Air Force
side for making this a good study and actually finding out what's going
on. And it's nice to know that there are at least some parts of our
government that actually work the way you expect them to and that's
probably the part that I'll miss most of all out of this. Okay,
schmaltzy stuff aside. Let's --- no.

**M. GOUGH:** I\'ve been called upon to say something.

**N. RIVERA:** Your light needs to be on.

**R. TREWYN:** Your light is very dim.

**M. GOUGH:** It's a reflection of other things. Well, you know, I ---
yesterday when I got the e-mail with the attachment of Chapter 4 \...

**N. RIVERA:** It's not on, sir.

**M. GOUGH:** I'm sorry. Yesterday, when I got the e-mail with Chapter 4
attached, and I looked at it and I thought, "Well, I'm off the
Committee, so I don't need to print this one out and read it" --- all
1,100 --- 1,700 pages. Is that what it's going to be?

**J. MICHALEK:** Approximately.

**M. GOUGH:** So for those remaining on the Committee, enjoy yourselves.
I have a thought: I think that --- I think that this has been a really
good relationship between a research group that's doing a very difficult
and very important study and an advisory panel that's generally been a
good advisory panel. So I think we did well. I'm sure you'll continue to
do well; you're going to need a lot of manpower. When I\'m corrected
about political correctness by Bob Harrison, indeed. I already have a
great big plaque from the last time I went off the Committee.

**R. HARRISON:** Two plaques should provide some balance and everything.
Okay. Any other comments, or questions or statements? Very well. I think
we're finally to Dr. Butler and the Vietnam Veterans Health Studies at
the National Academies. Dr. Butler?

**D. BUTLER:** Thank you. I'm going to take just a moment here to call
up my particular set of slides if people will indulge me until then. Dr.
Michalek was kind enough to let me borrow his system here. My name is
David Butler and I am a Senior Program Officer with the Institute of
Medicine of the National Academies. I wanted to start out for just a
moment and explain what our institution is and what it isn\'t.
Importantly, what it isn't is a part of the federal government. We were
chartered by the Congress back during President Lincoln\'s
administration to be an independent non-governmental institution whose
job it was to advise the government on various science subjects.

Our first bit of advice actually was to the military who asked the
original members of the National Academy of Sciences to advise them on
how to build compasses that would work on iron clads --- a very
important issue of the day. The Institute of Medicine itself is a
relatively new part of the National Academies. We were chartered in 1970
as a part of the institution whose specific mission it was to look at
medicine and public health issues. National Academies studies follow a
common outline.

Importantly, for this --- for what I'm about to talk to you about ---
all studies must start with the Governing Board's Executive Council
reviewing and approving study conduct. The research that I'm going to be
speaking with you about later has been submitted to our Governing Board,
but the Governing Board hasn't yet acted on it. So what I'll be talking
to you about is speculative at this point, although I have every
expectation that the Governing Board will approve this study to go
forward.

Presuming it does, what we will do is to form a committee of volunteer
experts who will then research the topics that we\'ve been asked to look
at and write a report based on literature reviews, public hearings, and
workshops, and written testimony and other information. In other words,
we are an information gathering body. And we will need a lot of input on
this study and we'll certainly be looking for it. When we've completed
the report process, our final reports are subject to an external peer
review before they are made public.

The National Academies and the Institute of Medicine were asked to do a
number of controversial pieces of research over the past couple of
years. I've picked out a few hot button topics just to cite that we have
a rather broad mandate for looking into tough science questions in
advising the federal government. Our studies of Vietnam veterans health,
of which there are several, were mandated originally under the Agent
Orange Act of 1991. That Act instructed the Secretary of the Department
of Veterans Affairs to enter into a contract with us to conduct
research.

This set of studies evaluate both the statistical association between
wartime exposure to herbicides and health impacts; that's a task for
which we use information from the Air Force Health Study, and numerous
other research studies, and also a separate project where we looked into
the means and methods of retrospectively evaluating herbicide exposure
of veterans. There have been a number of reports that have been issued
from us over the years. There's a complete listing of them on the back
page of the slides handout that I gave you.

The two most recent are the *Veterans and Agent Orange: Update 2002*
report and a report that closed out the second section of work that I
just mentioned on the *Characterization of Exposure of Veterans to Agent
Orange*. All of this information and information on our other studies,
including those of Persian Gulf veterans and veterans of other wars, are
on a web site that just went live in December of this year and now
serves as sort of a central point for getting information on all of our
veteran studies.

More specifically, the reason that I was invited to come here today is
the Veterans Benefits Act of 2003. That Act was signed about a month ago
into law and contains a section requesting that the Secretary of
Veterans Affairs enter into a contract with the National Academies to
conduct a study on the disposition of the Ranch Hand Study. That
legislation contains five separate elements that were to be addressed in
the study. The first of these is to evaluate the scientific merit of
retaining and maintaining the medical records and all of the other
pieces of information that Dr. Michalek and his staff have gathered over
the years past the scheduled termination date of the study.

The second primary element is to evaluate all of the issues related to
retaining and maintaining those medical records, including importantly
privacy concerns of the veterans themselves, and of course, the issues
like informed consent. The third is the advisability of providing some
independent oversight of these records and other data, and if
independent oversight is deemed appropriate, a mechanism for providing
such oversight. So the first three elements of this are all related to
retention and maintenance of samples and records, the advisability and
the mechanism that would underlie it.

Element four comes to a separate topic: the advisability of extending
the study and some evaluation of its potential value and relevance, its
cost and the entity that\'s best suited to continue the study if it is
extended. And finally, the advisability of making the laboratory
specimens available for independent research; that is, as I understand
it, research outside that\'s strictly specified by the Air Force Health
Study, and the value and relevance of such research and its cost.

So in brief what we've been asked to do is take a comprehensive look at
this huge longitudinal study, the information that's been gathered in it
over the years, and to offer advice on how best to manage that
information, and whether to extend the study as it presently stands.
Just briefly, in the course of this study, we will be posting
information on our progress. Information on that study and on any other
study that the National Academies conducts can be found on our current
projects web site, which can be reached through the web page that I\'ve
listed here.

And as I indicated before, all of our reports are up on the web for open
access of anyone who might like to read them through the National
Academies Press. Because we haven't yet signed a contract for this
study, it hasn't yet been approved by our Governing Board, there isn\'t
a whole lot I can tell you about the details of the conduct of the
study. I have every expectation that the study will be approved by our
Governing Board; a contract will be signed.

Given that that\'s the case, we would expect that we would hold public
meetings of this committee; that we would gather information from
numerous sources, including this Committee, including veterans, the
Department of Veterans Affairs, veteran service organizations, other
individuals who wanted to have input on the questions that have been
outlined. And at this point, I\'m in an information gathering mode. I'm
looking to learn from the Committee today, looking to simply inform
people that we are looking for information and for input on this study.
And I'm supposed to mention that I'm looking forward to this because it
sounds like a fascinating study and I'm eager to see how it turns out.
Dr. Gough?

**R. HARRISON:** Thank you. Any questions?

**M. GOUGH:** Am I on?

**R. HARRISON:** You're on.

**M. GOUGH:** Dave, do you have a --- once it's approved, it looks like
a relatively tight timetable. And what is the nature of this report? Is
it going to be advice to the Secretary of the VA that this is what we
would consider doing with study --- with the Ranch Hand Study?

**D. BUTLER:** The Secretary has been advised, has been told to enter
into a contract with us to do this research, but the advice is not
specifically to the Secretary of Veterans Affairs. It is general advice
on what should be done with the study. The timetable is still being
worked out. You're right; that legislation has specified a rather tight
timetable for the conduct of the study.

**M. GOUGH:** David and I used to work there. We know the VA doesn't
give enough time for projects. What do you think --- what do you think
realistically, once it's --- once you get approval from the Governing
Council to do it, how long do you think it'll take?

**D. BUTLER:** That's up to the contract that we make with the
Department of Veterans Affairs and we haven't finalized that yet.
Clearly in the best of all worlds, Mike, we would like to have a little
bit more time to think about this. There are some pretty heavy issues
\...

**M. GOUGH:** Oh yeah.

**D. BUTLER:** \... that have been outlined here and we want to make
sure that a thorough and thoughtful job is done of it. We\'ll be talking
with the Department of Veterans Affairs on that and we'll see, once we
sign a contract with them, what timetable they feel comfortable with
given the Congressional mandate.

**M. GOUGH:** And I have one other --- one specific question. Is the
National Institute of Aging aware of this and do they know about the
study? I mean, this is the biggest, longest longitudinal study of guys
ever. And it has a --- and it has a disadvantage there are no women in
it, but on the other hand, it does have a racial mix, which is unusual
for a study like this. And it seems to me that they --- there might be
interest in other agencies in the government, NIA for instance, in
participating in the discussion of what's going to happen with these
samples and whether additional information is going to be collected.

**D. BUTLER:** I think you make an excellent point. In talking about who
we would want to have on the committee, we thought that certainly
representation from a gerontologist would be appropriate given the
makeup of this population. I haven't specifically thought about the
National Institute of Aging, but now that you mention it, I certainly
will bring it up with them and see if we can ask them for some advice on
this because I agree; this is --- this is a fairly large population.
They\'ve been studied, followed for such a long time.

In the *Update 2000* report --- I don't have it in front of me --- I
know that the committee who wrote that report specifically pointed out
that notwithstanding the value of the study from a Vietnam veteran's
health point of view, that that committee thought that there might be
other valid reasons for following --- continuing to follow this
population given the information that\'s already been collected.

**R. HARRISON:** Yes sir?

**R. TREWYN:** Since I know that the committee will reach out looking
for members, I would just suggest that, you know, there are a couple of
geriatric members of this Committee that will be stepping down soon and
would have a wealth of knowledge that could be, I think, invaluable. And
at least looking at them as a resource, if not as members, might be
something to think about.

**D. BUTLER:** We're certainly happy to take recommendations for
individuals who should be considered for membership and whether or not
people make it on to the committee, as I said, we'll be holding public
workshops for gathering information.

**R. HARRISON:** Mike?

**M. STOTO:** First of all, I want to say I think this is great news
that the Congress asked for this study and the Academies seems willing
to do it. I mean, this is something that's really very important and I'm
glad that we --- that David was able to come talk about it and even
happier that they --- looks like they\'re going to do it. I also want to
second the point that Mike made about the value --- the potential value
of this to beyond Ranch Hand and even veterans health specifically. And
so I'm glad to see that item number five is in the --- is in the charge
and I think that NIA is a good one.

I suspect that there are other parts of NIH that might be of interest as
well; I mean, the environmental side and potentially others as well. I
mean, given the findings on diabetes, it suggests that there would be
some interest conceivably there. And the point that I think we\'ve tried
to make in the past bears repeating here; is that if the scientific
community, and particularly a funding agency like NIH knows about the
resource of the materials that are available, they're in a position to
provide funding for studies through normal NIH funding channels; that a
combination of their funding and the Air Force's resources are a
potential gold mine. And I think that point --- that connection needs to
be made.

Now there are issues about whether the data can be used for purposes
like that, which will also have to be addressed as well. But, you know,
it's not that we're asking the Air Force to put more money into --- or
the VA to put more money into doing more studies on this. It's that the
resource that's available would be useful for scientists funded through
other means and that point needs to be explored and clarified.

**D. BUTLER:** Assuming the interest of the study participants in
allowing this information to be used in other forms, I agree that there
is tremendous potential to learn from this information.

**R. HARRISON:** Before you say something, Kwame, can I --- can I make
what I think is a point? And it's a human subjects issue that I'm not
sure I quite understand. But I know that the subjects that we spoke
with, the Ranch Hand participants that we spoke with out in California,
would be quite willing to agree to allow their samples and so forth to
be used in other studies. It's just not clear to me that that's --- that
you can do it post-hoc. I think the biggest sticky wicket in this whole
thing is how to deal with the protection of human subjects issues that
comes up from trying to retrospectively obtain agreement to utilize
materials and samples that you already have which has a coercive value
that's very difficult to understand. That's --- okay. Mike and then
Kwame.

**M. STOTO:** On that point, first of all, I agree with you; that is, I
think, the most difficult issue that needs to be addressed. And the
other point though is that I believe that --- and I\'ll ask Joel now ---
is that in the last round, the study participants were asked about their
willingness for the data to be used in the future for Ranch Hand
purposes --- or I guess Agent Orange purposes --- and for other health
purposes and it'll be interesting to know what the results were. Can you
tell us?

**J. MICHALEK:** I brought those; those slides are on my machine. I
think I showed them at the March meeting and I can show them again when
I stand up, the percent who complied, so I have those numbers with me.
They were a very high percentage --- over 90 percent.

**K. OSEI:** Yeah, David, is this going to be open to other private
institutions to compete because, you know, the National Institute may
not be able to do all these? The ideas may have to come from outside and
the question comes in: would you, you know, is the National Institute
going to allow, say Ohio State, or any other institutions to apply to
participate rather than individual, you know, groups?

**D. BUTLER:** Well, in the conduct of this particular study \...

**K. OSEI:** Okay.

**D. BUTLER:** \... we will be --- we will be doing this particular
study. As to the disposition of the materials in the future, one
possibility --- just talking hypothetically --- is that there could be a
competitive process for determining management of the --- of the samples
and data, but that simply exists as a possible option. Our present
concern with this study is this is something that where we will be
conducting this work and generating the report. The National Academies
does not in general contract --- subcontract out pieces of studies that
they've been requested to conduct by the Congress.

**K. OSEI:** But there may be other --- the reason I\'m bringing this
up, for example, if you look at the Physician Health Study where we have
all these males who are in their 70s who are comparable in age, so that
may be, if you look at the health of, you know, people who have never
been exposed to, you know, Agent Orange, asbestos Agent Orange, and all
the variables that can come in. And that will have to come from outside
for you to be able to actually look at a control group that is
comparable to what we are looking at.

**R. HARRISON:** Kwame, it sounds to me like you\'re talking about two
different things. David and the National Academies is being asked by
Congress --- I mean, as things presently stand, in another year or so,
Joel and his crew are going to take all these Revcos, and computers and
optical drives, put them in a big hole somewhere and pour concrete on
top of them, and the whole thing is going to be done. And Congress is
asking is there something better we can do than that?

And what you're asking is once the --- you're assuming that the decision
is going to say "Yes, let's use it for other stuff." And then you're
talking about what gets done after that; those are two separate items.
And that second item, the one you're asking about, is something I don't
think the National Academies is going to do anything about other than
say that, you know, maybe the NIH should provide some funds or someone
else should provide some funds. Am I --- am I understanding you
correctly, Kwame?

**K. OSEI:** I think what I'm talking about \...

**R. HARRISON:** I think what happens after the samples are available
\...

**K. OSEI:** Right.

**R. HARRISON:** \... for other use and that's not what David is here to
talk about.

**D. BUTLER:** Right. In general, the National Academies does not
conduct primary research.

**R. HARRISON:** Correct.

**D. BUTLER:** And we are not a funding organization and don't have any
money to support others' primary research.

**P. CAMACHO:** So your recommendations would be confined to the value
of keeping the data, not particularly managing and the management
structure of the data: the whole piece, access? Because he's talking
about who's going to get access to the data \...

**K. OSEI:** Exactly.

**P. CAMACHO:** \... assuming it was around somewhere. So \...

**D. BUTLER:** The committee might choose to offer advice on the process
by which such decisions would be made, but not the details.

**P. CAMACHO:** There's no end result, but rather approach limits on
what they ought to be doing?

**D. BUTLER:** That's correct.

**M. STOTO:** And the --- and the Academies hasn't been asked to
actually manage it.

**P. CAMACHO:** That's --- yeah; that's what I'm getting at.

**M. STOTO:** We have a distinction between recommendations about and
managing.

**R. HARRISON:** Precisely. What we've talked about over the last
several meetings is there's this treasure trove of data and biological
samples that if we follow the road map as it's presently drawn out,
there's this --- there's this end right at the edge of this very deep
crevice, and everything just drives over the edge and drops out. And NAS
is being asked, "Is this the right thing to do?" That's all they're
being --- my understanding of it is that's all that they're being asked.

**D. BUTLER:** That's correct.

**R. HARRISON:** And I know you're aware of this, but I just feel like
it ought to be said anyway; and that is, there isn't a Revco good
enough, or Forma or whichever to keep biological samples indefinitely.
And I sure hope that the committee emphasizes that not only if the
committee does decide to recommend that other things be done with this
material, that it's not only important, but that as far as the
biological samples are concerned, it's desirable that it be done quickly
rather than at a snail's pace.

**D. BUTLER:** Well, we --- I --- we would seek to include, either on
the committee or in the workshops, expertise on the long-term management
and maintenance of biologic samples. And to get back to your earlier
point, also to include individuals who have experience in bioethics,
treatment of study subjects and materials from study subjects.

**R. HARRISON:** Kwame?

**K. OSEI:** So from what you're saying, this decision has to be made
before September when the --- September 30^th^ of 2006, right, because
that\'s the end of this, you know, whole Ranch Hand Study? So you have
to move very quickly because this is 2004.

**D. BUTLER:** Yes.

**K. OSEI:** And so, you know \...

**D. BUTLER:** No. We\'re very aware of the time-lines here and \...

**K. OSEI:** Okay. All right.

**M. STOTO:** I mean, and that the Congress has asked that it be done in
120 days. I think that we should thank Dr. Butler for coming and, you
know, express our willingness as a Committee to interact with the
committee that the Academies sets up and bring the expertise that we've
developed to bear on that.

**R. HARRISON:** I agree. Thank you very much. I wish that I had the
power to award you a plaque as an honor. But it --- I think I speak for
everyone who\'s participated in this process and participated in the
discussion about the disposition of the Ranch Hand materials; that we've
all felt that this was a truly important set of materials to --- even if
--- even if you all decide that nothing should be done with it, I'd be
much more comfortable that there's a sound scientific discussion and a
reasoned decision made rather than just things dropping out. And I'm
happy to see that and I hope that the decision is positive, but we very
much appreciate that it's being looked into.

**D. BUTLER:** Well, the National Academies *Update 2000* --- *Veterans
and Agent Orange: Update 2000* --- report pretty much echoes what you're
saying. That report does not reach any conclusions on this, but simply
identified a need for there to be a reasoned discussion and evaluation
of what ought to be done on it. And, you know, speaking from the
standpoint of the committees, I'm sure they're pleased that that
recommendation is now being followed up.

**R. HARRISON:** Anyone else? Thank you again. Not included in the
agenda for today is time for public comments. And what I would like to
suggest, and would hear disagreements if there are any, is that we're
going to still try and finish the morning session --- everything in the
morning session. We're about twenty minutes behind now, but Joel is an
expert at compressing his --- at data compression and I'd like to
suggest that we do public comments immediately after lunch --- 1:00. And
I would like to ask anyone who plans to make a public comment to give
your name and affiliation to Ms. Campbell, who was introduced earlier,
so that I'll be able to introduce you. But if someone has not introduced
--- has not given Ms. Campbell the information, but wishes to make a
public comment, you will certainly be able to do so.

**P. CAMACHO:** You may have people show up at the --- before then. Why
don't you leave it that they can make the public comment to her; that
they --- for the record or do you want to \...

**R. HARRISON:** No, public comment is public. I mean, they get to say
\...

**P. CAMACHO:** Well, I'm not saying that they don't have to --- well,
if you --- they \...

**R. HARRISON:** We have one more item after \...

**P. CAMACHO:** What if they come in at 3:00?

**R. HARRISON:** We'll be gone.

**P. CAMACHO:** What if they come in at 2:00?

**R. HARRISON:** If they come in at 2:00 and it turns out that they wish
to make a comment \...

**P. CAMACHO:** Fine.

**R. HARRISON:** \... we'll discuss it. But I'm assuming that most of
the people who might be interested in making public comments are already
here or will be here before lunchtime; that's the way it usually works.
But no, I'm not going to shut anyone off if --- I'm not going to shut
anybody off period. I'm just trying to organize it so it flows a little
better.

