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MONDAY, JUNE 17, 1996

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The Committee met in the Superior Room, The Renaissance Madison Hotel, Seattle, Washington, at 9:30 a.m., Joyce C. Lashof, Chair, presiding.






HOLLY L. GWIN, Deputy Director/Counsel



MARK A. BROWN, Senior Policy Analyst

JOSEPH S. CASSELLS, Senior Advisor for Medical and Clinical Affairs

KATHI E. HANNA, Senior Advisor for

Policy Implementation

JOHN D. LONGBRAKE, Research Assistant

THOMAS C. McDANIELS, JR., Policy Analyst




Call to Order and General Remarks: 6

Marguerite Knox

Public Comment:

William Pleas (Seattle, WA) 8

Debbie Marois (Ferndale, WA) 17

Anthony Willner (Spokane, WA) 28

Terry Camille Painter Davis 45

(Lewiston, ID)

Evelyn Hazen (Walla Walla, WA) 52

Theodora A. Tsongas (Pullman, WA) 64

Caroline Mills (Oregon City, OR) 69

Don Johnson (Seattle, WA) 79

Frank Schilling (Tacoma, WA) 85

David Troy Smith (Lewiston, ID) 97

Julian M. Johnston (Ferndale, WA) 107

William Skellenger, (Coeur d'Alene, ID) 112

Joe San Miguel 119


AGENDA (Continued): PAGE

Biological Plausibility: Teratology, 133

Ovarian Toxicity, and Spermatotoxicity

Robert L. Brent, 133

Alfred I. duPont Institute/

Children's Hospital

Bernard Robaire, 163

McGill University

Questions and answers 186

Staff Briefing: 210

GAO Report "Operation Desert Storm:

Questions Remain on Possible Exposure to Reproductive Toxicants"

Mark A. Brown 210

Reproductive Toxicology, 224

Hazard Assessment, and the Gulf War

Michael D. Shelby, 224

National Institute of

Environmental Health Sciences

Questions and answers 236

Epidemiology of and Research on 248

Infertility, Subfertility, Fetal Loss,

and Birth Defects in the U.S.

Anjani Chandra, 248

National Center for

Health Statistics

Robert Spirtas, 264

National Institute of

Child Health and Human Development

Questions and answers 280


AGENDA (Concluded): PAGE

Evaluating Rates of Congenital 289

Anomalies in Children of Gulf War Veterans

Maria R. "Happy" Araneta, 289

San Diego Naval Medical 301

Research Center 314

Questions and answers 298


Richard Olney, 305

Centers for Disease Control

and Prevention

David Cowan, 328

SRA Technologies, Inc.

Questions and answers 337



(9:30 a.m.) MS. KNOX: Good morning; how are you? I'd like to go ahead and call this --

can you hear me now?


MS. KNOX: Okay. I'd like to go ahead and call this meeting to open. Dr. Joyce Lashof, who is usually the chair of the meeting, had something personal to arise, and she will not be here probably until later this afternoon.

For those of you who've been at previous meetings, I'm Marguerite Knox. I am a Gulf War veteran who spent four months in the Persian Gulf at King Khalid Military City with the Army National Guard. I'm from South Carolina.

And so we welcome you here this morning. We are very interested in your public comment and care about what you're going through right now, and so we want to do everything we can to make it possible for everyone who has something to say to be able to testify today.


I would ask that you limit your testimony to five minutes so that we can have five minutes for questioning after that. And then if we have time left over at the end for those people who are not on the agenda, we will put you in later.

So at this time I'd like for everyone

on the panel to go ahead and introduce themselves. There is one other Committee member here, Rolando Rios.

You can go ahead.

MR. RIOS: Yes. My name -- my name is Rolando Rios. I am a Vietnam veteran and a disabled veteran, so I have had experience with dealing with the government insofar as claiming

disabilities. I'm from Texas. And I want to welcome you all for being here. Your testimony is important and essential, as far as us being able to evaluate what you recommend that we say to the President. Thank you for being here.

MS. GWIN: I'm Holly Gwin. I'm on the Committee staff.

MR. CASSELLS: I'm Joe Cassells. I'm


medical consultant to the Presidential Advisory Committee.

MS. KNOX: Start at the end.

MR. McDANIELS: I'm Tom McDaniels. I'm Committee staff.

MR. BROWN: I'm Mark Brown. I'm a chemist and toxicologist, and I'm on the Committee staff.

MS. HANNA: I'm Kathi Hanna, and I'm Committee staff.

MR. LONGBRAKE: I'm John Longbrake, and I'm in charge of public comment, and Committee staff.

MS. KNOX: Okay. We'll go ahead and get started with the public comment. I think we have -- our listing first is William Pleas. If you'd like to come forward at this time -


MR. PLEAS: I'd like to thank the Committee for allowing me to speak today. I've done a lot of talking in private groups, and everybody says, "You should get out and tell what you know."


I'm a sergeant first class in the U.S. Army Reserve. I activated at Fort Harris in the Gulf in November of 1990. I was sent to the Riyadh Military Hospital in Riyadh, Pittman General Hospital. I had a little problem dealing with the doctors and nurses, and volunteered to go to the front. And I had the honor of serving in the U.S. Marine Corps during that, during the war, as a medical liaison officer. Of course, we didn't have any officers who had medical experience enough to deal with Marines and -- either that or they didn't want to. And I served with the Marines in the Vietnam War, so I took great pride in serving with them again.

As a side note, my son was in the active Army at the time. He was in the 3rd Armored Division in Frankfurt, Germany. He was activated, and he also -- he happens, unfortunately, to be unable to attend today, because he's in Yakima with the National Guard for two weeks.

The points that I wanted to cover and the reason I want to cover them is because I've seen


a -- what looks like a concerted effort to put all the problems from the Gulf War into one little package and say, "Well, if you don't meet these, one of these requirements that all Gulf War vets have, then you're not sick."

And one of the advantages that I had over a lot of people who were sent to the Gulf was,

I saw the entire Saudi Arabia and Kuwait area. I know how big it was. And I know there were units that were settled in one specific area that didn't get around the country.

And I know that there were environmental problems out there that are not indigenous to the United States. An example would be, when I first showed up with the Marines, we were at an area called Hafer Al-Atim, about seventeen miles from the border. And we had to dig in; we had to dig bunkers. After we got down through the hardpan about four feet down, we started digging up seashells. Now, I know that those things were there for millions of years. And you know, whether there were any bacteria, microbes, little bugs of any kind


in those seashells, we don't know. You know, we just knew that's where we slept, was in those holes.

I know that some people did get sick

when we were in Riyadh in Saudi Arabia. We moved into buildings that had been unoccupied by human beings since their building about eighteen years prior. We cleaned out sand and pigeon droppings for three days. And as a result of that, according to an ENT specialist here in Seattle, I have what's called rhinitis. The VA says, "Well, no, you can't have Gulf War-related illness, because that's been diagnosed. We know what it is; therefore, it's not Gulf War; therefore, it's not service-connected."

And they have decided that I'm crazy.

But the more I say, "You know, I've got this

respiratory problem that I'm being treated for at the VA," the more the administration of the case says, "Well, okay; you're a little bit crazy, you know, but you still don't have this respiratory problem, because it's been diagnosed."

I saw people come in from the field and were sent to KKMC to the 10th Field -- or 10th


Fleet Hospital down in Dhahran, covered with the dust and dirt from the battles at Umgadar, the oil fields at Umgadar, the battle at Mutalah Ridge.

Some of the people from the Marines

who went on and helped the Kuwaitis and the Saudis liberate the airport were firing these depleted uranium rounds. After the -- after those battles ended, the Bravo company and Charley company, the Graves Registration people and the medical people from the 502nd Forward Support Battalion moved in, took wounded out of those vehicles while they were still burning, some of them -- some, there were no survivors to the blast. They got covered with the smoke from those. You know, in addition to the smoke from the oil fields, they were covered with the smoke and dust from the tanks and the armored vehicles from those rounds. Those people were shipped immediately to rear area hospitals. The corpsmen and nurses who took care of those people didn't decontaminate them before they -- before they started working on them. God knows what kind of stuff was scattered to the hospitals around that


area, and what -- you know, they wonder why people are sick and say, "Well, no, it's all psychological." I'm here to tell you it's not psychological. There were people actually being exposed to environmental hazards and the hazards of war, and they are sick from it.

I would really like to see somebody do a study of the Gulf War syndrome from a regional aspect. In other words, divide the country up into areas. Okay. The people that were here in the rear areas were exposed to this environmental hazard; those who worked in the hospitals had other exposures. Those who were on the front lines, God knows what we were exposed to up there.

I remember the second day of the war, and when we went across through the elbow in Kuwait. It was so dark from the smoke of the oil fields that we had to use our flashlights to read our maps. That night at midnight, the sirocco came in, blew the -- blew the stuff up into Kuwait or into Iraq, and we didn't need our flashlights to read our maps at midnight, because of the starlight and moonlight.


I mean, it was like day and night was reversed over there; everything was backwards. And then we come back to this country after the war, and it seems like everybody's still looking at things backwards. They can't seem to get out of that tunnel vision that "Well, if everybody isn't sick, then nobody's sick; and if everybody doesn't fit into these little pigeonhole baskets that we have built for our sick

people, then they're not sick.

And the consideration -- one of the things I would like you to consider is, the VA Hospital here at Seattle has treated me absolutely fantastically. The medical staff there, they're wonderful people.

The administration of the regional office here in Seattle, those people are stuck back in the Korean War era, I think. They don't believe that anybody can be sick. They're still dealing -they're still having trouble dealing with Vietnam veterans, and then all of a sudden these Persian Gulf veterans come in; they don't know how to deal with them.


MS. KNOX: Mr. Pleas, I'm going to have to go ahead and stop you to allow time --

MR. PLEAS: Okay.

MS. KNOX: -- for questions and give everybody else an opportunity to testify, too.

MR. PLEAS: All right. Thank you. MS. KNOX: I'm real happy to hear you

say that about the Seattle VA. And I do want to mention that we do have a representative here today from the VA, whose name is Mr. O.J. Karnes. For those of you who are veterans or who have dealt with the VA and have any difficulty, I would refer you to that gentleman.

So do we have any questions from the panel of Mr. Pleas?

MR. RIOS: Mr. Pleas, when did you

first discover that you had respiratory problems? MR. PLEAS: The fifth day in-country. MR. RIOS: And did you file a claim

right away or --

MR. PLEAS: Well, I kind of selftreated in the emergency room. A couple of doctors


that I worked with gave me some -- there was a broad-spectrum antibiotic that was pretty popular over there; it was what we took for anthrax, as a prophylaxis for anthrax before we went across the border.

MS. KNOX: Cipro?

MR. PLEAS: Cipro is correct. And I took some of that. But unfortunately, when the 816th Convalescent Hospital came out with their study on L-S Can [phonetic] disease, which is what I think I had, they said you had to go through a full spectrum of treatment for the L-S Can disease. I didn't do that.

When I got back to Fort Hood, I still had this nasal drip that I still have today. I reported that to the doctor who did my out-processing physical. He told me he could put me in the hospital or I could go home and let the VA take care of it. I chose to go home. I'd been away from home for six months. I went to the VA and was told, "Oh, no; you have medical coverage, so you can't be seen at the VA." It took me a year and a


half to get into a comp-and-pen exam at the VA. MR. RIOS: What's the status of your

claim right now?

MR. PLEAS: I'm in an appeal process. The claim is supposed to be going to Washington, D.C., only because I'm still fighting to get them to recognize the respiratory problem. They have me disabled at 100 percent, but the reason why they have me disabled at 100 percent, I disagree with.

MR. RIOS: Thank you, sir.

MS. KNOX: Any other questions? Thank you, Mr. Pleas.

MR. PLEAS: Thank you.

MS. KNOX: We appreciate your comments.


Ms. Debbie Marois. Welcome. STATEMENT OF DEBBIE MAROIS

MS. MAROIS: Thank you. And it's Marois.

MS. KNOX: Marois.



I came prepared for a little bit different than what we just heard. I came to talk about more of my symptoms.

MS. KNOX: Okay.

MS. MAROIS: I was a United States Navy corpsman, and I was sent over to the USNS MERCY. However, I feel my exposure would have taken place in Bahrain before I had even got to the ship; that's where we were being bombed.

And my biggest -- biggest symptom is my headaches. I have headaches constantly. I don't mean frequently, I mean constantly, every day. And they do -- they get so bad that I do end up in bed. I end up with doctor care, sometimes for a week straight.

I'm seeing a civilian doctor, and he claims they're migraines. I really -- I just have a hard time believing that migraines last so long and for such extended periods of time.

I also have the respiratory problems. I have continuous nasal drip. I have lots of chest pain, coughing, cough up stuff a lot. And not long


after I had come home from the Persian Gulf, I'd say within a year, I ended up in the hospital with pneumonia, and it was so severe that antibiotics weren't treating it. And it was just -- it had been five or six days on antibiotics, and I finally was hospitalized for a week to try to help me clear this stuff up.

And throat problems that they seem to think are like strep throat or something like that, but the tests always come back negative and -- but my tonsils are really swollen and my throat's really sore and raw and red.

And I've had lots of rashes. They just come every now and then. They're really, really itchy and red, like red patches almost.

And I have lots of memory loss; I had to write everything down, as though I could


And another big thing is sexual intercourse with my husband. He claims that I burn when I reach climax and climax. And it's painful to me and to him; so therefore, it's limited.


And he has started complaining of some symptoms that coincide with mine, so I'm fearful that maybe I am exposing him or infecting him.

And another -- I had a daughter a year and a half ago, and I was real concerned. And I stressed to my OB doctor that I was concerned about this, and my pediatrician. And everybody said, "Well, I don't know much about it," so basically they -- kind of the way the gentleman just said, everybody kind of thinks you're kind of crazy. They just kind of said, "Okay; we'll keep that in mind, but I don't know what to look for or what to do." And so we kept it in mind. She has lots of respiratory colds, if you want to call them that. Antibiotics don't really help right away; it takes a long course for her. Nausea and vomiting and diarrhea that just kind of come periodically, no fever.

I know me personally, I've been labeled with PTSD, so a lot of times the doctors look at me and say, "Hum; okay. So how are you


doing with your psychiatrist? You've been seeing

him lately?" -- when my symptoms start coming. So I feel that they definitely think I'm kind of a wacko crazy, blaming everything on the Persian Gulf.

Now my biggest concern is that I went there voluntarily. I put in a chit to even go to the Gulf, because I at the time was not married and I didn't have family around. I was stationed in South Carolina, and I didn't have kids. So I wanted to go ahead and -- all my friends and kids and families and everything around. So I asked to go ahead and go.

Now I'm afraid. If I had infected myself, that's okay. But I don't want it to be starting to affect my husband and my kids. And if it is, that's a concern of mine; I want to know what we can do to stop that, 'cause they didn't ask any of this to happen.

And I think I've hit pretty much everything I was going to.

MS. KNOX: I just have a couple of questions. Can you tell us, did you take the PB


tablets and the vaccines as well?

MS. MAROIS: I believe so. A lot of this I blocked out.

MS. KNOX: Uh-huh.

MS. MAROIS: I honestly don't remember. I remember taking some pills. I remember getting some injections. But as to what they were, I'm sorry, I don't --

MS. KNOX: So you don't remember taking any medication and your upper respiratory

symptoms occurring at the same time?

MS. MAROIS: Right. Right.

MS. KNOX: Okay.

MS. MAROIS: I -- just before I'd left, I had fallen and seriously injured my knee, and I never even felt the pain until I came home.

So I mean, I just kind of mentally wasn't even there any more, after I had learned I was going.

MS. KNOX: So do you receive a VA pension?

MS. MAROIS: For my knee, for PTSD, but I do not for any Persian Gulf-related stuff.


Another thing I had just remembered is that not long after I'd come home, within six months I had a Pap smear. Because I was supposed to have been rotating out of country for my orders, and the Pap smear had come back "high-level dysplasia," which was very concerning, I had to treat right away. And the year before, there was nothing at all. So that may be related, may not, but it's something concerning.

MS. KNOX: How has your treatment been at the VA facility that you've been utilizing?

MS. MAROIS: I've had quite a rough

time at the VA, I think partly because I'm a woman and partly because I am young. I have gone to set up appointments, and basically when I went through the Persian Gulf exam, they had told me that it was -- especially with my headaches, that they would document it. They couldn't do anything else but

document it. So I felt kind of let down.

MS. KNOX: Were you hospitalized at the VA for your pneumonia?

MS. MAROIS: No; it was outside.


It's been within the last year and a half that I've realized things have been tying back to since I came home. So I mean, a lot of this is really outside help.

MS. KNOX: Any other questions from the panel?

MR. CASSELLS: When you went to the Gulf, were you an active-duty member at the time?

MS. MAROIS: Yes, I was.

MR. CASSELLS: When you came back, how much longer were you on active duty before you left?

MS. MAROIS: I was discharged about eight months after.

MR. CASSELLS: So that was prior to the CCEP program, so you had no involvement with that. Is that correct? Which is the Department of Defense equivalent of the VA Registry.

MS. MAROIS: No, I hadn't, before that.

MS. KNOX: So you didn't have an exit physical when you were discharged?


MS. MAROIS: Well, they were trying

to decide if they were going to go ahead and let me

try to go on or if they were going to discharge me, so it was a physical to do with that. It was kind of like they were getting ready to send me out of country, a physical that they just went ahead and used to discharge me.

MS. KNOX: All right.

Mark, did you have a question?

MR. BROWN: Yeah. You mentioned that you remember an exposure when you were in Bahrain -

MS. MAROIS: Uh-huh.

MR. BROWN: -- that you thought maybe was related to your health. Did I understand you correctly?


MR. BROWN: And what do you think -what happened? Is there some incident that -- some exposure incident that you recollect, or something that --

MS. MAROIS: Well, we walked off the plane. Flying over, we flew commercial. We walked


into the airport. We weren't all the way even in, and we had been bombed. And everybody in the airport, the Saudis and everybody else that was there, had their MOPP gear on. Well, at the time, we didn't have -- everybody on the plane that went over did not have their chemical warfare gear. And we didn't have a chance to even -- the people that did have it didn't even have a chance to get it, 'cause it hadn't come off the plane.

MR. BROWN: Well, do you know when that occurred, when that date -- the date of that?

MS. MAROIS: I'm sorry?

MR. BROWN: What the date was when you --

MS. MAROIS: I would have to look probably through my records.

And then we had gotten to the base in Bahrain, and we were all put into a gymnasium. There was about 400 of us. And we were trying to sleep. About an hour and a half after everybody had settled down, we were woken, because a Scud missile had hit, hit a -- a bomb. And the roof was shaking,


so we were woken up then, and didn't know what was going on, didn't know if it was chemical or not. So we just sat and waited. And then the same the following night. We were there, I think, three days before we made it to the ship.

MR. BROWN: Thanks.

MR. McDANIELS: Do you know of any other people from your ship that have experienced illnesses?

MS. MAROIS: I've lost contact. I don't know. I would be more concerned with the people I went with than the people on the ship, 'cause I don't know -- maybe there was, you know, some chemicals in the air from land or something. But my concern is the people I had gone over with that, you know, were at the airport with me, that were in the gym with me in Bahrain. Those are the people I would feel that may have had more exposure.

MS. KNOX: I don't think we have any

more questions.

MS. MAROIS: Thank you.

MS. KNOX: Thank you so much for your




I think the next person that we have listed is Carla Willner. Carla Willner. Great.

MS. WILLNER: Tony's actually going

to speak.

MS. KNOX: Mr. Anthony Willner is going to speak? Okay.


MR. WILLNER: Yes. Thank you. I've got to apologize first; I'm extremely ill. I've been pretty much bedridden since October, and before then suffering horribly from multiple chronic ailments.

I wrote this down, and I'll try to go rather quickly. We have an overhead, just a couple of things.

MS. KNOX: Okay.

MR. WILLNER: I wish to express my most sincere appreciation for this opportunity to finally speak out and be heard. I hope and pray for this Committee's full attention and response to all


issues, without bias or compromise.

My name is Anthony Eugene Willner. I am a specialist in telecommunications and alarm and

indicating systems. In the Navy, my past five commanders rated me at 4.0 evaluations, with only "Outstanding" comments. I was a supervisor and lead technician for over three years of the six years enlisted.

I believe that congressional testimony proves the existence and use of biochem agents and experimental drugs during Desert Storm. My testimony today provides the physical evidence to support this.

I'd like to first address the USS KISKA's -- that was my command at that time -desalination system alarms. They measure minute particle contaminants of water with extreme accuracy. My extensive background in alarm and indicating systems qualified me as an expert witness on the performance of these systems. Dirty still water is the worst-case scenario where desalination system alarms may go off, at the most, a few times a



Fact: during Desert Storm, multiple controlled tests verified the optimum efficiency of the desalination system alarms.

Fact: while steaming through the Gulf's clear and open water, the desalination system alarms went off at least once every hour, sometimes even more. The engineering operational logs extensively documented these alarms, which started during the coalition bombings and continued for two months.

Fact: sometimes these alarms went

off immediately after cleaning the sensors.

Fact: often these annoying alarms were turned off by the other engineers, because their cause could not be ascertained.

Fact: Mark Hergersheimer, one of my junior technicians, often cleaned these systems without gloves. Thereafter, he constantly picked off dead skin from his fingers. Although he was in premium health before the war, within one year he suddenly was transferred off the ship with serious


medical symptoms closely related to the Gulf War syndrome.

I was also in charge of the KISKA's distilling plant contamination monitoring systems. This is a potable water supply. These alarm systems rarely ever went off during my two and a half years on the ship on these systems.

Fact: during and for two months after coalition bombings, these alarms went off several times a day, on the average. The engineering operational log extensively documents these alarms which started during the coalition bombings and continued for two months.

Experimental vaccines and tablets.

Many service members also received experimental drugs during Desert Shield/Storm to protect them from biochem agent exposure. The majority of the KISKA crew did not receive these special medications.

Fact: on or around December 13th,

1990, hospital corpsman first class Charlie R. Hill,

Jr., independent duty corpsman for the USS KISKA,


gave me an inoculation and two brown tablets, despite my verbal inquiries and concerns, at no time was I informed that they were biowarfare vaccines or antinerve agents.

Fact: for three days, beginning December 15th, 1990, I became violently ill, with severe bouts of diarrhea, and nausea with vomiting. Although I was extremely healthy prior to the Gulf War, my medical record attests to the fact that I have often had bad reactions to inoculations in the Navy, which of course I'd get over.

Fact: due to the highly unusual circumstances of this incident, it is burned into my memory. None of the usual medical procedures was followed, including allergy disqualification. Because of time limitations, I will provide the Committee a written accounting.

Ionizing radiation exposure. I have had long-term exposure to ionizing radiation exposure for two to four years. These include on the USS VINCENT, a nuclear-powered aircraft carrier, where I was a supervisor of the alarm and indicating


shop, and then on the USS KISKA in the Gulf War as the command supervising coordinator and technician of the special weapons alarm/security systems, which of course I cannot elaborate on further.

Fungus growth. There were numerous reports and complaints on the way back from the Gulf of a black stain or growth on the outside intake filters.

Regarding my illnesses, I've been experiencing major, severe disruptions to my immune and neurological systems since June of 1993. It started on the way back from the Gulf in February of 1991, with minor but annoying immune problems, including chronic flu and colds, itch, and chronic cough, and circulatory and temperature stability problems.

I have been dealing with the VA for over three years. And to sum it up, it has been a very bad nightmare.

Finally, my wife Carla has been suffering from multiple illnesses since my return from the Gulf. Her symptoms include chronic fatigue


syndrome, consecutively missed menstrual cycles, severe heavy menstrual bleeding, clots, and cramps, decreased libido, chronic yeast infections, and noticeable hormonal disruptions.

Fact: although we are young and want to have children, the existence of Gulf War babies has made us reconsider this choice at this time.

Today Gulf War veterans suffering

from multiple chronic illnesses deserve the benefit of any doubt. They deserve to be treated fairly and justly. Empirical evidence alone overwhelmingly provides proof, despite the promises of President Clinton and Jesse Brown, we are not getting help.

