DEPARTMENT OF HEALTH AND HUMAN SERVICES

 

and

 

FOOD AND DRUG ADMINISTRATION

NATIONAL CENTER FOR TOXICOLOGICAL RESEARCH

 

 

convene the

 

 

Ranch Hand Advisory Committee Meeting

 

 

Rockville, Maryland

January 21, 2004

 

 

 

                                                                                       

 

Certified Verbatim Transcript

                                                                                       


TABLE OF CONTENTS

 

Page

 

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

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

Dr. Leonard Schechtman

RHAC Executive Secretary

 

Ms. Kimberly Campbell

Committee Management Specialist

 

U.S. Air Force Representatives

Col. Karen Fox, M.D.

Lt. Margaret Montgomery

Dr. Joel Michalek

Lt. Col. Julie Robinson

 

U.S. Air Force Contractors

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

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

January 21, 2004

Rockville, Maryland

 

Certified Verbatim Transcript

 

 

 


Text Box: Opening Session

 

 

 

 


 [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.

 

Text Box: Approval of Previous Meeting Minutes

 

 

 


            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.

 

Text Box: Program Management Update

 

 

 


            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.

 

Text Box: RHAC Membership

 

 

 


            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 14th — 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 19th, 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 30th, 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 30th, 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 1st, 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 14th of October 2003 as I mentioned.  On the 20th 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 22nd, 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 20th after all attempts had failed in obtaining the waiver approval.  I then sent an e-mail dated November 19th 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?

 

Text Box: Vietnam Veterans Health Studies at the National Academies

 

 

 


            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 30th 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 2000Veterans 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.

 

Text Box: Air Force Health Study Update

 

 

 


Serum Dioxin and Four Biochemical Parameters of Adipose Tissue

            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

            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 130th 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 11th 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

            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 11th 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

            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

            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

            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

            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.

Text Box: Protocol Completion

 

 

 


            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.

 

Text Box: Public Comment Period

 

 

 


            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.

 

Text Box: RHAC Business

 

 

 


            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 15th.

            S. LEFFINGWELL:  The 16th.

            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 16th and the following Friday is April 23rd.

            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 3rd?

            P. CAMACHO:  This is on the first day of classes.

            L. SCHECHTMAN:  How about the 3rd?

            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 16th.

            M. STOTO:  Okay.  I’ve got that.  Where are we at?  The 16th 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 23rd of April?  That’s a problem for you?

            D. JOHNSON:  Only that one Friday.

            M. STOTO:  How about the 30th?

            P. CAMACHO:  The 30th 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 30th.

            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 1st.  Is that — no, Labor Day would be the following.

            R. TREWYN:  The 6th.

            K. OSEI:  Labor Day would be the 6th, 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 1st is before Labor Day, so that’s often a bad week for people.  Yeah, so how about if we say the 8th?

            K. OSEI:  The 8th.

            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 8th.

            K. OSEI:  September 8th?

            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 10th is a — is a — is a bad one for me.

            R. TREWYN:  The 17th.

            K. OSEI:  The 17th would be good.

            M. STOTO:  Should we do 17th?

            L. SCHECHTMAN:  No; that doesn't work for me.  I have a conflict.

            M. STOTO:  Okay.  How about the 3rd?

            J. ROBINSON:  The 3rd 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.

 

Text Box: Closing Session

 

 

 


            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

 

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 27th day of January, 2004.

 

 

 

                                                                                                            /s/                               

                                                                                    Nadine Rivera

 

                                                                                    My Commission Expires:

                                                                                    August 1, 2006

 

                                                                                    [Seal]