**P. CAMACHO:** Thank you.

**R. HARRISON:** Any other questions or comments? Okay. So let's get on
now to \...

**M. STOTO:** Could we maybe take a break for a minute before we get
started?

**R. HARRISON:** Okay, Dr.; the bathroom is around that corner. Five
minutes.

**\[BREAK 9:31 A.M. - 9:46 A.M.\]**

**R. TREWYN:** At your advanced age, this is five minutes? Is that
right, Bob?

**R. HARRISON:** Okay. Well, just wanted to make sure Mike had plenty of
time to accomplish his mission. Okay. So we now have recent findings:
Dr. Michalek and Committee discussion. Joel?

**R. TREWYN:** You have twelve minutes.

**[Serum Dioxin and Four Biochemical Parameters of Adipose
Tissue]{.underline}**

**J. MICHALEK:** All right. This is the first of several presentations.
The activity is to understand at the cellular level whether dioxin is
implicated in the metabolic pathways leading to diabetes mellitus type
2. This study was launched several years ago. It's based on data
collected at the cycle 5 or 1997 physical examination. The primary
scientists involved: Phillip Fujiyoshi and Fumio Matsumura are the
toxicologists; I am the statistician. Haejo Hwang was a --- one of the
toxicologists involved with actually performing the measurements, but he
was replaced by Phillip.

Remember that I am a statistician; I am not a biologist. I am not going
to pretend to talk about mechanisms. I do not have the mechanisms
memorized. I will just display the data for you from my point of view
and you can interpret as you please. To cite some information at the
top, right off the top before we start any slides, you should know that
this is a completely new molecular epidemiologic approach that has never
been done before --- ever. It is unprecedented.

This is the first time the method of preliminary --- polymerase chain
reaction measurements have been made in human tissues for the public
health issue of importance that we have here today in front of us.
Measuring the expression of metabolic intermediaries in the diabetic
pathway through gene expression is --- was considered the best way to
determine whether there really is a causal pathway between dioxin and
diabetes. The criteria to establish exactly what should be measured were
written by Dr. Matsumura in his initial proposal to the Air Force.

The first is that the measurements must be --- must have been proven in
animal experiments to have been related to TCDD and diabetes. Every
parameter in the study must be expressed in enough quantities in human
adipose tissues to be measured in the first place. Every parameter must
be clearly recognizable from other parameters. They must be amenable to
standardization. They should be quantitatable and the laboratory methods
should be reliable enough to be carried out by reasonably trained
people. All of those criteria are met by this study.

I hope that in future presentations, either Phillip or Fumio will be
here to tell you what all of these data mean. We are --- we are
attempting to determine whether dioxin is adversely associated with one
or more of the components of the biochemical pathway leading to
diabetes. The study was launched prior to cycle 5, which was the 1997
physical, based on data collected at cycle 4, which was the 1992
physical. We envisioned that about 50 percent --- well, first of all, we
did not have the resources to collect adipose tissue specimens on all
2,000 study subjects.

Not only did we have --- not have the resources, it was not even
logistically possible to have done that because you would have to have a
surgical procedure done, namely liposuction, on each of thirty people
--- or sixty people every week and there weren't enough resources at
Scripps Clinics to handle that. So based on the logistical and fiscal
limitations of the study, we --- and based on power calculations that I
--- that I constructed along with Fumio Matsumura, based on animal
studies, we concluded that approximately 300 study subjects would be
sufficient to establish statistical power that was reasonable.

We expected 50 percent compliance due to a variety of reasons: refusals,
medical deferments and other such things. So we prepared a roster by a
random --- a random selection process and a factorial design from the
cycle 4 data of 650 subjects who were then entered onto a roster and
were flagged at the cycle 5 exam to be invited to provide twelve grams
of adipose tissue by liposuction. The selection factors in the factorial
design were grouped: obesity, age and diabetic status. And all of these
components were prescribed before-hand in a study protocol that was
reviewed by the Committee and by us, and was approved and funded with
the University of California at Davis.

Of the 650, 313 actually completed --- volunteered and completed the
adipose tissue liposuction very close to our expected 50 percent
compliance. The four biochemical parameters that were actually measured
are glucose transporter 4, C-SRC, NFκβ and C/EBPα. And these parameters
were selected through an iterative procedure by Dr. Matsumura based on
feasibility and state-of-the-art measurement techniques in current
research. And there you see a description of what these are and why
they're important.

Here's a breakdown of what happened to those 650 individuals: 10 percent
--- 10.2 percent actually refused; 16 percent roughly were deemed too
lean by the surgeon to draw any fat at all and so that\'s good news for
some of those people. I had enough fat to have been drawn on the
practice run of this procedure and it was an interesting process. So
there you see what happened. The final bottom line was that 313 or 48.2
percent of the original roster completed the procedure.

And here's a final sample size layout of the factorial. In the columns,
you see the obesity determination --- lean and obese --- and on the far
right is the total. And there you see the breakout by age. The cut point
for age was the median in the --- at the baseline exam --- 42 years at
baseline. And diabetic status was based on our old diabetic
determination before the new ADA criteria and I'll talk about that on
the next slide. The older criteria was simply that the individual had to
have an elevated two-hour post-random glucose or a physician\'s
diagnosis of diabetes.

**M. GOUGH:** Joel?

**J. MICHALEK:** Yes?

**M. GOUGH:** When you made this cut at 1942 for birth date \...

**J. MICHALEK:** No, age. Let's go back up. Let me see what that cut
was; I forgot it already.

**M. GOUGH:** Yeah, it was --- it was the \...

**R. HARRISON:** It said "1942."

**J. MICHALEK:** It did? Okay. That was the median birth year of
individuals at baseline.

**M. GOUGH:** Did that result --- does that result in there being more
officers and enlisted men in the old group?

**J. MICHALEK:** Yes, of course, because officers are older than
enlisted; that's true.

**M. GOUGH:** So that's a --- that's a real complication then because of
socioeconomic?

**J. MICHALEK:** Occupation --- military occupation is in the analysis
as a covariate. So \...

**M. GOUGH:** Okay.

**J. MICHALEK:** \... it was deemed important to adjust for age. Doctors
in level, of course, too is in the analysis.

**M. GOUGH:** I was more concerned about \...

**J. MICHALEK:** Yeah, socioeconomic. Right. Yeah.

**R. HARRISON:** Hold on, Joel. Mike has a question.

**M. STOTO:** How about the exclusion of the people who were too lean? I
mean, presumably, they have less body fat.

**J. MICHALEK:** "Too lean" means they have not even enough body fat to
be extracted by liposuction; that's true.

**M. STOTO:** So \...

**J. MICHALEK:** Yeah, you're right. I mean, we're dealing here with ---
these are people and some of them don't even want to have it done in the
first place, like those 10 percent. Some are taking medications that
they were --- confessed to the surgeon; that was the first question he
asked. He asked me. And so the surgeon decided in certain cases, "No,
you\'re not going to have this done."

**M. STOTO:** You know, I mean, I understand that. I'm just thinking
about what biases may have \...

**J. MICHALEK:** Biases, right.

**M. STOTO:** \... been the cause of that that are unavoidable \...

**J. MICHALEK:** Yes.

**M. STOTO:** \... but need to be \...

**J. MICHALEK:** They'll be discussed \...

**M. STOTO:** \... acknowledged, yeah.

**J. MICHALEK:** \... right up front. And this table will appear in the
subsequent journal article that is in preparation. All right. Diabetic
status, as you know, has changed. Our definition of diabetes has changed
from 1995 to 2002. And this slide doesn't even represent the latest
change, which was to the ADA definition. This just represents changes to
our own understanding of diabetic status from cycle --- from 1995 to
2002. The roster for the selection of the individuals for the adipose
tissue study was developed in 1995 based on information we had at that
time. Since then --- since then, our information has changed.

For example, individuals that we thought were diabetic in 1995, eight of
those were subsequently found to be not diabetic because those eight ---
there was something in the doctor's diagnosis that was qualified: "He's
not diabetic; he's borderline diabetic." And so we backed off and
redefined them as non-diabetic in 2002. And of some of those that we had
originally decided were non-diabetic in 1995 were subsequently
classified as diabetic because they produced a very high or abnormally
high glucose measurement subsequent to 1995. And so this definition is a
little bit in flux, but you see on the diagonal elements there, the
large number down here and the 39 people up here, those are people that
have been consistently designated; these are diabetic or non-diabetic.
And this visit \...

**R. HARRISON:** Excuse me for a minute, Joel.

**J. MICHALEK:** Yes sir?

**R. HARRISON:** Kwame, would you like to comment on the borderline
diabetes? Or if you don't, I would.

**K. OSEI:** No, Bob, the problem with all these --- we talked about it
before. The change from the WHO criteria to ADA changes a little bit,
but not dramatically if you use the two-hour, you know, post-glucose
challenge. And I think, if I remember, that's what you guys did. Okay.
So that actually helps a lot, but whether you were a diabetic in 1995,
you are not diabetic in 2002 depends on what you did to your life. If
you're --- if you're a diabetic and you lose weight or you exercise
more, you can eventually become normal. So that means that they were not
diabetic; what they said is that they've done something, you know, to
themselves to make them "un-diabetic," if there's any word, you know,
like that.

The most important thing is the list of medications. I think if you were
diabetic, somebody might be taking care of them, giving them medication,
they're seeing a doctor for intervention and that will influence your
GLUT4, you know, transporters. And they, you know, change the things
that you are measuring so it will be very important for us to know
precisely what were they taking; they were taking current medications,
and so on and so forth. And I hope you're going to show us that, you
know, the list of those medications.

**J. MICHALEK:** That will part of the next presentation. The detail is
not here today, but I have given those list of medications to Drs. Fumio
and Fujiyoshi. And they --- I must admit --- they are a bit overwhelmed
by the amount of data available because they're used to doing animal
studies on rats, mice and guinea pigs. And so this is --- we are working
in an unprecedented area here, an unprecedented complication.

**K. OSEI:** But the \...

**J. MICHALEK:** The medications are part of the complication, yes.

**K. OSEI:** Right. The pile of data in animals, are you --- can we have
access to that? Do you have the \...

**J. MICHALEK:** The animal data?

**K. OSEI:** Their data in animals.

**R. HARRISON:** I don\'t think, Kwame, that he's saying that there's
pilot data \...

**J. MICHALEK:** No, this is published data.

**R. HARRISON:** \... generated by these investigators. He was just
making the general comment that these guys were more used to working
with animals than people.

**J. MICHALEK:** It was based on their published data that this study
was launched.

**K. OSEI:** Okay.

**J. MICHALEK:** So I can tell you that the diabetic status does
influence the value of their measurements. And so you're right; this is
an important factor, however, whether we use the '95 or the 2002
definition is fairly irrelevant. As I understand it, the DNA resides in
the aqueous portion of the cell and these are adipose tissue cells.
There's a fat droplet in the cell. The larger that fat droplet, the less
DNA is available.

And so they expected to see a negative correlation with body fat and
they did between their measurements and the body fat measured in 1997,
which was the body fat exhibited by the men as they were having their
adipose tissue drawn. There was a significant correlation between these
measurements, which they view as artifactual because of the physiology
of the cells. Together with the four measurements that are prescribed by
the protocol \...

**R. HARRISON:** Oh wait, whoa. I\'m sorry Joel. There's something that
got missed in terms of what was being done. I mean, these people are
doing, are measuring these levels. They're measuring levels of messenger
RNA \...

**J. MICHALEK:** Messenger RNA; I'm sorry.

**R. HARRISON:** \... using a reverse transcriptase \...

**J. MICHALEK:** Yes.

**R. HARRISON:** \... polymerase chain reaction assay they have to
normalize. So what they do is to extract RNA from these cells and
probably use primers that find a very short, unique segment of the RNA.
In order to do that assay, they have to know how much RNA they're
putting into each test tube. So the fact that each cell by volume has
less RNA or DNA in it than a non-adiposite cell doesn't enter into the
equation because they should be using the same amount of RNA in each
test tube. So it can\'t --- I can\'t imagine that this correlation with
percent body fat is a simple matter of some cells having a lot of fat in
them and other cells not.

**J. MICHALEK:** Well, this is where we run into our problem of me
presenting this material. Let me read to you from the script, which was
written by them. "The log transform values were negatively correlated
with percent body fat at the time of adipose tissue sampling, suggesting
an effect of fat droplet size on messenger RNA yield. The transform in
GAPDH level was not significantly different between diabetics and
non-diabetics --- a p value of 0.02 --- suggesting that if this gene
were used to normalize the others, it would not introduce artifacts
related to diabetes." So what they were trying to do was find a way to
standardize these values in such a way that they would not introduce an
artifact. And they believed that these correlations were related to the
fat droplet size.

**R. HARRISON:** Okay. So it sounds like they didn't try and assess ---
okay.

**J. MICHALEK:** And in fact, I'm going to stay with the script now. I'm
not going to ad lib at all.

**K. OSEI:** Joel, one --- before you move forward, when you talk of
"percent body fat," how do you measure that?

**J. MICHALEK:** To do that, we measured body mass index, which was
weight over height squared in metric units, and we multiplied \...

**K. OSEI:** But that's not body fat.

**J. MICHALEK:** No. We measured --- the percent body fat calculation
has been used in all of our big reports. It's something like --- Bill
Grubbs, you can correct me on this --- 1.24 times BMI minus 13 roughly.
And that little linear equation was derived from a study done twenty
years ago on Army veterans to find a correlation between BMI and PBF.
And that's the --- that's the little linear equation we use. And of
course statistically, it makes no difference whether you use BMI or PBF;
the correlations are the same because one is simply a linear function of
the other.

**K. OSEI:** Which body segment did you get the fat --- the biopsies?
Was it the abdomen?

**J. MICHALEK:** Oh, it was the --- it was right here.

**K. OSEI:** On the front?

**J. MICHALEK:** The "love handles" so to speak, right in here. So they
decided to use GAPDH as the --- as the gene to standardize the others.
GAPDH is considered a housekeeping gene expressed at a constant level
regardless of external factors and is thus often used to normalize the
PCR-determined values of other genes for comparison among samples. The
literature\'s ambiguous about whether total RNA or GAPDH is a better
measure of normalization. But as our GAPDH ranges --- values range over
four orders of magnitude in one microgram total RNA, it is clear that we
must discard one of these measurements for normalization.

As obesity confounds values normalized by total RNA, GAPDH is a better
candidate. GAPDH, let's see, GAPDH eliminated --- that's this slide ---
GAPDH normalization eliminated the correlation of NFκβ and C/EBPα with
percent body fat. As you see on this slide, the significance is gone,
demonstrating that GAPDH is a suitable housekeeping gene for
normalization to remove the effects of obesity on messenger RNA.
Interestingly, GAPDH normalized C-SRC and GLUT4 still correlate with
body fat after normalization. However, the r squared is small.

That's the point they're making; that minus 0.23, if you square that,
you get about 0.05. So in other words, only about 5 percent of a
variation in GLUT4 was explained by body fat. So what we're talking
about here, our findings are now right on the threshold of knowledge and
there's little they can say except that it's interesting. They've never
seen this before. In fact, that's the --- that's the theme. I myself as
a statistician, I'm going faster than they can keep up with me in the
--- in the results. I mean, they're --- I produced a couple, two-three
hundred pages of statistical analyses that they're still trying to
understand.

**R. TREWYN:** As we all are.

**J. MICHALEK:** Yes. The genes were normalized by dividing by GAPDH
values and mean values were computed by group diabetic status and
percent body fat. I can tell you right now that there are no --- let's
back up one slide; I'm not here --- okay; there are no overall Ranch
Hand to comparison differences on these four measurements. However,
dioxin interacts very strongly with these measurements as you'll see.
And in particular in this slide, there's an interaction between diabetic
status, comparison exposure group and GLUT4 --- glucose transporter 4
--- in that this value right here, this 0 minus 0.61, is significantly
different from the other values in the comparison group, but not so in
the Ranch Hand group because there's something different about the Ranch
Hand group among lean non-diabetic individuals, and correspondingly,
lean non-diabetic individuals in the comparison group as regard to
glucose transporter 4. And that interaction reaches significance ---
less than 0.05.

There's something --- the statistical analyses which these are detecting
a significant change in the relationship between diabetic status and
glucose transporter 4 between Ranch Hand and comparison groups among
lean non-diabetic individuals; namely that this --- there's a
significant increase in the glucose transporter 4 expression among lean
non-diabetics in the comparison group, but not so in the Ranch Hand
group.

**P. CAMACHO:** Not so?

**J. MICHALEK:** Not so. This is, in other words, in the Ranch Hand
group, there is no such, but there are other correlations in the Ranch
Hand group that are significant. But I'm just pointing out one; I know
that there are many.

**P. CAMACHO:** You talked about the lean people.

**J. MICHALEK:** These particular --- I'm just isolating a particular
example of what we would call a three-factor interaction between group
diabetic status and GLUT4.

**P. CAMACHO:** All right. For us sociologists, does this take us back
to the issue of the two lean people that we left out?

**J. MICHALEK:** We're talking right now only about those individuals
that are left in and these are the individuals. These data are
summarizing the 313 people who are actually in this study.

**P. CAMACHO:** But if we had --- but the lean issue is what I'm \...

**J. MICHALEK:** If there was some --- perhaps some way to have included
those that were deemed too lean to be in the study, perhaps the results
would've changed. But then it may be true about other people who weren't
included in the study either. I\'m just telling you \...

**P. CAMACHO:** Yes.

**J. MICHALEK:** \... what we find among 313 that are in the study.

**K. OSEI:** Were the diabetics in the Ranch Hand Study different with
respect to BMI than in the comparison group --- the comparison diabetic
group? Could that make a difference?

**J. MICHALEK:** I'm sorry I don't have that demographic information;
all I have for you is this. These are the sample sizes. To the extent
--- I can answer your question to the extent of the design; that these
individuals who are diabetic --- sorry; let's go down here --- the older
Ranch Hand diabetics, five of them were deemed to be obese. And the old
--- of the older diabetic comparisons, nine of them were deemed to be
obese meaning they --- these nine and those five both have percent body
fat greater than 25 percent. You want to know whether the average body
fat of those nine was similar to the average body fat of those five? I
don't have that slide handy, but I can maybe get it over lunch for you
guys. I have the data on my laptop.

**K. OSEI:** Given the small sample size you have right now \...

**J. MICHALEK:** Small numbers.

**K. OSEI:** \... do you have power to look at this?

**J. MICHALEK:** For individual sample size --- little cells like this
one of three people --- obviously we do not have a lot of power there;
that's true. But we do have power as you'll see for combinations of
these --- of these factors.

**M. STOTO:** Can I make a comment? I'm clearly not familiar with the
biology here, but it strikes me that when you're looking at third-order
interactions, that's --- you're on pretty thin ice in statistical terms
and it's hard to interpret those in the best of situations. But when you
have sample selection issues like we talked about earlier, I could
easily imagine those causing third-order interactions and us not really
understanding how that would be the case.

**J. MICHALEK:** That's true. You can easily produce many, many
third-order interactions there beyond the ability of them to interpret
and the problem is to sort your way through all that. And there are ---
there are ways and I'm leading to that on the last few slides. So you
can go off and produce all kinds of things that are not interpretable.

**R. HARRISON:** Why don't you lead on, Joel, and \...

**J. MICHALEK:** Okay.

**R. HARRISON:** \... and maybe what we'll \...

**J. MICHALEK:** Your points are well taken.

**R. HARRISON:** \... maybe what we'll do is let\'s let Joel \...

**J. MICHALEK:** Finish.

**R. HARRISON:** \... dig a --- dig a little bit deeper \...

**J. MICHALEK:** Hole.

**R. HARRISON:** \... before we start shoveling on him.

**J. MICHALEK:** Thank you. Well, here's another example of an
interaction which now involves dioxin. I have to tell you that the
normalized --- the values for GLUT4 or the raw values show similar
trends with dioxin as when they're normalized by GAPDH or even when
they're normalized by other genes further validating the GAPDH
normalization. GLUT4 is down-regulated in lab animals exposed to dioxin.
This is one of the results that led to this particular study. However,
among lean diabetic Ranch Hands, GLUT4 increases with dioxin --- with
dioxin load.