In fact, we're being ignored and ridiculed. And I'd like to emphasize I went through every procedure very politely, very cooperative, and assisting in every way. And my story is so atrocious, I cannot go into detail -- and believe me, my story is only mediocre, compared to many of these veterans'. I know people who have lost their homes and went bankrupt, who before were outstanding service members. This is an injustice.


How many people will have to die before the government realizes that ignoring us will not protect their secrets? The truth will come out. Like the Vietnam experience, America will not forget the emotional and psychological stress placed on veterans because of apathy, neglect, deception, and outright abuse, outright abuse by their government. Our country established these agencies to help veterans, not blame them at taxpayer expense. We did not choose to be sick. We all deserve to have peace. Please give us that peace.

Thank you very much for your time. I'm now open for questions, and I'll try to answers as best I can, as I'm pretty dizzy up here now, and stuff, so --

MS. KNOX: You're welcome to sit down, if you'd like, Mr. Willner, in the chair.

MR. WILLNER: I'll be all right. MS. KNOX: That's very concerning to

all of us on the Committee. We want veterans to receive the care that we feel like they deserve.

Have you been treated also at the


Seattle VA?

MR. WILLNER: No, I've not. I'm from Spokane, Washington. And I also went down to a special study. After begging for two years for help through all the protocol, I went to West Los Angeles VA Medical Center, which in many aspects was a big shim-sham joke. Although there are a few highly professional --


There's a lot of scapegoat technique, is what was going on there. And I'm currently filing several civil tort -- civil and tort claims against blatant malpractice and neglect down there.

But there were a few very prominent

doctors that cared, like such as Dr. William Baumschweiger, a specialist in neurology and psychology and a psychiatrist. And then there was also a pain clinic specialist who -- he was in anesthesiology. A really good pain medication was Altram; he prescribed me. And he gave me spinal epidurals directly into my spine, because it feels like my spinal cord has been eaten for the past


couple of years.

And I got up here to the local VA at Spokane, and again they've denied me medications that was prescribed. I mean, my wife witnessed these atrocious acts. And I'm having to deal with

them one by one, let alone -- I can't even hardly deal with my health, let alone having to fight this.

MS. KNOX: Are you receiving any


MR. WILLNER: No, I'm not; none at all. For three years I've been trying to process a claim. I've -- I was a highly successful telecommunications specialist, and I'm currently on a medical leave of absence from Washington State Department of Corrections, of their Information Services Department, which is a high-security and responsible position. They've beared with me for quite some time, and I had inmates to do all my heavy work for me. But basically, I drained my savings and I've been living on charity. The people out there are so -- they're just blessed Christians and wonderful people. And I've had like almost a


thousand hours of shared leave donated. But other than that, month by month I did not know what my income would be. And it was a horrible thing to go through, let alone being so sick I could hardly function. Imagine the stress of dealing with all these other things.

MS. KNOX: I'll open it for questions. Go ahead, Rolando.

MR. RIOS: What is the status of your claim?

MR. WILLNER: I would like to know, sir. What is the status of my claim?

MR. RIOS: I don't know.

MS. KNOX: Dr. Cassells?

MR. CASSELLS: Yes. I'd like to go back to the KISKA. You said the independent duty corpsman gave you an inoculation and some pills.

MR. WILLNER: Yes, sir.

MR. CASSELLS: Some brown pills, you said.

MR. WILLNER: Yes, sir.

MR. CASSELLS: Was that given to


everybody on the KISKA?

MR. WILLNER: Definitely not, sir. And I have sworn statements from service members that it was not. And it was a very unusual circumstance, being called up after normal work hours, where medical -- the medical office was evacuated, except for just him. And he called me into a back room. He'd called me up. He said he needed to update something in my medical record.

I got up there. And I'd heard that he was kind of an odd sort of fellow, but, you know, I have an open heart towards anybody, usually, so -and I went up there. And I just felt uneasy, and I just thought it was because he was a little bit arrogant or apathetic. He didn't have my medical record. He had an individual sheet there; he was documenting some things.

He said, "Oh, you need to get this flu inoculation." And I said, "Oh, really? Oh, you know, I don't like getting those, 'cause I never get sick except when I get those stupid inoculations." And he said, "Well, you need to take this," and I go


"Okay." He didn't ask me if I had the normal allergic reactions, which are required.

And then he handed me these two brown tablets in a little packet, and I said, "Well, what are these?" And he goes "Well, they're malaria tablets." And I go "Oh; I haven't heard of any malaria threat for our deployment." He goes "Well, you need to take them." And then I -- he didn't ask like if I was allergic to quinine, and asked --

I turned around again, because I just felt uneasy. I said, "What about not giving blood?" Remember, I'd been on several long-term deployments before; I'm used to the cattle-call medical regime of all those drugs. It was just something unusual. But me -- I'm not like an overly suspicious individual. I just thought, well, maybe he's odd. And then three days later I began with all those illnesses, which were just horrid.

MR. CASSELLS: Do you know of anyone else on the KISKA who received this?

MR. WILLNER: At this time I decline to comment. Thank you, sir.


MS. KNOX: Go ahead.

MR. McDANIELS: The corpsmen on ships are supposed to conduct frequent tests of the drinking water. Do you know if any of these tests came back unsafe?

MR. WILLNER: I respectfully decline

to comment on that, sir.

MS. KNOX: I'd like to further ask you a question about your claim. We can't help you unless we know what information you've received from the VA. Have you received any information back concerning your claim?

MR. WILLNER: Yes, I have. I've tried to follow up as best I can. There is -- the assistant director, Ron Porzo, at Spokane VA Hospital, has been very helpful. I don't usually go -- we went to him at the last resort, and we went through the whole chain of command. And basically, apathy, neglect, and mostly ignorance on this issue, and not realizing how severe and how many people are suffering.

A year ago, finally after begging for


help, although I met all the criteria for the quote/unquote "mystery illnesses" and so forth, so on and so forth, I went down to West Los Angeles, and they did diagnose with a chronic fatigue dysfunction. They diagnosed a, quote, "chronic lumbosacral sprain," which was probably misdiagnosed, and pharyngitis, and they skipped several other things.

After I had one interview with a psychiatrist, which the only thing I can liken it to was a Nazi Gestapo interrogation, and weren't addressing it individually -- and I think that when we bring it before a court or before justice of a psychiatric court she'll be stripped of her license, without a doubt. And this is pretty much the common

protocol for the veterans that were going down there for help and assistance.

And I'm all -- I have received help. The only reason I'm here now is because I found some really good naturopaths, alternative health specialists, and like my primary care physician and other specialists. I've had to get -- the only help


I've been able to get that has been helpful, I've had to go directly outside the VA at my own resource and expense.

MS. KNOX: So you're continuing the effort to have a claim with the VA? It's still pending?

MR. WILLNER: Yes, I am. It's still pending.

MS. KNOX: Okay.

MR. WILLNER: And I'd also like to add that it was very interesting. I called the administrative medicine's chief of staff, Dr. Ronald Hamm, and I called him on several of these things. And he said blatantly several times -- I had him because there were so many blatant negligence in the things, discrepancies. He said, quote, "We clearly dropped the ball here in several areas," unquote. And he was currently trying to review some of my things.

And it was interesting that this report, when I was discharged by him and by a junior intern of those prior things that they identified --


and they skipped over several other things and several red flag markers of my immune system disruption. Then I get this report that -- I just still don't know who wrote it. But all of a sudden, the two top diagnoses, number one was depression, and two was post-traumatic stress.

I remind you, I was a technician in the Navy. I was a supervisor. My shop was air-conditioned, had TV, Nintendo, VCR, stereo. My guys were my brothers in there. It was pretty chilled out. And I've been -- pretty much had a very strong ability to deal with any type of situation: chaos, casualty, or technician. Because of my faith as a Christian, life doesn't bring too much stresses to me; it's all a state of mind, basically of attitude.

And it's real -- and it's interesting that final report was not signed by that junior intern, who I have a statement from and contacted. He's totally denying the validity of that report, and he's also stated about the negligence and the position of the VA against -- basically, they're


against the benefit of the veterans dealing with that. And it wasn't signed by any of the senior medical staff. And that's real interesting, because that seems to be this big weapon, of now mental disorders. And it's very odd, especially for I've been held in positions of high security clearance, working for the State of Washington, we're dealing

with people, being a children's minister. And so I guess, if I'm so mentally disturbed, it would be really odd that I could literally get hundreds of people to give affidavit statements, sworn, of my mental condition and personality.

MS. KNOX: Thank you so much for your testimony, Mr. Willner.

MR. WILLNER: Thank you very much. I appreciate it.


MS. KNOX: Next we have Terry Davis. Good morning.


MS. DAVIS: Thank you for this chance to speak. I'm Terry Davis, a Gulf War veteran and a


mother of -- a mother of three children. I've been an art teacher in the public schools and a freelance illustrator, but currently I am occupied full-time as a nurse to my sick children. I am a member of the Retired Army Reserves. I reside in Lewiston, Idaho.

My twenty years of service included four years of active duty, Air Force. I was an X-ray tech, seven years National Guard as an illustrator, five years Army National Guard field medical X-ray, and four years in the Army Reserves medical X-ray.

I served in the Persian Gulf War five months, January through May 1991, in northern Saudi Arabia, with the 947th Medical Company (Clearing) of the Colorado National Guard. My duties included

supervising a ward of sick Iraqi prisoners, setting up X-ray facilities, and taking X-rays. Our platoon of thirty-six people were tasked with treating up to 1,200 sick prisoners a day. We treated 53,000, then we treated 2,300 American soldiers, and it was a demanding schedule.


Individually, I was tasked with writing the weekly news about our camp for the battalion newsletter stationed with our rear element.

When I left for the Gulf, my records will show that I was extremely fit. While there, I began to experience some minor health problems, though none of them seemed significant. I had a few rashes, infections that were easily treated. And when I returned home, I seemed fairly normal at that time.

However, over the course of a year this changed. I caught colds all winter that were hard to shake, and that was new to me. In May of '92 I got pneumonia, without even catching a cold. This happened in good weather, and no one else had it. My spouse also began having some odd health problems. His allergies grew worse, and he contracted Bell's palsy; he looked as if he'd had a stroke. And he was twenty-nine years old at the time.

Sixteen months after the Gulf War I


became pregnant with twins. They both were diagnosed with heart defects at five months in uterum [sic], and this was not a hereditary condition. At birth, both girls received pacemakers. One daughter -- Talisha's defects were much worse at birth. She needed constant oxygen therapy for a month. And at four months of age she had a valvoplasty to correct a life-threatening condition.

At this time my husband's allergies grew worse. My lungs continued to give me problems, and I got my first ever reproductive tract infections, and I was treated for that. Eventually my husband was diagnosed with adult-onset asthma, and there is no record of asthma in his family.

In February of '95 Talisha caught an RSV infection. For most people this is an ordinary cold, but it's deadly to infants or older children with heart or lung weaknesses. She was twenty months old at the time. Talisha developed congestive heart failure and was hospitalized. Upon release, she suffered a stroke and was


rehospitalized. A heart transplant was required for her survival.

Then my health deteriorated, and I was diagnosed with lung disease. Other tests revealed that my system was full of sediments, an indicator of poor health.

Talisha underwent a heart transplant September of '95 at Children's Hospital here in

Seattle. She had the worst cardiomyopathy they had ever seen. She's undergoing drug therapy for heart transplant and rehabilitation for the stroke.

Today we seem to be recovering

somewhat from last year's traumas. But Talisha will always have a depressed immune system. Tamesen will always need a pacemaker. Fortunately, my nine-yearold daughter is normal, and she's the only one of us who is not sick. Our health problems continue, but we are coping as best we can with available therapy.

My career options are very limited

because my time is spent in medical facilities, since my twins are at constant high risk. And this morning Talisha is in the hospital for a checkup


here in Seattle.

MS. KNOX: I'm sorry that you've had such a difficult time.

I don't have any questions. Does anybody on the panel have any? Go ahead -- yes, Kathi.

MS. HANNA: Mrs. Davis, how were the twins heart defects first detected? You said it was in utero.

MS. DAVIS: Yes. On a sonogram. They were not expected to live, but we got lucky. We had a lot of prayer.

MS. HANNA: And when they were born was anything -- was any intervention done immediately?

MS. DAVIS: Oh, yes. I -- ordinarily I would have had my twins at the hospital in

Lewiston, but because of the problems, I had the twins at Sacred Heart Medical Center in Spokane.

MS. HANNA: Are they identical twins? MS. DAVIS: Yes, they are.

MS. HANNA: And how old are they now?


MS. DAVIS: They'll be -- they're almost three.

MS. KNOX: So do you remember being exposed to any incident that you could relate to your illness?

MS. DAVIS: I know that -- well, I've heard since I've been back from the Gulf that there was depleted uranium used in the weapons on the tanks. And I was walking around those tanks, and I'm concerned that perhaps I had exposed -- been exposed to radiation, which may have caused these heart defects. And I was far enough north that I was around those oil fires. I was in Kuwait City for a couple of days.

MS. KNOX: But you had your protective gear?

MS. DAVIS: We had our protective gear, but we didn't know we -- we didn't know we needed it for being around the tanks at that time, and we were not warned that there was any radiation coming off of them.

And also, when I was on a ward


tending to all these Iraqi prisoners, who knows what

they had? There's a lot of birth defects coming out of Iraq right now.

MS. KNOX: I don't have any further questions. We thank you for your testimony.

MS. DAVIS: Thank you.


MS. KNOX: Evelyn Hazen.


MS. HAZEN: This won't sit -- I can't sit down and use it, can I?

MS. KNOX: Yeah, you can.

MS. HAZEN: If I need to sit down, I'll just sit down.

Yeah, it is a new day and a new kind of warfare. America needs to sit up and take notice about sending their sons and daughters into this kind of warfare. It's different than Vietnam and the Korean War and World War I altogether.

And take a good look at me, because I have become -- I have become the enemy, part of the enemy. I didn't mean to, and I didn't know I was.


When they called me in 1990 from the Pentagon and said, "Would you come and relieve some folks at Madison -- Madigan Hospital so they can go to war?" I said, "Sure." I wasn't dragged screaming; I went willingly. I was in good shape; I weighed 126 -passed my PT, over forty tests, everything. Unlike the others that came later -- my unit was called up later, and I knew I would go to Saudi when they were called. Unlike them, I had an OAR from the places

that I had worked out there. And I did an outstanding job. And I'm not here to brag on myself; I don't think I need to prove myself to anyone. That -- we're taking up a lot of time doing that.

But I can assure you I'm three times my normal size. Never wore glasses, never wore hearing aids. My liver is enlarged. I have blood and protein in my urine. I have a positive ANA. I have Shogrun's [phonetic] syndrome; they just jerked my teeth out a couple of weeks ago, because my mouth's so dry my teeth are loose. I lost hair in the beginning.


What happened to me January 4th, 1991: I was running with my unit on lock-down, prepared to go to Saudi, passed everything, and I keeled over with a heart attack. But they left me. I mean, they left me standing there in the road, having a heart attack, a major heart attack.

But being a nurse, I knew that when I woke up in the unit and I was getting blood, that something else was going on -- hematocrit in the 20s. Later in the summer they wanted to give me more blood for a hematocrit in the 20s, and I said, "No. Find out what's wrong; please don't expose me to AIDS."

I had begun to lose hair. I could barely walk. I had to lift my right leg to put it in a car. I slurred speech, had memory loss.

People were passing me around like a

hot potato at Madigan: "No, there's nobody else

like you." I was an accident; I don't think I was supposed to happen. I think I was supposed to happen in Saudi; we would've been there in twenty-four hours. But we'd had all these


inoculations, you see, just before this happened to me.

And we'd had some sort of virus go through our unit. People were -- their heads were hanging over in the auditorium. They could barely hear the speaking, the teaching that we were supposed to be learning to save our lives over there.

But we were a good group; we passed everything. We were fit. And when I started getting passed around like a hot potato, a doctor told me "The reservists are unfit." I said, "Excuse me?" And I was very angry, and I did shout at him, because my people -- at that time my people were being barraged with missiles in Saudi.

I said, "Sir, those people are fit enough to die, and that is fit enough for me. They passed everything and they were sent there, and the American people expected them to perform. They did perform. I don't know what other faces you saw, but the faces I watched on television from the coronary care unit were happy, smiling, go-get-'em faces,


healthy looking."

And this is a sham. Look at it.

Look at these few chairs here today. There's supposed to be more veterans here today. How do I know I'm the enemy? Because there aren't more chairs. Because it wasn't put out in the press. I called the VA Hospital this morning and asked them. I asked the media people "Did you know about this meeting?" I wanted to make sure this was real. I hadn't heard about it. Someone gave me a phone call. And this is the way it's been all along, and it continues to be, even today, as we stand here and sit here. More veterans should be in this room, but they don't know about this. And we had no time to tell them.

Now I want to tell you something. I've been in the VA. I'm a nurse. I'm not afraid to criticize. I'm not afraid to stand up for my patients and for other people, because I've done it before -- and nearly lost my job doing it. When people were overmedicating patients to the point of death, I let it be known. I wasn't going to walk in


on my shift and give them something, let them keel over on me. They did their little investigation, slapped them on the hands, and that was it. And of course, I suffered. I suffered for that. But I kept a few veterans from being killed from overmedication. I only say that because I know that things go on.

There's good people in the VA, and there are people standing in the way. And there's some people standing in the way just to protect

their jobs, because they don't know better, and also because of the information they're getting from up high.

I told a doctor, I said, "Look, I'm having these same symptoms the other veterans are having. You should tell your superiors that I'm here and I exist." Not this doctor. He said -- and I have his name; if you want it, I'll be glad to give it to you. I have names of an IG at Madigan Hospital. I filed a formal complaint because they weren't caring for me properly there. My liver was getting bigger. I was having blood-and-diarrhea


stools. Something was wrong. I knew it wasn't right. I said, "Could this be happening to other veterans?" They said, "No, no." So my concern isn't just for myself.

I'm at 100 percent right now; I'm not going to walk away from this, because I know there's some sick kids. And America has got to learn that this is a new kind of warfare; we've got to face it differently. We've got to do something now.

And we could've lost that war because of the silence of everybody in this country, including civilian doctors, the press, everybody. This is ridiculous. This is like Russia. Why are we sitting here having these hearings?

And like Russia, we make them crazy. I have the same diagnosis as everybody else in here. I'm a nurse. If I were healthy enough, I couldn't even work anywhere, because I have a psychiatric diagnosis.

One of the nurses that was with me at Madigan, she had a cattle-car accident. But she had some of the symptoms I had. She overheard the IG


that I made the complaint to. She overheard him. Her name is Barbara Letch. She's not afraid to tell you so. She's a lieutenant from the Army. She heard him say at a dinner table with other nurses and doctors that he had "run me off" with my complaint; "run me off." So you see, it started way back, way back in the very beginning, before I knew these other people existed. They kept me out there a year and a half and let everybody else go home, because I had complained. They punished me.

I went through a bankruptcy. I went through congresspeople, and I have their names. Nobody's helping. I went to the VA. Oh, they knew I was coming before I got there. Yes, they did. So I've become a major problem -- you see, I'm a major. But I know I'm a major problem.

And I'm the enemy. And I know I'm the enemy, because I know people turn away from me. They misdiagnose you: fibromyalgia, chronic fatigue, depression, possible lupus. All of it's there. I tested positive for Epstein-Barr virus, hepatitis. I didn't have these things before, and I


have records to show. I had the hepatitis test

about six months before I was called up; I was

negative. Now I'm positive. Something's wrong.

What happened? Was it the blood they gave me -- maybe some of their blood? Because I came early. And we give blood to each other in the Army, you see. So some people had been in the Gulf for six months. But I know people who'd been in the Gulf for several years, because we'd been giving them inoculations to go over there and do things for several years. So I think some of this had started before. I think people had been getting sick and didn't know it.

And I think it's a cover-up, and I think it's time America just stood up, took their punches like these kids do, and do something about it. I don't want my boy going into this.

And there's not enough time here today to say what needs to be said. You're so busy defending yourself. I'm unlike the other vets. I used to see the vets come in the hospitals carrying their briefcases, their little suitcases full of


paperwork to prove it all. Why do we have to prove anything? You saw us. You saw them kids go over there. We know what they were exposed to. And yes, it will make them sick. Oil fires make you sick; firemen get sick from oil fires.

MS. KNOX: Evelyn --

MS. HAZEN: And why does America have to spend all this money for you people flying all over and hearing all this? And we don't know where it goes and what they do with it, because they don't -- because we never get any feedback. They never

bring us in the same room together. We can't find each other. We have to go on Internet, we have to spend money on long-distance calls that are eating our families alive.

I can't do this any more. My husband can't do it any more. He got sick after I got sick. My daughter got asthma.

What is going on? You don't want America to know. I'll tell you that's what's going on. Because America will be scared when they -when America finds out. This is not going to stay


with the veterans. No.

And we're trying to help. We're trying to help it from happening. We're still fighting. We went into a war and we have never, ever come out. And we are the enemy. You made us the enemy, not us.

MS. KNOX: Evelyn --

MS. HAZEN: And I'll tell you something. In The Art of War it says, "Do not press a desperate enemy; an exhausted animal will still fight as a matter of natural law." We learned well. We're not wimps.

And I have suffered, and I don't have to -- I have a record this long [indicating]. I don't have to tell you what I suffered through, but I have suffered.

I'm a nurse, and I know these kids have some sort of autoimmune disorder. It's plain. A layman can figure it out by reading the newspapers.

MS. KNOX: I'm going to have to stop

you in order to give everybody else adequate time.


MS. HAZEN: Thank you very much. I'm sorry for being so angry; it's what I've learned to be.


MS. KNOX: Evelyn, I would like to say, though, that the meetings are publicized on the federal registry, and --

MS. HAZEN: We don't know about that. We never heard of it.

MS. KNOX: Well, let me tell you the next meeting will be July 8th and 9th in Chicago at the West Ambassador Hotel. And so we've tried to have these meetings in all the different states so that veterans can be exposed to the other testimonies and they're aware of them. We have found that the veterans groups have had excellent communication between and among one another, and they have spread the word.

MS. HAZEN: I called the VA Hospital. The media person hardly knew about it himself. I said, "You mean to tell me it wasn't in the newspaper?"


MS. KNOX: Well, we have a VA representative here, so you might want to -- you might want to talk to him.

Let's go on with the next testimony.

Theodora Tsongas -- is that correct?


MS. TSONGAS: Good morning. Thank you for permitting me present my testimony to you today.

I'm Theodora Tsongas. I'm assistant professor of environmental science and regional planning at Washington State University. I've spent the past twenty-two years evaluating the adverse health effects of human exposures to environmental contaminants. My research has included studies on potential reproductive hazards in the occupational and the ambient environment settings. Further details of my experience are contained in my written testimony, which you should have there.

Because my time is short and I want to give a chance for the other veterans to talk today, I will just talk about a particular part of


my testimony relating to reproductive toxicity. During the past few months I've been

working with a group of Gulf veterans, trying to identify their concerns and help them with interpreting the medical literature and the scientific literature.

The reproductive system, as you know, is a sensitive system with many potentially vulnerable windows for toxins to act and many potential outcomes that may be affected.

For both males and females, manifestations of toxicity may be delayed for many

years. Effects on fertility, for example, may not be recognized until pregnancy is attempted. And even then, reduced fertility may not be noticed. Genetic effects on the ova may also not be noticed until a pregnancy results in adverse outcome, and then it is very difficult to discern the cause of a malformation or spontaneous abortion or stillbirth.

It is for this reason that I believe

the time limit on claims to be made by Gulf veterans to the VA for health problems is inappropriate.


Furthermore, biological and chemical agents may also have delayed neurotoxic effects, and it's not unlikely that they may have delayed toxicity affecting other organ systems as well.