And there's dioxin across the horizontal axis up here in this cell and
you see a significant trend --- a p value of 0.02 on that trend ---
whereas, you see no corresponding pattern in the control group. You see
it in the Ranch Hand group, but not in the control group and that change
from this slide to this one is significant. That's called an
interaction. They speculate that perhaps GLUT4 expression has become
uncoupled from glucose regulation in the Ranch Hand group as influenced
by dioxin. And there I've brought you almost to the threshold of
knowledge to the point where I cannot push these two guys any further on
interpretation for another couple of months until I visit them again.

Now how do you make sense of all this data? Well, one way is to use
existing biological pathways that they believe up until now had been
established in animals. And this is accomplished by a means of path
analysis, another statistical procedure which is now heavily dependent
on the subject matter specialist to provide beforehand, before even
seeing the data, to provide a pathway. And then the job of the
statistician is to ask whether the data is consistent with the pathway.
And this is a new field which has been applied a lot in sociology and
psychology, but only now for the first time to this area of toxicology.

What you have here is a path diagram which was postulated by Dr.
Matsumura before ever having seen the data. This is a pathway that he
had derived from his animal experimentation: that he believed the dioxin
should influence C-SRC, and body fat influence NFκβ, and that those two
would be upstream from the outcome, which was diabetes measured here by
fasting glucose. The job of the --- statistical job is to invoke a SAS
procedure called "PROC CALIS" to describe this pathway, which is called
"recursive" in this case because we're --- well, this is called --- this
is an example of recursive pathway, which there's a causative pattern
from left to right.

The arrows mean that dioxin is supposed to cause changes in C-SRC; C-SRC
causes changes in C/EBPα and so on to GLUT4, and finally producing a
diabetic state. In fact, of course, they will point out very quickly
that there are feedback loops involved in the process. And to a
statistician, those are called "non-recursive" paths. The procedure or
the SAS procedure that estimates these parameters and p values is fully
capable of incorporating feedback loops and I've invoked those. However,
there's a complication in the method itself to produce a path that is
not only biologically sensible, but which is in fact numerically
solvable. And you can easily go off and produce a path which is not
numerically solvable. This path is; this path diagram is solvable.

The diagnostics in the software will tell us whether or not the path
diagram is explaining the data. And in this case, this path diagram is
--- according to the diagnostics --- is fitting in the Ranch Hand
cohort, but not in the control cohort because the null hypothesis is
that the path is explaining the data. The alternative is that it's not
and so our rejection, a large Chi-square as you see in the comparison
group, indicates that this path is not holding in the comparison group.
But the p value above 0.05 in the Ranch Hand group indicates that the
path is explaining the data in the Ranch Hand group.

Other diagnostics in the software will tell us whether paths exist that
we had not taken into account, whether there's a statistical basis for
paths that were not in the original diagram. The path from dioxin to
GLUT4 was not in the original diagram. The original diagrams provided by
Dr. Matsumura did not include paths from dioxin directly to GLUT4 or
from PBF directly to GLUT4. Invoking the SAS procedure on the path
diagram without those paths produces a diagnostic that tells us that
literally, SAS wants to put a path from dioxin to GLUT4. And if you
don\'t put a path from dioxin to GLUT4, you're going to degrade your
fit. That\'s the procedure.

The method is supposed to be conducted in close coordination with a
biologist to determine every step of the way whether the paths make
sense biologically. Following the diagnostic from the SAS routine and
the input from Drs. Matsumura and Fujiyoshi, I drew a path from dioxin
to GLUT4. And when you do that, you find a significant link from dioxin
to glucose transporter 4 further upstream than they had thought. They
didn't expect to see this. And not only did they not expect to see it,
they expected to see a negative correlation, and in fact, it's positive,
which is consistent with the scatter diagram I showed you on the
previous slide, suggesting to them that there is something being
disrupted by dioxin and its connection with glucose transporter 4 and
diabetes.

There, I have brought you to the final interpretation. There's nothing
more that they can say at this point; I expect to visit them again in a
couple of months. The analysis is very difficult and can only be done
together in front of a computer with interactions with them. So what
we've got is a data set that is, to put it mildly, complicated.
Interactions, to put in terms --- statistical terms --- prevent simple
interpretations. Interactions prevent the analysis of main effects, to
put it in statistical terms. There are no simple main effects, but there
are interactions. And as you saw on the previous slide, some of those
interactions may be interpretable.

And as you already realize, small sample sizes prevent more detailed
path analyses. Path analyses have been applied to a very large data set;
it's over 1,000 subjects. We have 300. And the limitations of the path
analysis is that they must include normally distributed data. So I can't
include a single path for all --- both cohorts combined because I can't
include a group flag Ranch Hand control. The data must be normally
distributed. So I have to make a separate path and apply it to Ranch
Hand and a separate path and apply it to comparison. So when I do that,
I have to cut the sample size in half. So now we're down to about 120
subjects, which is pushing it to the --- to the limit of believability.

And of course, the power of the drill path analysis is to --- is to
invoke a model to fit it to a data set and then replicate, conduct the
study over again somewhere else on a different cohort. And of course,
that's not possible. And finally, there may be other factors that we
haven't measured. In the path diagram associated with each of these
components is an error term --- a statistical term which is there to
measure error. Those error terms are supposed to be uncorrelated; in
fact, in the data set they are. And that's a flag to indicate there are
probably other factors involved common to these which we have not
measured and that's causing correlations between the error terms. And so
that will be mentioned in the final discussion section of the paper.

So what we've got is that this is the first study of dioxin and gene
expression ever done. It has been done under strict quality control. We
have complete data on every subject. We have good follow-up and many
risk factors were measured that includes medications which haven't even
been dealt with yet in this presentation. And of course, the limitations
are --- which you've already pointed out --- sample sizes, interactions,
replication is not possible, and unmeasured factors. So the bottom line
at this point today is that the data suggest dioxin may be disrupting
the normal diabetic pathway through interaction with GLUT4. However,
they will be quick to say that more study is needed, including more
thinking about the complex regulatory mechanism of diabetes and other
pathways. Thank you very much.

**R. HARRISON:** Who shall cast the first stone?

**M. GOUGH:** I have two questions: one's about the biology. What is the
--- I don't know about animal studies they're depending on. But
typically, animal studies of biochemical interaction or biochemical
studies with dioxin are done at doses that are thousands of times higher
than those experienced in human beings. What is the \...

**J. MICHALEK:** Well \...

**M. GOUGH:** What is the ratio here between the animal studies and what
people have --- these people have?

**J. MICHALEK:** Good point. In fact, those are --- that was the reason
why we focused on Dr. Matsumura's research in the first place. He was
working in a --- in a --- in a dose range which is compatible with what
the Ranch Handers received in Vietnam. In other words, he was working
with less than one-tenth of a microgram per kilogram body weight
exposure to the animals. The animal --- other animal studies you're
talking about were very heavy exposures to the point of toxicity. These
are very light \...

**M. GOUGH:** Yeah. Yeah. Okay.

**J. MICHALEK:** \... very, very small doses. And I think they can
defend that point and it will be defended in the --- in the introduction
to the --- to the paper.

**M. GOUGH:** Okay. Well, that's good. The second thing is on the ---
you have a slide entitled "mean raw gene expression."

**J. MICHALEK:** Yes.

**M. GOUGH:** Those numbers were the --- I mean, those numbers between
the comparison to the Ranch Hands were the same so far as I \...

**J. MICHALEK:** That's a display of the fact that there are no --- what
we would call "main effects" in the data set.

**M. GOUGH:** Yeah. So why shouldn't I --- given reservations about
sample selection, and exclusion of people and then what Mike said ---
and I don't --- I'm taking his word that a statistician said that these
third factors \...

**M. STOTO:** Third-order interactions.

**M. GOUGH:** \... third-order interactions being weak, why shouldn't I
walk away from this saying there's no difference at least between the
Ranch Hands and comparison?

**J. MICHALEK:** You can easily do that. In fact, you can do that \...

**M. GOUGH:** Good.

**J. MICHALEK:** \... at any time you want to.

**M. GOUGH:** But in fact, you're getting into this morass. What I ---
I'm not a statistician; I'm also not a diabetologist.

**J. MICHALEK:** I know what you're saying. Go ahead; I'm sorry.

**M. GOUGH:** But you're just getting into this morass of analyses and
I\'m not --- it --- I'm not sure if it\'s informative. It's not
informative to me; I don't know if it's informative to anybody. And I'm
wondering about what the endpoint in your mind is?

**J. MICHALEK:** To me, the endpoint is about this slide right here:
it's to reach a consensus by the biologist that this path --- a pathway
like this or similar to this --- is either supported or not supported by
the data.

**M. GOUGH:** Can you do that with the qualifications about who was
excluded and who was included and \...

**J. MICHALEK:** Let's --- actually, all I can tell you about that \...

**M. STOTO:** Can I respond to that?

**J. MICHALEK:** Yes, go ahead.

**M. STOTO:** First of all, I want to say that I think it's important
that this kind of study be done. I mean, this is --- this is an example
of how the Ranch Hand Study is providing information that's potentially
very valuable for understanding the causes of diabetes, the natural
history of diabetes. Now that doesn\'t mean it's easy to sort out what
these --- what this all means and --- but, you know, when you do
observational studies in humans, this is always the case; that you have
to sort of do the best you can and then when you write up the
interpretation, say, you know, is it possible that what you found is due
to the limitations in the study? And you just have to look at that
carefully and make a judgment.

And I think that the --- that the key issues here that need to be looked
at --- and I have every confidence that they will --- are, is whether
issues in the sample selection --- I mean, you don't have complete data
on everybody. You have complete data on people who weren't lean and who
weren't on medication. And both of those things seem to me to have the
potential for putting bias into this study and there needs to be careful
thought about whether that is the case. And that's what a discussion
section of the --- of the paper ought to do and I presume you will do.

The other issue, potential I think that needs to be looked at is that
when you look at the two slides that have to do with the --- with the
scattergrams --- it's just the one above this and the one before that
--- one thing that you see and you've --- we're not surprised is that
the Ranch Hands have more dioxin body burden than the controls. That's
the very nature of the study. And I mean, it strikes me that, you know,
the relationship that we see --- I mean, I think the key thing here is
that in the --- on the right --- the two graphs on the right goes up on
the top and it goes down on the bottom when if you go to the comparison
slide, who knows whether that would be the case if you had people with
more dioxin?

I mean, it's simply not enough, particularly in the --- there's simply
not enough people with high levels of dioxin to see whether the slope
goes up that way. So I mean, I think that you have to look at this and
you have to consider that, but that\'s an important thing that needs to
be \...

**R. HARRISON:** Kwame?

**K. OSEI:** Yeah. Joel, I'm so very confused about whether dioxin
increased or decreased messenger RNA of GLUT4. So far, I haven't seen
it. And as you know --- maybe Phillip might've talked to you about the,
you know, what GLUT4 does. GLUT4 is just a plain glucose transporter
that pushes glucose into the cell. And the two components over it is the
number of GLUT4 and the activity of GLUT4.

So you can have any of these variables being changed that will impact
on, you know, diabetes. What we know in diabetes in humans is that GLUT4
is either the same or down-regulated to give you an inability to
transport glucose. That's when you become diabetic. So far, I don't see
any --- the connection at all from the evidence that you have; either
you have true diabetes. And so, it's not explainable to me by what
you've provided so far, you know. So probably Phillip needs to sit down
and look at this very carefully.

**R. HARRISON:** Kwame, what you\'re saying is that if dioxin produced
diabetes, you'd expect GLUT4 to go down, but the data looks like it goes
up?

**K. OSEI:** Right.

**R. HARRISON:** Is that what you're saying?

**K. OSEI:** That's what it is.

**R. HARRISON:** Okay.

**K. OSEI:** The data is saying that \...

**R. HARRISON:** You just have to explain this for a country boy from
Mississippi.

**K. OSEI:** Yes. You have to increase your --- actually, if you
exercise, you increase your GLUT4 and that prevents you from becoming
diabetic. So if I take dioxin, which I'm not going to take, and to
prevent --- I hope that it will prevent diabetes if what you're saying
is true; that I should increase my GLUT4 numbers with proper activity.
If I don't do that, then something else is wrong. It means either the
GLUT4 is not representative or reflective of dioxin effect and there has
to be some other variables, you know, that you need to go back and look
at.

That's where the whole idea of exercise becomes very important, and the
physical fitness becomes important and other medications that these
people were on. But we know a lot of these medications may, you know,
influence GLUT4 levels, such as TZD, and so on and so forth. So it's so
important that you tease out all that before you even you start doing
all these pathways because I think you muddy the water by excluding, you
know, not including all those variables.

**R. HARRISON:** For the transcription, that\'s "TZD" ---
thiazolidinediones.

**M. STOTO:** I think that what these graphs here on that slide are
showing is that there's a positive relationship between dioxin in GLUT4
in lean people and it's a negative in obese people. And then the other
set of slides shows that there's --- that it's no such relationship to
either one for the non --- for the control group. Now what that means, I
don't know, but that's --- I think that's what they've --- I think
that\'s the key thing they found, right?

**J. MICHALEK:** So far. This is all I'm willing to talk about at this
point. They have a lot more on their table than this, but \...

**R. HARRISON:** Just to --- just to --- a couple of other points: and
that is that there's intracellular feedback mechanisms that require one
at some point in time --- I'm not suggesting that it needs to be done
now --- but it requires you at some point in time to establish that the
changes in messenger RNA levels that you're looking at here are actually
reflective of changes in protein transcription or changes in protein
levels and not some other, for instance, a reduction in GLUT4
degradation, which then essentially feeds back on the GLUT4 message and
reduces its activity. So at some point, you're going to have to make
that kind of correlation.

**J. MICHALEK:** Yeah. Exactly. Yes.

**R. HARRISON:** The \...

**J. MICHALEK:** I wrote code to run a feedback loop from GLUT4 to PBF
and from C/EBPα and of NFκβ.

**R. HARRISON:** Those are all --- you're all looking at, with the
polymerase chain reaction, you're looking at MRNA levels. And I'm saying
that actually, the assumption implicit in that is that MRNA reflects the
amount of protein being synthesized. It's the protein that does the
work, but that's not always the case. And someone\'s going to ask you at
some point to show that protein levels are actually changed either by
immunohistochemistry, which is kind of qualitative, or by some other
means of actually measuring the amount of GLUT4 in the cell.

**R. TREWYN:** The activity part of it.

**R. HARRISON:** Yeah. Yeah, even as far as activity is concerned. The
--- almost the point I should've made first is that I view all this as
phenomenology that says that this phenomenon occurs. And until you
actually have the mechanism or mechanistic explanation of what's
occurring, I think we all understand that what we're looking at here are
phenomena. And what we see in this study is not a mechanistic
explanation, but is an investigation of phenomenology at the cellular
level as opposed to the investigation in large population groups.

The last thing I want to suggest, Joel, is that there are a number of
projects around now that are doing cell simulations, computer
simulations of cells. And the one that comes particular to mind is a
Japanese project that I believe is called "E-CELL" --- E hyphen CELL.
And I just remember that they've done a lot of work with glucose
metabolism in this simulation and there's some non --- there are
non-intuitive things to be found when you start actually putting these
simulations together. And I think that this plays right to your
strengths in terms of how to analyze data and would be a different way
of looking at this than a straight statistical --- these are --- these
are actual --- they're actually cranking in all the different parts and
then tweaking little parts at a time.

**J. MICHALEK:** Thank you.

**R. HARRISON:** Oh, and I --- and I would like a copy of the manuscript
when you --- when you all \...

**J. MICHALEK:** As soon as they're ready to let go of it, yes.

**R. HARRISON:** Yeah.

**J. MICHALEK:** Just another note: these asterisks mean that the
coefficient is positive and significant --- statistically significant
--- connecting C-SRC, and C/EBPα and NFκβ, C/EBPα, which is completely
consistent with their --- with their preconceived ideas regarding what
the pathway really is. So they see that as a strength. That's all I had
on that study.

**R. HARRISON:** Now we have Syndrome X?

**J. MICHALEK:** Yes, I think. No. We have cancer in the comparison
group and Syndrome X comes --- if you want, we can do Syndrome X next.

**R. HARRISON:** I'm sorry, Joel. The agenda says Syndrome X is next.

**J. MICHALEK:** Syndrome X, all right.

**R. HARRISON:** I --- go ahead. I'm not --- no; no, seriously. I think
the papers are arranged in the cancer order.

**[Cancer Prevalence in Comparisons]{.underline}**

**J. MICHALEK:** Okay. During our analysis of the data which will soon
be published in the *Journal of Occupational and Environmental
Medicine*, we discovered trends in the comparison group that were
unexpected and the purpose of this presentation is to show those to you.
First off, Marian Pavuk is with us here today. Fatema Akhtar no longer
is with us; she moved to the University of Texas. This is the bottom
line: cancer prevalence is adversely related to years of service in
Southeast Asia in the comparison group. And as you will see, this has
apparently nothing to do with dioxin or Agent Orange.

And like I just said, we discovered this pattern while analyzing Ranch
Hand data. We\'re using the same materials and methods that were used in
the Ranch Hand cancer analysis --- the same data set. Cancer prevalence
is determined through 31 December 1999; all cases confirmed by record
review and this includes all individuals who were either partially or
fully compliant to any physical exam through the 19 --- to the fifth
one, which is up to 1997. Currently, we are updating our databases and
should have the new data up through the current physical ready within a
couple of weeks.

This analysis includes people who were what we call "partially
compliant," which meant they simply came, and were interviewed and then
refused to take a physical. And most of those partial compliants
occurred in the baseline exam. And of course, you know, adds an sample
size, but no physical exam data for those people. Time to onset is
measured and this is different; we'd never done this before: measured
from the end of the last Southeast Asia experience to the earliest
occurrence of cancer, death or end of follow-up.

In all of our previous reports, we had measured time to onset from what
we would call the "qualifying tour," which was the tour that was used to
identify an individual to be in the comparison group in the first place.
But because we found this association between years in Southeast Asia
and cancer, we've decided to extend the cut point to the last Southeast
Asia experience in an attempt to imitate exposures that would occur in
industry, for example, where time to onset is measured from the last
exposure period.

We assumed a fifteen-year latency, which meant cancers that occurred
within fifteen years of the last Southeast Asia experience were not
considered. They were intentionally excluded. And anyone who didn't have
fifteen years of follow-up from the last Southeast Asia experience was
excluded. So people, to get into this study, had to have fifteen years
of follow-up after the last Southeast Asia experience to be in this
study in the first place and that didn't exclude very many people
because of the good follow-up we've had. Did you want to ask a question?

**R. TREWYN:** Yeah. Southeast Asia, because the comparison group
consists of individuals who were stationed outside of Vietnam and those
who were stationed in Vietnam, has that been segregated out in this
study?

**J. MICHALEK:** Not yet. I'm showing preliminary information.

**R. TREWYN:** Okay.

**J. MICHALEK:** What you will see is that --- and it may surprise you
--- that the Southeast Asia tours occurred between 1942 and 1982.
There's a spread of Southeast Asia tours that coincide with World War II
and move all the way up to the present time. There are tours from those
early years all the way to the present. And the maximum amount of time
spent in the Southeast Asia region among comparisons is about fifteen
years. We're using the same cancer definitions that we've used in the
other papers we're working on --- all of them prescribed by the National
Cancer Institute Surveillance Epidemiology End Results section, the SEER
cancer category definitions.

In particular, the all-site SEER category includes all cancers except
basal cell and squamous cell carcinoma, which we call "non-melanotic
skin cancer." And throughout the entire analyses, we used proportional
hazards modeling, which includes not just a flag as to whether or not
they had cancer, but includes the actual time from exposure to onset.
All of that is taken into account along with other risk factors. Other
risk factors for all-site cancer that were accommodated in the model
include year of birth, race, military occupation, skin reaction to
sunlight, eye color and pack-years of smoking.

Pack-years of smoking is measured from baseline because to use
otherwise, to include pack-years of smoking up until the present time
would induce an artifact because then we would have a --- what's called
"time-dependent covariate," which would continue to accumulate value as
the years passed and it\'s not a good idea. Respiratory cancer is
adjusted for, of course, pack-years, and age, race and military
occupation. Prostate cancer --- the same covariates we used, in fact, in
the Ranch Hand paper which is soon to be published. And digestive system
cancer is year of birth, military occupation.

These covariates are derived from our knowledge of the literature and
are subject to change depending on new information about covariates. And
there's a set of covariates for the skin cancers; they were restricted
to non-black veterans which include about 92 percent of the cohort
adjusted for those variables: skin exposure, and eye color and military
occupation, year of birth. We began with 1,785 comparisons who were ever
partially compliant or fully compliant to any exam between 1982 and
1997.

For the purpose of dioxin summaries, we excluded people with no dioxin,
of course, but those were not used. This dioxin reduction was not used
in the main analysis. It's only used in one place and that's only to
show you that the data we have are unrelated to dioxin level. It's the
sample size 1,785 that's important for cancer analysis. Using standard
methods to display data, we broke the range of years spent in the
Southeast Asia region by up into quartiles and that produces a balanced
design of approximately equal numbers of subjects by interval of time.

It does not produce nice intervals, but it does produce a balanced
design which gives us better statistical properties. So what you\'ve got
is that about 50 percent of the cohort spent less than 2.1 years in
Southeast Asia, for example. So 2.1 is the approximate median of years
spent in the Southeast Asia region. Demographically, we have a situation
where there's a strong age effect. Those individuals who were there
between 3.6 and fifteen years were born in approximately 1934 and those
that were there for a short time between 0.1 and 1.3 years were born in
1945. There's about a ten-year difference in age there, which is
accommodated by the analysis.

And their age as represented on the second line --- laser pointer just
quit; oh well --- represents their age during the qualifying tour. Thank
you. Qualifying tours were primarily during the Vietnam war period.
Baseline pack-years of smoking, you see a strong trend of increased
smoking with increased years in SEA; the analysis accommodates that too.
Let's see; which way do I have to --- got it; there we go. Smoking ---
and of course, it's flat with regard to dioxin. These men are all at
background levels and what you see there, perhaps a slight age effect.
We know that dioxin levels increase with age, so what we might be seeing
there is an artifact simply due to the age differences.

And the tour years coincide, like I said, with the --- is the qualifying
tours with the war itself and the body fat is the body fat measured
during their qualifying tour. They were all relatively lean then. Days
in SEA, of course, they go up with years spent in SEA --- up to 1,500
days in --- that's the median in the high category. And days in Vietnam,
there's a trend too down to 75 days, median in the lowest category. And
all the other variables are fairly stable. Enlisted ground individuals
are less represented in the longer time periods in the region and
officers are slightly more represented.

All of these variables are statistically accommodated by the
proportional hazards model. These are data on the reported exposures
that we gleaned from the National Opinion Research Center questionnaires
that were given during the physical exams. This --- the question was,
"Have you ever been exposed to asbestos --- yes or no?" This is very
rough data. "Were you ever exposed to insecticides in your whole life?"
And so you see these numbers and they're fairly stable across the years.

Well, here's the bottom line. On the highest years in SEA category, we
have a significant increase in the risk of all-site SEER cancer in the
comparison group: relative risk 2.9, p value less than 0.001. And
there's a significant trend of increased risk with increased years in
SEA: a p value less than 0.001 in the comparison group. That's after
adjustment for age, smoking, skin color and eye color, military
occupation and all the covariates I\'ve listed before.

A significant increase in the risk of cancer of the digestive system ---
smaller counts --- prostate cancer in the high category. In other words,
high years of exposure is a relative risk of 8.7, p value 0.003. We have
done supplementary analyses to probe this data to make sure that the
proportional hazards model is not leading us astray. And we have
demonstrated that that is the case; that the SAS proportional hazards
procedure is in fact not leading us astray and that we are not --- we
are not simply displaying an artifact due to age.

Cancer of the respiratory system is there's a weak trend overall, but no
significant increase in relative risk in the high Southeast Asia
category. The numbers in melanoma were too small to analyze and there
was no significant trend or increase in relative risk in any Southeast
Asia category with regard to basal or squamous cell carcinoma. And here
are the other sites: and you see lots of zeroes, and small numbers and
which is the reason why these were not analyzed. There's nothing here
that stands out as a --- as a cause for alarm in other words.

And just to show you what happens if we give up the fifteen-year
latency, what happens then is the findings go away and so it seems to be
important that there be a fifteen-year latency. In fact, you can --- you
can change your latency definition and find a continued statistical
significance if you push it out to even twenty years. And here is one of
our checks on the proportional hazards model to make sure we weren't
simply seeing an artifact; and that is, we stratified by year of birth,
and by Southeast Asia years and we considered prostate cancer. And you
find that if you --- if you combine the first two years of birth
categories and assess trend using a Chi-square method called the
"Mantel-Haenszel," a Chi-square test for trend, you find a significant
trend of increased risk among individuals born prior to 1944.

So in other words, this supports the idea that the proportional hazards
model is giving us a non-artifactual outcome. And here's the histogram
of those tours running all the way from World War II up to the present
time --- the bulk of them, of course, occurring during the Vietnam war.
So the issue, of course, is why are we seeing this? And all we can say
at this point is that it appears that whatever it is, appears to be
unrelated to dioxin or any exposures to dioxin-contaminated herbicides
that may have occurred somehow during the war.

Where were they when they were over there? Well, that question itself is
obvious, but difficult to answer. We're still working to create a
database of exactly where they were during all of those tours from World
War II to 1982. That's a very labor-intensive goal, task because these
men have many tours: TDYs all the way up to PCSs which are all recorded
and require line-by-line study and interpretation because unit
designators change with time. An individual that may be with the 130^th^
Air Tactical Squadron may have been stationed in Taiwan in 1965, but may
have been stationed in Alaska in 1972, you know.

So you have to know you can't simply use the designators as your
information. You have to study these and we've been working to do that;
we're not done yet. We're still creating a database of location ---
exact locations and dates. And we'll have that, but we don't have it
today. And of course, we don't have a detailed exposure history of
information from these men while they were there. That was not
collected, unfortunately. We only measured one chemical and that is
dioxin in these men. We didn't ask them about what they did over there,
about their diet and about their exposures. We never did that.

The strengths, of course, are the same strengths applied to the whole
study: everything is verified up to three times by record review; we
have rigorous quality control; and dates of onset are all determined by
record review, not by the individual's opinion. So what could be the
reason? We believe intuitively that what we're seeing here is that the
Southeast Asia --- time in Southeast Asia is a surrogate for something
else and we don't know what that something else is.

A candidate --- speculation is something in the environment, something
in the water, or the food or perhaps insecticides. During the Vietnam
war, the World Health Organization implemented an extensive campaign to
eradicate malaria in the entire Southeast Asia region and that\'s been
documented in the literature. And of course, there are the tropics
themselves and everything that goes along with that.

So what we've got is a strong effect in the comparison group which has
confounded our analysis of cancer in the Ranch Hand group and will
continue to do so as long as we're with this data because this isn't
going to go away. We're talking about trends that were produced years
ago and are not going to change. Whatever we're seeing has nothing to do
statistically with dioxin and we don't know what it is. Thank you.

**R. HARRISON:** Mike?

**M. STOTO:** Well, I think this is very interesting and this is another
good example of the kind of work that can be done with these data and
nicely done as well. The thing that troubles me is the big difference in
smoking between the people who were there a long time versus a short
time. And I understand that you\'ve done your best to control for that
statistically, but you know, that's never --- there's always a
possibility that you can't control all of it statistically.

It is reassuring that the things that you've --- that the --- that the
cancer sites that you found to be significant, digestive and prostate,
are the ones that are not generally thought to be associated with
smoking. So that suggests that smoking may not be the problem. The fact
that there is a trend though in respiratory cancer suggests that maybe
there might be something there, but the sample size may not have been
big enough. So I guess one thing I would suggest is to maybe group
together, you know, the five or ten cancer sites that are most thought
to be associated with smoking in some sense and maybe see whether you
find anything there just as a check.

**R. HARRISON:** If memory serves me correctly, there's more liver
cancer in Asians than there is in Americans, which would come under the
heading of digestive system. And it led me to wonder if this difference
between the occurrence of digestive and prostate versus respiratory and
skin might be reflected in people who have always lived in Asia versus
people who just passed through there during the military; that what
we're reflecting is something environmental, but something that's --- if
it's environmental, it should be reflected in the indigenous population
as well as the visitors.

**M. STOTO:** Isn't it thought to be associated with hepatitis?

**R. HARRISON:** Well, my guess would be that it's associated with
viruses that like to live in hepatic cells; I'd be a little more general
than that. It may even in some cases in some particular areas be related
to parasitic infestations that involve the liver as well. Yes sir?

**S. LEFFINGWELL:** Leffingwell. I think I have heard about an
association between human papillomavirus and prostatic cancer, which
would lead to the possibility of sexually transmitted diseases and
prostate cancer. And I wondered if we had either a serological method of
looking for HPV antibodies, or as a surrogate, looking at treatment for
sexually transmitted diseases during their tours in Vietnam. Similarly
if it should turn out that the liver is in fact the site in the
digestive system that's high, then certainly looking at hepatitis B and
C, which also might correlate with treatment for gonorrhea --- it
certainly does in the civilian population --- might be helpful. Now why
that would or would not correlate with dioxin exposure isn\'t at all
clear, but there may have been some unit factors, morale sorts of things
that would affect it.

**J. MICHALEK:** Let's see. Dr. Pavuk has done a literature review on
this.

**R. HARRISON:** Dr., if you could come to the microphone somewhere,
it's going to help us. Otherwise, Mike Stoto's going to get on us about
transcription and everything.

**N. RIVERA:** State your name, sir.

**M. PAVUK:** Actually, I would've \...

**R. HARRISON:** State your name, please.

**M. PAVUK:** Marian Pavuk. I'm an epidemiologist; I work with SpecPro
on the Air Force Health Study as a contractor with Dr. Michalek. I
worked previously on the study when I was still at the University of
Texas with Dr. Schecter also. Concerning the digestive system, there
have been 26 cancers of the digestive system. And of those, there were
--- there was only one liver cancer identified in those cancers. There
were six cancers of colon, nine cancers of rectum-to-stomach cancers,
and three pancreatic cancers.

So except for a slightly different proportion of colon and rectal cancer
which usually is a little higher --- more colon than rectal cancers in
the general U.S. population --- we didn't --- we couldn't see, because
of the small numbers, couldn't really say, you know, with just one liver
cancer whether there was something unusual about the distribution of the
cancers --- digestive cancers in this group. You correctly stated that
infectious diseases or parasitic diseases in the --- in the region are
really related to liver cancer. For example, Thailand has the highest
rate of liver cancers in the world reported related to those other
diseases.

**R. HARRISON:** Yes sir?

**R. TREWYN:** Any correlation to head and neck tumors? That
nasopharyngeal carcinoma is very \...

**M. PAVUK:** Is another \...

**R. TREWYN:** \... characteristic \...

**M. PAVUK:** Is another characteristic group of cancers in this area. I
don't think we had any numbers --- really, very small numbers in those
areas. I don't think really, there was only two brain and central
nervous system tumors all in all at this point and no nasopharyngeal.
But that's not what the doctor is suggesting.

**R. HARRISON:** Mike Gough?

**M. GOUGH:** Just two things: one is when the members of the Committee
and you guys review these slides, I --- you --- I would appreciate, I
think other readers would appreciate if you would pay attention to the
labeling of the slides because the "all-sites" --- you have a slide
called "all-sites cancer" and that's really the slide where you
eliminate the latency period.

**J. MICHALEK:** That's true.

**M. GOUGH:** And it \...

**J. MICHALEK:** That slide needs a better title.

**M. GOUGH:** And it --- I've had that feeling in the --- in the earlier
discussion too. I read the title of the slide and it wasn't very
informative; it didn't focus me.

**J. MICHALEK:** Yeah.

**M. GOUGH:** The second thing is I think you're biting off much more
than anybody should chew than try and thinking you're going to be able
to find an exposure or exposures to associate with these excesses; 25
percent of us get cancer and very, very, very rarely can anybody point
to what caused it. And I just --- I mean, I think looking at the unit
locations may be a reasonable thing, but beyond that, I\'m not --- I'm
sure you have more valuable things to do.

**R. HARRISON:** Any other --- yes?

**M. PAVUK:** Yes, if I may, that's, you know, the stored samples which
include blood samples for the Ranch Hands and the comparison veterans
would still be analyzed for the whole battery of other organochlorine
compounds and investigate, for example, if DDT, or DDE or pesticides
used in Southeast Asia has any association with this cancer trend
observed.

**R. HARRISON:** Thank you. Anyone else?

**R. TREWYN:** One more point: I also think chlordane was used a lot,
which has been banned in that part of the world at least during that
period of time, and might be another candidate if you feel compelled to
search for possible associations.

**R. HARRISON:** Thank you very much. Let\'s see. We're running almost
--- well, we're running at least a half hour behind. We were supposed to
have a break at 10:30. I feel the urgent need for --- to have --- to
have --- to have a cigarette. Does anyone else object to us taking a
break now and for let's say ten minutes and resuming? We can perhaps run
just a little late into the lunch hour, and try to catch back up and
maybe even change the format by holding our questions until the end of
the presentation rather than sprinkling them through the presentation.

**R. TREWYN:** Is there any reason we can't work through lunch?

**R. HARRISON:** Yes.

**L. SCHECHTMAN:** If I can comment there, we're having lunch brought in
so that we can --- we can make that judgment as we proceed through the
morning depending on how much time Joel needs. So I'll take the
executive secretary's prerogative, and if need be, overrule the
chairperson.

**R. HARRISON:** Fine with me; last time. Ten minutes.

**\[BREAK 11:02 A.M. - 11:20 A.M.\]**

**R. HARRISON:** Okay. Dr. Camacho is back; we can get started.

**J. MICHALEK:** Let me make a correction; I made a mistake. I'm going
to back up right here; that's not it. Right there. I said that this
slide described the all-site cancer without regard to latency; that's
not true. This is --- yeah --- this slide is still with the fifteen-year
latency, however, we are now using literally all sites and we're
throwing in basal cell and squamous cell together with all the other
SEER categories. And now we're expanding, in other words, to literally
all sites.

In other words, this is the definition that we had used in older
published research from the study. And when you do that, all the
significance goes away. So in other words, there's something happening.
There's something special about basal and squamous cell carcinoma. By
excluding those, we see the overall trend with years in Southeast Asia.
Yes sir?

**R. HARRISON:** I don't understand why you do that, Joel.

**J. MICHALEK:** Why did I make this slide?

**R. HARRISON:** Because I don't think anybody thinks that all cancers
have the same bases. And so when you do something like this where you
throw in all sites, it's like taking the average temperature of the
world irrespective of the seasons and saying that that describes
something that happens, you know. People are going to be really
surprised when they wind up in Rochester, New York in the winter
expecting it to be whatever --- sixty --- whatever the average
temperature for the year is --- sixty degrees.

**J. MICHALEK:** I understand that we always have that problem when we
combine or we lump together different disease categories and your point
is well taken.

**R. HARRISON:** It makes sense to go by systems.

**J. MICHALEK:** Yes.

**M. STOTO:** And that's also an issue with the all SEER sites where
they found the significant relationship.

**J. MICHALEK:** That's right.

**M. STOTO:** So \...

**J. MICHALEK:** All SEER sites \...

**M. STOTO:** \... I mean, normally you would expect \...

**J. MICHALEK:** \... are right here.

**M. STOTO:** \... that by lumping \...

**J. MICHALEK:** Yeah.

**M. STOTO:** \... lumping things together, you wouldn't find anything
for exactly the reasons you said. But when you do, at least you have
something that you've got to scratch your head and think about. And then
I think that what they did was then --- was appropriate; is that they
broke it down by looking at specific sites.

**R. HARRISON:** I guess the question I\'d have is, I wouldn\'t even try
and --- I wouldn't even try and show the all SEER sites.

**M. STOTO:** There's certainly --- I mean, I think I would've agreed
with you from the outset; that that's not the way I would've analyzed
the data. But having done it and they found this, then you have to sort
of figure out what it means. And they've gone the next step beyond that.

**R. HARRISON:** Let\'s go on, Joel, and we'll ask questions ---
everybody take notes. We'll ask questions at the end of the
presentation.

**J. MICHALEK:** Well, there are two more cancer presentations. This one
is really a repeat of what you saw in March 2003. I mean, it's only here
because the paper describing these slides will be published on the
11^th^ of February of this year in the *Journal of Occupational and
Environmental Medicine*. I'm putting this here asking you whether you
would like to see these slides again or should I just skip them and move
on?

**R. HARRISON:** All in favor of Joel \...

**M. GOUGH:** Can I ask one more question? It's not a --- it's --- let's
--- Joel, I --- one question: I finally figured out these tiny little
numbers down here. On your slide 81, which is "cancer incidence and
mortality," does that have a latency period in it?

**J. MICHALEK:** I can\'t see the numbers on the slide.

**M. GOUGH:** It\'s called "cancer incidence and mortality."

**J. MICHALEK:** Okay. No. Those slides --- these slides do not consider
latency.

**M. GOUGH:** Okay.

**J. MICHALEK:** But they could.

**M. GOUGH:** Well \...

**J. MICHALEK:** And in fact, subsequent \...

**M. GOUGH:** \... there should be some \...

**J. MICHALEK:** Yeah.

**M. GOUGH:** Again \...

**J. MICHALEK:** Yeah.

**M. GOUGH:** \... you know, the people who are going to read these
things \...

**J. MICHALEK:** Yeah.

**M. GOUGH:** \... and they're going to say, "Well, how does that
relate?" And in fact, it's all right to present it two different ways so
far as I'm concerned, but you just have \...

**J. MICHALEK:** To be careful on the title of the slides. Yeah. I
should tell you that in the prostate presentation, we do consider
latency of twenty years and that's in the title of the --- that's in the
methods section. Regarding prostate cancer, I'm suggesting that we move
the prostate presentation adjacent to this one so we will have looked at
all the cancer data together before moving on to memory loss because
right now, the prostate talk is at the very end.

**R. HARRISON:** So unless there\'s an objection, we're going to skip
what's been presented in a previous meeting.

**M. GOUGH:** Well, I just want to register, I sent Joel an e-mail in
October. I do not understand why their analysis was restricted to men
who were --- among the Ranch Hands, why the analysis was restricted to
men who had served less than two years in Vietnam.

**J. MICHALEK:** Okay. That --- I have a slide show on that too and
that's coming.

**M. GOUGH:** Okay. I just \...

**R. HARRISON:** So do you want this?

**M. GOUGH:** No. No, I just want --- I just want those two things. I
--- one --- I'm finished.

**R. HARRISON:** Okay.

**M. GOUGH:** Let me turn off my mike.

**R. TREWYN:** Can I make one quick point? Because in answer to your
question, there is one aspect in here with the 100 percent of Southeast
Asia service being in Vietnam for the Ranch Hand and 0 percent of that
being in Vietnam that I think is an important discriminator and that I
would hope would be fairly easy to apply to other groupings that you
have so one could quickly note does that pull out any differences. So I
think that is an important component that I only see in this --- in this
particular section and I would hope that this is something that we could
review in the future.

**R. HARRISON:** Well, for the sake of lucidity then, why don't we go
ahead, and do the presentation and discuss it because there are points
to be made? And otherwise, they're going to be sitting here isolated.
And when the minutes come out and Mike has to review them, it won't make
sense. So Joel, let\'s go ahead, but I agree with moving the prostate so
that all the cancers are together. Okay.