A well known exposure route for families of occupationally exposed workers is seen when a worker carries home chemical or biological agents on his or her clothing or person that can be transmitted to other family members. This appears to be a concern of members of the medical community who have taken the veterans' complaints seriously. Medical advice transmitted over the Internet by veterans' groups suggests that unprotected sex is not advisable, due to the potential for transmission of communicable disease organisms to spouses.

Veterans and their spouses have

reported stinging or burning perspiration that is associated with development of rashes in spouses. Wives have reported that semen of veterans burns or stings. Wives of veterans have found it unpleasant to have physical contact with their husbands. These

symptoms are a manifestation of a reproductive


toxin, in that they interfere with the reproductive capability of Gulf veterans and their wives. Thus, the potential for various manifestations of reproductive toxicity is apparent for these veterans.

It is possible that they have been exposed to a number of chemical and physical agents that have been found to be harmful to the -- excuse me -- harmful to the reproductive system in other settings. Thus, depending on the level and intensity of exposures sustained, these toxins could exert similar effects among Gulf veterans.

The veterans that I've spoken with have complained consistently of a lack of response and a run-around from agencies and physicians that are bound to provide them with health care.

And there are some ethical issues that I would at least like to very quickly point to here. It appears that the members of the military -- some members of the military are not permitted to have access to their medical records for the time during -- the time they were in the service.


Also the rules for informed consent required in other medical situations may not apply to the members of the military, and I'd like to ask why not.

And finally, the rumors about

exposures sustained in the Gulf War are allowed to circulate, with very little attempt to provide accurate information about what's happened, as well as we can tell at this point. We know that we don't know the answers. We need to say that, and say we're trying like heck to find out why.

These people deserve to have medical care and the help that they need. They are not malingerers. They are responsible American citizens who have taken the deal seriously: "You go and fight for us, and we'll back you up in the long run." Well, we haven't backed them up, and it's appalling and embarrassing to me to see what's been going on in this situation.

Thanks for your attention. (Applause.)

MS. KNOX: Anyone have any questions?


Okay. We will take a ten-minute break and return about 10:45.

(Recess, 10:35 a.m. until 10:55 a.m.) MS. KNOX: I'd like to call the

meeting back to order, please.

Just for your information, I'd like to make a correction. Some of the members from the VA who are here are Roy Chamberlain, Carol Whitson, who is a patient representative, and B.J. Searbes, who is an outpatient services representative. So they'll be able to see you today if you have any questions.

Our next person who is supposed to

speak is Mr. Don Johnson. Is he here? Don Johnson? How about Caroline Mills?

Before we start, Ms. Mills, I'd like to ask you to hold your testimony to five minutes so that we'll have time to ask questions, if we could. Go ahead.


MS. MILLS: Five minutes, it's very difficult to say anything really coherent, but I


will do what I can. If it doesn't make sense to all of you, I have given them a complete version.

What do we know about the effects of uranium on reproduction? The Encyclopedia of Occupational Health and Safety says in experimental animals uranium was recovered from the placenta, fetus, and milk of females, and from the tissue and urine of progeny fed milk from exposed females.

The U.S. Army Environmental Policy

Institute's June '95 report "Health And Environmental Consequences of depleted Uranium Use in the U.S. Army," hereafter called the AEPI '95 report, says, "Work with animal models shows the potential for chemically-induced teratogenic effects when the mother is exposed to high levels of uranium. Effects ranged from low birth weight to skeletal abnormalities for doses at which the mother exhibited signs of chemical toxicity. Extrapolation of these results to human exposures is difficult because of the limited amount of data on the placental transfer of uranium."

These statements tell us that uranium


is at least a potential threat to the children born to women exposed to uranium and to children breastfed by those women.

The second statement also indicates that so little is known about the placental transfer of uranium in humans that predictions cannot be made, only estimates of possible risks.

What can we say about the effects of depleted uranium exposure in field conditions on reproduction? Essentially, nothing. The substance has so recently transformed from a waste product, about which our main response was safe disposal, to a weapon and armament, that our main source of information must be the U.S. military who developed it.

The following statements are quotes taken from the AEI -- AEPI reports of June '94 and '95 and from messages and papers put out by the U.S. Army Armament, Munitions, and Chemical Command. They express the Army's own assessment of risks associated with depleted uranium, hereafter called DU:


"If DU enters the body, it has the potential to generate significant medical consequences. The risks associated with DU in the body are both chemical and radiological."

"When a DU penetrator impacts a target surface, a large portion of the kinetic

energy is dissipated as heat. The heat of impact causes the DU to oxidize or burn momentarily. This results in smoke which contains a high concentration of DU particles. These uranium particles can be inhaled or ingested, and are toxic."

"As much as 70 percent of a DU penetrator can be aerosolized when it strikes a tank. Aerosols containing DU oxides may contaminate the area downwind. DU fragments may also contaminate the soil around the struck vehicle."

Continuing to quote:

"Recovery and maintenance soldiers working in and around DU contaminated vehicles can inhale or ingest resuspended DU particles."

"The potential for internalization is high enough that the Army should further investigate


and analyze the risks." The Army has not analyzed the risks.

"If a burned-out vehicle" -- that's a quote. "If the burned-out vehicle must be entered, precautions must be taken to avoid inhaling or ingesting DU particles. Respirator or protective mask should be worn at minimum, along with gloves, protective clothing. After exiting the vehicle, hands should be washed thoroughly. Protective clothing should be discarded."

These quotes have been collected from several texts, and compressed and organized here to present a certain point of view. However, the statements made are clear, not conjectural, and are

based on the Army's own findings.

The two AEPIs both conclude that incidental DU exposure, and that incurred in scenarios such as the retrieval of stuck vehicles, is not a significant risk and doesn't need to be further investigated, despite their own statements to the contrary.

How do they evaluate the Army's own


research which makes the basis for their conclusions? The following quote also comes from the AEPI record June '95:

"Reports should be reviewed inside and outside DOD to increase the number of expert reviewers and to enhance the credibility of reports. Independent review is crucial, because too often studies are performed by or for an organization that has a vested interest in the results," end of quote. This statement demonstrates the AEPI authors' own reservations about some of the methods and content upon which recommendations are made.

However, the authors go ahead and make their own estimates of risk. Quote:

"It is unlikely that significant internal exposures occurred to other individuals who either had incidental contact with contaminated vehicles or breathed smoke from the plumes from burning vehicles impacted by DU penetrators. These scenarios, however, should be evaluated to quantify the risks."

Another quote:


"'It is unlikely that any of the DU exposure scenarios described in this report will significantly affect the health of most personnel.' In several areas, neither the scientific community nor the Army have adequate medical or exposure information to defend this assertion," end of quote.

We are basing our decisions about the

health needs and risks to our soldiers upon research, some of which the Army itself calls incomplete and poorly reviewed, and are making decisions based on conclusions drawn by the military they themselves concede they can't necessarily defend.

More than 300 tons of DU fragments remain on the battlefields of Kuwait and Iraq. The U.S. fighter plane accidentally shot down by the Japanese was hit by a DU projectile. The question of the safety of manufacturing, transporting, using, cleaning up, and living near DU-contaminated sites needs to be resolved for the present and for the future.

The number of people already possibly


suffering harmful exposure levels is disturbing. A survey of 10,051 Desert Storm veterans taken by Vic Sylvester and Operation Desert Shield/Desert Storm Association shows that 82 percent of the surveyed veterans had entered Iraqi captured vehicles. None of the veterans I have talked with donned protective equipment, nor knew it was necessary. Indeed,

General Calvin Walker on NBC's "Dateline," February 22, '94, stated that neither he nor General Schwartzkopf had been informed of either the hazards of DU or of the protective recommendations in dealing with it.

There are no threat -- there is no threshold at which we can state the level of exposure to radiation is too small to cause cancer or genetic effects, or large enough to guarantee such effects. There is always a risk associated with exposure for non-threshold radiation effects. There are no immediate telltale signs to warn us: no burns, no seared lungs.

We have only a national and international standard of what constitutes an


acceptable risk. The debate on safe exposure to all kinds of radiation has been going on for years. Atomic veterans, armament workers, towns near factories producing radioactive substances, all have questioned the accuracy of standards of safety.

MS. KNOX: Ms. Mills, I've given you

seven minutes, so I'd like to take this time now, if we could, to ask if there are any questions from the panel.

MS. MILLS: May I read my


MS. KNOX: Sure can.

MS. MILLS: Conduct studies outside the governments on the effects of DU exposure, including reproductive effects.

Conduct a PAC meeting specifically dedicated to further investigating the dangers of DU to Gulf vets, civilians, and for those who continue to work with DU in our armed forces.

Make testing for DU a standard part of VA and DOD exams for Gulf vets and family members, particularly family members with birth



Ensure that those serving on active duty and working with DU are tested for exposure on a regular basis.

Recommend issuance of appropriate protective gear, such as masks and gloves, to minimize exposure.

And last, question the appropriateness of the designation "conventional" for DU armaments, since their effects cannot be limited in time, nor their damage restricted to the conventional idea of a target, any more than can the effects of chemical, biological, or nuclear weapons.

MS. KNOX: Thank you.

Any questions from the panel? None? Thank you so much for your testimony. (Applause.)

Unfortunately, we can't receive everyone's testimony. Please know, though, that if you have written testimony that you would like to submit, we'll be glad to accept it. And for those who have walked on or today expected to testify, if


we -- if we don't have time, we are willing to take your written testimony.

I think the next person -- Don Johnson did come in. Is that right? If you'd come forward, please -- here you go. Welcome, Mr. Johnson.


MR. JOHNSON: Thank you very much. I'm Dr. Don Johnson. I'm team leader

at the Seattle Vets Center. I understand that Dr. Thomas Garthwaite is here to give an overall on the VA Readjustment Counseling Service, which the Vet Center falls under, which was established in 1979 to provide readjustment for Vietnam Theater veterans from the effects of post-traumatic stress disorder.

In looking over the agenda, I

requested time to speak to you, noticing that it focuses almost entirely on the physical illnesses of Gulf War veterans. In the Vet Centers we are seeing an increasing number of Gulf War veterans who are having the same sorts of marked PTSD severe problems in connection with their Gulf War service.


The Gulf War was an especially bloody war -- fortunately, not for U.S. troops. However, the atrocities that were encountered there were as severe as any in any war that I'm familiar with. These ranged from a medic who is a Vet Center client, who was asked to assist a Kuwaiti medic in removing the contents from a building that had been used by the Iraqis. The second and third floors

were filled with stacks of women's bodies who had been raped and tortured.

The Vet Center offers comprehensive outreach and a professional-level psychological assistance with the effects of traumatic stress. We are in the process now of seeing more Gulf War veterans. Unfortunately, a great many of the Gulf War veterans are also exhibiting the alienation kinds of phenomena that we've seen from Vietnam veterans and veterans from other periods of conflict.

The Gulf War veterans are remarkable, in that they feel that their war was too short to have caused them any serious problems. The 100-hour


war was indeed brief; however, the severity of post-traumatic stress disorder is not determined by the duration, necessarily, of the trauma.

The Vet Centers, as I said, are seeing an increasing number. We have seen only a total so far in the Seattle Vet Center of about seventy-five Gulf War veterans from this area. I understand that the state program operated by the Washington State Department of Veterans Affairs is also seeing an increasing number. And Mr. Tom Schumacher, who's here today, advises me that these amount to about seventy-five cases per year in the State of Washington.

A great many of the cases that we're seeing on the east side of the mountains are also some of the most severe cases in terms of their

alienation from the system, their distrust of authority figures, their processes of denial and avoidance of dealing with their problems.

I don't want to go into a lengthy discussion of post-traumatic stress disorder. I would simply like to raise it to your consciousness.


I would like for you to consider this in your recommendations to the president concerning Gulf War veterans' illnesses. I believe that the psychological factors that are involved with posttraumatic stress disorder also bear significantly on all of the other problems, physical, mental, whatever, and would like to see this included in your recommendations for treatment for Gulf War veterans.

This is basically the end of what I came here to say today. I understand Dr. Garthwaite will give a more complete summary on the VA system as a whole. If you have any questions, I'd be glad to entertain those.

MS. KNOX: I don't have any. I would like to say, though, that the Chicago meeting will focus on the subject of stress.


MS. KNOX: So we are definitely looking at stress.

MS. GWIN: Excuse me, Marguerite. MS. KNOX: Is that right?


MS. GWIN: That's actually our Cincinnati --

MS. KNOX: The Cincinnati meeting? Okay. Can you give us the dates on that, Holly?

MS. GWIN: It's July 23rd.

MS. KNOX: In Cincinnati, Ohio we'll focus on stress.


MR. RIOS: I have a question, though. MS. KNOX: Okay. Go ahead.

MR. RIOS: Do you know what the status is of the -- how the VA handles these types of claims and whether --

MR. JOHNSON: I'm sorry; I can't hear you, sir.

MR. RIOS: Do you know what the status is of the -- how the VA handles these particular type of claims, these post-traumatic stress claims, and whether or not they've been actually granting some kind of disability on them?

MR. JOHNSON: I am, of course, only

familiar with the limited number of clients that


we've seen at the Seattle Vets Center and our local VA regional office and their adjudication board. My experience to date has been that they've been very appropriate in their adjudication of claims for post-traumatic stress disorder for Gulf War veterans. I see no disparity in their actions. I think their performance has been superb.

MS. KNOX: Joe, go ahead.

MR. CASSELLS: You said that in your

center you had seen about seventy-five Gulf War veterans.

MR. JOHNSON: Yes, sir.

MR. CASSELLS: Is this seventy-five total Gulf War veterans, or seventy-five Gulf War veterans who you believe to be PTSD or similar?

MR. JOHNSON: One hundred percent of

the veterans who have come to the Vet Center with -from the Gulf War have been evaluated to have posttraumatic stress disorder. More than half of them, that has been diagnosed as chronic and severe posttraumatic stress disorder.

MR. CASSELLS: Is that a similar


finding in the rest of the State of Washington? You alluded to approximately the same number throughout the rest of the state.

MR. JOHNSON: I really can't speak to that. Mr. Schumacher probably could, and he's here today.

MR. CASSELLS: Thank you.

MS. KNOX: Any other questions? Thank you, Mr. Johnson, for your

testimony. We appreciate it very much.

MR. JOHNSON: Thank you very much. (Applause.)

MS. KNOX: Next we have Frank Schilling. Good morning, Mr. Schilling.


MR. SCHILLING: Distinguished ladies and gentlemen of the panel, I am grateful you're


My comrades in arms, I am grateful that you have come here and are voicing your feelings to this group.

I'll apologize to you all, first of


all, for the tears I will probably shed. And secondly, I apologize for my stuttering. And if Heavenly Father is as strong and as good as I believe with every fiber of my being, He will permit me to continue without trouble from each.

I have retired from the Army Reserve after twenty-seven years of service, ten years of active duty, including service in Vietnam and other overseas assignments. I have had several assignments that has taken me away from my family many times.

I, before service in the Persian Gulf, am what is called a volunteer. I volunteered in my school system, in my church, in the Scouting programs, I was active in the Reserve, and did much teaching and other activity. I am an employee of the Veterans Administration. I repair medical equipment. And I have been a long-time employee and have served well. In all of my activities I have performed very well.

I was also a pastor of a congregation of over 600 members. In that congregation I had


lawyers, doctors, and other professionals to whom I

gave professional counseling as a minister to their marital situation and other personal problems. I would like to consider myself a caregiver.

I do not like receiving care for myself, nor being one who is considered ill. Least of all do I like the idea of being considered as one who has lack of integrity in their communication.

As I have tried after returning from

the Persian Gulf to obtain help, both from my personal physician and from the Veterans Administration and from my own church, I have been denied the value of my word because it has been made -- statements that we are goldbricks, that we want to gain from the system something that will financially benefit us.

I can tell you the only thing I want in my pursuit is to be well. I would like to enjoy the mental health that I had before, the emotional stability that I had, the trust from other professionals who considered me a levelheaded individual, and that they would seek counsel from.


All of that is gone.

My family's situation has

deteriorated to a point where my marriage with my wife held by the silken thread of a spider's web. And if it were not for strong encouragement and recognizing the seriousness of my situation, I would not have sought help. I drug my wife, who came to all of my treatment, so she would see that I was actively engaged in trying to heal and see help.

One of the great tragedies is that

the care providers to me did not believe my words, did not believe my symptoms, did not understand, and gave me platitudes: "Why, Mr. Schilling, you're just growing old; there's nothing wrong with you." All of my test results came back normal, and I'm a healthy individual.

What did I give my family in what I believe to be my belief in integrity and duty to my nation? I gave my wife a problem with her reproductive system. I created pocks on her body, like the pocks I have the joy of wearing. I gave her a husband who was full of anger. I gave my


children an example of how to be hostile and non-communicative. And it has been very hard to regain what I would like to believe is the respect of my family, the respect of my community, that soldiers whom I respected spread the party line that we are not seeking to be well, but to live off the system. And I'm sorry.

I put in a claim over two years ago. I have not heard anything from that claim. I put a claim in a year before that, and it never said anything. I have had little communication about what the status of my claim is. I have gone to see physicians at the Veterans Administration in American Lake. And I have heard those doctors say to me that "It's all in your head." I have had other doctors say to me, who were employed by the Veterans Administration that we were goldbricks.

I measure equipment empirically. I

used that equipment for me -- on me, for over twenty years, measuring my own system as a reference. And when my SAO2s -- SO -- SAO2s are all in the low 90s and I'm a healthy individual, something's wrong. I


finally had a nose surgery about two months ago, and my SAO2s are now up in the 98 and 99 area, where they should be. There's other things.

And I had to get my civilian provider and convince him I had something up here, that I had acquired in the Persian Gulf, that I had to get cleaned out of my head. The VA wouldn't help. I'm sorry.

I think that I believe in the inherent and innate goodness of my nation. I believe my nation will do that which is correct, that which is just. And therefore, I'm grateful you are here to do such.

I am just a little person; I'll never be more than a little person. To my family, I would like to be something special. I hope I have not lost my family, which is more important than anything this earth has to offer. My bride is the most important thing that I have. And unfortunately, I don't know enough about her; I've only been married to her twenty-seven years, and we're striving to renew our relationship.


I think it would be best if I just

read to you a statement from -- oh, there's one

other thing I'd like to make a point of.

MS. KNOX: You have about three minutes, and then we won't have any time for questions. If you could --


MS. KNOX: -- summarize it, I'd appreciate it.

MR. SCHILLING: I will. As I was in the Persian Gulf in the city of Riyadh in a place that everyone called Escon Village -- and the word "Escon" means "housing"; there were some ten villages established for this purpose -- one of my soldiers, an E-8, a female, never left the compound except to go to Riyadh and back. She was given a 100 percent disability for fibromyalgia from the Seattle VA. In January she died. She's forty-nine years old. She is not -- one would not expect someone diagnosed with fibromyalgia to die.

I think I'd like to read a statement from my son:


"I am now sixteen years old. Before Desert Storm, I had a father who was willing to do various physical activities and play around. Since he has returned, we have had no father-and-son activities which require any physical exertion. Staying very basic and not going into great detail, that has been what it has been like, excluding my father's own personal health, in which he has had serious joint pains. He had body lesions and other varied problems which were not there before his service in Saudi Arabia. Because I wish not to let

my father to know, to let my father see truly how much I am hurt or to let others see the depth of the emotion involved, I choose to end further comment on the situation. Thank you for your time. Sincerely, John Schilling."

I have two other children, and they have said, "It's not like having a father."

MS. KNOX: Mr. Schilling, I want to thank you for your comment today. I know it's been a difficult time for you, and we empathize with you.

What has been your experience at the


VA that you've received care at?

MR. SCHILLING: My experience at the VA has been that my doctors do not understand. They are not receiving information. Their testimony to me is that they do not know, they don't understand, and there's no way to gather the information. I took to them --

MS. KNOX: And can you tell us which VA that is you're speaking of?

MR. SCHILLING: American Lake. It is now under the Puget Sound Health Care System. It was just recently integrated into the Seattle VA.

MR. LONGBRAKE: Mr. Schilling, could

you describe for us incidents of exposure that you've experienced?

MR. SCHILLING: I was in the Kingdom of Saudi Arabia. I did not go into Iraq or -- into Iraq.

I was in the proximity, immediate

proximity of Scud explosions, and chemical alarms did go off in and around our area often. We were told that the equipment was malfunctioning. I also


had the opportunity to test some of the equipment and the people that we had working on the equipment whose prime responsibility was that -- were very well qualified. The equipment was functioning.

MS. KNOX: Are there any other

questions from the panel? Dr. Cassells?

MR. CASSELLS: What diagnoses are you carrying now, Mr. Schilling?

MR. SCHILLING: None. Primarily -primarily --

MR. CASSELLS: You referred to a pox that you carry.

MR. SCHILLING: Yes, sir. They have said about this pox that I get, that it is nothing. They have no way to determine what it is. They have taken no samples of the pox itself. They -- the eruptions that I have, the eruptions that occur in my mouth, they have not taken any samples of them. The burning liquids that come out of my nose have not been investigated. They're -- they say that they -- that that is not related, and they can't segregate it from the other problems.


MR. CASSELLS: How often does this occur?

MR. SCHILLING: It has diminished

since I had my nose surgery, but it would happen every other week. I had a series of them on my lower body, and on my right leg they had formed in such a way it reminded me of someone who had been stitched with an M-60 machine gun. They left the same kind of crater as an M-60, or a small arms round.

MR. CASSELLS: You say that at one point you were referred to the Army for evaluation.

MR. SCHILLING: Yes, sir.

MR. CASSELLS: What occasioned that referral?

MR. SCHILLING: My chronic nose infection, my head infection, whatever it was, my extreme headaches. They did a CT. They found what they thought was a sinus infection. They -subsequently, several doctors said there was no indication of a sinus infection. And I took the diagnosis that the first individual gave, that there


was an indication of sinus infection, and then my improvement over using an antibiotic to stop the symptoms. I then went to my civilian doctor and really pushed to have it straightened, or opened.

MR. CASSELLS: So this was a sinus

operation that you had. Is that correct?

MR. SCHILLING: A deviated septum. They straightened that, which caused an improved drainage.

MR. CASSELLS: Okay. This referral to the Army, then, was specifically for the evaluation of that problem and not for anything


MR. SCHILLING: And surgery. MR. CASSELLS: And surgery. MR. SCHILLING: And --

MR. CASSELLS: You were not entered into an Army protocol?


MR. CASSELLS: For Gulf War veterans? MR. SCHILLING: No. Surgery was

scheduled in December for my nose, and the doctors


canceled it at Madigan, said that there was no need; "You're well."

MR. CASSELLS: Okay. Thank you. MR. SCHILLING: Yes, sir.

MS. KNOX: Thank you so much for your testimony.

MR. SCHILLING: Thank you. (Applause.)

MS. KNOX: Debbie Smith -- I'm sorry; David Smith. Good morning.


MR. SMITH: Morning, Honorable Chairman and Committee members. Excuse me.

My name is David Troy Smith. I'm a former United States Marine who honorably discharged July 12th, 1991 after nine years of service. My military service began by earning the Marine Corps Leatherneck Award for outstanding recruit during Marine Corps boot camp. I continued by earning six All-Marine athletic certificates and four

certificates of achievement from the Department of

Defense. The final achievement for me was to serve


at war for my country, and that I did, serving with the 1st Marine Expeditionary Force, 1st Battalion Reconnaissance Intelligence Group, 1st Marine Division, 9th Communications Battalion, during Operation Desert Storm from August 10th, 1990 to April 28th, 1991.

And even with this behind me and the fact that I was told in December of 1994 that my medical condition was considered terminal, this Marine finds it very difficult to stand before this Committee and tell of my experiences. Yet I feel it must be done, because any veteran who loyally serves this country should not have to endure the substandard treatment I have personally experienced throughout the Veterans Administration.

Enclosed is a list, a chronological list of evidence and copies of that evidence in support of my experiences. I gave that to Miles.

Two weeks prior to the ground war

starting, I became very ill with flu-like symptoms and bad diarrhea. We were approximately nine kilometers from the Kuwaiti border, but it was --


but it subsided, and I continued to perform my mission.