**[Cancer in Air Force Veterans of the Vietnam War]{.underline}**

**J. MICHALEK:** All right. Thank you. So we're now going to talk about
the paper.

**M. GOUGH:** What\'s the journal again, please?

**J. MICHALEK:** The *Journal of Occupational and Environmental
Medicine*. The paper is a summary of these slides. The paper was
submitted in the summer of 2003. It was peer reviewed up to October of
2003; it was accepted for publication. It was edited to --- in our
response to the referees. It was --- has been typeset and we have edited
the typeset version. And that's been sent to the publisher and it will
be published on the 11^th^ of February. The paper has been selected by
the journal for CME training, which means that the front end of the
paper has CME learning goals printed right into the first page. I
believe that means that any physician who's taking CME training will be
possibly assigned this paper to be studied as an example of good
epidemiology as remarked by the --- by the editor.

**M. STOTO:** Isn't this the one that was rejected by *Epidemiology*?

**J. MICHALEK:** Yes sir, it is.

**R. HARRISON:** All comments after the presentation.

**J. MICHALEK:** Good point, yes. So these are the authors you've seen
before: David Garabrant is at the University of Michigan. Since then,
we've added a new author --- Norma Ketchum --- on our staff. By the way,
probably I should tell you this; that Fatema Akhtar left the study last
year and is now at the University of Texas Health Science Center at San
Antonio. And when she left, I asked Norma Ketchum, our on-staff
statistician, to check everything that Fatema did --- everything. And
she made an independent check of all SAS code and all analyses and found
no mistakes.

I think that's an important remark to make because subsequent to that,
we submitted this to the *Journal*. It's important that Norma on staff
can reproduce any of these analyses at any time because she now has all
of the SAS code that Fatema wrote under control. And Fatema wrote a lot
of code in SAS macro language that now Norma is now the on-staff expert
in this --- in this paper. So that's --- it well states the depth of our
knowledge on our staff. We have four statisticians or epidemiologists,
which you've met already one --- Dr. Pavuk.

And David Garabrant himself did an independent check. Garabrant is not
just the --- what you would call an administrative co-author. He is a
co-author; he's an M.D. epidemiologist at the University of Michigan-Ann
Arbor. And when he co-authors a paper, he wants the SAS code and the
data sets and he makes his own independent checks of everything we do.
And by the way, a final remark is that I never show anything to you
unless it's been checked and rechecked many, many times.

The methods are similar to what you just saw. It's the same data set:
end of follow-up is 31 December '99; records were confirmed by ---
outcomes were confirmed by record review, ICD codes, category
definitions. The paper has two parts: it has contrast with external
national rates for U.S. males and internal analyses by dioxin category
stratified by different ways to isolate issues of interest to veterans:
namely, presence or absence in Vietnam, amount of time spent in
Southeast Asia region. Those factors were considered here and the years
in which you were actually in Vietnam were considered. Those were never
considered before in our analyses. To isolate those years where Agent
Orange was most heavily sprayed, those analyses were included in the
study.

The two-year cut point is important and you'll learn more about that
when I show the slides responding to Dr. Gough. But you already have an
idea from the previous presentation that there is a trend in the control
group and that two years is about the median years in the Southeast Asia
region among controls. And I'll have more to tell you about that. And in
a little while, I'll also give you more information to tell you why we
went to the 100 percent, 0 percent adjustments.

And here are the covariates; you've seen this before for all-site SEER
cancer, for melanoma, prostate cancer. There are many ways to approach
the data to arrive at a two-year cut point. One way is to simply graph
the percentage of time spent in Vietnam on the vertical and the number
of years in Southeast Asia, and you start to see patterns. And then look
at the Ranch Hand group. What you see if less than two years is that
you're --- when you stratify less than two years, that you're pulling
off a lot of Ranch Handers who were there 100 percent of the time. The
very upper part of the graph there, there's a lot of people piled up
right there.

And on the comparison side, it's sort of the other way around. It's not
as pretty, but there are a lot of people down here with only a short
amount of time in Vietnam --- less than two years in Southeast Asia. And
I'll give you more justification for that two-year cut-point in a few
minutes. So beginning with all Ranch Handers who ever were compliant,
either partially or fully compliant to any of the first five exams ---
and those same 1,785 comparisons with the same entrance criteria ---
threw away or excluded people who had cancer before or during their
tours of duty and that led to 2,965 people who were available for
contrast with external rates. And then when considering internal
contrast based on dioxin exposure category, we excluded anybody who had
a missing dioxin level, which brought the sample size down to 2,438.

And this is the same dioxin category definition you've seen in many of
our papers. And I won't dwell on that very much, except that the data
shown here with respect to whites only. And we had to do this racial
restriction because of the way the national rate tables are made.
They're made by racial category --- whites, non-whites --- and that's
just the way it is. And so we had to do these and so we decided to be
consistent throughout. In all these slides, we\'re talking about white
people. But we did consider blacks, but many of the slides are whites
only.

And here is one of the main slides against national rates. We're finding
some increases and some decreases. In cancer of the genitalia, it's
almost identical to cancer of the prostate. There's only a three-case
difference and we're seeing a significant increase in cancer of the
prostate against national rates and a significant increase in melanoma.

As brought out in the latest and final version of the article, one of
the referees suggested that we may be seeing these increases due to the
very close scrutiny that we're giving these men at the Scripps Clinic in
subsequent follow-ups where they're being examined by a dermatologist.
They're being examined by a doctor of internal medicine. They're being
given a rectal exam and PSAs. And they've been done --- we've been doing
this since 1982, although PSAs didn't come into play until 1992. The
first physical occurred in 1982.

And so they asked us to --- the referees asked us to delineate which
cancers were a direct result of the Scripps physicals. And it turns out
that of the melanomas, four of the 17 among the comparison group were a
direct result of the Scripps physical exams and a certain number that I
forgot on prostate were a direct result. And that\'s specified in the
paper now. So the --- there's a possibility that at least part of the
increase we're seeing here could be due to the close follow-up that
these men received. Just jumping to the bottom end of the paper in the
corresponding picture in the comparison group, is that we see a
significant increase in cancer of the prostate, but no significant
increase in melanoma and decreases elsewhere.

For example, backing up one slide, we see a significant decrease in
cancer of the digestive system against national rates, but no
significant decrease in the comparison group against national rates. The
paper cuts the data many ways following ideas we received from you over
two years ago. And that\'s an important point too; that we just didn't
make this up. We got this by talking to you, and therefore, departed
from our previous analyses which was published in the *American Journal
of Epidemiology* where none of this was done. And we simply combined all
cancers together against dioxin category.

In particular, in year of tour, the period --- in the period of heaviest
spraying, we see an increase in prostate cancer among Ranch Handers and
control were --- controls who were there during that period. But
melanoma, we see an increase in Ranch Hands only during the Agent Orange
period and that's brought out in the article. And here you have a
summary table against national rates done two ways: once less than two
years in SEA and the other using the 100 percent, 0 percent cut.

And what you see on the 100 percent, 0 percent is the SIR; it's the
standardized incidence ratios are increased even though we have
decreased the sample size because of our cut. And, you know, this
melanoma that we saw before is now a relative risk of --- or SIR of
3.05. And the same thing occurs with prostate cancer, although the
significance isn't as great. The --- numerically, the SIRs are
increased. And here\'s the dioxin category analysis, which is displayed
in the paper, which is among those who were there less than two years.
And the analysis on two years was done because --- less than two years,
greater than two years --- because we found that years in SEA was
statistically a confounder and we adjust for confounding by
stratification.

And by stratifying here on the median years spent in SEA among controls,
we have this significant pattern in the Ranch Hand group with increased
risk with increased dioxin body burden. The relative risk of 2.0 in the
high category reached statistical significance as did the relative risk
in the low category on all-site SEER cancers. And on the 100 percent, 0
percent analysis, we see increased numerically larger relative risk,
smaller sample sizes that reached statistical significance on all-site
SEER cancers.

So in conclusion --- you\'ve seen this summary before; I won\'t read it
to you --- that we see increases against national rates on prostate and
melanoma. And in internal analyses after adjustment for this confounder,
we see increases in all-site SEER cancer, prostate and melanoma. And
then we see the same thing on the 100 percent, 0 percent, but the
significance is restricted to all-site cancer. Now I'd like to move to
--- well, unless you have questions. I know there's a series of
questions I answered for Dr. Gough and they come on another slide show
that I can show in a few minutes.

**R. HARRISON:** Go ahead, Mike.

**M. GOUGH:** I just have some specific questions. Yeah, I guess the
first one is on the "melanoma by exposure opportunity category," which
is your \...

**J. MICHALEK:** The 100 percent, 0 percent in the less than two years?
Yes?

**M. GOUGH:** That --- no, you've gone too far.

**J. MICHALEK:** It was melanoma.

**M. GOUGH:** Oh, that's it. Yeah. In the 100 percent of SEA versus
Vietnam --- I mean, 100 percent of SEA, is that restricted to men who
were there for less than two years?

**J. MICHALEK:** No.

**M. GOUGH:** So that's all years?

**J. MICHALEK:** This is all years. The only restriction on the Ranch
Handers was they had to have 100 percent of their SEA service in
Vietnam.

**M. GOUGH:** Okay.

**J. MICHALEK:** And this is all comparisons who spent no time
whatsoever in Vietnam. And notice among those comparisons, we observe
two and we expect two \...

**M. GOUGH:** Yeah.

**J. MICHALEK:** \... a relative risk of almost one. In the Ranch Hand
group, it's three times.

**M. GOUGH:** Right, I see that. The other --- then in your conclusion
in the internal contrast \...

**J. MICHALEK:** Well, that's different. Internal contrast, right here.

**M. GOUGH:** Yeah. Yeah. I'm just going to ask you this question.
Internal --- the first thing it says is "less than or equal to two years
in SEA" and then "high category." That means that's where you compared
just within the Ranch Hands?

**J. MICHALEK:** Now we're asking --- we're giving the restriction that
they were there less than two years.

**M. GOUGH:** Yeah.

**J. MICHALEK:** Is there a difference between the high category and
comparisons? And the answer is statistically yes \...

**M. GOUGH:** Okay.

**J. MICHALEK:** \... by a relative risk of 2.0.

**M. GOUGH:** Okay. Thanks.

**J. MICHALEK:** Okay.

**R. HARRISON:** Anyone else?

**M. STOTO:** On that one there, is there a p value or something?

**J. MICHALEK:** There is in the paper. I didn't put it on here.

**M. STOTO:** Oh, so red --- the red --- the red \...

**J. MICHALEK:** Red means significant.

**M. STOTO:** Okay.

**J. MICHALEK:** And the p value and confidence interval are in the
paper.

**M. STOTO:** Okay.

**J. MICHALEK:** I have the paper actually right here.

**M. STOTO:** No, that's okay. I just --- I was looking at this and my
copy doesn't have red.

**J. MICHALEK:** Right. Sorry.

**R. HARRISON:** Moving right along.

**[TCDD and Prostate Cancer in U.S. Air Force Veterans of the Vietnam
War]{.underline}**

**J. MICHALEK:** Okay. Connected with that, we have a separate paper
strictly on prostate cancer, which is in submission to a journal, in
fact, and which has been --- has been presented. I wanted to show you
those slides right here. First author is Marian Pavuk, myself and then
Arnold Schecter. This presentation considers prostate cancer in more
detail.

**M. GOUGH:** Where is it?

**J. MICHALEK:** This is the very --- near the very end.

**R. TREWYN:** Page 18.

**M. GOUGH:** Okay. Thanks.

**J. MICHALEK:** Okay. Just a little background --- these slides were
made by Dr. Marian Pavuk. In the first few bullets there, you'll see
prostate cancer is common in older men, second only to lung cancer. TCDD
has been classified as carcinogenic in animals and humans. And the
National Academy has indicated "suggestive/insufficient" evidence to
declare TCDD associated with prostate cancer. The study goal here is to
investigate in more detail an association to TCDD and dioxin in this
study.

Now here we have some data up through the year 2002. Dioxin is measured
through 1997, which is all --- which is true for the whole study. And
Marian, was this on the first five physicals only, fully compliant?
Yeah. So this is the same entrance criteria we had on the previous talk
and diagnoses up to 31 December 1999. And now we have introduced a
latency requirement that they had to have at least twenty years
follow-up after the last --- after their qualifying tour. And so cancers
that occurred earlier than twenty years after a tour are not counted and
only individuals who had at least twenty years of follow-up are counted.
This is now more stringent than what you saw in the previous talk.

In addition, we did not simply use the measured dioxin level. We
computed area under the curve, which is sort of a favorite metric in
animal studies, which is a metric which is proportional to the
bioavailable dose. And we did that using the latest information on
dioxin half-life --- 7.6 years. And so now he's breaking that measure
out into tertiles on the Ranch Hand group into low, medium, high, and
comparing each of those with the comparisons, and once again, excluding
individuals with less than twenty years of follow-up. And all of the
analyses are done using the time to onset flag --- a time to onset as
well as a flag for cancer using a Cox or proportional hazards models.

And so here you see the total sample size and the exclusions, which are
necessarily tied to dioxin and less than twenty years of follow-up. We
lost twenty comparisons and eight Ranch Handers who did not have twenty
years of follow-up in other words. And we restricted to white
individuals to remain consistent with previous papers. And here's a
display of the demographics by Ranch control and you see the good
concordance on age and other factors that were matched --- that are
matching factors for this study.

BMI is similar; time in Vietnam is not similar. The Ranch, of course,
the comparisons spent less time in Vietnam than the Ranch Handers did.
Time in SEA, the other way around; the comparisons spent more time in
the region than the Ranch Handers did on the average --- on the median.
Pack-years of smoking --- no remarkable differences there or on alcohol
use. And this is more demographics on the dioxin levels. You see, of
course, increased dioxin levels among the high area under the curve
category: 59 ppt on the mean; dioxin in the high area under the curve
category, which is expected because that's how you compute.

And down here, you see the actual area under the curve --- 2,499;
ppt-years is the unit --- ppt-years. And the range --- and the full
range down here after 24,569 ppt-years, which is about --- it's a
fraction of what the chemical workers received in the NIOSH study and I
think it's like less than 50 percent --- maybe less than 20 percent than
what the chemical workers received in the United States who made
herbicides. And here's a picture of the cumulative TCDD level by area
under the curve category and, of course, they're going up. Covariate
associations with prostate cancer --- nothing remarkable here except
time in SEA is a clue that there's something happening with years in
Southeast Asia, which you already know about because I showed you the
other talk.

It turns out that, in fact, yes; there is a correlation in the control
group between years in Southeast Asia and prostate cancer and that's
what this analysis is pulling out --- this 1.5. And so, and here you see
another representation than what you saw on the previous talk. In the
comparisons and Ranch Handers, you see in the comparison group a
significant increased trend of increased risk with years in the region,
whereas, not so in the Ranch Hand group.

This is the point --- this fairly subtle point --- of the published
paper; that the less than two-year cut point has to do with trends we
see in the comparison group and not in the Ranch Hand group. It appears
counter-intuitive to the --- to the --- to the reader that we should see
increased risk in the less than two-year stratum because people would
think, "Gosh, more than two years is where you should see the effect,
right?" Well, the reason we're seeing that is that the trend in the
control group is driving that cut point --- not the Ranch Hand group.

And here you see that the area under the curve categories are unrelated
to dioxin level. I'm sorry; the area under the curve in the comparison
group is unrelated to years in --- years in Vietnam, whereas, in the
Ranch Hand group, they are, which is consistent with the idea of an
exposure experience in the Ranch Hand group, but not in the comparison
group in Vietnam.

**M. GOUGH:** Joel, that is days in Vietnam for the comparison, not days
in SEA?

**J. MICHALEK:** No, it's days in Vietnam. Separately, if you --- if we
were to do a slide on days in Southeast Asia, you would see roughly the
same picture. This is just another look at the data. And so here it is:
the overall analyses without adjustment for that confounder and what you
see is pretty much nothing. You see a flat picture of relative risk that
are all near 1.0. So without regard to the confounding, you are led to
conclude that there's nothing happening in this data.

However, if you adjust for the confounder by carrying out the
stratification, you find that among those that were there less than two
years, you see a significant increase of the risk of prostate cancer in
the high area under the curve category relative to comparisons and you
see a significant trend right here. This AUC column is a --- indicates
the change in risk with a unit change in area under the curve and that
reaches significance too. But you don't see that on the greater than two
years. And intuitively the reason for that is that once you go to the
greater than two-year category, now you\'re bringing in those
comparisons that are already experiencing increased risk associated with
years in Southeast Asia, which I don't know why that is, but that's
what's happening. And so as soon as you do that, you lose your
adjustment and you lose your effect.

So what we've got is that without accommodating this confounder, we see
no association. But after accounting for it, we see an association and
that's what's new about it because previous publications --- the article
published in the *American Journal of Epidemiology* 1998 --- does not
include adjustment for this confounder. And so you are led to conclude
based on that paper there is no association, but now we do see one
because we have discovered this confounder. And the reason we discovered
it is through our discussions with you.

And this shows the --- more characterizations of the prostate cancer
cases looking only at those 47 comparisons who did have prostate cancer
more than twenty years after SEA in the 33 Ranch Handers by age and
surgical procedures that were used to treat their prostate cancer.
Finally, we considered the Gleason scores that were extracted from
medical records and found no connection between Gleason scores and the
--- is there a cite for that? No; between Gleason scores and the area
under the curve categories.

**R. TREWYN:** What are Gleason scores?

**J. MICHALEK:** Gleason scores are a medical determination by the ---
Marian, can you tell us briefly about Gleason scores? Microphone. I'm
sorry it's not here.

**M. PAVUK:** A Gleason score is a --- is a measure. It's made from a
pathological examination of prostate tissue obtained either on biopsy or
surgery, preferably on biopsy at the time of making a diagnosis. And
it's a measure of a --- of a --- of a stage of prostate cancer, one of
--- one of several and it's a combined score. There are at least --- it
combines --- at least two areas have to be evaluated on a pathological
slide and maximal --- it's a scale from 0 to 5 and the minimal level is
prostate cancers that have scored about 7. You can have two scores from
1 to 5 and then it's combined for a total Gleason score. And those with
a level above 7 have a worst prognosis for survival, but we didn\'t see
in this data an association with dioxin levels.

**J. MICHALEK:** That ends this particular presentation, however, I
still have slides to respond to Dr. Gough.

**M. STOTO:** Three quick comments: one is that I think this is great
detective work separating out, you know, that --- those different groups
and seeing what was going on. Second, in the background slide, the term
that the IOM uses is "limited/suggestive," not the words that you have
here to describe prostate cancer. The third one is a question; it's
about using the area under the curve. If you use --- if you assume
everybody has the same half-life, does area under the curve just become
proportional to their \...

**J. MICHALEK:** Yes.

**M. STOTO:** \... their measured level?

**J. MICHALEK:** If everyone had the same length of follow-up.

**M. STOTO:** So but length of follow-up, does \...

**J. MICHALEK:** Yeah. Right.

**M. STOTO:** \... it differ with length of follow-up? Okay.

**J. MICHALEK:** Right. But we --- but we --- what we did was we
accommodated this twenty-year. Explain the area under the curve
calculation for me, please.

**M. PAVUK:** Well, just to answer your question maybe: first, no; it's
not totally proportional to their dioxin level because dioxin level as
measured is just a number at a certain point of time --- their actual
level. Area under the curve reflects how long --- how long they've been
followed up and how long from the exposure this also happened. So it
approximates their body burden a little better than \...

**J. MICHALEK:** Cumulative body burden.

**M. PAVUK:** \... cumulative body burden instead of just one
measurement at one point of time, but it's an estimate still.

**M. STOTO:** If they all had the same amount of follow-up, then the two
would be proportional, but they do have different levels.

**M. PAVUK:** Correct. I mean, at this point, there are developments ---
ongoing ones that would allow us, you know, to use not just the average
half-life and accommodate other functions as, you know, hepatic
metabolism or other excretions of dioxin to make better estimations of
area under the curve or body burden, or even better, the, you know, the
initial levels at the --- at the end of the exposure in Southeast Asia.