I returned stateside and discharged with no major health problems, moved to New Jersey,

and secured a carpenter job. Then training began to try and pick up my athletics as prior to the Persian Gulf service. It was difficult to recover from my workouts, but I kept going on. And I won the New Jersey State powerlifting championships at the 242pound weight class, as I was unable to regain my predeployment weight of 263 pounds. My diarrhea was coming more often, and the headaches were bad. This was affecting my lifestyle.

In July of 1992 I returned home to Idaho and lived with my father until my flashbacks became bad enough he asked me to move out. I then turned over my weapons, because a recent flashback found me putting a gun to an innocent female as I yelled that I hate redheads. And yet I remember nothing. These blackout episodes continued to come while in -- during stressful situations. I sent a man to the hospital for swearing at my workers.


Finally it happened, and I hurt my wife. And I remember nothing.

I then admitted myself to the psychiatric ward on October 2nd, 1995 at Walla Walla VAMC. On the second day there I violently attacked another patient who was about to attack the evening nurse. My wife and children witnessed this act of violence, but I have no memory of this incident.

My caseworker stated that I would not

be discharged until a fee basis had been arranged. He felt that it was too dangerous for me to be in Lewiston, 110 miles from the Walla Walla VAMC, without psychiatric support.

After fourteen days of no treatment except for medication, I left against medical advice and returned home to my family. This medication -then the medication was stopped and treatment discontinued. This is an example of substandard medical care by the Walla Walla VAMC after my discharge from the Persian Gulf Protocol -- Extended Protocol Center.

The difficulties prior to admission


at the West L.A. VAMC were unavoidable. The doctors at the Walla Walla VAMC do not believe in problems that could be given -- could not be given medical terminology.

I was then forced to fight for medical treatment I thought I earned by being a veteran of the United States of America.

Reporting to Walla Walla VAMC in 1992, September, for chronic diarrhea, headaches, and joint pain, mostly lower body, I was seen by a physician's assistant, Lyle Hatley, who placed me on Lomotil and Salcionate [phonetic], I believe is the correct pronunciation, for headaches.

There were basic gastrointestinal workups, including upper GI, that could not be completed, as the barium exited my rectum approximately ten minutes after ingestion. This allowed for only a couple of pictures before I was -- before I used the restroom. The first reaction of the technician was disbelief until viewing the barium in the stool, and "rapid transit" was noted

on my file.


The Lomotil continued to be increased to try slowing the diarrhea, also fiber supplements, restricted diet to the point of a brat diet, prior to admission to the West Los Angeles VAMC.

By the spring of 1994, my vision problems continued to worsen since my initial VAissued glasses. I saw another outside consultant for ophthalmology. The results were another prescription for glasses and follow-up work strongly recommended to rule out Grave's disease versus hyperthyroidism. Upon return to Walla Walla VAMC, no follow-up work was ordered, and the glasses were also denied.

In July of '94 I received the results of my Persian Gulf registry examination. It read, "Chronic diarrhea, unknown etiology, and chronic joint pain despite lack of radiographic findings."

By September of '94 my battle with my

medical conditions continued to worsen, to the point maintaining my wood shop supervisor position was very difficult.

By October of '94, I felt Walla Walla


VAMC could no longer provide adequate treatment. And after contacting Dr. Patricia Olsen from the Senate Committee on Veterans Affairs and Senator Kempthorne's office, a referral was made to the Persian Gulf Workup Center.

I remained hospitalized for thirty-nine days undergoing extensive medical and psychiatric tests. Upon discharge, the diagnoses -diagnosis was "Irritable bowel syndrome; hepatomegaly, unknown etiology; hematuria, unknown origin; sinusitis; orchitis; possible depression; perivascular lymphocytis," and nine medications accompanying this, including hydromorphine at 24 milligrams a day for pain, which I was left on for two and a half months.

Occasionally, Dr. William Baumschweiger calls from the West Los Angeles Hospital to check on my condition and phone in medications to our local pharmacy, where I pay for them.

I and many other veterans served willingly, without question and almost blindly at


times, yet now we are sick. The Veterans Administration has documentation for proof from their own doctors, and still they would believe we are not ill.

Thank you for this opportunity to speak before this Committee.

MS. KNOX: Thank you very much.

Can you tell us, do you receive any pension from the VA?

MR. SMITH: Now I receive a 20 percent for traumatic brain disease and hyper- -hypertension. And that was prior to that. That was prior to being seen out here. That was when I first got out of the service. Those are service-connected


MS. KNOX: Any other questions from the panel?

MR. CASSELLS: Yes; would you clarify something for me?

MR. SMITH: Yes, sir.

MR. CASSELLS: Earlier in your testimony you said you had been diagnosed as a


terminal --

MR. SMITH: Yes, sir. There's -MR. CASSELLS: What did you mean by


MR. SMITH: In the package --

MR. CASSELLS: What did you mean by that?

MR. SMITH: That's what -- I don't know, sir. That's what the VA doctor from -- Dr. William Baumschweiger told me, from California. And there's a letter in the packet stating as such -

MR. CASSELLS: That's in --

MR. SMITH: -- that my condition was considered terminal. That's all he said.

MR. CASSELLS: That's in the package you gave to Miles?

MR. SMITH: Yes, it is.

MR. CASSELLS: Thank you.

MS. KNOX: Any other questions? Mark?

MR. BROWN: Some of the -- excuse me; some of the -- I'm not a medical doctor myself, but


some of the symptoms that you described, having blackouts and so forth, sound pretty serious.

MR. SMITH: Yes, they are.

MR. BROWN: Did you ever get a diagnosis of what that might be due to at all?

MR. SMITH: PTSD is all they've told me. I'm now receiving -- I was unable to receive treatment through the VA. I have a letter in the packet stating I was not -- I did not rate treatment for post-traumatic stress, even though they had treated me from '92 up to now. I'm now being seen by the VA Outreach Center, by a private civilian, and the VA Outreach Program is paying for it.

MS. KNOX: Would you tell us, Mr. Smith, were there situations that you were exposed to during Desert Storm that you feel like could have caused such traumatic stress?

MR. SMITH: I'm a soldier; I don't know. I don't really say as I have post-traumatic stress, 'cause that's what I went over there to do -- to do. Go to war, I mean.

MS. KNOX: But you wouldn't deny --


MR. SMITH: I have -- I don't -MS. KNOX: -- that they were very


MR. SMITH: No; I had a lot of contact. I buried a dead Iraqi soldier in front of my lieutenant, Mike Gunny. We were in oil fires. I

mean, our vehicles were covered within ten or fifteen minutes of coming under that cloud. I mean, just -- we couldn't get the oil off. I went out -I was -- I went all the way into Kuwait City. I was in Kuwait City the morning of the cease-fire. I believe it was the morning. However, that evening -- by noon that day. I could have been exposed to anything. I became very ill up front, but that subsided.

MS. KNOX: Thank you very much for your testimony.


Julian Johnston. Thank you, Mr. Johnston, for coming.


MR. JOHNSTON: Master Sergeant Julian


M. Johnston. I served during the Vietnam war as a combat medic and also was a surgical scrub nurse with the 53rd General Hospital, Desert Storm.

I've got a packet of VA Hospital, probably six to eight inches thick, of the medical problems I've suffered, both post-traumatic stress and also Persian Gulf syndrome.

I had surgery approximately a year and a half ago on my colon when it ruptured. They removed twenty-two inches of my sigmoid, did a sigmoid resection, part of my colon. I've had six colonoscopies in the last four years. Each time they've removed precancerous tumors.

I suffer from fatiguedness, chronic fatiguedness, muscle/joints. I've now been

diagnosed as rheumatoid arthritis. They say I've got the stomach of an eighty-year-old man.

Prior to going to the Gulf I was

healthy. I've raised eight children. My wife and I had a very active life: travel, everything else. Now I do nothing but want to sleep, stay in my room.

I was in a senior management position


in my civilian job. I lost that when I got back from the Gulf. I've had to work as a common laborer. We're deeply, deeply in debt. We've got credit cards that we can't even make the payments on now. And all I can see is bankruptcy as a solution, if something doesn't happen soon.

I went down to -- I've been in the program for post-traumatic stress twice. I served twenty-one days the first time. Then in January I got very suicidal. I wanted to commit suicide. I had no reason to live; I couldn't see any reason to go on. And they admitted me again there, and while I was there I started having real bad blood in my stools, and they discovered I had more polyps. So they did a colonoscopy, and they found I've got another fissure in my colon ready to erupt. I've been sent home to wait until it happens. I mean, this has gone on for four years.

I've had two comp-and-pension exams, one year apart. This last one was in January. They said they lost all my records on the first one a year ago. Did not bother to contact me. I have


been told repeatedly my claim will be settled. I was told in January it should be less than ninety days. I am still waiting. I have no idea. I have to drive 110 miles to come down here for treatment. My civilian medical insurance would not cover me. They said it was an act of war -- my injuries, my sickness. The VA says, "You are not yet determined a cause of military conflict," so I'm in limbo. I pay for my copayments for my medication. I pay to come down here, my time off. My life's been a mess.

My wife now suffers from same of the

-- some of the many problems I have. She has horrible migraines. I sweat, and my sweat burns at night; you can see my outline on the sheets. I wake up 2:00, 3:00 o'clock in the morning, horrible nightmares. My children do not know me. They're afraid of me. My grandchildren, they want to know if grandpa's "in his mood."

My life has been pure hell. I've got six years of college, medical field, and I cannot work.

I had two sons in the Gulf at the


same time, and they've gone through many of the numerous problems too. One of them was a Marine, one with the Navy. My wife has had to deal with the three of us, and it's been very, very hard on our marriage and very hard on her.

And all I ask, you know, we get the help that we deserve.

I read an article yesterday that just floored me. Of the thousands of claims in, they've only settled less than 400. Now, that's ridiculous.

And daily I think the only way out is

suicide. I used to be a happy, fun-loving, going man, and now I don't see any tomorrow. Every day is a pain. My arthritis, I take nine prescription drugs a day to keep going, and I ache all the time. I get confused. I don't even know my mother's phone number; I have to look it up every time I call my own mother, my own children. It's that bad.

And yet I get no satisfaction. I call, and they say, "We're working on it" or "We lost your records," "They've been sent to Arizona; they're in Phoenix," "They're in St. Louis," "We


can't find your Reserve medical file." It goes on and on and on. And I get so tired of even trying any more. What's the sense?

That's all I've got to say.

MS. KNOX: Is there anybody that's got any questions from the panel?

Thank you, Mr. Johnston, for your testimony.


Lieutenant Colonel Skellenger. Welcome, sir.


MR. SKELLENGER: Good morning. Thank you for this opportunity.

I'm a new entrant into the evaluation process, having just made an inquiry to the system

within the past week.

I'm William Skellenger. I'm with the 141st Medical Clinic, 116th Air Refueling Wing, Washington Air National Guard, Fairchild Air Force Base. I've been with the Guard since 1981 -- excuse me; '83 to the present time.


I spent time with Desert Shield/ Desert Storm from December 1990 to April of 1991. I was in Jiddah, Saudi Arabia, working with the refuelers. We had a very significant -- or essentially 90 percent of the air refueling resources on the ground in Jiddah at that time. During that time that I was Jiddah for combat support missions, I was awarded an Air Medal and also an Air Force Achievement Medal.

I returned to the Middle East in September of 1994 to Kuwait City with the search and rescue helicopter operation, and spent a month in that timeframe when we were doing essentially a southern watch patrol and running frequent helicopter missions out to the border of Iraq. During that period of time of flying combat support missions, I was awarded an Aerial Achievement Medal.

I continue as a senior flight

surgeon, with over 350 hours of flight time in a KC-135.

In -- on March 10th of this year, following laboratory investigation for some sore


heels, after a number of laboratory studies, a diagnosis of chronic myelogenous leukemia was arrived at for myself. It was sort of an incidental white count, but there was an addition -- an initial white count of 128,000. This was followed within a day or two with a -- with a bone marrow, which substantiated the diagnosis of chronic myelogenous leukemia. I was placed on a chemotherapy, a relatively mild agent at that time called hydroxyurea. Over the course of the next two months my blood counts came down from 128,000 to normal. At that, when the counts returned to normal, I was then placed on alpha-interferon, which is an immune modulator type drug and is the drug of choice in most situations for chronic myelogenous leukemia at this time.

Not to bore the Committee members, but chronic myelogenous leukemia has a genetic defect associated with it, or a genetic change that is known as the Philadelphia chromosome. And it represents a translocation of a portion of chromosome 9 to chromosome 22, creating this


abnormal chromosome called the Philadelphia chromosome. That seems to allow an increase in the myelogenous elements from your -- from stem cells.

What's the course of CML? Nobody's

really sure, but with the mildest forms of treatment, which would be the hydroxyurea that I was on, that the course of the disease is probably three to five years before the disease goes into a rather

rapidly deteriorating or blast form, which the outlook is not good.

Using alpha-interferon, the outlook for chronic myelogenous leukemia is somewhat -somewhat different, and we really don't know what that outlook is at the -- at the present time. If things go extremely well, that outlook could be eight or ten years.

The -- it's one of these situations where the treatment may be as difficult as the -- as the disease. The alpha-interferon in most people causes a flu-like syndrome, so that you just -- you feel sort of achy and a poor appetite, and just generally not feeling very well on a daily basis.


And this is the -- the interferon is administered on a daily basis. My current dosage is 10 to 12 million units per day, which really doesn't mean very much, but that's enough to give you significant side effects. The cost of that treatment is approximately $100 a day.

There are about 4,000 to 5,000 new cases of chronic myelogenous leukemia per year in the United States, but it's relatively rare. We do not have any family history, significant family history of neoplastic disease, and certainly no hematologic disease.

And I'm here simply to ask a question to -- are there -- are there other individuals that have been involved in the Persian Gulf where there are a significant number of hematologic defects present? And that's my inquiry at this point.

I've made no other -- I've just made a contact with the -- with the VA system. I've had no evaluation either offered or involved in, as far as the VA. Everything so far has been private investigation, which has included an investigation


at the Fred Hutchinson Cancer Center here in Seattle.

MS. KNOX: Thank you for your testimony.

I don't know that I can answer that question correctly. Maybe you can, Dr. Cassells. Do you have a --

MR. CASSELLS: We're still gathering the data in terms of what is being found in both the Department of Defense CCEP Program as well as the DOD VA Registry Program. There are not a large number of hematologic diagnoses uncovered at this point in either of those registries.


MS. KNOX: I would ask you just -I'm just a nurse-practitioner and not a physician. But having the Philadelphia chromosome, is that -does that always present later in life, or is that just a heredity tendency to occur? Everyone that has the Philadelphia chromosome, in other words, does not get CML. Is that correct?

MR. SKELLENGER: I don't believe


that's true. I think that the Philadelphia

chromosome is the sine qua non of the disease. Occasionally there will be people that present with what appears to be CML without the Philadelphia chromosome, and that -- people just don't believe that happens. So it --

MS. KNOX: And you say the symptoms that you had originally were -- was pain in your heels?

MR. SKELLENGER: I had -- yeah, I was having difficulty with pain in my -- in my feet, and we started doing some laboratory things, basically looking for possible gout. And we came up with some other enzymes, an LDH that was abnormal, and then subsequently a CBC that was abnormal.

MS. KNOX: Were there any specific instances during your service that you can recall that you may have been exposed to chemicals or -

MR. SKELLENGER: No. But there's

some thought that there may be a relationship with exposure to ionizing radiation. And in the flying environment and the radar environment, why, that


risk exists.

MS. KNOX: Are there any other members of your unit who have hematologic disorders that you're aware of?

MR. SKELLENGER: None that I'm aware of. And I think I would be aware of it.

MS. KNOX: I don't have any further questions. Any more questions from the panel?

Thank you so much for your testimony.

MR. SKELLENGER: Thank you. (Applause.)

MS. KNOX: I think next we're going to hear from Sergeant Joe San Miguel.


MR. SAN MIGUEL: Good morning. I'm Sergeant San Miguel. And I'd like to thank the panel for allowing me to speak, even though as the panel is dedicated to Gulf War veterans. I am not a veteran at this time; I am still active duty.

And that's one of the problems I'm facing, because I'm having to go through the Madigan Medical Center down at Fort Lewis. And they have a


registry there. They have a panel there that is supposed to do evaluations on people that have possible Persian Gulf War syndrome. That would include PTSD and other problems that we're facing.

The biggest problem I find is, I had

to get the physical done twice, because the first time it was done on paper. I had a nursepractitioner that did the evaluation, and all she did was ask me "Do you feel this? Do you have this?" but she did not do an actual physical exam. She was just asking me. She was going through the procedure on paper. And then it was signed off by a doctor that I never saw. And I asked about that, and they said, no, that usually the records are reviewed by the doctor. Well, that's fine. He reviewed someone's doing a paper shuffle of an exam.

So Lieutenant Bayer, a very helpful

individual, he had me reevaluated, basically on the

same day, got me in as soon as he could, and I was examined at that time by a physician.

At that time they also had me go for a complete workup. They diagnosed me as PTSD. I


had also been before trying to prove that there were that I had breathing problems. And it took me almost two and a half years to get into Pulmonary.

I'm not -- I don't want to just speak

about my problems, because there are a lot of soldiers right now that are at Fort Lewis that are facing the same problems. They don't even know about the Persian Gulf War syndrome. They're not informed about it until they're getting ready to retire, they're getting ready to ETS. They're told "You need to file a claim," that this should have been documented, at the latest, two years after the war. And we weren't told about it until well after the fact. I mean, they -- we were told -- like, I was notified maybe about six months before my twoyear window was up. And even then I had to prove -I had to document it. I had to have it documented. And the doctors at Madigan did not want to document it. They kept on insisting that the problems I faced and the problems other soldiers were facing were "Sarge, you're getting old." I was told point blank like that so many times.


I was told by a colonel, a physician

that had been in Vietnam, that he downplayed Agent

Orange. He said that was a minor issue, and that if I suspected Persian Gulf War syndrome, that, one, I was out of line, and that he didn't believe in it. And that's when I tried to get an evaluation.

They evaluated several of us and said we had these different problems, but since we're active duty, it would conflict with our careers. So now we're faced with the issue: do we press the issue, and then with the downsizing get forced out of the military without getting any benefits?

And then we're told by -- I've been told several times by different VA representatives that any claims I want to file, I should not write it up as Saudi-related, even though I did not have any problems before Saudi. And several other veterans were told the same thing. A whole classroom of us were told not to claim Saudi as the reason, because the VA would not allow it. Now, that's what a VA rep was telling us. And that is -and Madigan has been telling us "It's not a problem;


you don't have a problem. Here, take some antidepressants." That's if they're even willing to listen to us.

We're promised all kinds of benefits. We're denied it. Then we also have to try to prove that we had the problems after Saudi, but then we're told two years later that you have a two-year window. We have -- what? Now it's been five years, and I'm still trying to prove, as active duty, that I have all these problems. There are other soldiers

that I've been talking to in my unit right now that aren't even aware of the investigation or the hot line.

I have received one letter that was from the Committee that stated that spouses and dependents were also going to be included in the investigation. I called the hot line, and I received a recording that said spouses and dependents were not eligible for VA care at this time.

My wife, and I know other spouses have been having problems. But they're denied


benefits. They go to Madigan, and because of the downsizing they have months to wait before they get seen, months to go before they're followed up.

Now, if I'm active duty and other

soldiers are active duty, and this is the care we're receiving as active duty, with a modern up-to-date, equipped hospital -- the VA is supposed to be smaller, supposed to have fewer resources than an active duty soldier. What am I expecting to receive when I retire? What are my family members subject to receive, and the other soldiers that are out there?

I wore my uniform because I felt it was an easier way to represent myself and display the commendations I had received. The commendations will not put any meals on the table, they will not put any medication that I need. They're a nice salad bar. That is how I feel about it.

The treatment as active duty soldiers

that we're receiving at Madigan is pathetic. The treatment our spouses are receiving is pathetic. Their whole atmosphere at Madigan is "It's all in


your head," whether they have physical documentation. And that's if they will document it. They'll tell you "You have this." They say I have irritable bowel syndrome. They haven't done any tests to rule out other things. They say I have Ritter's [phonetic] syndrome, possibly. They haven't followed up to do anything to document the fact that it is Ritter's syndrome. It could very well be something else. Excuse me. They do not follow up. They give a diagnosis without testing that.

You know, there's medical personnel on the board, on the panel. Would you diagnose someone, give a diagnosis without running tests? Would you not try to eliminate other possibilities before you just say, "It's this; have a nice day," and not offer any treatment?

At this time, that's about all I have to say. Thank you.

MS. KNOX: Sergeant Miguel, help me understand. You've undergone phase one for activeduty soldiers to -- for the comprehensive clinical


evaluation program. Is that right?

MR. SAN MIGUEL: Yes, ma'am.

MS. KNOX: But you feel like you

still have symptoms, that maybe you need to go to phase two, and you've not received that?

MR. SAN MIGUEL: I've been to phase two. But I'm -- what I'm speaking about is the fact that there are soldiers out there that are activeduty that have not even received phase one. And since they haven't, and it's well past the two-year window, they're left out there flapping. They are left out there without any possibility, because at that two-year window they're told "You don't qualify to get the care."

MS. KNOX: The two-year window to undergo the CCEP evaluation, or the two-year window to get compensation?

MR. SAN MIGUEL: To follow up on claims to get compensation.

MS. KNOX: Compensation.

MR. SAN MIGUEL: I'm still activeduty. It's six years after the fact -- or excuse


me, five years after the fact. Does that mean I'm eliminated? Do I not get -- did I not serve? I've got commend- -- I've got -- received three commendations in Saudi. I'm a -- I'm a dental hygienist, but I worked as a medic. The command I worked for also had me work as a machine-gunner.

By admitting that, I'm subject --

leaving myself open to a court-martial because of the Geneva Convention. But if I didn't do it,

someone else was going to get hurt. We didn't have anyone qualified. Now I work as a medic, I work as

a gunner. Contradictions in terms. So that aggravates the PTSD. There were other medics out there. You know, it's one thing to have a weapon to defend the patient. By Geneva Convention, we're not supposed to have offensive weapons. That is what a larger-caliber machine gun is, offensive. That's the position I find myself in. I either do this or I don't do that.

The active-duty personnel, when I go in for a physical, "Sarge, the reason you're having problems and you're slowing down in your running is


because you're getting old."

It took me two and a half years before they finally sent me to Pulmonary. And the pulmonary specialist, both the staff doctor and the resident, admitted that the only reason I picked up on the asthma so early was because I had been in such good shape. I'm a marathoner. I would notice a difference between running a twelve-minute, twomile pace, versus a fourteen-minute mile pace, all within a year's time.

MS. KNOX: Any questions from the panel? Dr. Cassells?

MR. CASSELLS: Yes. Do you have a medical profile? You've been given these diagnoses. Do you have a medical profile?

MR. SAN MIGUEL: Yes, sir I have a temporary profile -- which again, you know, reflects on my career. Because by the temporary profile, I cannot take a physical fitness test, which kept me from getting promoted.

MR. CASSELLS: When does that profile

get reevaluated?


MR. SAN MIGUEL: In July. It gets reevaluated every three months. The problem has not improved any. All they say is "You have a chronic problem with your heels, you have a problem with your knees, you have a problem with your joints. And if we give you a medical profile, a permanent one" -- I'm subject to getting medically boarded and being removed from the service, which would -- at that point, would eliminate my pension.

That's the position myself and a lot of soldiers are facing right now. If we go in front of a medical board, we ruin our careers. We are forced out of the military after giving seventeen, twenty years, however many years we've already put in. We are kicked out. And it ought -- at that time we might get a separation bonus, and then also not be allowed any benefits as far as medical care that we incurred on our medical injuries that we received while on active duty, trying to protect our country.

MR. CASSELLS: If you are discharged with a medical diagnosis and it is a medical


discharge, it does not terminate your benefits. MR. SAN MIGUEL: That's true, sir.

But what it does is, it would say -- give me -- if I were medically boarded out, they would say, "You're

rated at 40 percent." If I complete my twenty years of active duty, then I'm entitled to 50 percent of my active duty base pay, which is significantly more.