**M. STOTO:** Well, one of the --- one of the ongoing themes that we\'ve
had here is whether to assume that the --- that the half-life is
constant.

**M. PAVUK:** Well, I think it becomes very clear that it is not
constant over all --- over the whole period of time; that the half-life
is shorter at the very beginning of the exposure, especially of high
exposure, and then the half-life becomes longer. However, still using
some half-life or having an estimate of half-life approximates a little
better the estimated levels than not having any half-life at all.

**M. STOTO:** Well, what I --- what I --- what I had in mind is that
variation across an individual's half-life and in particular, for
something, you know, that the guys with more body fat are likely to have
a longer half-life than I think we're seeing.

**M. PAVUK:** Yes, you're \...

**M. STOTO:** If that were --- if that were a risk factor for prostate
cancer, then it would be important, but I think that \...

**J. MICHALEK:** Right, it\'s not.

**M. STOTO:** \... it's not.

**J. MICHALEK:** Actually, you're alluding to and you're opening up the
idea of giving up these assumptions and we're on a --- right on the
threshold of doing that. We are co-authoring an effort with EPA to
introduce physiologically-based pharmacokinetic modeling to accommodate
changes in half-life with time, and with lipid content and body fat. And
that's under the works right now. There\'s a paper in submission to the
*Lancet* on our new pharmacokinetic modeling of half-life in the Ranch
Hand cohort. And subsequent to that, we'll develop a new initial dose
estimate based on the very latest modeling, which will then preempt
whatever you're seeing here today.

**R. HARRISON:** Just one comment: I\'ve never understood how you are
likely to extrapolate back to the initial dose without having data from
the initial period because all of the measurements that you're basing
the --- your new half-life study on comes long after that fast initial
slope is gone.

**J. MICHALEK:** True. In fact, that data was presented to the Committee
perhaps a year ago when we combined Ranch Hand and Seveso data into a
single analysis. We had something like forty Seveso males, adults who
were exposed during the Seveso accident in 1976. We combined that with
the 300 or so Ranch Hand veterans in the --- in this study who had
repeated dioxin measurements. And when you put the data together, you
find in log units a linear pattern way back to within three months of
the initial exposure.

And before that, you see a non-linear decrease, a very rapid decrease
which Marian also already alluded to, which is highly significant. In
other words, you do see a non-linear pattern real close to the initial
dose. And so our analysis --- this analysis you're seeing here today
does not accommodate that non-linearity; however, new analyses that are
coming in the next few months will.

**R. HARRISON:** If I --- if I recall things correctly, what you see is
in the initial curve is a --- what happens with a lipid soluble compound
when you essentially inject it intravenously; and that is, a lot of it
gets cleared real quickly because it\'s not water soluble and then a lot
of it gets stored \...

**J. MICHALEK:** In the --- in the liver.

**R. HARRISON:** \... mostly in fat and in cell membrane.

**J. MICHALEK:** In the liver too.

**R. HARRISON:** So then the --- that second half-life or that longer
half-life then is really more dependent on body shape almost than it is
anything else and \...

**J. MICHALEK:** The seven-year half-life \...

**R. HARRISON:** \... I've still never understood how you --- I guess
the point I\'m making is that if you were --- if you --- if you had
enough fat to have a dioxin level of 100, the peak dioxin level could be
100 or anything above 100 and anything after the three-month mark will
look the same. So you --- it\'s hard to use that data to go back and
decide what the peak level was, which is \...

**J. MICHALEK:** I think I\'ll have something to show you later this
year perhaps on that in more detail.

**R. HARRISON:** Not me, but that's okay. All right. Yes, Dr.
Leffingwell?

**S. LEFFINGWELL:** I had a couple of questions for orientation. In your
twenty-year exclusion, was that from first or last exposure?

**J. MICHALEK:** That was from their qualifying tour, which is the tour
that was used to decide eligibility for the study.

**S. LEFFINGWELL:** And do you remember about how many were excluded on
that basis?

**J. MICHALEK:** Very few; in fact, I have that slide right here: twenty
comparisons. And of those five cases in eight Ranch Handers, of those
were two cases of prostate cancer were excluded based on the twenty-year
follow-up. So I'm near the bottom of the slide right here --- these
numbers.

**R. HARRISON:** Let\'s do --- we\'re, I believe, one, two, three
presentations short of where we\'re scheduled to be before we break for
lunch. I think at least one of us has a fairly early plane this
afternoon. And so what I would suggest is that we do one more
presentation, take approximately ten minutes to gather our lunch
material, and then munch as Joel continues his presentation. He looks
well fed and can probably last until that time without any undue harm.
Is there any objection from the Committee or from any of the
participants at our doing that? One more presentation, ten minutes to
gather food and then we just keep chugging on through. Okay, Joel.

**[Adjustments for Ethnicity and Cut Points]{.underline}**

**J. MICHALEK:** A few months ago, Dr. Gough wrote us a letter with some
questions about the slides you just saw and this --- these slides
respond to two points that he made that I thought were really very good
and instructive. In particular, why --- what happens to the melanoma
analysis when we adjust for ethnicity? The idea being that Scandinavians
--- the blue-eyed, fair-skinned Danish or Swedish individuals --- have a
much higher risk of melanoma than individuals with darker skin. And what
happens there if you tried to accommodate this ethnicity?

So we have one of our physical exams, we asked people what they thought
of themselves regarding their ethnicity. And this is a quagmire of
issues about the mother and the father, and what are they and what are
you, you know? And you can't probe this very far if we start running
into some serious issues. But we simply took at face value what these
people said about themselves and so we produced a single covariate. It
was, "Are you Scandinavian or are you not --- yes or no?" And to
approach this data, we are going to again, use the same methods and data
sets you just saw: the 2,965 people and we\'re going to be considering
the same melanoma analysis one more time.

And so here are the results of ethnicity on the 2,965 broken out by
Ranch Hand by these --- by these categories: comparison, background,
low, high. And here, I've highlighted Scandinavian --- people who
declare themselves as Scandinavian; about 5 percent across the board
think of themselves as Scandinavian. So I created a new covariate, which
was a 1 if you\'re Scandinavian; it's a 0 otherwise. And we introduced
that covariate into the melanoma model.

And there --- well, you might as well stare at this slide. I mean, you
can see that quite a large percentage for some reason are Irish; I don't
know why. But 15 percent to 20 percent of this cohort are Irish. They
think of themselves as Irish. And there are the rest of the ethnicities
here on the next slide, small percents, and a fairly large percent
consider themselves French; and 10 percent or so American Indian; and no
response, 12 percent of the comparisons didn't want to answer the
question at all; and all the Ranch Handers answered. I don't know why
that is either.

So and here is, again, I just again reproduced the same table that's in
the article just for your reference on melanoma --- less than two years
in SEA. So what we're going to do is take this same model and without
any changes, just introduce that single covariate on less than two
years. And when you do, you find it's a continued significance. In other
words, the modeling is not disrupted and the conclusions are not changed
by introducing this additional covariate. Now I have to say as a
statistician, I really don\'t like pushing the data this far because
these are small counts. They're small counts and so I only answered your
question, which is what happens if you introduce ethnicity and that's
what happens.

**M. GOUGH:** Actually, I asked specifically about Kelts because John
Nichols --- who was the Director of IARC? John \...

**J. MICHALEK:** Okay.

**M. GOUGH:** I can't remember his name. Anyway, he published a paper
showing \...

**J. MICHALEK:** On Kelts? I'm sorry. I thought you meant \...

**M. GOUGH:** \... showing Keltics \...

**J. MICHALEK:** Okay.

**M. GOUGH:** \... people from the British Isles. If you go to Australia
and South Africa where those people went, skin cancer rates are --- or
melanoma rates are very high. So \...

**J. MICHALEK:** Well, maybe then Irish would be closer to what you were
talking about because we don't have Keltics.

**M. GOUGH:** Well, I think English and Welsh. I don't --- no; I said I
don't know how you define them either.

**J. MICHALEK:** I don't either.

**M. GOUGH:** But yeah.

**J. MICHALEK:** Okay.

**M. GOUGH:** Well, I\'m glad you did this though. I think that you've
provided a great service for somebody who wants to look at it because I
--- because there is such a tendency. I mean --- I mean, my --- I\'m a
dermatologist\'s dream as are several other people around this room and
I suspect you are too, close to it. So anyway, I --- but I appreciate
you doing that and I appreciate you digging that out. And I know what a
--- that you can't rely with a great deal of confidence on what people
think they are.

**J. MICHALEK:** Yes sir, that's true.

**M. STOTO:** Two quick things: one is that this is the way it's done in
the census and almost every other way about ethnicity.

**M. GOUGH:** Unless you're Tiger Woods and you're mixed.

**M. STOTO:** Right, and then --- so this is as good as you can do.

**M. GOUGH:** Yeah.

**M. STOTO:** The other thought is that if you want to pursue this, one
way to --- you might be able to do this is to look at national rates and
try to find the countries that had the relative high rates of \...

**J. MICHALEK:** Melanoma.

**M. STOTO:** \... melanoma. And yeah; I would imagine they would be
English, Scottish, Irish and Scandinavian out of this list and look at
them as a group rather than just the Scandinavians.

**J. MICHALEK:** Okay.

**R. HARRISON:** Yes sir?

**S. LEFFINGWELL:** The problem with looking at country data would be
there'd be a latitude variant, which is why their skin color differs
too.

**M. GOUGH:** Well, that\'s true.

**M. STOTO:** Yes. I'm just --- I'm just trying to find a somewhat
objective way of dividing the ethnicities into ones that are prone to
melanomas and others not.

**P. CAMACHO:** Well, you were the one who brought up the eye color and
all of that stuff. I mean, isn't that more ability to --- of those eye
color and all that, are they kind of indices? All right, then so divide
people by \...

**J. MICHALEK:** We've done that already.

**P. CAMACHO:** All of --- all of us with blue eyes get over in a
corner.

**J. MICHALEK:** Yeah.

**P. CAMACHO:** Isn't that pretty objective?

**J. MICHALEK:** The analyses \...

**R. HARRISON:** I\'d prefer you move \...

**J. MICHALEK:** \... of the blue eyes \...

**R. HARRISON:** I'd prefer you move a little further.

**J. MICHALEK:** Yeah. The analyses in the paper already adjusted for
eye color and skin reaction to sunlight.

**M. GOUGH:** You know, I wasn\'t really --- perhaps I didn't read the
slides in the last presentation correctly, but I wasn't aware that you
did adjust for skin color. So I think that's \...

**J. MICHALEK:** Skin reaction to sunlight. It's not \...

**M. GOUGH:** Whatever --- I think that's fine.

**J. MICHALEK:** Okay.

**R. HARRISON:** The one possible explanation, by the way, for the high
Irish count might be that the largest St. Patrick's Day celebration in
the United States is in Savannah, Georgia. The South was populated by
English that lived at the English-Scottish Border, the most violent part
of England back during the 1700s. This is in a book called *Albion Sea*.
And when they left England, they want to two places: they want to
Northern Ireland and the American South. That\'s why the --- that's why
the North would\'ve lost if the South had had just a little more ---
little more capital behind it. It's, and still to this day, it's
probably the most violent part of the country and just --- it explains a
lot about Northern Ireland.

**J. MICHALEK:** All right. The other part of our talk regarding Dr.
Gough's comments is this issue of the two-year cut point. And so we want
to see what happens when we play with that cut point --- change it. So
here are the demographics according to a quartile of years in SEA ---
and you already saw these quartiles in the earlier presentation --- to
show you that there is a trend on year of birth in the comparison group
and a slight trend on pack-years. And in the Ranch Hand group, there's
of course the change too. And the individuals who spent a long time
there are relatively older.

And I guess this is the slide that is probably our best indicator of why
the two-year cut point is important as regarding adjusting for this
confounder. If you look at up to two years --- up to 2.1 years in SEA,
you're talking about 6 percent of the --- of the comparisons are
experiencing cancer; whereas, up here, it's 12 to 16 percent. If you
look down here at the Ranch Hand group, it's fairly flat as compared to
years in SEA as relative to the Ranch --- comparison group. So what's
going on is there's a dynamic going on in the comparison group that we
don't understand and no corresponding dynamic in the Ranch Hand group.

But what you do have in those down here is a --- is an increased risk of
cancer in the comparison group among those who were there less than two
years. And that's just a reflection of the --- of the data that is
driven by a statistical analyses that I'll tell about --- talk to you
about in a few minutes. And here's a display of the percentage of time
spent in Vietnam, a percentage of their SEA service actually spent in
Vietnam according to years in SEA. And what you've got here is an
indicator of why that would turn out to be an important confounder too
because among those Ranch Handers who were there less than two years,
you tend to pull off people who were there a lot.

They were --- there are --- nearly 100 percent of their Southeast Asia
tour was in Vietnam, whereas, not so in the Ranch --- in the comparison
group. It's pretty flat around 20 percent. And so the years spent in SEA
may itself be a surrogate for something else: namely, how much time did
you spend in Vietnam? That\'s what this slide says and that's one of the
reasons why we used the 100 percent, 0 percent approach in the paper. I
have to remark that I expected the referees to tell us to dump one of
those two approaches, but they left both in the paper.

Now here is the table and this is the summary of a so-called interaction
model, which is critical to our decision to cut the years in SEA. There
is a, in the interaction model, a significant years by dioxin by group
interaction --- p value of 0.05. And to a statistician, what this says
is that the relationship between dioxin and cancer is changing. It's
changing; it's not constant. It varies with years in SEA and group. And
that says, "You'd better do something about this." It says that the
straight main effects model, which is the basis for most of our paper,
is not working here; that there is a change in the relative risk. And
the main effects model, which would be the basis for sort of the naive
approach to the analysis, is not appropriate. And so \...

**M. STOTO:** Group is?

**J. MICHALEK:** Ranch Hand and control.

**R. HARRISON:** But Joel, didn't a couple of slides ago, looking at the
Ranch Hands as being flat across time and the comparisons climbing with
time, what that suggests is that the dioxin exposure is producing
cancers earlier, which would mean that you would not want to do a cancer
comparison of people after --- I\'m not sure how to think about this.
But it means that you should see a greater difference between Ranch
Handers and comparisons if you look after only five years of exposure
versus --- five years of latency versus fifteen years of latency; that
the difference should be greatest at time 0 and less at fifteen years.

**M. STOTO:** I think you may be confusing years of follow-up versus
years of service.

**R. HARRISON:** No, I was --- I was thinking of latency. I was thinking
that earlier --- I mean, what he's been saying is \...

**M. STOTO:** No, I --- but this year here refers to years of service.

**J. MICHALEK:** Years of service in SEA. Latency is not \...

**R. HARRISON:** No, all I'm responding to on this slide is Joel's
statement that there's a change with time; that's all I was responding
to and it made me think --- made me think about the previous slide. When
I was looking at it, it said to me that the change in time was that
Ranch Handers get cancer right away and the comparisons have to wait for
two --- not get cancer, but the years in South --- it \...

**P. CAMACHO:** The Ranch Handers did one thing.

**R. HARRISON:** One may be an effect of just aging like in the
comparisons. As you get older, you get more cancer. In the Ranch
Handers, the aging one picks up there because if you've --- but maybe I
am confused.

**R. TREWYN:** Do we know on this one? I mean, it looks like we're
seeing the same trend down there. I mean, I assume death was considered.
It isn't that out at the 3.6 to 14.5, they were just dead? I \...

**J. MICHALEK:** No sir.

**R. TREWYN:** Okay.

**P. CAMACHO:** But isn't one of the presumptions the Ranch Handers
constantly handled this material versus the comparison group in SEA? I
walk into a certain sector in the DMZ where there was defoliant spray
and I\'m doing a three-week operation there. I walk out of that and now
I'm down below Group 9, you know. I mean, I walk in \...

**R. HARRISON:** Yeah. It\'s almost like a dose-response.

**P. CAMACHO:** Yeah. Well, I mean, I don't think \...

**R. TREWYN:** I noticed this same thing and I was trying to figure out
where that \...

**P. CAMACHO:** It seems to me that \...

**R. TREWYN:** Paul, I just want to address you. I think most of it is,
as far as exposure is, anybody who was in Vietnam in a base camp, they
sprayed the "be-jeebers" out of every one of those base camps with
herbicides. There wasn't a blade of grass growing anywhere and so if you
were in there --- now whether it was Agent Orange versus one of the
others that didn't have dioxin in it, so I don\'t think it was walking
through the DMZ.

**J. MICHALEK:** Correct.

**R. HARRISON:** Well, while everybody's running down on one thing,
Joel, there's one other last thing. A comment that was made earlier
about self-reported --- I mean, this is not on this paper; this was on a
previous paper. But I wrote it down, then I forgot to mention it; it was
self-reporting exposure to venereal diseases. And at least when I was in
the Navy, you got \...

**P. CAMACHO:** Yeah, you got \...

**R. HARRISON:** \... you got punished if you got a venereal disease. So
if you were on good relations, if you had good relations with the
medical staff, you got treated, but you didn't get reported. So I don\'t
think self-reporting is a reliable --- that\'s one instance where
self-reporting is not a reliable tool.

**P. CAMACHO:** Well, moving right along.

**J. MICHALEK:** All right, moving along --- I just wanted to point out
this slide has nothing to do with dioxin. It only relates to years in
SEA with cancer and group.

**M. GOUGH:** That includes basal?

**J. MICHALEK:** This is SEER cancer; this does not include basal and
squamous.

**J. MICHALEK:** And this is simply a reflection that the relation
between dioxin and SEER cancer changes with years in group. Now I'm
coming down to Dr. Gough's comments. Actually what we'd like to see,
different year categories instead of the old quartiles, which are these
sort of odd-ball decimal years, lets you see a nice progression: 0 to 2,
2 to 4, 4 to 15. So we did that. And of course too, it approximates the
same cut point you saw on the previous slide and so you see the same
pattern once again of reduced. Here you see reduced cancer in the
comparison group less than two years: right there --- 5.9 percent.

And so we go to these nice round digital cut points like this. You're
going to see right here; this is the old analysis published in the paper
--- less than two years and you see almost identical results. We're now
using a two-year cut point. If you go 2 to 4, it goes away. So what's
going on is that if you change your cut point, you give up the
adjustment. The adjustment was the stratification. When you give up the
adjustment, you lose the effect and that's the whole purpose of the
adjustment. And 4 to 15, it further goes away.

Once again to illustrate the effect or the attenuation of the
adjustment, if you --- if you decide, "I don't like two years; I'm going
to use three years," you again attenuate the adjustment because now what
you're doing, you get 7.1 percent in the comparison group down here. And
the reason you get a higher percent is that now you're pulling in
comparisons who were in that upper strata and you're inflating your
cancer rate in the comparison group. And so that's going to make it
harder to detect a treatment effect in the Ranch Hand group and sure
enough, that's what happens.

When you increase the cut point, you lose significance in this category,
which is still maintained. And if you go greater than three years, you
lose it altogether. When it's greater than three years, it's totally
gone. So the conclusions are that years in SEA is a confounder; not only
that, it induces an interaction. And that's the second bullet. And we
also see, as we've seen many times now, the --- in the comparison group,
there's an increased risk of cancer with increased years in SEA. And
following the book, the textbooks, we adjust for confounding by
stratification.

And if we decide we're going to change that cut point and increase it,
what goes on then is that we attenuate the adjustment. And if you keep
increasing it, there's no adjustment anymore; you lost it. And the
bottom line is that years in SEA is a surrogate for something else in
the comparison group that we don't know what it is. But years in SEA is
certainly an obvious risk factor for cancer, but it's a surrogate for
something we don't understand in the comparison group. Thank you very
much. That ends our cancer presentations.

**R. HARRISON:** Any further questions before we take our ten-minute
break to raid the food bar? Ten minutes.

**\[LUNCH 12:20 P.M. - 12:34 P.M.\]**

**[Dioxin and Memory Loss]{.underline}**

**J. MICHALEK:** We've looked at this confounder --- years in SEA --- on
diabetes and on birth defects and we see no confounding. So what we're
seeing --- and whatever is happening with Southeast Asia is happening on
cancer so far only and not on diabetes or birth defects. Once we saw
this, of course, then we wondered, "Well, what happened with all the
rest of the things we've studied over the last twenty years?" And number
one is diabetes and birth defects, and it was fortunate that somehow,
years in SEA seems to be specific to cancer and not to endocrine-related
conditions or diabetes --- birth defects.

So the study is unique in many ways. In one way is that now we have
paired Wechsler Memory Scale on 2,000 people spaced twenty years apart.
We measured their short- and long-term memory at baseline in 1982 with
the Wechsler Memory Scale and we also measured it again in 2002. And we
have published that there is an adverse association between memory loss
and dioxin the Ranch Hand Group. And that was published in
*Neurotoxicology* last --- in the year 2002, which was about a year and
a half ago.

And I guess I had previously presented this to the Committee, yeah. Drue
Barrett is at CDC --- she's our psychologist co-author --- and John
Cary, Scripps Clinic. And this talk is very preliminary because Barrett
and Cary haven't even seen this yet. And it's also preliminary because I
don't have a full data set. At the time I made these slides, I didn't
have a full data set of covariates, but I put it in because I thought
you should see the latest information.

And there's the hypothesis; that dioxin and memory loss are adversely
associated with --- in the Ranch Hand group. And that hypothesis is
driven by information from animal and human studies. In particular,
children exposed to PCBs from mother's breast milk show intellectual
deficits against children who were not exposed. And they also see those
things in animals; we see cognitive deficits in animals exposed to
organochlorine chemicals.

And there you have the summary of the Wechsler Memory Scale as
administered in both 1982 and 2002. And these are the components:
logical memory, immediate and delayed; associate learning; visual
reproduction, immediate and delayed. Logical memory is derived from, as
I remember, a recall of a paragraph that's read by the --- by the
psychologist. And you're asked to recall components of the little story,
one of which has to do with activities in New York City, and the other
one, I forgot.

Associate learning is a --- is a drill: opposites, for example. She'll
say "high;" you say "low." And you have to do that in a rapid sequence
and she scores you. And visual reproduction, you are given a pattern and
very quickly, you have to reproduce it on pencil and paper. And your
ability to do that is scored, whether you can get the components of this
pattern properly. And immediate and delayed means in the stories ---
logical memory --- you are asked to recount the story immediately after
it's read and then again a half hour later.

And the same thing is true with visual reproduction. They give you a ---
they flash a pattern in front of you; you're asked to reproduce it on
pencil and paper. And then they come back a half hour later and say,
"Hey, let's do that again." And then you get --- but they don't show you
the pattern again and you have to do it again. So what we've got in the
published paper in *Neurotoxicology* 2002 was a significant deficit in
the high exposure --- dioxin exposure category on immediate recall from
the Wechsler Memory Scale.

These scores --- these negative indicate that the score is significantly
lower among these Ranch Hand veterans in the highest exposure category
as compared to the comparisons, about a half a point, and that reaches
statistical significance. And the covariates from the journal article
are listed here at the bottom. And those include exposures to
psychotropic medications, and diagnosed psychiatric problems and things
like that, and marital status and drinking. And this covariate data is
--- was available to us for our published paper, which has only now been
completed for the current round. And I don't have that data yet to show
you.

So this is just a recount of what's been published and this was already
reviewed by the National Academy of Sciences. And here you have another
significant decrease in the delayed immediate --- delayed logical
memory: a deficit in the highest exposure category, not as strong
statistically as the previous one. And in all other components of the
Wechsler Memory Scale at baseline were non-significant. There was no
significant deficits in any of the Ranch Hand categories on immediate
visual reproduction, or on delayed visual reproduction or on associate
learning at baseline. And so that's in the paper if you want to see it;
it's out there.

So now we have the new data on Wechsler Memory Scale given in the year
2002 at cycle 6. And here I've displayed missing data in the upper panel
of the table. So one person in the background category had missing data
probably because for some reason, he refused to cooperate during the
Wechsler Memory Scale administration. And three to four comparisons had
missing data. And so the bottom line sample sizes are in the bottom
panel and there you see about 1,170 comparisons and then the sample
sizes for the background, low, high category with complete data.

And here's what the group looked like at the cycle 6 physical of those
who took the Wechsler Memory Scale, which is nearly everybody. Mean age,
about sixty to 65 years; dioxin levels, of course, increased with dioxin
exposure category; BMI is pretty stable around thirty --- around thirty;
and high school education is an important indicator of ability to do the
test. And there you see 67 percent have only a high school education
over here in the high category. And 34 percent have only a high school
education in the background category, reflecting the fact that many of
the people in the background category are officers and many of the
people over here are enlisted. That correlates highly with military rank
and there you see it down here again.

**M. GOUGH:** "High school" means that's as far as they went?

**J. MICHALEK:** I think Bill Grubbs can answer that. I got that
covariate from one of Bill Grubbs' data sets.

**W. GRUBBS:** They completed high school.

**M. GOUGH:** And went on to college?

**W. GRUBBS:** If you've got a college degree like an associate's, that
is acknowledged.

**N. RIVERA:** What's his name?

**J. MICHALEK:** Bill Grubbs.

**R. HARRISON:** So 34 percent of the background completed high school
or to put it another way \...

**J. MICHALEK:** Had only a high school education.

**R. HARRISON:** \... 66 percent of the background did not finish high
school?

**J. MICHALEK:** No. No; 34 percent of those in background had only a
high school education. In other words, about 65 percent had a college
education.

**R. HARRISON:** You're saying everybody had a high school education?

**J. MICHALEK:** No, the key word is "only." No. In the background
category, 30 percent had at most a high school education and 67 percent
in the high category had at most a high school education. So in other
words, the background category is less educated than the --- than the
background category.

**M. GOUGH:** But the presentation\'s incomplete because we don't know
about beyond high school.

**R. HARRISON:** Let me ask you this question. How many, in any of those
groups, did not finish high school?

**J. MICHALEK:** Oh, we can find that out. I'm just --- when I say "high
school," I believe that means a high school diploma.

**R. HARRISON:** Yeah, but how many did not get a high school diploma?

**J. MICHALEK:** We can find that out. I don't have that at my
fingertips, but I can certainly get that for you --- meaning a GED
degree or something like that?

**R. HARRISON:** No. I mean, just those who didn't finish high school.

**M. STOTO:** Yeah, because this essentially groups the people who
didn't finish high school with the people who got a Ph.D. So this should
be cut point "high school or less" or something like that.

**J. MICHALEK:** That's right; it's high school or less versus more than
high school --- high school or less.

**M. STOTO:** But it does mean that? It does? It \...

**W. GRUBBS:** What you just said is correct.

**M. STOTO:** Bill is saying that it does mean that.

**W. GRUBBS:** What you just said is correct.

**M. STOTO:** That it's high school or less. Okay. Thank you.

**J. MICHALEK:** And by the way, we've looked at this data in the past.
It's very complicated. There are all --- every possible scenario is
realized: all the way from a little technical, you know, less than high
school education all the way to a Ph.D. It's all in there. And so we
could --- we find this definition of education without any --- with some
difficulty, but we can do it.

**M. STOTO:** I mean, this is what you'd expect; is that the guys ---
the technicians, the ground crew would be in the high category and \...

**J. MICHALEK:** Mostly high school.

**M. STOTO:** \... less likely to have a --- beyond high school
education.

**J. MICHALEK:** So what happens if you repeat the analysis at cycle 6?
Now here, I'm adjusting only for age and education because I don't have
all that other data available yet. When I made this slide, I didn't have
psychotropic medications; I didn't have diagnoses; I didn't have any of
that. All I had was age and education, and so, I did the best I could.
And in the subsequent weeks, this will all be done over again using a
full set of covariates which is now available, which became available
only a few days before this trip to come here.

And so we see nothing. We see, actually, an average score of 5.67 over
here in the high category and 5.78; they're doing slightly worse, but
not significant --- a p value of 0.37. So there's nothing happening at
cycle 6 regarding logical memory immediate as opposed to baseline where
we did see something. And the same thing is true, logical memory
delayed, no significant decrement at all. In fact, in the background
category, they're doing a little better than the controls: almost
significant --- a p value of 0.08.

Associate learning, cycle 6: no significant findings there either. I did
not analyze visual reproduction in cycle 6 because I didn't know how to
resolve that with baseline. That's still something that has to be worked
out with Dr. Cary and Drue Barrett, so that is yet to come --- the
analysis of visual reproduction at cycle 6. Now one of the strengths of
this data, of course, is the paired nature of the data. We have Wechsler
administered twice: once in '82 and once in the year 2002.

And so this final analysis is --- the analysis takes both of those
measurements into account and exploits the paired nature of the data:
two scores on most of these people spaced twenty years apart. And so
this slide summarizes sample sizes for those people that went to both
baseline and cycle 6 and you see some of them didn't. And those are the
people up here who --- or actually, these are the people with missing
data for various reasons.

The final sample sizes are down here. There's 200 people in the high
category, for example, that had complete data on associate learning at
both cycle 1 and 6: 846 comparisons with complete data at both cycles.
So now we see the demographics among those people who were fully
compliant at both cycle 1 and 6. Another way to put it, these are the
demographics at cycle 6 who were also compliant at baseline and you see
almost the same pattern we saw in the previous demographics. These
people are not unusual as compared to everyone at cycle 6. For example,
on high school education, again, it's around 68 percent of the high
category had at most a high school diploma and about 34 percent in the
background had at most a high school diploma.

So now we're going to analyze changes in the Wechsler Memory Scale,
which are three subjects computed as the baseline value minus the cycle
6 value. So positive values are detrimental. You expect people to do
worse at cycle 6 because they're twenty years older than when they took
it the first time. And so you see the averages are positive meaning yes;
they are doing worse. For example, the average is at 1.32 in the high
category. That means they dropped 1.32 points on the average for this
scale over the twenty-year period.

And the comparisons dropped 1.88 over the one-year --- twenty-year
period; however, there's no significant decrement --- no significant
differences between any of these. Now however --- actually, I'll take
that back. There is one here on the high category, but it's in the ---
it's in the positive --- it's in the good direction. They didn't ---
they didn't drop as much, so they're doing better actually than the
comparisons on their change from cycle 1 to cycle 6.

**M. STOTO:** Or actually, they --- well, I think what it means is they
did worse the previous time.

**J. MICHALEK:** Yeah. Right. That's a good point. They were worse at
baseline and so this could be a reflection simply of that; that they
were lower at baseline. And remember that these are unadjusted for those
other covariates that have already passed peer review and weren't
available yet. And so all of this is going to be done over again pretty
soon. And all of the other results on the paired analyses are negative.
There are no significant results here yet. Here once again in the high
category, you see significance, but it's in the --- it's in --- not in
the detrimental direction. And associate learning, and here it was not
significant.

And finally just to show you changes from baseline, the Box and Whisker
Plot shows a flat pattern all the way across, which indicate
statistically no dose-response here, here or here. And so here are the
limitations I've already talked about. We're still looking for
confounders. We do spend a lot of time doing that on every study. We
have not resolved visual reproduction data and we will do that. And then
the strengths are --- you know all these already. So we have no data to
support the hypothesis that dioxin is detrimental to your memory at this
point in time.

**R. TREWYN:** Did you look at years in Southeast Asia and all that
stuff?

**J. MICHALEK:** We have not checked years in Southeast Asia on this
data yet, but we will. Right now, we're sensitive to that confounder and
we have that data set available to merge with this and do the check.

**M. STOTO:** So, I mean, so that suggests that the original result may
just have been a false-positive?

**J. MICHALEK:** Yeah, it may have been artifactual.

**R. HARRISON:** Anything else? Okay. Let\'s move on.

**[Dioxin and Syndrome X]{.underline}**

**J. MICHALEK:** Okay. The last time I gave a talk on hypertension and
that frustrated some of you --- Dr. Osei in particular --- that we
analyzed just a single endpoint: hypertension --- not very interesting.
So we expanded that paper to include metabolic syndrome, which is also
called "Syndrome X." And that is defined in our recent publication as
having three or more of any of the following conditions: a big waist 102
centimeters or more, which it comes out to about forty inches or more;
high triglycerides; low HDL; high blood pressure; or high glucose or a
diagnosis of --- by ADA criteria of diabetes. All of these put together
comprise a pattern called "metabolic syndrome." In other words, you're
getting basically old, and fat and sick.

**R. TREWYN:** The opposite of Generation X.

**J. MICHALEK:** Just like us, yeah. And we're going to analyze this
data --- or these data and we do using the very latest data from cycle 6
at the 2002 physical and 2003 from Scripps. We're excluding people with
missing dioxins. You see very few exclusions because we have almost ---
we have so many with complete dioxin data now in this study. The sample
size is above 1,000 in the comparison; it's about 775 Ranch Hand.
Demographics, as you expect, about 62 years on the average. Everything
there is similar to what you've seen on previous slides.

Family history of diabetes, about 20 percent; family history of
hypertension, which are going to be important covariates, about 40
percent; and about 42 percent of both groups have Syndrome X --- 42
percent, which I thought was remarkable --- not remarkable to those who
served as monitors at Scripps Clinic, I guess, including Karen Fox and
Dr. Julie --- Colonel Julie Robinson. Here are the dioxin measurements
according --- by dioxin exposure category and you've seen this --- these
data before too: dioxin is increased in the high category.

Finally, here's the bottom line. We have a significant increase in the
risk of Syndrome X in the high exposure category, which is consistent
with what we saw with hypertension and diabetes: 1.4 --- a p value of
0.04. And we have a significant trend, but that's not printed. And this
is adjusted for all these variables you see listed at the bottom of this
table of the slide. This work is still in progress and it's a puzzle to
us as with diabetes; that in the background category, we have a
significant deficit of metabolic syndrome, and at the same time, a
significant increase in the high category --- the same pattern we saw
with diabetes.

**M. STOTO:** And the same puzzle.

**J. MICHALEK:** Same puzzle.

**M. GOUGH:** Or the same puzzle is that if you stratify the comparisons
into three dioxin categories, or four or five dioxin categories, you get
the same dose --- the same slope of the line. It's just displaced down
toward lower dioxin levels, isn't it?

**J. MICHALEK:** That's true. In the --- I have those slides.

**M. GOUGH:** Which is --- which is --- I think it's one of the oddest
puzzles that's come out of this whole thing.

**J. MICHALEK:** Yeah; that we have trends in the comparison group that
are, to put it bluntly, no one wants to see. When we show dioxin data in
the comparison group, we have significant trends that are parallel to
the Ranch Hand and only on the range 0 to 10 ppt.

**M. GOUGH:** I know a number of people who would like to see this.

**J. MICHALEK:** Except the journals we submit those to don't want to
see it; our papers keep getting rejected. You like it and I like it, but
anyway for your reference, here's the --- what happens with hypertension
by itself, a similar pattern. The relative risk is 1.5 in the high
category, a p value of 0.01. Again, we have a deficit in the background
category. Now when we further --- by the way, I have to tell you that
Syndrome X is not adjusted for body fat index because body fat index is
part of the endpoint. In order to have Syndrome X, you had to be
overweight, hypertensive and diabetic or have high lipids.

So we didn't put BMI in the model because BMI is intrinsically ---
already is a dependent variable. And hypertension, here this model is
not adjusted for BMI. And when you rerun the hypertension model with
adjustment for BMI, the finding is attenuated somewhat. The p value on
the high category is now 0.047, relative risk 1. --- I mean, odds ratio
1.4. So putting in BMI attenuates the result, but doesn\'t make it go
away.

So here are the usual limitations. There's always the possibility of
other confounders we haven't considered. And the same strengths as
others and we have a published case definition. And the conclusion, you
already saw. And here's the reference for our case definition of
"metabolic syndrome." It comes from the National Cholesterol Education
Program --- NCEP --- an NIH publication. I think that \...

**K. OSEI:** You may have one of the highest rates of Syndrome X in the
world because the national numbers look like 25 percent. So you're
talking about 42 percent and you're talking about predominantly male.
And I think probably the advantage you have is the gender and, you know,
it's very difficult to get all the variables in females where it's more,
you know, clear cut in men. So I think having, you know, a group that's
predominantly male is driving your numbers little higher, which is very
good.

**J. MICHALEK:** Yeah, which makes the data set so interesting.

**K. OSEI:** Yeah.

**J. ROBINSON:** For the last briefing of the day, it will be, as it
says, brief. As you know, the protocol ends 30 September '06. We've
already heard from Program Management in regards to the funding. And in
the previous meeting, we talked about the fact that the Air Force had
developed a variety of options ranging from the study once it's
completed in September '06 that that would be the end and what the
associated cost would be up to doing another physical exam.

Now this is something that's very difficult to read in your handout. And
actually what I wanted to reinforce here is the fact that we in the Air
Force are working toward completion of our protocol. So we have a
time-line and the entire protocol time-line is at the bottom. We're
required to give an IRB final report and we've programmed that in July
of '06. Up at the top, if not in the middle, you'll see that we talk
about the Ranch Hand Advisory Committee meeting again this year at three
different months --- April, September and November as we had discussed
in March --- to do the chapter reviews.

And so far, I believe you have received at least two chapters for
review. In that attachment which you will find, I will just reiterate is
you'll have a first draft. That was the draft that was sent from SAIC to
the Air Force for initial review. We then put together another
attachment that you'll also have for each chapter, which is a resolution
comment. So we put in our comments, and then with SAIC and the Air
Force, came up with resolutions to those comments. So you will have that
so that it --- the third attachment is the second draft that
incorporates our comments and the changes as a result of those comments.
So you will have all three documents as you requested.

Additionally, I provided kind of an instruction sheet, and an
explanation of those very attachments, and included my number that if
you had any questions, you could call me and I would help you with any
issues that might arise from your review. What we're hoping is that by
the middle of February, you will have at least five of the chapters. We
have to do a review of a couple of second drafts and then I will get
them off to you as soon as possible. So I'm hoping that under Dr.
Stoto's leadership, the meetings will be able to come about as planned.

**M. STOTO:** So the two that you sent us yesterday are essentially
samples of the kind of things we'll be expecting to get?

**J. ROBINSON:** Yes, and \...

**M. STOTO:** We\'re not expected to review them today?

**J. ROBINSON:** No sir.

**M. STOTO:** Okay.

**J. ROBINSON:** No, that's for April; we'll start the chapter review.
Hopefully, we'll get them so that you have at least two months prior to
that meeting. That will give us --- we have completed seven --- at least
five second drafts. There's twelve chapters, so we're way ahead, and
they can be spread out as you see necessary over those three meetings.

**M. STOTO:** Okay. So maybe we should --- we should sit down, and think
about the order, and who we have to review them and what --- which ones
you might need before other ones, and whether it makes any logical sense
to do some first and things like that.

**J. ROBINSON:** The \...

**R. HARRISON:** The other thing that you\'re going to have to really
take a look at is the Committee's expertise and \...

**M. STOTO:** Right.

**R. HARRISON:** \... early on, identify some consultants for review of
the sections.

**M. STOTO:** Yeah.

**M. GOUGH:** Well, each chapter is written by an expert, right?

**J. ROBINSON:** The chapters are written. There is literature research
that was done by an outside group that was contracted through SAIC. I'm
looking toward Bill Grubbs for some assistance with this. And then each
of the chapters had a lead writer, an expert to assist with that.

**M. STOTO:** Do we know anything about who those people are?

**J. ROBINSON:** We could provide you a list of those for each chapter
\...

**M. STOTO:** Yeah.

**J. ROBINSON:** \... if you'd like to know. Okay.

**M. STOTO:** Yeah.

**J. ROBINSON:** We can do that. Along with the chapters, you will have
various appendices that will come with them as well; not each chapter
will have an accompanied appendix for the review.

**R. HARRISON:** Okay. So one of the things that needs to be discussed
is the actual --- when the Committee will meet, try to get some dates
organized. We also have a few other Committee-type things to discuss as
well. Are you finished with your --- do you have \...