MR. CASSELLS: That's correct, but it does not terminate benefits.

MR. SAN MIGUEL: It doesn't -- it doesn't --

MR. CASSELLS: I don't want anyone -MR. SAN MIGUEL: It doesn't -- excuse


MR. CASSELLS: -- in the audience to misunderstand you.

MR. SAN MIGUEL: All right. I stand corrected. It reduces it significantly. And then I would be entitled to just the medical care, depending on what the medical board finds. It would not include a pension that I'd counted on after


working eighteen, twenty years. And I'm not the only one. There's a lot of soldiers out there that are in that position.

MS. KNOX: Go ahead, Tom.

MR. McDANIELS: You said you were notified six months before your two-year window ended. That was of the CCEP exam?

MR. SAN MIGUEL: That is correct. And I was notified by anyone. I was -- I found it out --

MR. McDANIELS: How did you find out? MR. SAN MIGUEL: I found it in a

magazine article.

MS. KNOX: What magazine?

MR. SAN MIGUEL: Veterans of Foreign Wars magazine.


MS. KNOX: Any further questions? Thank you so much.

MR. SAN MIGUEL: Thank you.

MS. KNOX: We appreciate it. (Applause.)


I want to thank each one of you this morning for your public comment. You know, we do know that you served in the Gulf, and we're very appreciative of it. The freedom that we have as Americans is not free, and we know that. And we are listening to you. We hear you. We will make our recommendations to President Clinton, and hopefully he will make some actions based on those recommendations.

We're going to break now for lunch, and we will return at 1:15. Thank you so much for coming.

(Whereupon, the meeting recessed.)



(1:25 p.m.) MS. LASHOF: I think we're ready to

start the afternoon session.

I'm Dr. Lashof, Chair of the

Committee. I was in Chicago yesterday, and just came straight from the airport, so I'm sorry I missed the morning session. But we'll catch up with staff on that.

I want to thank Dr. Brent and Dr. Robaire for coming before us today and for all the material they submitted to us. And the floor is now yours. Dr. Brent, I believe you want to start.



MR. BRENT: Dr. Robaire and I wanted to know whether we can speak from the podium.

MS. LASHOF: Certainly, by all means. MR. BRENT: I think you're two slides




MR. BRENT: I also -- I don't know who arrived first, Dr. Lashof; I just landed also.

Well, good afternoon, members of the


And I was asked to introduce the topic that we're talking about today -- namely, birth defects. And the question I was contacted about a week and a half ago or maybe two weeks ago and sent all that material to your Committee -- the question I had raised was: is there an increase in incidence of birth defects in the offspring of Desert Storm personnel?

Sometimes when you're asked a question, you don't necessarily -- you're not

necessarily able to provide an answer. But I thought I would just introduce the topic.

First of all, we're talking about --

all right. We're talking about congenital malformations and birth defects. And to the families who are affected, it is a very traumatic event. It's probably the most personal thing that happens to us, to have children. And then to have


them not normal is a tragedy.

And if you look historically as physicians, I can tell you that physicians can't handle certain diseases. That tells you how difficult they are. And the diseases that we see that create anguish and guilt and ill feelings and disturbances are cancer, mental retardation, psychiatric illness, genetic diseases, and congenital malformations. In fact, if you go back in Babylonian times, if a mother delivered a baby that was malformed, they put her to death, because she must have done something very bad to have a child --

One John Spence, in 1640 in the United States, was put to death for having fathered a cyclopean pig. Unfortunately, he had a "lewd and profane spirit," and the Puritans in New Haven decided that he must have had intercourse, 'cause the poor man had a cataract. And they couldn't tell the difference between a clouded cornea and a cataract, and they came to the conclusion that he had fathered this abnormal offspring, and so he was


put to death.

So it's a very troublesome area. And then on top of it, in our health care system these children fall through the cracks. They need complicated medical care. And unfortunately, we don't have a health care system that takes care of the most complicated illnesses. And that produces even further anguish.

Now, we're talking about two events that cause birth defects. And one is the field that I spend a great deal of my time in, the causes of birth defects from environmental agents. And the background incidence of birth defect is quite high, as I will show you in a minute.

But the fact is, if you expose somebody to a drug like thalidomide or a cancer chemotherapeutic agent that causes birth defects -birth defects, they respond in a -- what we call a toxicological dose-response curve, below which there is no effect.

If you give a mother one milligram of thalidomide, nothing happens, as there's no risk.


If you give her 50 milligrams at the right stage, she has a significant risk to have a birth defect. So the big difference between drugs and chemicals that we give or that occur during pregnancy is that they have a threshold -- namely, that there's a safe dose for all those compounds. And most of the time,

environmental agents are below that dose, if you're pregnant.

On the other hand, what we're talking about is preconception exposures, exposures that occurred in men who were in Desert Storm and then came home. And those are what we call mutagenic effects primarily, although Dr. Robaire will talk about other methods whereby you could have a reproductive effect.

But by and large, we're talking about genetic effects. And they do not have a threshold. In other words, when we suggest maximum permissible exposures for mutagenic agents, radiation, cancer chemotherapeutic agents, we project that there is no dose that doesn't present a risk.

When you get down to very low levels,


the risk may be below the spontaneous rate. But we're talking about the fact that there is no exposure for a known mutagen which doesn't present a risk.

Now, one of the problems is that, as the human species, we do not expect to have normal reproductive histories. In other words, if you look at the human -- and the National Institute of Environmental Health Sciences did a study that was published in the New England Journal: at least one in three conceptions are lost due to a chromosomal abnormality or some other effect as a miscarriage or a spontaneous abortion that we don't know about: one in three. And then clinically, out of a million, this would be 350,000 out of every million

conceptions are lost. 150,000, or 15 percent, we recognize the mother knows she was pregnant, or the doctor knows she was pregnant, and the pregnancy is lost.

And then if we look at the incidence of genetic disease -- and this comes from the BEIR Committee report from the National Academy of


Sciences -- about 110,000 out of every million people who are born alive will have some sort of early- or late-onset genetic disease. That means 11 percent of us. Whether we end up with a coronary from hyperlipidemia at the age of thirty-five, or Huntington's chorea, or cystic fibrosis, genetic disease is a very big component of the human reproductive history.

And then if you look in here, according to the International Mutagen Committee -it's a worldwide committee -- they estimate about less than 3 percent of this 110,000 genetic diseases are due to new mutations. And these are considered to be spontaneous mutations that occur. And that's why we will see a child with a dominantly inherited disease born, and yet their parents, neither one of them has it. And that's because a new mutation has occurred in that generation.

The major malformations, something that we're talking about today -- according to the CDC, those that need surgery, hospitalization, affect the mentation of the patient -- in other


words, the person is less than normal physically or mentally -- account for 30,000 out of every million, or 3 percent. And then, of course, we have the problem of prematurity and fetal growth retardation, stillbirths. And then 15 percent of couples are stillborn. That's our reproductive history; that's what we start with.

So you can see how difficult it is when an environmental agent is introduced to demonstrate that there's been an increase in these problems.

In fact, people will say to me "I can't believe that. I grew up on a farm, and animals don't have these kinds of problems." But remember, as a species we do not breed for reproductive perfection.

In a democratic society, every woman and man who wants to have a child, we foster that. And it doesn't matter what disease they have or what genetic history they have, we foster that. And so now we have women with diabetes who deliver, who didn't deliver, before insulin. We have women with


lupus erythematosis and other diseases, and many diseases which made for reproductive imperfection before. They couldn't have a child, so we -- those genes that contribute to that are being added to the human species.

And one of the misperceptions is that birth defects are increasing in our society. This

comes from actually Dr. Edmonds' shop, the Center for Disease Control. Godfrey Oakley, the head of that division, sent me this slide. And it shows the increasing percentage of children dying in the United States from birth defects. We're up to probably around 25 percent now. But it's not because the incidence of birth defects is increasing; it's because we've taken care of other diseases. We don't have children dying of diarrhea and malnutrition, diphtheria, scarlet fever, and tuberculosis -- although that's increasing. As we eliminated other causes of death, the proportion of children dying from birth defects increases.

The same thing is true of genetic diseases. People -- you'll see in the news media


"The Incidence of Genetic Diseases Is Increasing." Actually, that's not true, either. The fact is that we know more about genetic disease. And if you looked at Dr. McKusick's book on Mendelian inheritance of man, you will see that, you know, in 1950 there were 1,500 genetic diseases; in 1990 there are 7,000. But that's not because they're increasing, it's because more and more data has been collected and we're identified rarer and rarer and rarer diseases, so that the number of genetic -different types of genetic diseases are increasing, but not the incidence of the disease.

Now, one of the problems that you face in trying to determine whether something has increased the incidence of birth defects is the fact that we have a high incidence of birth defects: 3

to 6 percent -- 3 percent major, 6 percent if you include all minor malformations. And therefore, major and minor -- the expansion and clarification of these syndromes can only be derived from careful epidemiological studies. Case reports can be very misleading, very misleading in this area, 'cause


they're so common.

And if you look at the way we evaluate this, how do you go about determining whether you have an increase in birth defects? Well, we have various tools; we can look. And the most important, of course, if we're interested in birth defects in the human, is to look at human epidemiological studies. Well, it just so happens we don't have very many with regard to the -- to the Desert Storm personnel.

We look at secular trend analysis, which we don't have here. In other words, that would be, for instance, the introduction of a drug or a chemical or the withdrawal of it. Is it associated with a change in the incidence of birth defects? It's too small a population to use secular trend analysis.

The animal studies can be helpful here. As I will mention, most of these agents are not potent teratogens if given to, say, a pregnant woman. And they also are not mutagens. You know, they're not agents which would produce a increase in


mutations in the genome. And then, of course, this is something that we would get into in animal studies.

And then a very important principle: sometimes we're left with -- we're stuck with the idea, is the suggestion biologically plausible? Does it make common sense? Does it -- you know,

does it fly in the face of biological principles, or does it make sense? And that's what I will address.

Well, what do we have? We have

epidemiological studies involving exposures to mutagens agents of all types. And I'll mention a few of those, 'cause they're important. We have to go back in history.

We have the epidemiological studies involving personnel in Desert Storm. Now, there is one study that is published, involves like fiftyfour people and three or four malformations. I can tell you it's negative. I can tell you a study that small is meaningless with regard to genetic effects; it's just too small.

According to the National Academy of


Sciences, they estimate that, for instance, for low-level radiation to demonstrate effect, you need like 200 million people in the study. There aren't enough people in Desert Storm to demonstrate genetic effects for a potent mutagen, no less agents which haven't been demonstrated to be mutagens.

So the fact that they're negative studies, with these small numbers, don't mean


Then the types of congenital malformations reported. If you're looking for genetic effects, then you should want to find an increase in genetic diseases. I mean, that's like "Who's buried in Grant's Tomb?" If you're -- if you've got a mutagen that is making for an increase in mutations and congenital malformations that are genetic, then the diseases that you find should be genetic diseases.

Appropriate animal studies. And the animal studies would be things that demonstrate mutation, and you can do that in animal studies.

And then, of course, the nature of


the agents that we're talking about and the biological plausibility.

So what I'm telling you is that we have a lot of voids in the information to help us make a conclusion, with the question, at least, that has been raised to me.

Now, where do we get information from? Well, we can get them from case reports. And as you know, after thalidomide, The Lancet was filled with individual reports of "Tetracycline Causes Limb Defects," Librium does this -- and they just were filled with them. People were just sending in these case reports -- which, of course, turns out to be meaningless.

And then clusters, where we do learn something from them. But most of them, as you will see, are wrong.

And then the cohort studies. And I hope that Dr. Edmonds will talk about the kinds of studies that the Centers for Disease Control and the case control studies, the two major studies that would be considered, you know, classic


epidemiological studies.

And the problems with these types of studies are their accuracy. The case report is very sensitive. Of course, you have a child, took a drug, has a malformation. Very sensitive. The problem is, it's accuracy is almost zero, from the standpoint of -- you know, for every 900 -- of every 1,000, 999 are wrong with regard to coming to a conclusion about causality.

As we go into clusters, their sensitivity is less, but their accuracy -- at least there's some positivity in the fact that Dr. Greg discovered rubella as a teratogen, caused the syndrome of the rubella syndrome, in a cluster in his office. Now, he could have been wrong, but it was the epidemiologists who then confirmed his finding.

And as you go to case-controlled studies, they're less sensitive, but they also are wrong on occasion, you know, because you have to match controls and exposed. And it's not easy. So there you will sometimes come up with associations


that may not be causal or may not even be

statistically relevant.

And the cohort studies, which are less sensitive -- frequently correct.

And this is what the epidemiological has to deal with here, with regard to the fact that when they do a study, it may not be correct. And remember, we have a lot of birth defects. If you do a large study, there are sixty-odd birth defects, maybe. And if you just set the regular statistical significance at .05 in every epidemiological study, if you look at all the birth defects, three of them are going to come up positive just by chance. You would expect that.

And that's why we say epidemiological studies have to be consistent. In other words, you should find the same birth defect in three and four and five epidemiological studies in order for them to have meaning.

Now, theoretically, what medical effects would you expect in the -- in the offspring of the personnel in Desert Storm? Of course,


genetically-determined congenital malformations and genetic diseases and cancer. You would also -- if these were potent mutagens, you could also have problems with sperm production and infertility. You know, the people who have been treated with cancer chemotherapeutic agents, a major problem that they have is that they may be infertile, or they have decreased sperm count.

And these chromo- -- so there could

be either chromosome abnormalities, which are genetic effects, or abnormalities of the DNA at the molecular level. So these will be the two things, and they will make up the syndrome of the genetic diseases that we see in the human population.

Now, on the other hand, mutations and chromosome abnormalities that occur or are induced in sperm or eggs prior to conception must go through a very complicated process before their genetic alterations will appear in the next generation. Most chromosome abnormalities are lost during sex cell development and early embryonic development.

The risk of sex cell death becomes


prominent when the mutagenic effect approaches the spontaneous mutation rate. And I'll show you a slide to clarify that.

A high proportion of induced mutations are recessive and, therefore, are unlikely to be clinically observed in the F-1 generation. If you go back and read the Nobel prize-winning paper of Dr. Muller in 1927, he pointed out that in X-rayinduced mutations -- and this is true of a lot of mutagens -- 85 percent of them are recessive, which means you don't see them in the next generation.

Now, does that mean that it's not

bad? No, it doesn't mean it's not bad. But it means that -- it shows you the difficulty of demonstrating. Only 7 percent are dominant mutations that you might see in that generation, and the rest are pregnancy losses.

Now the question is: name four

environmental agents with mutagenic capabilities for which an increased incidence of genetic disease in exposed human population has been documented. This is a slide I put up for the medical students.


Unfortunately, I can't list one, and yet I know that environmental mutagens produce mutation. And let's see why. Why is it that it's so difficult?

Is there any data to indicate that mutagenic environmental agents could increase the incidence of human disease? Absolutely. It's cancer. I mean, the fact is, the same mechanism that involves the change in the genome also leads to carcinogenesis. And that's very clear. We have many environmental agents that increase the risk of cancer. So we know that we can demonstrate carcinogenesis with environmental mutagens. Why can't we demonstrate genetic changes? Why is it so difficult?

Now, this is just radiation. This is all cancers that have been induced by occupational exposures or the atomic bomb, various levels of radiation or therapeutic doses of radiation. I could show you another slide for chemicals. In fact, we have both chemical mutagens and radiation mutagens that have increased the increase of cancer in exposed populations.


Why can we demonstrate that some

mutagenic agents can increase the incidence of

cancer, but not the incidence of genetic diseases? Somatic cells, the cells in us that

get exposed to mutagens, don't have to go through a complicated process. If they become carcinogenic, all they have to do is grow and survive in us, and then we have cancer.

In order for a mutation to be manifested in the next generation, it has to go through a very complicated process. In fact, many chemical agents have both mutagenic and carcinogenic potential. Yet there are numerous instances in which epidemiological studies have demonstrated a causal relationship between exposure to chemicals and drugs and increase in cancer in the exposed population.

Populations exposed to the same mutagenic agents rarely demonstrate an increase in mutations. Why? Loss of the affected germ cells during the mutagenesis. You know the man, for instance, goes through his spermatic cycle in sixty,


seventy days. A lot of those chromosome abnormalities are gone if they're not used. If they're not transmitted at that time, they're gone.

Decrease in capacity to fertilize or

be fertilized, if you happen to have a chromosome abnormality or a new mutation.

Embryonic loss during the preimplantation or very early organogenesis period.

Lapse in time from exposure.

Low or no exposures in the exposed


So these explanations -- these are theoretical explanations that account for the fact that it's so difficult to demonstrate an increase in mutations in the human population exposed to the same things that cause cancer in that population.

Now, I don't -- I'm not going to

spend a lot of time on this, but I just want to show you that this is the risk of ionizing radiation, one of the most potent mutagens. And it -- what it indicates is that if you expose a mammalian species to radiation, the risk of a mutation is 10-7 per rad


per locus in the genome. If you want to double the mutation rate, you'd have to give 100 rads, which is a very large dose of radiation, and that would only double the mutation rate.

Add 100 rads in, say, a developing embryo with a high mitotic rate. By that time you're killing 70 percent of the cells that are rapidly proliferating. It's almost nature's way -I don't know if anybody planned it that way -whereby, before you get a very large increase in the mutation rate into rapidly dividing cells, you kill the cells. By the way, that's why, with I-131 therapy for hyperthyroidism, you practically never see cancer in those patients, 'cause you killed all the cells. The radiation is a mutagen, but it's also a cytotoxic agent.

And so with agents that affect the genome, either the chromosomes or the molecular biology of the genome, once you get up to

reasonable doses where you expected increases in the mutation rate, you begin to see the death of those cells that could possibly be fertilized or



Now, the agent that have been -- that at least have -- I've been taught by the CDC and others with regard to the exposures we have: the pyridostigmine; we had vaccines; we had pesticides, many of them that were used; and the oil products, heaters that were used in tents, the question of the type of fuel that were used; and oil well fires. Now, we don't have a final answer on all of these agents. And there may be others.

For instance, I don't know what Saddam Hussein used that we don't have any knowledge of. But the fact is that it would be very helpful to know whether some of these things had potent mutagenic capacity. I can tell you, at least from the literature search that I went through, they don't. They're not potent mutagens like the cancer chemotherapeutic agents or ionizing radiation.

Now, this is a very, very anxiety-

provoking area. In the -- in the '70s, when the Mutagen Society first developed, you heard all these things: "The threat of genetic disease is our


number one health problem." Marvin Legator said

that in 1968, and then all these people -- the

surgeon general disagreed. Dr. Crow disagreed.

But there was a famous -- the woman who discovered chemical mutagens, mutagenesis, Charlotte Auerbach -- I think she was a Dane; she was knighted and given great honors, and she was quite a woman scientist, quite a scientist and quite a woman. "I think it is absolutely" -- this is what she said:

"I think it is absolutely essential that we do not delude ourselves about the magnitude and complexity of our task. The general public is easily scared, and when they are scared, they may form pressure groups to push governmental agencies into action. These agencies are scientifically naive and have to rely on our advice. We should be very careful not to give advice that is itself naive -- that is, advice based on oversimplified tests and facile interpretations."

What she's saying is "Give me data, and I can make an interpretation; without it, I



And Bruce Ames, the man who discovered the Ames test, he has made a complete turnabout with regard to environmental mutagens. He says, "The world is full of mutagens, carcinogens, and reproductive toxins, and it always has been. The important issue is the human exposure dose. And fortunately, the exposure is usually minuscule."

Okay. Now let me just tell you about

a few studies that have been done to try to demonstrate mutagenesis in our society.

Dr. Neel has spent his whole life -Dr. James Neel from the University of Michigan -- to look at what happened to the F-1 generation, the survivors of Hiroshima/Nagasaki. What happened to them genetically? And he found no -- in 80,000 -and this is a small study: 80,000 offspring of the people who were exposed to radiation in Hiroshima/ Nagasaki. No statistically increased significant effects emerged with respect to eight different indicators. And he estimates the doubling dose for this very potent mutagen, about 200 rads, 2.2


sieverts. So the fact is that they were unable to demonstrate this.

You want me to close?

MS. LASHOF: Pretty soon.

MR. BRENT: Okay.

MS. LASHOF: A couple of minutes. MR. BRENT: Well, I'll -- there are

five other studies. I'll skip them. I can close whenever anybody tells me to close.

And there are five other studies that are negative: leukemia survivors; the NIH, probably -- this was done at the National Institutes of Health. They looked at people who had both radiation and cancer chemotherapeutic agents: their incidence of birth defects was not increased. And still, even though it seems like a large study, 1,400 people, it's not a large study for demonstrating mutagenic effects.

And the leukemia survivor study. And ABCC. Notice they don't even

predict, if a whole population received a rad of

radiation, any increase in recessive disease, no


chromosome abnormalities.

It's very hard to increase this, because of the loss of these genetic effects as it goes through the process of trying to form a new child.

And I will skip this so that I can conclude, but this is a calculation that demonstrates the low risk of mutation from environmental mutagens.

And what it points out is, if we had an atomic bomb holocaust where everybody in the world got 100 rads, how would a disease like cystic fibrosis change, a recessive disease? And what would happen would be that, for every case of spontaneously occurring cystic fibrosis, only one in 6.25 million would be due to radiation. That's just the nature of the low risk of mutation induction.

Okay. Conclusions. Well, if you

don't have data, you can't make very many conclusions. But I'll give you the conclusions that I can make at the present time.

There's not enough epidemiological


information to refute the suggestion that there is an increase in congenital malformations in the offspring of Desert Storm. I mean, fifty-four patients with three malformations, when you're

talking about genetic defects, is a very small study. There is no epidemiological information to support the suggestion that there is an increase in congenital malformations in the offspring of Desert Storm. What that is, is what Charlie Auerbach said: no data.

The nature of the malformations, the types of exposures, prior studies involving human exposures to mutagenic agents, and the concept of biological plausibility make it very unlikely that there is an increase in the incidence of malformations in the offspring. But that is not proof. That's just taking into consideration the things that are left, and based on our prior history of looking at mutations in our society.

We would not be in the present dilemma -- and I'm not from the CDC, by the way, but I'm making a pitch for the Centers for Disease


Control. We would not be in the present dilemma if we had a national program of congenital malformation surveillance involving every birth in the United States. If we had such a program, we could answer the questions that you have discussed, rapidly and accurately. And I always point out that they have the expertise, they have the facilities, they have the technique, they have the personnel, they have the skill -- but they don't have the funds. And it's really a crime in our country that we don't monitor in a very sophisticated way every birth defect. Then your Committee could go to them, and

in a month or two they could answer the questions that you're raising here today.

I point out that the money that we waste in other areas that could be put to good use down at the CDC would help us in so many situations when these questions arise. I said that -- I already said what I said about the Center.

And finally, the most sensitive marker for environmental mutagenic effects is not an increase in birth defects, but an increase in cancer


in exposed population. And I would suggest that that's where you ought to put your money from the standpoint of looking to see whether there are agents there that have the potential for mutagens. If you don't see an increase in cancer, at least from the mutation standpoint, you're not going to see an increase in genetically-produced birth defects.

And that's why I always put down the fact that mutations -- oops --

If you look at the risks of high exposures of -- say of a mutagen like radiation, acute exposures, mutation will be at the bottom. And if you look at the risk of exposures to protracted low dose during pregnancy -- actually, even if it were before pregnancy, mutations would also be at the bottom. It's the lowest risk of the three effects that we are talking about today.

And I'm sorry for going over, but -MS. LASHOF: Thank you very much.

We'll come back to questions. And I think we'll

just proceed with Dr. Robaire and then have


questions for both of you after his presentation. BIOLOGICAL PLAUSIBILITY:


MR. ROBAIRE: I'd like to thank the Committee for giving me the opportunity to discuss with you the question that you asked me to address, which is the use of animal models in assessing male-mediated adverse progeny outcome.

Before starting, let me point out that what we will be talking about for the next few minutes is what happens when chemicals -- and I'll use that interchangeably: chemicals, drugs, environmental chemicals -- when they affect the genome of the mother or the father. And I will not at all be discussing the issue of drug exposure during pregnancy. I think Dr. Brent has dealt with that very well. I will touch on some of these points here.

Before beginning the discussion, I'd like to make a few specific comments to lay the background on oogenesis and spermatogenesis. I'll


then touch on a couple of environmental studies, studies that have been trying to look at occupation and the consequences of these occupations on reproductive outcome. And then we will change gear and look at the animal models, and what they can

tell us and cannot tell us. Okay.

A few key points about the male and the female.

In the female, all of the mitosis, all of the cell division that takes place in the ovary, takes place during fetal life. And in fact, by the time of birth, there is approximately 2 million eggs, and those -- that number keeps on dwindling throughout the lifespan.

Meiosis is triggered during fetal life in the third trimester. There is an arrest. And that arrest is prevented, and a few eggs will start cycling on an ongoing basis every month throughout life until there are no more eggs. But there is no mitotic activity. So that if a drug were to have an effect on the genome in the female, it would have to target that one cell that will


happen to be ovulated during that month, that will end up being fertilized.

The male is a very different story. In the male, from puberty on, there's in the area -it's about 100 million sperm every day. Okay. That's 3 billion sperm per month. Those cells divide through several mitotic divisions and meiotic divisions, and those are continuously ongoing. It's an incredible complex process. It has been studied extensively in the last thirty years, and we are beginning to understand how it's controlled.

To orient you, this is a schematic representation of a testis. In the testis you have

a bunch of tubules; they're called seminiferous tubules. And it's inside of these tubules that spermatogenesis takes place. It is continuously ongoing, independent of age pretty much, from puberty on, and very much independent of frequency of ejaculation.

The sperm are released from the testis. They look like normal sperm cells. They are haploid; they have half the number of


chromosomes. They are immature; they cannot fertilize eggs. They then have to pass through this long duct, the epididymis, where they acquire the ability to fertilize eggs. They are stored in the cauda, the tail of the epididymis, and they -- it is from here that they are ejaculated at the time of intercourse. Okay.

A single germ cell undergoes five mitotic divisions. Each one will then undergo two meiotic divisions. It will shed all of its cytoplasm, and basically remain a little bullet, which will have the nucleus that has the chromatin in it, it will have the mitochondria, which is the energy source that propels the sperm forward, and it will have a tail that will help it swim through the various layers around the egg.

I'm putting this slide up to indicate that there is a remarkably active new DNA synthesis continuously ongoing inside of the testis. It is a tissue where most new cells are made per gram of tissue anywhere in the body, in a male and during adult life. The complexity would take several hours


to explain.

Let me just point out one fact that was alluded to by Dr. Brent, and that is that the time course for spermatogenesis is extremely tightly controlled. There is no way of speeding up or slowing down the process. There are many ways of blocking it, but you cannot change the speed. In man, the time is sixty-four days. Different species are different amounts of time.

For the rat, the different times here are interesting, because, in fact, different strains of rat will have specific amounts of time. Very tightly controlled process.

After sperm are made in the testis, they take about ten to twelve days to pass through that epididymis, that duct system where they mature. So that there is a about a three-month period in man, just under three months from the beginning of spermatogenesis until sperm cells come out.

If you give a drug that is going to have an effect on day one on the making of new sperm, on the cell -- that first cell division, you


may not see an effect for three months. Okay.

In fact, this time course can be taken advantage of. Because by giving a drug at a given time, we can then see when an effect does occur.

And if the effect is occurring in the

first week, we know that we will have had sperm that were in the epididymis, that were in the process of maturing. If it occurs a few weeks later, we will be looking at sperm that had -- that were already haploid. If we look earlier, they were undergoing meiosis, and earlier still, they're undergoing mitosis.

So by looking at various regimens, we can assess where a drug is acting, assuming that the drug is acting at the moment you are giving it.

And let me open a parenthesis here,

that we're talking -- we're going to be talking about single-drug exposure, by and large. And we're talking about drugs that will not stay around for months or for years, in fact, that will not accumulate and then be gradually released. These


are complicating factors that can be taken into account, but obviously makes it much more complicated.

Okay, let's -- under phase two, what do we know about male reproductive development toxicity? A couple -- a meeting was held about two, three years ago, organized by Dr. Madison, and some of the people here were there. And several chemicals were shown to have effects, either on decreased fertility, spontaneous abortions, stillbirths. These chemicals are associated with specific professions. They are epidemiological studies; they are not proof.

I would like to reemphasize what some

of -- some of what Dr. Brent said: to establish a proof for any of these chemicals is extremely difficult. Primarily, they have a -- there are associations. There are good epidemiological studies.

The other point I want to stress is that when you look at a couple and there is lowered fertility, to prove that it is the mother's problem


or the father's problem is an extremely difficult thing to do. Because if the defect -- if the problem is the father's, and the result is that you produce a fertilized egg that can only undergo two or three divisions before it is so defective that it cannot continue, that will simply be seen as low fertility in the couple. There may not be even an increased amount of blood loss at menses, there may be regular menses, and the couple will perceive infertility. And trying to identify whether it's one or the other is very difficult.

There are some professions that are associated with having a high incidence of abnormal progeny. Again, it's interesting to point out the professions, because in fact we do not know which facets of that, of that profession, is causing the problem. They could -- it could be the way they are sitting. It could be the kind of chemicals they are exposed to. It could be what they do. It could be the stresses. We don't know what the cause is. We know that there is an association, and there is a great deal of work to be done to understand what the


causes are.

And these are where there has been very extensive epidemiological studies, and there is some pretty good data starting to come out. Clearly, we don't have anywhere near that type of data with the -- well, for veterans. Okay.

Now let me make a transition into the animal model issue. Why bother looking at animal models? Well, there are many good reasons.

Animal models are going to have certain advantages and certain disadvantages. One of the major disadvantages of animal models is that an animal is not a man. That may seem obvious. But there are obvious -- clearly, there are differences between man and animal. Before we try to extrapolate, we've got to make sure what can and cannot be said in using animal data when we look at man.

One of the points made by Dr. Brent, which is very much the case, is the fact that spermatogenesis, for example, is incredibly poorly -- incredibly defective in man. If you look at the


normal individual, the normal human male, you have to go beyond 40 percent of normal sperm before he's declared to have a problem with his fertility. If you look at the rat, you have to go beyond one percent before he has a problem.

We do everything we can to damage our spermatogenic process from a developmental

perspective. Some people have asked why. Well, the fact that we stand up, we keep our testes between our legs, the fact that we wear clothes, are all things that go towards going against the protective mechanism of the temperature gradient the testes need to make optimal spermatogenesis. That's another topic.

We can manipulate animal models in order to be able to test specific chemicals. And again, we usually look at one chemical. We can do it in a controlled manner. We can understand specifically what that chemical does or does not do. We cannot, and we have -- it would be destroying the purpose of the animal model to put a mix of fifteen chemicals, sort of randomly exposing the animals and


saying, "Is anything going to happen?" In a way, this is what happened in Desert Storm, and it's very, very hard to try to dissect any of these effects. Okay.

In looking at potential mechanisms by which drugs given to the male can affect progeny outcome, we are going to stick to the rat model.

And we are going to stick to one

drug, cyclophosphamide, which is a drug we have been working on. Several other labs have worked on it, as well.

And we are going to be looking at the types of mechanisms that are possible. I want to emphasize that not all these mechanisms have been shown for a whole bunch of different drugs. I'm

presenting it as an approach to try to understand the nature of the potential problems.

We're going to look at whether drugs in semen -- drugs in semen can have effects on progeny outcome, and whether drugs can affect sperm when they are beyond the testis in the external duct system, as well as when they are in the testis.



There is a number of drugs that have been shown to accumulate, to be present, and to -and/or to be concentrated in semen. This is a very partial list; right now that list exceeds thirty chemicals.

Can drugs in semen affect progeny outcome? Let me show you results of one study looking at pre-implantation loss. That's the number of implantations -- the number of corpora lutea, minus the number of implantation sites in the uterus. That tells you there has been a defect somewhere between the ovulation and the implantation point.

And you can see different doses of a drug being given: single dose, once, making -- one or three hours after the administration, and you can see that there is a dose-dependence effect that becomes highly significant at this dose. And so you can have a pre-implantation effect in a situation where you know that there is no effect via the genetic material of the sperm; it is directly via


the chemical present in semen. And a number of studies have been done to demonstrate that. So that's possible, but you've got to get to very high concentrations, and it's -- you've got to have a mechanism by which you can prove that that is, in fact, causative.

The second is post-testicular. So we're making our way back from semen. Beyond the testis, are sperm protected? And there was a longstanding theory that when sperm left the testis, they're in a -- they're in a protected structure, they had condensed their chromatin, they had gotten rid of all the cytoplasm, and you could not affect them afterwards.

Well, in fact, there are many drugs that are known to affect the epididymis and the vas deferens. Again, this is a partial list. Some of these have been proposed as contraceptive agents. Some of these are environmental chemicals. Some of these are anticancer drugs.

Let me show you one study that demonstrates that, in fact, you can have such an


effect. Here we are looking at pre-implantation loss. That's what we should be for, which is the number of implantation -- the number of corpora lutea minus the number of implantation sites, opposed to implantation loss, which is the number of implantation sites minus the number of fetuses.

We're looking here at three different

times and at three different doses. And what we can

see is that there are very low levels after one day of exposure. By four days there is a significant increase. It becomes highly significant at seven days.

Now, at this point all the sperm are still in the epididymis. In fact, experiments have been done to tie off the input from the testis to prove that when sperm are in the epididymis, they are still susceptible. So the concept that sperm in the epididymis are protected from drugs is not true. It is possible for them to be hit at that point.

Now let's move back to the approaches

at the level of the testis, where we can see whether drug exposure can affect -- can have effects on


progeny outcome. And I'm going to show you a few protocols and show you the types of approaches that one can follow.

In this type of study, drugs are given in a chronic base -- chronic basis, different doses. And at different times during the -- during the treatment the males are mated. Twenty days later the females are sacrificed, and what happens is, resorptions, implantation sites, and so on are all quantified.

By doing this kind of protocol, you can have some idea as to when drug effects start, based on what we talked about earlier with stages of spermatogenesis.

This is a summary of one of the studies. At the top you see pre- and post-

implantation, also abnormal progeny, as a function of time. And this is in a control population, which are percentages.

If you treat with a drug, a dose of cyclophosphamide, you can find a dramatic increase in post-implantation loss. That means an effect on


the progeny after implantation has occurred. You also find an increase in pre-implantation loss at another time, and you find a small increase in abnormalities. And I'll show you some of those in a minute.

Now, keep in mind this is during drug exposure. So the male is being treated. As he's being treated, he's being mated. And we're seeing the effects.

This is an example of a control male rat embryo on the left, and an embryo from a treated litter. You can see differences in size, as well as some abnormalities.

The next question would be, are these effects reversible? Okay. So using the same kind of protocol as I showed you before, you can treat animals for the same amount of time. You then stop your treatment, and you start mating every couple of weeks, and you see are those effects reversible. Same approach.

And indeed, what you can find -okay. Let me explain this slide. We're looking at


the number of fetus -- number of pups. And we can see here that the amount of resorption, as we increase dose, goes down. Therefore, the number of pups decreases, versus live births.

If we wait two weeks with no drug, with a high dose we can see that the number of pups is going back up -- that's the red. With the blue, we're back to control level. So within four weeks, this rather damaging effect here has been completely reversed. And what that tells us is that the drug is hitting the germ cells when they're haploid, when they are divided, when they have half the number of chromosomes in this particular situation. So we can get -- trying to get an idea of potential mechanisms or sites of action.

The third type of approach I wanted to point out is, can these effects be passed on? And here we have a situation where males are treated. The progeny of those males are mated to each other. And in this particular study, the progeny looked perfectly normal. Most of the progeny died off. As I showed you before, we had 80


percent resorption. But those that made it looked fine. They developed to adulthood.

There's another group in France that has done extensive study on these animals as adults, Professor Rue's [phonetic] group, and they have demonstrated that there were some learning deficits in these progeny.

We mated these to see what would happen to their children, to their progeny, to the

F-2 generation. And what we found is that in two generations there was no change in pre-implantation loss. There was an increase in post-implantation loss that was dependent now on the dose that the father -- grandfather had been exposed to, and a fairly big increase in abnormal progeny. And this is a range of the -- this is the control, and these are five different types of progeny that were found. So it is possible -- very rare, but it is possible.

So to summarize to this point, we

know that giving a drug to the male can affect -can have effects on pre- and post-implantation loss. We also know that these effects can be reversed, and


there is a potential for them to be passed on to the next generation. Okay.

Let me turn now for a few minutes to other types of approaches we have to try to get at the defect within the DNA, within the sperm.

This is a schematic representation of a somatic cell and its nucleus, and this is the nucleus of a sperm cell. Sperm is very different. The DNA in sperm is very differently organized. It's very compacted, and it's really designed as a bullet to deliver its message to the female.

All these effects that we've -- these effects that we've demonstrated must -- are via the genome, via the nucleus. And therefore, there has to be ways of trying to understand whether that nucleus is different or not. And is it, in fact, different?

So we can do a test like sperm decondensation and try to understand whether the ability of the sperm to decondense over time is altered by drug exposure. We can use different treatments, try to find out different windows of


exposure, and look at decondensation.

What we see on the left are controls, so this is different time points. And you can see that the DNA -- the blue is the DNA of a sperm; it's a hook-shaped sperm. And with time, it decondenses and eventually all the DNA dissipates; it's completely open.

After drug treatment, what we find is that it begins opening at the same rate, but the ability to completely dissipate is lost, that the DNA has, in fact, been cross-linked, and the structure of the DNA is altered. Okay.

Other approaches would be to look directly at the nuclear DNA. And one can look at total DNA damage, or we can look at specific gene expression. And there are some very elegant methods -- that paper has just been released, actually -- on looking at specific genes in sperm, using a fresh method that allows to see whether given genes are expressed with -- with or without different drug treatments.

One can look at whether the DNA is


damaged overall by using a method such as alkaline

elution, where the -- you can assess the number of breaks and the extent of breaks and the extent of cross-links in DNA by putting DNA on a filter and passing a base through that filter, and then looking at the DNA that comes out.

We can also see whether the function of the DNA as a template to make new DNA is affected. What's the first thing that will happen to it? It's going to work as a template to -- for the dividing cells. And there are simple assays now that are possible to give you handles on whether the sperm genome is normal or is not normal. Again, all these methods have been used with these drugs, with -- somewhat with other drugs. And we can show data, but that's not my point here. But this is a range of the types of methods available to get a handle on the mechanism of male-mediated adverse progeny outcome.

There are many, many questions that remain. I've outlined some of them here.

In trying to assess whether a drug


has an effect, we've got to be worried about a number of issues. What are the drugs we need to look at? What are the doses that people -- or that animals are going to be exposed to? We have to worry about the types of mechanism. We have to worry about whether there can be synergistic interaction between these various drugs. We -

Again I want to stress that almost

all laboratory studies look at one compound in order to try to give -- get a Yes or No answer. Very few

studies have tried to go -- to put two compounds, certainly never more than two compounds. And trying to look at five, ten, fifteen interacting compounds would become a drug -- an experimental design nightmare.

So the bottom line is that there is a remarkable amount of research that is needed. What I have shown you is with a prototype drug. Cyclophosphamide is a drug that we know is a mutagenic agent. We know it's a teratogenic agent. We know it's a carcinogenic agent. We were trying to figure out exactly how it was working, and could


it have effects via the male. The answer is clearly yes. But for compounds for which that kind of track record hasn't been established, we need to determine whether there will, in fact, be such effects.

I would like to make a further recommendation. That is that, if we know that chemicals do not have effects, if they've been tested and they're not mutagenic, they're not teratogenic, they're not carcinogenic, then there's no point in worrying about male-mediated adverse progeny outcome.

However, if we're going to be exposing man to chemicals and we do not know where the potential effects are, I believe it would be a wise approach to suggest that the sperm get banked before the exposure.

The Royal College of Geneticists in Canada has moved about three years ago to the

position that men who are going to be treated with agents such as cyclophosphamide should have their sperm banked before treatment starts. There we know there's an effect.


MS. LASHOF: Can I ask you to wrap up?

MR. ROBAIRE: That's it.

MS. LASHOF: Okay; that's a good spot to wrap up on.

MR. ROBAIRE: That's, in fact, it. QUESTIONS

MS. LASHOF: Thank you very much. We're open to questions. And if I

may, let me start.

Dr. Brent, you made several points of importance -- well, everything you said, but I was looking also at the material.

One of the points was the question of whether there's a specific defect, whether you could expect a single type of -- like spina bifida or anencephaly, as a result of exposure. And if I understand your point, it's if there is ongoing chemical exposure during the pregnancy, such as there was in thalidomide while the woman is taking the drug during pregnancy, or if she's exposed to other chemicals during her pregnancy, like fetal


alcohol syndrome, you can expect a single syndrome.

But if the exposure was prior and is not ongoing

during the pregnancy, then you would expect that it would have to be mutagenic, and what defect you would get is up for grabs and you couldn't expect it to be any particular one. Is that a correct interpretation?

MR. BRENT: If you're talking about the induction of mutations, and from just a cytotoxic or mutagenic compound, then of course what -- you don't have a propensity to affect one gene or produce one type of chromosomal defect. So that what you would expect is an increase in the incidence of genetic disease.

We in the laboratory -- not myself, but people who are working in molecular biology do develop mutagens that are called site-directed, but it takes years for the -- they've got to know the gene and they've got to know the nucleotide sequence, and then they can make a mutagen that may affect one locus, one site.

But by and large, if you're just


breaking chromosomes or you're producing point mutations, what you're going to see is a -- and you can do this in animal models. You will find an increase in mutations at many, many loci. But you're not going to produce, you know, one group of birth defects that are going to be increased, at least from the standpoint of genetic changes.

MS. LASHOF: It's an important issue in looking at the epidemiology in the -- in the Gulf War veterans, because one of the questions has been whether the epidemiological studies focus around a

specific defect, or whether they look generally at all defects and would not try to break that down into what are the specifics.

MR. BRENT: Remember that when you look at the defects, first of all, one thing you want to look at, is it a genetic defect? Unfortunately, a lot of defects are in the unknown category, and we see hereditary -- that that's passed on heredity in a few families, but most of them it doesn't appear to be hereditary. So sometimes we can't be sure about the genetic


component of it.

But the other thing that Dr. Robaire talked about, and that is that experimentally he is able to produce, by giving high dosages of a compound that is cytotoxic, that the male can deliver the compound to the animal during pregnancy, you know. And from the seminal fluid, by repeatedly inoculating it through the semen, you could get a teratogenic effect that way. But that would mean that the exposure would have to be continued for many, many, many -- in the case of the human, for years after the person left the site where that exposure occurred. In other words, these compounds don't have half-lifes of months or years; they have half-lifes or hours or days.

MS. LASHOF: Dr. Robaire, you want to comment on that too?

MR. ROBAIRE: Yes. I agree with what Dr. Brent said. The only potential alternative way

would be that the chemical would have affected the stem cells in the seminiferous tubules. There is no mechan- -- and that this effect would have been


random. I'm trying to see whether it's possible for this to occur. It's theoretically possible, but I would not be too concerned. There are no mechan- -there are no drugs today that have been shown to do that.

We do not know how stem cell renewal is controlled. We don't know whether defective stem cells are eliminated. But it is possible that drugs could affect stem cells, and that these effects could slightly modify the genome.

MR. BRENT: Yeah, but wait a minute. That would be in one family.

MR. ROBAIRE: Sure. Sure.

MR. BRENT: In other words, if what -- I don't want people to get confused with what he said. He said that in one family, if you affected the stem cell, then that might be part of that man's spermatogenesis, and he could have more than one child with that same genetic effect.


MR. BRENT: But in the overall population if you're looking at, you know, thousands


of people exposed, that should not occur with a mutagenic effect. It should be as you said -namely, a wide spectrum of genetic disease without

any concentration on one particular genetic effect. So I think that the --

MR. ROBAIRE: Right; we agree.

MR. BRENT: We agree.

MS. LASHOF: Yeah. Okay. To try to explore further the plausibility of Gulf War veterans having offspring that are congenital defects due to their service or their exposure, if I understand what you said, Dr. Robaire, unless the exposure of the veteran, if he came back, was within the three months -- I mean, if he's home for three months before his wife becomes pregnant, it's unlikely that it would have been any chemical that he was exposed to during the Gulf. Is that correct, or not?

MR. ROBAIRE: Yes, with two qualifiers, if I may mention them.

MS. LASHOF: By all means.

MR. ROBAIRE: The first qualifier is


that the drugs that he's exposed to are not lipophilic and will not stay in his body for several years.


MR. ROBAIRE: There are some drugs that we know will be accumulated in fat --


MR. ROBAIRE: -- and will be released slowly over time.


MR. ROBAIRE: Okay. So that's one qualifier.

MS. LASHOF: Right.

MR. ROBAIRE: The second qualifier is that the effects are not of a nature that have affected the stem cells. The data I showed you were all in that category. In other words, you're affecting, not the stem cells, but the cells that were dividing. So if you're affecting cells that are dividing, then you're absolutely right. A few months later, three to four months later there should be no further effects.


MR. BRENT: But even if it were a lipophilic compound, one of the things that you can never forget is the importance of dose. And even though a substance may be there, the fact is, as it drops off, even if it's a potent mutagen, the risk of that mutagen becomes less and less and less, to the point where you can't even begin to think about measuring its effect.

MS. LASHOF: Let me ask one more question about epidemiology, and then I'll throw it out to the rest of the panel.

You made the point about clearly case-controlled studies need to be done. What would you consider in the Gulf War, if we're looking at this, how many veterans we'd have to look at and what the control population -- generally, in most of the studies we're looking at now and the epidemiologic studies that are ongoing, clearly we're looking at those that were deployed, versus those who were non-deployed. The largest study, I

think, is 15,000.

MR. BRENT: If you study them all --


MS. LASHOF: Are we in the ball game? MR. BRENT: If you study -- I

estimate that based on the Mississippi study, I think that -- I did a little calculation that the -of the men that they collected or contacted, 26-odd percentage of them were fathers -- in other words, a little over a quarter of them. So that would mean if there were 750,000 servicemen and the same percentage prevailed, there would be about 200,000 offspring. If you study them all, you'd probably not have enough people to demonstrate an increase in genetic disease.

And I know that -- I think it was Senator Harkin, I believe, has gotten a study started in Iowa, and I believe that the number of people is like 5,000. That's a very small population to demonstrate genetic disease.

I would hope that they'd also be doing a carcinogenic study and following all of them there as well, because that's a much more sensitive tool from the standpoint of --

MS. LASHOF: We assure you, in Iowa


they are.


MS. LASHOF: And I think it's 10,000, isn't it, Miles?

MS. GWIN: 1,500.

MS. LASHOF: Oh, 1,500. It's smaller than that. It's 1,500. 1,500. But the other survey is --

MS. GWIN: The national health survey is --

MS. LASHOF: The national health survey is what? How many?

MS. GWIN: 30,000.

MS. LASHOF: 30,000. But what you're saying is, we're not apt to get our answers through epidemiology on this one.

MR. BRENT: In that, with those numbers, yes.

MS. LASHOF: All right.

MR. BRENT: And the other thing is that Dr. Robaire pointed out, like for instance, occupational exposures. One of the problems is that


they are a very -- a lot of them are very unsophisticated. They'll just say, "An increase in birth defects," but they don't tell you what the birth defects are. And if I did -- I sent you that article that I did in that conference. I happened to be one of the organizer of that male-mediated reproductive toxicity conference, and I reviewed all the data on occupational exposures. You know, half of them are negative and half of them are positive.

But one of the most important things

that I hope Dr. Edmonds will point out is consistency. In other words, if you do painters, in one study they find an increase in cleft palate, and

then another body -- person does painter, and he finds an increased incidence in clubbed feet. That tells you that's noise. You know, that's not an epidemiological study that has proved causality. So that these are very difficult studies to do. And they also have small numbers. You know, they may have 60 painters or 140 painters, so that they're difficult to interpret.