**J. ROBINSON:** One more item.

**R. HARRISON:** One more item.

**J. ROBINSON:** I'd just like to say is that we're planning to submit
articles to peer-reviewed journals up until about 1 January, and from
there, then we will turn any subsequent reports, remaining reports into
technical --- Air Force technical reports. And that's it, sir.

**M. STOTO:** 1 January of which year?

**J. ROBINSON:** \'06.

**M. STOTO:** '06. Okay.

**R. HARRISON:** Well, that would make sense; I mean, they wouldn't have
time to deal with the critiques and stuff. Any other questions of Joel
or the --- what we have remaining is a discussion of the approval
process for the March \'03 minutes; a discussion of the upcoming meeting
schedule; and it is almost precisely the time when we said we'd have the
public comments if there were any. That's what we have coming up. So
what I'd like to do is do the public comments first and then we'll do
the minutes --- decide how we're going to handle the minutes --- decide
how we're going to meet and then we'll be done.

**M. GOUGH:** Before we do that, Joel, what happened to hepatitis?

**J. MICHALEK:** We --- I did not include a discussion of hepatitis data
because the database isn't ready yet. And so next time we meet, I should
or next time we talk science separate from the reviews, I'll have some
hepatitis data to show you.

**R. HARRISON:** Yes, Mike? Oh, I saw your thing on --- your, excuse me,
microphone.

**R. HARRISON:** So do we have any public comment at this time, anyone
that --- sure we don't want the pharmacy students to make spontaneous
presentations? Okay. All right. Sure? Okay. All right. Okay. Okay.

**R. HARRISON:** Let's --- well, actually, let me --- let me do this and
I\'m going to do it awkwardly because my memory is bad and all the ---
everything that you all know. But we have two people here who are
attending as observers who are awaiting confirmation to join the
Committee. And I'd like to, number one, recognize them; number two, ask
me to tell them --- ask them to tell me their names again because
otherwise, I'll screw it up. Dave \...

**M. STOTO:** Would it be okay if they joined us at the table for this
discussion? No?

**R. HARRISON:** I think we certainly would like to hear from them
though in terms of the future meeting schedule. Go ahead.

**D. JOHNSON:** My name is Dave Johnson.

**R. HARRISON:** And you're with the Department of \...

**D. JOHNSON:** Yes, I'm the Executive Medical Director for the Division
of Environmental Health with the Florida Department of Health and \...

**R. HARRISON:** Wonderful. Well, we look forward to --- I will look
forward to hearing of what you do in the future. And a new Committee ---
yes ma'am?

**E. HASSOUN:** I am Ezdihar Hassoun from the University of Toledo
College of Pharmacy.

**R. HARRISON:** And I understand that she has knocked off innumerable
rats over the last twenty years with dioxin, so she should fit right in
with the rest of this group. We're going to discuss the minutes, which
is going to be the Committee discussion, then we're going to discuss
when schedules might allow another meeting to be held. And that even
though these --- they can't sit at the table, you all --- I hope you
have your calendars and will be able to work that through.

**M. STOTO:** Can I --- can I ask one thing? There are seven of us here,
soon to be diminished by two and replaced by two. Isn't the \...

**R. HARRISON:** Nine.

**M. STOTO:** Nine is the limit, right?

**L. SCHECHTMAN:** Nine is the upper limit.

**M. STOTO:** The upper --- it's the upper limit? So in other words,
we're going to be seven for the duration technically? Are we --- I guess
what I'm \...

**L. SCHECHTMAN:** Actually, there is a possibility that there may be
more appointments coming from the Department, but right now, we're
sitting --- we will be sitting at seven.

**M. STOTO:** Okay.

**R. HARRISON:** Well, our leader has suggested regarding approval of
the minutes that we use the process employed previously; that is that
you all will submit your suggested revisions and edits to the executive
secretary. And after the editing changes are made, the revised minutes
will be sent to the chair for review and approval. And the executive
secretary says that since Dr. Harrison served as chair of that meeting,
as such, he will be the signatory on those minutes, which is fine. I
have a consulting rate and I'll be happy to. Is there --- is that
process acceptable? Everybody has received their e-mail copies of the
minutes, so that can be --- that's not a problem?

**M. STOTO:** I don't --- it's not a problem. I have two things: one is
did we get them in Word format so we can do track changes and so on?
That probably would help if people could do it that way.

**L. SCHECHTMAN:** Yeah. In fact, that was in the cover e-mail message;
the request was that the editing changes be made in track changes.

**M. STOTO:** Okay. Okay. The second thing is do we want to set a date
that these are due? Oh, that's in there too? Oh great.

**R. HARRISON:** Does everyone know what track changes are or have a
secretary who knows what they are? Because I don't --- I actually don't
--- I don't use Word, so I don't --- I don't know what you all are
talking about. I'm a WordPerfect guy.

**M. STOTO:** It's a way to indicate your changes \...

**R. HARRISON:** So I have to go \...

**M. STOTO:** \... electronically.

**R. HARRISON:** So I have to go and find a copy of Word then, okay, and
learn how to use it?

**M. GOUGH:** You're the chairman. You don't have to.

**S. LEFFINGWELL:** Use redline and strikeout in WordPerfect and then
transfer it to Word.

**R. HARRISON:** Anything else? All right, on to meeting schedule. Mike,
why don't you conduct this piece of the business because I'm out of
here.

**M. STOTO:** Okay. Thank you. Thank you. The --- I guess --- I guess
the question is we're asked about April, September and November;
everybody is here who actually has to schedule. Do we want to --- do
people have their calendars? Are they prepared to do this?

**R. TREWYN:** No, but we can wing it.

**M. STOTO:** No? Okay.

**L. SCHECHTMAN:** Perhaps we could get our best guesstimates at this
point \...

**M. STOTO:** And then \...

**L. SCHECHTMAN:** \... and then we can resurvey by e-mail. Once we're
back in our offices, get a really quick response from everybody so that
we can nail these dates down because calendars fill up quickly.

**M. STOTO:** Okay.

**L. SCHECHTMAN:** Thank you.

**M. STOTO:** Okay. Let's look then. I'll just look at --- look at April
to begin with. Any particular dates we need to avoid in April?

**R. TREWYN:** The 15^th^.

**S. LEFFINGWELL:** The 16^th^.

**M. STOTO:** Okay. Is there --- is there from the --- from the Air
Force side something that we need to pay attention to there?

**J. ROBINSON:** No, we\'re open.

**M. STOTO:** Okay, and day of the week?

**P. CAMACHO:** Yeah, a Monday or a Friday.

**M. STOTO:** Monday and Friday are better?

**K. OSEI:** Yes, much better.

**M. STOTO:** Okay. Yeah. Wednesday like today?

**P. CAMACHO:** A Monday or --- a Monday or a Friday is good. We can try
a Friday and enjoy Washington in April.

**M. STOTO:** Yeah. In April, Mondays are bad for me.

**P. CAMACHO:** How about Fridays?

**L. SCHECHTMAN:** So toward the end of April? Is that what we're
considering after tax day?

**M. STOTO:** Yes.

**L. SCHECHTMAN:** Is that what we're looking --- okay. So the first
Friday after tax day is May --- April 16^th^ and the following Friday is
April 23^rd^.

**M. STOTO:** Fridays are not --- are out?

**L. SCHECHTMAN:** Fridays are no good?

**K. OSEI:** Wednesdays or Thursdays would be fine.

**L. SCHECHTMAN:** Wednesday or Thursday.

**M. STOTO:** Are they --- are they impossible?

**P. CAMACHO:** Well, then I have to get another --- I mean, I don't
know how many classes I can cut.

**L. SCHECHTMAN:** How about the 3^rd^?

**P. CAMACHO:** This is on the first day of classes.

**L. SCHECHTMAN:** How about the 3^rd^?

**P. CAMACHO:** Yeah, classes started this week, so I already got
substitutes on the first day of class. I have that on my syllabus.

**L. SCHECHTMAN:** Okay.

**M. STOTO:** So Wednesday and Thursday are bad days for you?

**P. CAMACHO:** Yeah.

**M. STOTO:** Friday is a bad day for Kwame.

**P. CAMACHO:** Tuesday, Wednesday, Thursday, but Monday's a nice day
for me.

**M. STOTO:** How about Monday? Is Monday \...

**K. OSEI:** Monday and Friday are not good.

**P. CAMACHO:** See, his classes are what --- Monday, Wednesday and
Friday? And mine are Tuesday, Wednesday, Thursday. So how about a
Saturday? We make a nice weekend out of it.

**S. LEFFINGWELL:** I do have a hard conflict on the 16^th^.

**M. STOTO:** Okay. I've got that. Where are we at? The 16^th^ we want
to avoid. That's one particular hard thing.

**P. CAMACHO:** Yeah. Is Saturday possible?

**L. SCHECHTMAN:** The government doesn't work on weekends.

**P. CAMACHO:** The government doesn't work on weekends.

**L. SCHECHTMAN:** The Sabbath begins at sundown Friday and lasts until
Monday at dawn.

**P. CAMACHO:** I'm married; I don't get any days off.

**J. MICHALEK:** All right; there\'s April.

**M. STOTO:** Okay. Do you have the same problem for September --- the
same days and the same of you?

**P. CAMACHO:** Mine will change.

**M. STOTO:** Okay. So yours will change? So suppose that we accommodate
--- how does that work? We have to accommodate Paul now because if we
accommodate you later, he may be able to make that one. Is that --- is
that --- is that fair?

**K. OSEI:** You can accommodate me later.

**M. STOTO:** Yeah. I mean, I want --- I want to spread the burden
fairly. So the first time through, we'll do it on a Monday or a Friday.

**N. RIVERA:** Turn your --- turn your mike on.

**M. STOTO:** Turn your mike on.

**K. OSEI:** Oh, excuse me. Since we're going to --- we have about
twelve chapters to review, you may not be reviewing endocrine on one
meeting date.

**M. STOTO:** Right.

**K. OSEI:** So the days that I need to be here, I'll be glad to. So if
you can accommodate me and then \...

**M. STOTO:** That\'s a good point.

**K. OSEI:** \... we can work it out.

**M. STOTO:** That's a good point.

**K. OSEI:** Yeah.

**M. STOTO:** So we will --- if there's one that you absolutely can't
make it, we'll make sure we don't schedule the relevant chapters \...

**K. OSEI:** Exactly.

**M. STOTO:** \... on that day. Okay. So that gets us to Monday and
Friday in April and then Tuesday, Wednesday or Thursday \...

**K. OSEI:** Wednesday.

**M. STOTO:** \... in September. Wednesday in September?

**K. OSEI:** Yeah.

**M. STOTO:** Okay. So we're back to Friday. How about the 23^rd^ of
April? That's a problem for you?

**D. JOHNSON:** Only that one Friday.

**M. STOTO:** How about the 30^th^?

**P. CAMACHO:** The 30^th^ is fine with me.

**M. STOTO:** Okay. That's okay for everybody except \...

**R. HARRISON:** Kwame.

**M. STOTO:** \... except you, then we'll work --- April 30^th^.

**K. OSEI:** Okay.

**M. STOTO:** Okay. For September, we want to look for a Wednesday.

**K. OSEI:** Right.

**R. TREWYN:** Let's get your calendar up there, come on.

**L. SCHECHTMAN:** Before we move on, that would mean people flying in
on Thursday afternoon or evening and flying out. Presuming we have a
single-day meeting similar to today, they would fly out Friday evening,
Friday afternoon/evening.

**R. TREWYN:** They can always stay around.

**L. SCHECHTMAN:** Or not, okay.

**R. TREWYN:** Right.

**L. SCHECHTMAN:** Okay.

**R. TREWYN:** There's always a problem getting out of DC Friday night.

**L. SCHECHTMAN:** Yeah.

**K. OSEI:** Yeah; that's why I don't want to be at the airport on
Fridays. It's always a problem.

**D. JOHNSON:** The third Wednesday of the month I sit on an IRB
committee which requires a quorum, so that\'s not good.

**M. STOTO:** Okay. So not the third Wednesday? The first Wednesday is
September 1^st^. Is that --- no, Labor Day would be the following.

**R. TREWYN:** The 6^th^.

**K. OSEI:** Labor Day would be the 6^th^, right.

**M. STOTO:** I'm clear every Wednesday as far as in that month.

**K. OSEI:** Yeah, and it's good for me --- any of those Wednesdays.

**M. STOTO:** Well, people --- September 1^st^ is before Labor Day, so
that's often a bad week for people. Yeah, so how about if we say the
8^th^?

**K. OSEI:** The 8^th^.

**J. ROBINSON:** And I just need to clarify; there\'s twelve clinical
chapters. There's like an introduction \...

**M. STOTO:** Yeah. Now my thought --- I mean, I guess there's two ways
to think about the different kinds of chapters: one is that we do all of
the kind of background chapters like that first and then do the
substantive chapters.

**R. TREWYN:** That\'s if they\'ve got them written.

**J. ROBINSON:** Yeah, they're done.

**M. STOTO:** But they --- okay; well, then if that's not --- yeah. I
mean, the other thought is to kind of do some background and some
substantive at every meeting.

**J. ROBINSON:** You're getting five background chapters for the
introduction and other sections.

**M. STOTO:** Okay. How do people feel about doing --- taking care of
those background chapters first?

**P. CAMACHO:** It's better for me; I mean, I'm not an epidemiologist.

**M. STOTO:** Yeah.

**J. ROBINSON:** We'll have them all ready.

**R. TREWYN:** That's what you're going to get so \...

**M. STOTO:** Okay. So now we need a date in November.

**P. CAMACHO:** What's the date in September?

**M. STOTO:** September 8^th^.

**K. OSEI:** September 8^th^?

**R. TREWYN:** How soon they forget.

**M. STOTO:** Now since Paul doesn't know what his conflict is going to
be in November, I think we'll still try to go for a Wednesday.

**K. OSEI:** Right.

**M. STOTO:** That's --- if that's --- yeah. Veteran's Day is in
November --- is a Wednesday in November. That actually would be a bad
one --- yeah; the 10^th^ is a --- is a --- is a bad one for me.

**R. TREWYN:** The 17^th^.

**K. OSEI:** The 17^th^ would be good.

**M. STOTO:** Should we do 17^th^?

**L. SCHECHTMAN:** No; that doesn\'t work for me. I have a conflict.

**M. STOTO:** Okay. How about the 3^rd^?

**J. ROBINSON:** The 3^rd^ of November?

**R. TREWYN:** Right after the election; right after the Presidential
election.

**L. SCHECHTMAN:** Vote your hearts out.

**R. TREWYN:** Everybody can come and bitch.

**M. STOTO:** Okay, and they'll all be in Washington? Okay. That sounds
like a plan. And then we'll --- maybe Len, and I and somebody from the
Air Force can talk about the schedule of which chapters are which.

**J. ROBINSON:** It'll probably be me.

**M. STOTO:** Okay. Thank you.

**R. HARRISON:** We have a couple more things --- at least one more
thing. I'm sorry; we have one more: a list of the --- a list of the
reviewers. Just a comment of my own, I mean, I recognize a couple of
names on here just because I know them. But if you\'re trying to figure
out who\'s doing this, don\'t you need to know where they're from or
something?

**M. STOTO:** So these are the people who are participating in writing
the chapters?

**R. HARRISON:** Right, and --- yeah.

**J. ROBINSON:** We can tell you right now that on "General Health,"
it's Dr. Ken Pischel who's \...

**R. HARRISON:** Well, that's what I mean.

**J. ROBINSON:** \... he's under the alternate list. For "Immunology,"
it's Dr. Ron Simon. For "Renal," it's Dr. Andrew King. I can tell you
that Dr. David Williams is at Scripps Clinic in La Hoya, California. Dr.
Roger Cornell is also a dermatologist at Scripps Clinic. I don't know
Dr. Dailey. They're all --- okay; they're all at Scripps.

**M. STOTO:** Including the alternates?

**J. ROBINSON:** Including the alternates.

**M. STOTO:** Okay. I mean, I guess I'm not likely to make much of this.
I mean, if they're --- if they're people who are Board certified, as you
said they would be, and they're at Scripps, which is certainly a decent
place, are we going to make --- what are we going to do about that?

**L. SCHECHTMAN:** There's --- there would be no perceived conflicts of
interest with these people in terms of them being at Scripps and some of
the activities are going on at Scripps as far as the collection of data?
We have to be very careful about that. So are these people totally
disassociated?

**M. STOTO:** Well, remember these are not reviewers. These are \...

**R. HARRISON:** The writers.

**M. STOTO:** They would be the writers, so they're part of \...

**L. SCHECHTMAN:** Okay. So that's okay?

**M. STOTO:** Yes.

**L. SCHECHTMAN:** And the reviewers will not be involved?

**J. ROBINSON:** Historically, they have. I know Dr. Dave Williams has
participated in writing chapters in previous reports.

**M. STOTO:** Yeah.

**J. ROBINSON:** And that's not been an issue in the past.

**M. STOTO:** Well, I think --- I think that, if I recall, the work
they're doing is part of the overall contract that --- with the --- with
Scripps.

**R. HARRISON:** Anything else or is our work done?

**M. STOTO:** Do we have the opportunity to identify consultants to this
Committee to review chapters that we need?

**R. HARRISON:** Well, that's what I'm suggesting; is that you and Len
need to get together, look at what expertise is just on the Committee or
coming on the Committee \...

**M. STOTO:** Yeah.

**R. HARRISON:** \... look at the chapter headings and decide do you
have an immunologist. And if you --- if you don't, then you need to get
one. And in the past, Committee members have been asked to identify if
they --- if someone that could serve in that capacity.

**M. STOTO:** You know, presumably, if we could --- especially if we're
down two people, and actually, there may be some resources there to hire
consultants.

**R. TREWYN:** Can I ask if there would be a restriction on taking ---
utilizing people in that capacity who have been on the Committee in the
past? And even separate from the ones who are here now, would it be
feasible to bring any of those individuals in as the consultants since
they would have some level of experience with it?

**L. SCHECHTMAN:** We can check with the Committee Management Office to
determine if that's allowable under the rules by which these committees
abide by, so we can get back and discuss that as a possibility as well.

**R. TREWYN:** Okay.

**R. HARRISON:** I know when Ron left as the executive secretary, he
came back as a consultant for a couple of rounds.

**M. STOTO:** Right, but that's somewhat different than a Committee
member coming back.

**R. HARRISON:** Oh yeah. Yeah, it's being a part of the Mafia.

**J. ROBINSON:** Dr. Harrison, I do have one thing I wanted to enter
into the record.

**R. HARRISON:** Oh yes; I'm sorry. Please go ahead.

**J. ROBINSON:** Barbara Jewell has spent at least fourteen years
associated with the Ranch Hand Advisory Committee, and thus, the Air
Force Health Study. I talked to her prior to her retirement and I think
she was pulling my leg; she said she'd be here for this meeting, which
she's not. But in recognition of her outstanding support in assisting us
in coordinating these meetings, the agenda and all, we have a
certificate that recognizes her now as an official member of the Air
Force Health Study Crew. And I'm going to give it to Dr. Schechtman to
ensure that it gets to Barbara, but we do thank her.

**PARTICIPANTS:** \[Applause.\]

**R. HARRISON:** Okay. Anything else? Going once, going twice, finished.
Thank you.

**M. STOTO:** Thank you and Mike.

**\[ADJOURN 1:27 P.M.\]**

**[CERTIFICATION]{.underline}**

State of Georgia )

)

County of DeKalb )

I, Nadine Rivera, do hereby certify that the foregoing transcript,
consisting of pages 1 -- 154 in total, was personally typewritten by me
and is a true, complete and accurate transcript of the proceedings
recorded by me.

I further certify that I am not related to, employed by, or attorney of
record for any parties or attorneys involved herein. I further certify
that I have no financial interest in this matter.

WITNESS MY HAND AND OFFICIAL SEAL BELOW.

This 27^th^ day of January, 2004.

[/s/]{.underline}

Nadine Rivera

My Commission Expires:

August 1, 2006

\[Seal\]