MR. ROBAIRE: I think it's important


on this question to say that it's extremely hard to give a negative answer.

MR. BRENT: It's impossible to give a negative answer.

MR. ROBAIRE: But if the sample is small and there's a dramatic positive answer, if it's very -- if the effect is very big, it will be seen, obviously, with a smaller number. And so the ability to come up with a negative is very different than the ability to come up with a positive. And I think that any epidemiologist will point that out to you.

MS. LASHOF: Yeah; I concur.

Well, let me open it up. Joe? Marguerite?

MS. KNOX: I just have a couple of questions. Of the -- of the chemicals that you know about that are lipophilic, do you know about any that the Gulf War veterans were exposed to, such as the PB tablets or anthrax vaccine or any of the chemicals that they might have been exposed to

through the Gulf oil wells? Are any of those


lipophilic that they may be having problems with? MR. ROBAIRE: I don't know.

MR. BRENT: Not by their chemical nature. You'd have to do the study. You're always surprised.

For instance, like the retinoids, the acutane, which is a drug that produces congenital malformations -- one of them turned out to be very lipophilic, just the isomer of another one. And unless you do the studies, you can't always -- maybe a good organic chemist could predict by just looking at it, but by and large, most of us would have to do the study to determine whether it gets deposited in the fat. But something like a pyridostigmine is not like -- it's so polarized that it doesn't even cross the blood/brain barrier. It's a very -- you know, it's a polarized compound. So I doubt whether that would -- and it disappears very fast. It's not going to be lipophilic.

MS. KNOX: Well, secondly, then, I would ask: is it possible for us to just recommend for future wars, for veterans to wait to procreate?


Or to, indeed, give a sperm sample before they go to war?

MR. ROBAIRE: Well, I think for my first recommendation, let's do the research on the chemicals before we expose our veterans to the

chemicals, our soldiers to the chemicals. That's my number one recommendation. If that is --

MS. KNOX: The problem is that we don't always know what chemicals we're going to be exposed to.

MR. ROBAIRE: Right. If we don't know that, I think a safe approach and a relatively inexpensive approach, is to recommend sperm-banking. It should not cause much anxiety, much trauma. It's relatively inexpensive, and it would guarantee that there would be a sample that is obtained prior to such exposure.

Now, that's assuming that the exposure is a question mark and we don't know what it is. If we know the exposure is going to be -- is not a question mark, and we know that those chemicals are not toxic, then certainly there is no


need for such banking.

MR. BRENT: I think, though, that recommendation is the kind of recommendation that needs more than one mind. I think you'd have to really think through -- because, you know, I showed you all the data that we'd been unable to demonstrate a mutagenic effect, even with potent mutagens.

You know, the question comes: where do you put -- I don't know how inexpensive it would be, Bernard. But when you talk about for one person, that's one thing, but when you talk about sperm-banking for 800,000 people --

There's also the social implication,

the anxiety-provocation in an individual. I mean, you're sending him off to do a job, and then you're banking his sperm -- it's like he's not coming back. And -- well, but that -- but the point is that these have -- these can create burdens themselves.

And I would like to see, you know, people more knowledgeable than myself sit down and go through that whole issue.


And maybe, as Bernard suggests, you know, we should be testing these chemicals, if we can, and pointing out whether they're mutagens or not. I think it's an issue that I would not like to come from one individual, at least with a -- with regard to agents that are not mutagens.

You mentioned that the genetics group in Canada recommends, if you have a potent mutagen -- and in fact, by the way, the National Council for Radiation Protection forty years ago said that if a person has had radiation therapy, that they wait for three months if you're a woman and six months if you're a man, after your therapy if you want to father or mother a child. So we've followed that recommendation for years and years and years.


MR. CASSELLS: In view of that, the fact that for the Gulf War we did not do the research in advance, not knowing what the exposures were going to be, have either of you been consulted by any Gulf War veterans?

MR. ROBAIRE: Yes. I've had --


MR. CASSELLS: What advice do you give them when they ask you about what kind of reproductive advice you need to give them?

MR. ROBAIRE: That we don't have the data. I mean, I have listed -- I must have had at least fifteen phone calls from different people around the country. And the -- I listen to their cases. The individual cases, they have all the flaws as all the case reports that Bob talked about in detail.

And the male may not be a link. There is no evidence today that there is a link.

The advice -- the only advice you can

give is that there is a normal incidence of abnormality in children. We don't know whether there is any -- there is no indication, there is no proof today that there is or that there isn't, and that if you really want to have another child, you can take a chance. You have to -- you may want to do antenatal diagnosis.

But we really don't know. I mean, the studies are not in. There is no way of giving a


positive answer. You can't give a simple Yes or No when you just don't have the data. And that's where we stand, unfortunately.

MR. BRENT: Well, I get about three calls a week on various environmental factors: radiation and chemicals and drugs. And I've had --

I haven't had fifteen calls, but I've had half a dozen calls from veterans.

And what I find, my perspective is, I can't -- I can't give them any more information without data. But if it's a particular -- like for instance, if it's a cleft palate, of which most of them are not simply genetic -- in other words, they're not hereditary malformations -- I can tell them that it's unlikely, but that they do need genetic counseling about that. They need to get some kind of advice.

But I can tell you what I find is that the tragedy is that so many people in our country with birth defects fall through the cracks in the health care system.

And then, on top of -- on top of


having a child with a malformation, our health care system doesn't provide the kind of support and care. Everybody wants -- the HMOs don't want to take care of him, this insurance company doesn't want to, and the service works for ways that they are not responsible. It just tells you the fact is, if you have complicated disease in our society, you're in trouble if you've got long-term care. And that's another issue than what you're facing, but our country has to face the problem of providing that kind of complicated care and support. Because it's bad enough to have such a tragedy, and then feel that you've been abandoned by your society. And that's what I see over the phone, more than anything else.

MS. LASHOF: Any other questions? MS. GWIN: I have one.

MS. LASHOF: Holly?

MS. GWIN: Dr. Robaire, in your presentation on animal models, you showed that there was substantial evidence for pregnancy loss as a result of a paternal exposure. But are there -- is


there evidence for malformations in offspring?

MR. ROBAIRE: Yes. I showed you one example of that, as well. It can occur. It's obviously much rarer than pregnancy loss. Pregnancy loss --

I should emphasize, by the way, that pregnancy loss that we are showing is false implantation loss.

If you look at the timeframe and you try to translate that to what happens in the human, this would probably be perceived as infertility in the couple, because it's occurring quite early on, in the very early phases after implantation.

There are cases of abnormalities. I should use some examples where -- and the effects, though, we found to be reversible when the treatment was stopped. So the effects were only seen while the male was actually exposed.

MR. BRENT: That's a very good question; all your questions are very good questions. But one of the problems with this particular area is, we've known about this for a


long time. It's called, way back in the -- after World War II, it was called the dominant mutation test. In other words, that's exactly what Dr. Robaire is doing. He's giving a mutagenic drug and then he's looking for pregnancy loss.

The problem is to know whether it's pre-implantation or post-implantation. You notice what he said? He said in the human you probably wouldn't know that you were pregnant, which means that, while there may be post-implantation losses in the rat, they're probably more likely, at least, occurring before the woman knows she's pregnant in the human. And that's because our pregnancy is so much longer.

The other thing is that in us -- if you just think about it theoretically, let's say that a sperm and a seminal fluid had a toxic compound in it. And this is a very important point. A teratogenic compound, a mutagenic compound.

In the man, the human inseminates a woman, and that egg gets fertilized. In the rat, if that compound only has to sit around for seven days,


if it could stay that long, before the embryo is during the period of organogenesis, when it becomes sensitive to a teratogenic agent -- in other words, if you could get that compound in through the vagina and seven days later that embryo is sensitive.

In the human, the so-called all-ornone period when the embryo is insensitive to

teratogenic agents, is about fourteen to sixteen days, which means in the human the seminal fluid would have to contain a compound that remained around for almost two weeks before the embryo becomes sensitive. So to apply animal data to the human in that particular instance is not exactly appropriate, because of the fact that you've got this time delay with regard to the dilution of that compound.


If I may complement, though, another way in which the animal model differs from the human model is that in animals, once pregnancy has occurred, there will be no more mating. In other words, there is a window during which a female will


accept to be mounted, and then she will not accept afterwards. And that's the only window when she can become pregnant.

In humans, there can be continuous exposure via potential drugs in semen. So even though what Dr. Brent said is absolutely correct, there can be continuous matings' exposure for several weeks and several months during the growth of a fetus.

MR. BRENT: But if he's getting continually exposed.

MR. ROBAIRE: Sure. That's what I'm saying.

MR. BRENT: He'd have to be on some kind of therapy --


MR. BRENT: -- in order for that to happen.


MR. BRENT: And the other thing with regard to the animal models, I can just refer to the work of Nomura. He demonstrated the same thing that


Dr. Robaire did, with using radiation and cytotoxic chemicals, that you get low pregnancy loss. And by the way, that's why you notice in one of my recommendations was not to look -- I didn't say, "We should be looking for an increase in miscarriage in the population," because the chances are very good that you wouldn't see it in the human, wouldn't pick it up.


MR. BRENT: We agree on that. in other words, it occurs too early in time for a mutation test in the human and --

But in the animal experiments, you do get an increase in birth defects in, like I say, the mouse or the rat, with a high dose radiation, if you open up the animals during pregnancy. But if you wait to term, you don't have an increase in malformations. And so that what happens, that socalled biological filtration -- I mean, that doesn't -- you could say, "Well, that's -- then, you don't have a problem of having to take care of a malformed child, but you do have the problem of the loss of an


abnormal embryo in utero."

MS. LASHOF: Rolando, questions? Mark, any questions?

Thank you very much. And I also appreciate all the material you submitted to us. Thank you.

Mark, you're next on the GAO report. MR. BROWN: Yeah.

MS. LASHOF: You want to brief us on that?



MR. BROWN: I'm going to represent --

I'm going to discuss a report from the General Accounting Office that was an early analysis of the possibility of reproductive toxicants and their possible -- the effects of exposure to reproductive toxicants by Gulf War soldiers. And I'm going to -representing GAO here, so I'll be prepared to answer any questions you may have --


MS. LASHOF: You will.

MR. BROWN: -- at the end of the talk, or before then.


MR. BROWN: The title of the GAO report that I'm going to discuss is "Operation Desert Storm: Questions Remain on Possible

Exposures to Reproductive Toxicants." And this

study was requested in January 1994 by Senator Rockefeller, who was at the time chairman of the Committee on Veterans Affairs in the U.S. Senate. The study was published six months later in 1994, August 1994. And so some of the findings and observations that the study made are a little bit out of date, of course; it's a two-year-old study.

Next. Senator Rockefeller asked GAO

to look basically at four questions.

The first question is "What types of assessments were performed before the deployment of troops to the Persian Gulf to determine the potential for exposure to reproductive toxicants?"

The second question was "Were


specific reproductive toxicants considered or identified as a result of these assessments?"

And the third question: "What types of protection were provided to active-duty personnel who might have been exposed to the toxicants identified, and what efforts were made to educate them about how to avoid the identified toxicants?"

And the last question was "To what

extent are active-duty military personnel and veterans currently monitored for reproductive dysfunction that may have resulted from duty in the Gulf?"

GAO's finding relative to the first questions about what type of assessments were performed before to deployment -- they had a number of findings.

The first is that DOD actually

performed numerous occupational health hazard assessments.

The second finding: DOD -- DOD's health hazard assessments reviewed reproductive toxicology as part of the materiel acquisition


decision process.

A third finding is that DOD relied on assessments performed by others. As an example, for the pesticides that were used in the Gulf War, DOD relied on EPA's teratogenicity and reproductive studies of those pesticides that were used.

Finally, of course, I guess it's

stating the obvious, but reproductive toxicants that were not acquired, that were not part of the acquisition process, were not considered by DOD before deployment. And this would include, for example, smoke from oil well fires, which was not an anticipated exposure.

GAO's findings relative to the second question, "Were specific reproductive toxicants considered or identified as a result of these assessments?" -- DOD [sic] found simply that DOD's health hazard assessment process generally endeavored to identify potential reproductive toxicants.

Next slide. GAO's findings relative to the third question they were asked, "What types


of protection were provided to active-duty personnel

who might have been exposed?" -- DOD found that the -- I'm sorry; GAO found that DOD's hazard assessment, the process that DOD goes by -- goes through for its health hazard assessments, produces a variety of things.

It produces directives on, for example, the proper use of chemical suit, directives on precautions on pesticide use, training on handling, for example, depleted uranium ammunition, training to defend against attack by chemical and biological weapon agents.

GAO found that, overall, DOD's health hazard assessments would, to use their own words, "likely have minimized exposure to relevant potential reproductive hazards."

Next slide. GAO gave an example of how, in response to the oil well smoke exposure that some Gulf War personnel were exposed to, DOD resorted to using armed force radios -- radio to carry announcements about how to -- how to deal with that particular hazard, to some degree.


Finally, GAO found that, although no efforts are targeted specifically against reproductive toxicants, rather, they are a part of the overall health hazard assessment strategy. I think this is somewhat comparable to civilian occupational health hazard assessments that we do.

Finally, the last question: "To what

extent are active-duty military personnel and veterans currently monitored for reproductive

dysfunction?" GAO had a number of findings.

They found that there were major shortcomings in DOD and VA efforts to monitor reproductive health status of Gulf War participants.

They found that monitoring efforts

did not address most forms of reproductive problems. And for example, VA's original Health Registry questionnaire did not include questions about infertility and miscarriages.

We've already heard something about the Mississippi study and the problems it had with the small sample size. Basically, this was an early study with a very small sample size that found no


reproductive health problems in this small group of less than 100 veterans.

GAO also echoed the criticism that the sample size was small, and that -- also, that the control group was possibly inappropriate.

They also criticized DOD and VA registries for not advertising themselves as well as they might.

And finally, a DOD study that we've heard of before, conducted by Commander Gray in San Diego, a study on birth outcomes, originally excluded Reserve soldiers, and failed to measure infertility and miscarriage rates.

Some of these complaints are basically the same complaints we heard at that meeting we had in San Francisco that examined some of these epidemiologic studies. Very similar complaints to what we found earlier.

Senator Rockefeller also asked GAO to, just to use their own words: "List substances likely to have been present in Operation Desert Shield and Desert Storm that could have potentially


resulted in reproductive toxicity."

GAO's findings -- they found a group of substances in the oil well fire, the smokes from the oil well fires, pesticides that were shipped by the Department of Defense to the Gulf for use by Gulf War participants, and certain decontaminating agents that were used in the Gulf War are all known reproductive toxicants.

These are known reproductive toxicants in the sense that somewhere there's a literature hit that somebody's done an experiment that shows, in an animal model perhaps, or some other source, that there are some reproductive health effects.

GAO made a number of recommendations. First they found -- they determined

that VA should re-register veterans who participated in VA's registry before it was revised to include reproductive health questions. And in a sense, this has been carried out. Well, this is VA -- the VA registry now includes questions on reproductive health outcomes, and they have, as I understand,


re-registered -- gone back to look at the soldiers

that they missed the first time around.

Secondly, DOD -- GAO recommended that DOD should research possible synergistic effects of multiple exposures. Their concern there was that perhaps an exposure to one agent might not cause an effect, or another agent might not cause an effect, but two agents together might somehow cause reproductive health problems.

And I think the answer to that is a little bit complicated. DOD is doing a number of studies on -- today, on multiple -- the effect of -the possible synergistic interactions from multiple exposures. But I don't -- as far as I'm aware, none of them are directed specifically to reproductive effects. They're looking at other types of toxic effects.

The third recommendation: DOD should consider collecting base line data on infertility and miscarriage rates, and on exposure to potential reproductive toxicants, before and after future conflicts.


And I think you can't argue with that, really. It sort of echoes one of the findings that our Committee made in its interim report on the basic idea of collecting some base line data before troops are deployed.

And finally, GAO recommended that DOD should better inform troops about possible reproductive toxicants before deployment.

Could I have the next --

MS. LASHOF: I don't know how you

can, if we don't know.

MR. BROWN: GAO identified a number of limitations in this study. First of all, they pointed out that determining a cause-and-effect relationship between exposure to reproductive toxicants and reproductive health problems is not possible -- referring specifically to the Gulf, not talking in general so much, as we've heard from Drs. Bernard -- Dr. Robaire and Brent.

But specifically in terms of the Gulf, the reason that this inability -- the reason that we have difficulties with cause-and-effect


relationships in this area is uncertainty about the effects, due to lack of certain data -specifically, lack of data on the presence of specific reproductive toxicants, whether they actually occurred, these exposures occurred or not in the Gulf.

Secondly, the actual exposure to reproductive toxicants -- that is to say, quantitatively, what levels of exposures may have occurred.

And third, the basic data on race and reproductive health problems. The epidemiologic studies are not yet available.

Finally, the bottom line is that the lack of exposure data to known reproductive toxicants means that risk assessment is not possible for reproductive health effects.

In our own analysis of this report, we noticed a couple of other issues that I think are

worth pointing out.

I think it's possible, unfortunately, reading this report, to come away with an impression


that it's possible to make conclusive -- to make specific conclusions about the reproductive health effects that Gulf War participants may be suffering today due to exposures that they may have experienced during the Gulf.

Nevertheless, when you read GAO's own analysis of their report, you realize that maybe this is -- this is overly simplistic, and maybe not even possible.

GAO points out in its report that it's clear that neither has reproductive and developmental dysfunction among the veteran community as a result of the Gulf War been disproven, nor can it be ruled out.

And for example, GAO classified among the reproductive toxicants that they identified -they classified five pesticides and fourteen oil fire components, simply basic things like benzene and other petroleum products, a decontaminating agent that they identified, and ethanol, into one or more of five types of reproductive toxicants.

And this included types of


reproductive toxicants -- they would list -- they

listed agents as being a paternal toxicant or a

maternal toxicant or a fetal toxic -- toxicant, and

so forth. And the problem is, they gave no further analysis of what that meant, of what that -- what that classification meant. No details of the class-- for instance, whether the classification came from animal tests that had been done, whether they came from epidemiologic or occupational studies that may have been done on that particular chemical.

And as a consequence, the basic

information within the GAO report is not there to help the reader assess the relevance of that particular toxicant to the Gulf War, the health of -- reproductive health of the Gulf War veterans today.

And I'll try and answer any questions that anyone has about what this report has -- says. There's copies of the report, I think, in our brochures.

MS. LASHOF: Questions?

I could act -- make you act like


you're GAO, and say, "Well, why did you identify toxicants and not tell us on what basis you decided they were toxicants?"

MR. BROWN: Well, if I were GAO, I would say that this is a serious limitation in my study, for which I apologize for eternally.

MS. LASHOF: Okay. Answered like a good bureaucrat, Mark.

MR. BROWN: But on the other hand -MS. LASHOF: You've learned well. MR. BROWN: On the other hand, GAO

was -- I mean, they were specifically asked to take a look at this by Senator Rockefeller, so --


And Kathi; I'm sorry.

MS. HANNA: And I would also like to add that they were invited to give this presentation themselves, but the person that was responsible for the study is overseas.

MR. BROWN: Left the country.

MS. LASHOF: No; I'm sure they weren't just ducking it. We do have it, and we can


get back to them with other questions if anybody has them, and let them speak for themselves. Okay.

Thank you very much, Mark.

Next let me ask Dr. Michael Shelby, from the National Institutes of Environmental Health Sciences, to come forward.



MR. SHELBY: Well, I want to thank the members of the Committee for inviting me to speak here this afternoon. It's an important issue, and I hope that I've got something to contribute to it.

My name is Mike Shelby. I'm a geneticist and head of the Reproductive Toxicology Group at the National Institute of Environmental Health Sciences in Research Triangle Park, North Carolina.

NIHS is one of the National

Institutes of Health, and the mission of our

institute is to conduct research and develop


strategies to prevent environmentally-caused diseases.

This afternoon, in just the next few minutes I would like to describe to you our plans to establish a center for the evaluation of reproductive risks in humans.

As has been made quite clear, I think, by Dr. Brent and Dr. Robaire, the human reproductive process is far from perfect. In fact, I'm -- the older I get, the more astonished I am that so many of us turn out as well as we do. It's a near-miraculous process, and its disturbance is not surprising.

As he's shown, perhaps 3 to 5 or 6 percent of newborns have or will soon demonstrate major birth defects. A big component of that, or a substantial component of it, is genetic disorders, my area of primary interest and expertise, I suppose.

And we know, as they also showed, that there have been many factors that have been demonstrated to adversely affect human reproduction.


They can affect fertility or development of the conceptus. And these range from everything from ionizing radiation to alcohol consumption, infections, chemotherapeutic agents, and a variety

of chemicals, metals, and so forth.

And the most obvious way to establish a link between an exposure and an adverse reproductive effect is by epidemiology studies. The problem with those is that their success depends on an adverse effect in a human population. And in our reproductive toxicology studies with my group, we attempt to identify potential reproductive toxicants in the laboratory before there is an effect on the human population.

These identification efforts are then followed by various courses of research, which are designed to provide more information on these reproductive toxicants, things like dose-effect relationships that are important for risk assessments, metabolism and distribution in the body of rodents or humans, various periods of sensitivity, and so forth.


All this information, taken together, is then used to assess reproductive risks. And considerable effort has gone into developing methods for assessing human reproductive risks, and a primary source of this effort has been regulatory agencies in the U.S. Government. There's some fine people there. A great deal of progress has been made, and better approaches are being pursued all the time.

One problem is that these various regulatory agencies have their own mandates and their own well-defined areas of responsibility. And

therefore, there is not always uniformity between the approaches to risk assessment. And probably more importantly, there are reproductive health issues and public concerns that arise which do not fall into the responsibility of any regulatory agency.

And in an effort to fill some of these unmet needs, our Institute is proposing to establish the Center for Evaluation of Risks to Human Reproduction.


To keep things brief, I'm going to go straight to my first slide, if I could do that, which pretty much sums up what we want to do.

And this simply presents the purpose and the product from this Center.

The purpose is to provide timely, unbiased scientifically sound assessments of reproductive health hazards associated with human exposures to environmental agents.

These issues, whether it's the Gulf War, whether it's a pharmaceutical product, or an occupational exposure, too often deteriorate into polarized arguments in which the scientific data are forgotten and emotion takes over the arguments.

There is a scientific approach that

can be taken to these issues. And as long as there are data, some conclusion can be reached on what the potential is for an agent to be a reproductive toxicant.

Likewise, where there are data, or even where no data exist, there is the opportunity

to recommend the types of studies that are most


appropriate to produce data that could be used to assess reproductive risks. And these are the two things that I think the Center that we were proposing could provide. And I think it's an important public health need -- that is, a thorough assessment, unbiased assessment, and scientifically sound interpretation of whatever data are available, and secondly, specific recommendations as to the nature of the studies that need to be conducted, whether these be studies of molecular mechanisms, rodent studies in the laboratory, human epidemiology studies, whatever is needed, can be recommended by an objective and unbiased body.

The product that we would hope would come from this is given below, and that's simply a report that would be intended for publication in the peer-reviewed scientific literature, and that would provide a consensus judgment on the potential human reproductive toxicity of the agent under consideration. And again, an important component of that would be recommendations for the types of research that is needed.


As we see this process, an agent or a situation would not simply undergo a single assessment, but it could go through it one time. Conclusions as to whatever extent are permitted by the data could be reached. Experiments, further

research could be recommended.

Once those studies were conducted, then the process could repeat itself in a more thorough assessment, with less uncertainty, to be conducted at a later time.

My next slide simply shows the structure of this, as we envision it today. This Center does not yet exist. The -- it's still in the process of being established. And in the federal government, that process can be fairly long, as many of you might know. But there would be four components to it, and this slide simply gives the four components on the left, with some indication of what we think the membership of those various groups would be, as well as what their functions would be.

There would be an oversight

committee, and the main purpose of this would be to


give approval to various actions of the Center. That oversight committee would be

made up of scientists, experts from the NIEHS, and representatives of other federal and state agencies -- this is a typographical error here -- public interest groups, and representatives of the private sector. Industry, other organizations have a keen interest in this kind of activity, and would likely be represented on the oversight committee.

That committee would monitor all activities of the Center, select topics or specific chemicals or occupational exposures or military exposures for assessment. They would approve the

list of people who would be drawn on, the experts, to assess that situation.

Perhaps most importantly is bullet number three -- number one, two, three, four -- I had my glasses -- bullet number four, which is to assure objectivity. It's of vital importance that the reports that come out of a center such as this be viewed as authoritative and unbiased. And the oversight committee, I think, would have that as one


of their primary responsibilities.

And finally, to approve reports. The core committee would kind of be

the working group of the Center. It would be made up of NIEHS scientists, Center scientists, and experts drawn from outside the Center or the Institute. These people would not be

representatives of any of the funding agencies that support the Center.

Again, their responsibilities are to review nominations. We view this as being open to nominations from any group: private, public, or otherwise, individual citizens, labor groups, whoever wants to make nominations. It's basically the same as the nomination process for the two-year cancer studies that we do at NIEHS as part of our National Toxicology Program.

They would review those nominations, recommend the topics that were most suitable for assessment, schedule panel meetings, schedule the meetings, and review draft reports.

The Center office is what we are


currently in the process of establishing. That would be an office outside of our Institute, but supported and partially overseen by NIEHS. It's going to be fairly small.

As we see it today, it would involve a director who would be a toxicologist, a reproductive toxicologist -- the director might also be one -- an information specialist, and secretarial or clerical support.

Their responsibilities would be to interface with the public, to establish a registry of experts -- this is a key component of their activity, because there's so many scientific disciplines that need to be represented in these assessments, from not just reproductive toxicologists, but pure geneticists, chemists, people in metabolism and distribution, statisticians -- you could go on for quite awhile. But you need a rather large registry, such that you can draw a panel of ten or fifteen experts to deal with the assessment of a single exposure or a single situation.


They would be responsible for literature search and acquisition, once a topic was selected, or even prior to its selection for assessment. Because one needs to review the literature to know whether there's actually enough information to justify an assessment, I believe.

They would be responsible for coordinating the panel meetings and for the production of the report that was produced by the expert panel, which falls at the bottom, and I suppose could be considered the foundation of this activity.

And those would be made up of independent scientists from the registry, and their responsibility would be to conduct evaluations and prepare the reports.

What has this got to do with the Gulf War? There are at least three possibilities that I could see after I talked with the people from the Committee.

The first is simply a thorough, objective, unbiased assessment of the agents that


the Gulf War veterans were known to have been exposed to. And this is a most difficult thing.

There are some. Pyridostigmine

bromide is a single agent and is relatively easy to study. And that's what we normally do in our laboratories.

The smoke from burning oil wells presents an immense problem. As Dr. Robaire said earlier, it's a nightmare to a toxicologist to try to think about conducting a scientific study on something like oil well fire smoke.

So individual exposures or components or chemicals could be evaluated.

Secondly, I think that as I pointed

out earlier, an equally important responsibility would be to make recommendations for research or testing that would improve our ability to assess the potential reproductive effects of exposure of the veterans there.

And third, this registry of experts would include epidemiologists. And I think that a panel of epidemiologists and other people, people


with different expertise, could be called together to either help design epidemiology studies or to evaluate epidemiology studies that were under way or had been completed.

I'll be happy to answer questions. QUESTIONS

MS. LASHOF: Let me ask -- you said in relation to the Gulf War, that one of your purposes would be to provide timely, unbiased, scientifically sound, et cetera. Considering what we do and don't know, what would you consider timely, and how possible do you think it is to do that job?

MR. SHELBY: Well, it's too late to be timely. I haven't seen any thorough assessments of even a single agent, of DEET, of pyridostigmine, of any of the -- they may be in the literature and I've missed them, but they should have certainly been done four or five years ago. When was it -'91.

MS. LASHOF: Well, there are various groups, and we'll be talking about that later, that


are looking at some of these.

But if I understand the role of your Center, it would only be able to evaluate those studies that are already done. You wouldn't be undertaking any studies. You could identify chemicals that you felt needed further study, but you would not have any authority to fund or support research to carry out those studies. Is that correct?

MR. SHELBY: The Center would not. MS. LASHOF: That is correct?

MR. SHELBY: That is correct.

MS. LASHOF: I see.

MR. SHELBY: I would like to think that our Institute is responsive to public health needs. I know my group is --

MS. LASHOF: Well, this is what I wanted to ask. Let me follow this further.

In terms of the role of the Center in relation to the Institute itself, the Institute must -- now, I know, reviews grants and sets some priorities and helps to determine what things ought


to be studied. What will be the difference in the role of the Center than what is now the methodology by which the Institute does set priorities for some of the research?

Because if I understand our problem in the reproductive hazards, it's not so much that no one's looked at all the literature and pulled it

together, it's that there isn't much literature out there and there isn't enough research going on. So I'm trying to understand how the Center could help in that aspect, in relation to the current role of the Institute.

MR. SHELBY: Not being at the decision-making level on what our priorities are and where our -- where our money goes, I don't know how to answer the question of what's happening now.

If the Center were in place and was recognized as authoritative and scientifically sound, and supported at least in part by NIEHS, I believe that both the extramural and the intramural programs would be responsive to the recommendations. They'd certainly take them into serious



MS. LASHOF: Yeah. Well, I guess what I'm trying to ask, and maybe you're not the person to answer it and I need to ask the director of NIEHS, is: what is their current method for deciding this, and what new information or new ability will the Center bring to the current decision-making process in NIEHS as they decide what studies to do, what studies NAS should do, what studies the toxicology ATSDR should do, et cetera.

MR. SHELBY: I can't answer your

question for the Institute or for NIH or DHHS. But I know that if there are clear and respected recommendations for the kinds of research that need to be done, that they will be given very serious


MS. LASHOF: Okay. I'm not getting to --


MS. HANNA: If I understand you correctly, another component of what you anticipate the Center will do is to provide some sort of a


consensus type document that could then be disseminated to the medical community, perhaps as a source of information on some of these more difficult issues.

And what I'm trying to get at is, I've heard from many physicians who are trying to answer the questions that Gulf War veterans have about their reproductive concerns say, "Well, until something appears in the peer-reviewed literature, I really don't know what to tell these people." And so I think you're right when you say that there's a need for this kind of information to be available.

And if that's part -- if that's one

thing that you're trying to accomplish, how will you get information out to the medical community? Because not all physicians read the peer-reviewed literature. Have you anticipate other ways of getting information out?

MR. SHELBY: We have discussed that. And in 1996, of course, a web page is the first thing that comes to young people's minds of how to get things disseminated broadly and quickly.


NLM has various modes of

communication with the -- with the medical community, both on-line and hard copy. It's something that I could -- I would be happy to listen to recommendations on. But it is important, not only to the medical community, but to the public as well, because it's the public health concern, I think, that we should be primarily responsive to.


MR. BROWN: I just want to make a couple of points.

First of all, as you probably know, our Committee staff are looking at various exposure risk factors that were present in the Gulf War. And we're trying to do sort of a basic literature searches to find out what kinds of information are available about a variety of effects, including reproductive effects. And contrary to what we expect -- we didn't expect to find much. We thought there was going to be kind of a vacuum, in fact, for many of these examples. And we're finding actually quite the opposite, that there's actually enormous


amounts of data available to be mined to make some kind of assessments about the health effects of some of these agents.

But the other point I wanted to make is that you compared this program to what the NTP is doing, how the NTP works, how the NTP nominates chemicals for review. And I wonder -- it's not clear to me how you're really different from the

NTP. I mean, the NTP normally nominates to look at carcinogenicity, but they could also nominate a chemical based on reproductive concerns, I think.

MR. SHELBY: That's correct.

MR. BROWN: And they can also -- they would also be able to nominate a chemical where there wasn't data. They could -- they could ask -they could actually have some -- you know, the appropriate research carried out.

So it seems to me that, as I understand it, you're limiting it -- you're sort of doing more the literature search. You're going to be limited to cases where there is data available, but nobody's gone through the exercise of pulling it


together, first of all, and rather than making research recommendations, for instance.

And secondly, the other area concern I had is, the NTP only nominates -- I don't know, five chemicals a year, or something like that. How many chemicals do you think this process is going to able to -- how fast are you going to be able to say -- get down the list to, say, chemicals of concern to Gulf War veterans, for example?

MR. SHELBY: To do assessments on them to produce documents or --

MR. BROWN: Yeah. Exactly.

MR. SHELBY: To produce data?

MR. BROWN: Yeah, the documents that would, you know, help answer some of the questions, some of the concerns that Gulf War participants may

have about them. How high of a priority -- you know, of all the universe of chemicals that you might look at, where --

MR. SHELBY: I don't -- It's going to be dependent upon funding and the availability of expertise. I mean, there's a limited number of


people out there that are willing to do this on a benevolent basis.

MR. BROWN: Well, how many chemicals a year?

MR. SHELBY: And that two, three, four chemicals a year, I think, is a reasonable expectation.

MR. BROWN: So it might may take awhile to get around to, say, pyridostigmine bromide, then, on that basis?

MR. SHELBY: No; if it's deemed a high priority.

I think one of the primary responsibilities of this Center needs to be the public health concerns. I mean, there are scientific bases for being concerned about chemicals that the public at large knows virtually nothing about. And there is public concern for chemicals which the scientific community knows very little about. But I mean, they pay our salaries and support my lab. And I think that you can't simply dismiss those as implausible or unworthy of study.


I mean, you need to document that. If that's going to be your conclusion, you've got to tell them why you've reached that conclusion.

MS. LASHOF: Let me try once more the question of what is the vacuum that you feel the Center is fulfilling?

MR. SHELBY: What the Center will fulfill is the --

MS. LASHOF: What's the vacuum there now? I mean, I have to assume that -- let me try it this way:

The Center is being proposed to identify chemicals that need to be evaluated, to do a consensus document, and to set priorities for research. Is there not a mechanism within NIEHS within the National Academy of Sciences, within CDC, within the NIH, that is doing that on different chemicals? I mean, do you see yourself as a coordinating role to look at all of those groups and say what's not being done and --

MR. SHELBY: I don't -- I am not aware of anyone that's doing that. I don't see that


role being fulfilled anywhere in the federal government or elsewhere.

And I think there's some -- what this offers is timeliness, which is important. I mean, we muddle around with chemicals and exposures for years at a time without coming to any real conclusions on them.

Secondly, I think it's a thorough and unbiased assessment of all the literature that's

available on that. And I don't see those appearing in the literature very often.

And thirdly, it does provide guidance, at least recommended guidance for the types of studies that should be done in order to improve subsequent assessments of reproductive hazards. And it's not anything particularly earthshaking, or not even very unique, I don't believe, but it's something that's not being done, and I think should be done. You see enough public debate, as we're here talking about today, that such a service --

MS. LASHOF: Now, I guess the real


question is, is the public debate there because we don't have the scientific data, or we haven't pulled it together? Mark says there's a lot more out there that hasn't been pulled together. So that's very supportive.

I look at how many years we've been looking at dioxin, and we don't have the data, and we don't know, we still don't know, and we still come up with --


MS. LASHOF: And I can't imagine that your Center would have solved that problem in a timely manner if the work isn't there.

MR. SHELBY: No; but I'd like it to be able to tie up what is available in a neat package, and set it out on the table and say, "There's where it is today."

MS. LASHOF: That's a worthy goal. MR. SHELBY: All right.

MS. LASHOF: Thank you very much. Any other questions? Okay. If not,

thank you. I think --


MR. SHELBY: Thank you.

MS. LASHOF: Thank you very much.

I will take a break, but we'll try to limit to ten minutes instead of fifteen. We are running behind by about fifteen minutes or so -half an hour. We're half an hour behind. But we were scheduled to quit at 4:20, and who wants to quit so early?

(Recess at 3:20 p.m. until 3:35 p.m.) MS. LASHOF: I think we'll resume.

Thank you very much.

Our next presenters are Dr. Chandra and Dr. Spirtas on the various research projects in infertility and subfertility.

Dr. Chandra, are you going to kick it off? All right. Thank you.





MS. CHANDRA: My name is Anjani


Chandra, and I'm a statistician for the National

Center for Health Statistics in Hyattsville, Maryland.

NCHS is part of the Centers for Disease Control, or CDC. I'm happy to be here to pass some information on the National Survey of Family Growth, or NSFG.

The primary purpose of the survey is to collect national data on factors affecting pregnancy and birth rates in the U.S. Infertility is only one of those factors. Some of the others are sexual activity, the use and effectiveness of contraceptives, sterilization, and pregnancy loss.

Data on use of family planning and

infertility services and demographic background characteristics are also collected. As you can see on this first figure, the NSFG was conducted in several years by NCHS. Prior to that it was done by -- under another name by some other organizations, but by NCHS in 1973, '76, '82, and '88.

Each survey was based on in-person interviews with about 8,000 women aged fifteen to


forty-four. The samples, procedures, and questions were comparable, so we can look at some trends.

The response rate for each survey was

about 80 percent, which is fairly good for large national surveys. To produce accurate national estimates, the sample data were adjusted for nonresponse to independent control totals from the U.S. Census Bureau.

Our latest NSFG was conducted in 1995, and will be available for public use at the

end of this year. In the '95 survey we do have the same basic measurement of infertility, so we can continue that time trend. And we also have more detailed information on the use of medical care for infertility.

The data from the NSFG have seven principal strengths which are listed there. The samples are large -- about 8,000 women, as I said, in each of the years '76 through '88. And in '95 we had about 10,800 sample women.

The samples are representative of the civilian non-institutionalized population of women


aged fifteen to forty-four. So national estimates of the percent infertile and the numbers infertile can be made without some of the concerns about selection biases that other studies face.

Two different definitions of "infertility" are used.

One we consider somewhat objective. It's the infertility measurement itself.

And the other is partially subjective, in that it's based upon self-report, and it's -- we call it impaired fecundity.

Both of -- both of these generate results that are fairly similar, and that increases our confidence in the validity of both measures.

The questions used to derive these

measures were comparable over time, so we have been able to study trends pretty much since 1965.

The questions occur in the context of

an interview about reproduction, so we find that they are fairly well received in that context.

Our data can distinguish couples with primary and secondary fertility problems, and we


report those figures routinely.

"Primary fertility problems" simply mean that the couple is having a problem having their first child, whereas "secondary" means they're having trouble having a second or later baby.

Doctors and researchers distinguish

primary from secondary infertility primarily, to use the same word again, because they may be related to different patient characteristics, as well as different clinical profiles and prognoses.

And lastly, the questions that we have on medical services for infertility allow us to look at what -- the characteristics of both the infertile population as well as the service-seeking population, and look at the selection factors there.

Turning to the next one, the survey

was designed to provide national, not local, information on the demographics, social, and economic correlates of pregnancy and birth rates in the U.S. In so doing, it helps us to explain trends and birthrates, profiles the population using family-planning programs, and provides a database


primarily for demographic and behavioral scientists.

The NSFG was not designed with

toxicologic or occupational studies in mind. And from that point of view, I wanted to point out the following limitations.

First of all, the data on infertility conditions that we have are not based on medical exams, and the services data are not verified by checking any medical records. Some of the women who have reported going for help may not be accurately reporting the services or diagnosis that -diagnoses that they received.

Mainly, we've not done these medical exams or record checks because both would be extremely costly. But also, some recent studies have focused on the epidemiologic evaluation of infertility procedures, and have called into question the prognostic value of some of the diagnostic tests that are out there, as well as the clinical relevance of certain diagnoses. We feel that it would be beyond the scope of a survey like the NSFG to collect sufficient clinical data that


would allow us to evaluate those aspects of infertility definition and management.

The second point up there, exposure and risk factor data, are hard to obtain, because most people do not know themselves what fertilityimpairing agencies -- agents they may be exposed to.

What we can do and collect in the

NSFG are selected, more proximate risk factors -that is, factors that are known to more directly affect the risk of the infertility and pregnancy loss, such as pelvic inflammatory disease and

certain sexually-transmitted diseases. Should we see a change in age-specific infertility rates, these risk factor data will allow us to suggest some hypotheses that could be assessed in more narrow -in more narrow, analytic studies.

And lastly on here, we don't interview men, and the reasons for that are listed there.

First, research has found that married or cohabiting women can report most demographic facts about their partners as well as he


can. We've also found that response rates for men are significantly lower than response rates for women, which means that estimates for them are more likely to be biased. For example, a recent national survey of men had a 70 percent response rate, as compared with our 80 percent, which is a significant reduction.

Third, data quality is sometimes lower for men. And just to take some of the topics that we cover as an example: a birth history can be particularly sensitive for men, insofar as it may relate to child support; and a marriage history could be sensitive, as it may relate to alimony.

In short, women are more likely to

participate in surveys and provide accurate data about pregnancy-related events than me.

And lastly, I just wanted to mention that the first national survey of women on topics related to reproduction was done in 1955, whereas

the first national such survey on men was not done until 1991. Clearly, surveys of men that ask about sex and reproduction will become more common in the


future, but right now there's more experience interviewing women on topics such as these.

Our data are based on two measures of difficulty in having a baby. We call these infertility and impaired fecundity, and both of these are based upon status at time of interview, and not -- they don't represent lifetime experience with fertility problems.

In the NSFG we define "infertility" primarily for married couples, because of various technical difficulties that reduce the reliability for unmarried women. And basically, it's twelve months or more of intercourse without contraception and without pregnancy. Infertility is, therefore, not a measure of sterility. It is simply a screening device that many doctors use to determine when along the way a couple's inability to conceive should be investigated.

A year timeframe is typically used because roughly 90 percent of couples will have conceived after twelve months, and 95 percent after two years. It's well recognized that the choice of


timeframe, as well as how you choose to define "primary" versus "secondary infertility" will affect the estimates of prevalence that you have.

Turning now to impaired fecundity, "impaired fecundity" in our survey means that a woman herself reported that it is difficult or impossible for her to get pregnant or carry to term.

And first what we do in order to

define this term is, we exclude those who are surgically sterile, either themselves or their husbands or cohabiting partners. And if they are not surgically sterile, we take them through this series of questions which I've listed here verbatim.

But basically what we're doing is,

we're first asking her if it is physical -- if she is physically able to have children, as far as she knows. And that's the key phrase there.

If she is physically able, then we ask her if, as far as she knows, would she have any difficulty getting pregnant or carrying to term. If she's married or cohabiting, we'll ask comparable questions for her partner.


And that last question is -- just asks her if a medical doctor has ever advised her never to become pregnant for any number of reasons.

And we do ask the reasons for these

answers if she answers that she's had some difficulties.

Our measures of fetal loss are fairly straightforward. We ask a very direct question about how each of her pregnancies ended. And these are the choices she's given: live birth by vaginal, by C-section, stillbirth, miscarriage, induced abortion. And then the last one, ectopic, we only

added as an explicit category in the '95 survey. Our proportions of pregnancies ending

in stillbirth and miscarriage, we found are in line with other surveys that do not use special methods of detecting fetal loss.

Now I'm going to mention a few of our findings, although I think that the primary interest of the NSFG for this Committee might be in the methodology we've used to measure infertility and pregnancy loss.


But for infertility, as I mentioned, we do generally report our findings limited to married couples, due to reliability issues with unmarried and their contraceptive and pregnancy history.

We find that 8 percent of married couples have been -- the infertility rate has remained at about 8 percent throughout the period of our 1965 survey to 1988. Recent studies in other industrialized countries such as England and Canada have shown comparable levels of infertility to the U.S.

The number of infertile married couples dropped from 3 million in 1965 to 2.3 million in 1988, and this was largely due to the reduction in the proportion of secondary infertility. Meanwhile, the number with primary infertility did increase between 1965 and 1976, but has since leveled off.

Turning to -- okay. We find that

about 8 percent of all women fifteen to forty-four

-- that is, regardless of marital status -- have had


impaired fecundity in both 1982 and '88. And that represents about one in twelve women in that age group. We find that the rate of impaired fecundity did not change significantly throughout the 1980s, either overall or in -- within any subgroup by age and parity.

We find that impaired fecundity does increase, as many other studies have shown, as a woman's age increases, especially for childless women who are experiencing primary infertility. And particularly, waiting until after age thirty-five to have the first birth increases the risk of experiencing fertility problems significantly.

Now, with the NSFG, because we can

produce national estimates, we can estimate the absolute number of women affected by fertility problems. And what our data have shown is that the number of childless women aged thirty-five to fortyfour with impaired fecundity increased from 450,000 to 620,000 in the 1980s. And this represents a 37 percent increase. Now, this was despite the fact that the age-specific infertility rate for that age


group remained unchanged.

This increase in the number, but not the rate, was caused by the aging and delayed childbearing of the huge baby boom generation.

These are the women that were born from 1946 to '64, and were twenty-four to forty-two at the time of our survey in 1988.

The annual number of women treated for infertility increased quite substantially as well in the '80s, from 1.08 million in '82 to 1.35 million in 1988. And that was a 25 percent increase

just over that short period.

But we also find that in the '88 NSFG, that less than half of the women in the survey with impaired fecundity had ever received medical help for it. Less than one fourth had received specialized infertility services such as ovulation drugs, treatment of fallopian tube problems, artificial insemination, or in vitro fertilization. Only 20 percent had had any kind of infertility testing on the male partner.

Of all those with impaired fecundity,


those who received medical help for it are disproportionately white, college-educated, highincome, over thirty, and childless. In short, they are not representative of all those with impaired ability to have children.

Turning now to pregnancy loss, our questions on pregnancy outcomes in the NSFG showed that pregnancy loss which -- since "ectopic" was only added in the '95 survey as an explicitly category; we just started defining it as "miscarriage" and "stillbirth" -- we find that it was a common occurrence in the United States. About 17 percent of women aged fifteen to forty-four, or

roughly over 9 million women, have had a pregnancy loss. This is about 26 percent, if you just consider women who have ever been pregnant.

An estimated 900,000 miscarriages and stillbirths occur each year in the U.S., and most of these are early loses. We can also compute pregnancy loss ratios which show the chances that a pregnancy carried to term will end in a pregnancy loss. This ratio is about 16 to 18 percent in the


U.S., and it's higher for women who have had pelvic inflammatory disease and for women aged thirty-five or older.

So just to conclude, as of 1988, representative samples of American women reported no change in infertility rates, whether infertility was measured objectively or subjectively with our infertility and impaired fecundity measures.

As of '88, this series of surveys suggests that physicians providing infertility services did not have more patients because of any increase in age-specific fertility or infertility rates, because those had not risen. It appears that they had more patients because more help is available, more people are aware that more help is available, and the baby boom generation is at the ages when they're most likely to make use of that help.

I hope that this information will be useful to the Committee, and I'm happy to address any questions or comments.

MS. LASHOF: Thank you very much.


We'll go ahead and hear from Dr. Spirtas, and then have questions.





MR. SPIRTAS: Dr. Lashof and members of the Advisory Committee, thank you for inviting me to speak with you today. My name is Robert Spirtas. I am an epidemiologist and Chief of the Contraceptive and Reproductive Evaluation Branch at the National Institute of Child Health and Human Development, NICHD, of the National institutes of Health.

The NICHD seeks to assure that every individual is born healthy and wanted, and has the opportunity to fulfill his or her potential for a healthy and productive life unhampered by disease or disability. In pursuit of this mission, the NICHD conducts and supports laboratory, clinical, and epidemiological research on the reproductive,


neurobiologic, developmental, and behavioral processes that determine and maintain the health of children, adults, families, and populations. The Institute administers a multidisciplinary program of research, research training, and public information,

nationally and within its own facilities, on reproductive biology and population issues; on embryonic development as well as maternal, child and family health; and on medical rehabilitation. The NICHD supports and conducts basic, clinical, epidemiological, and behavioral research in the reproductive sciences to develop knowledge enabling men and women to regulate their fertilities in ways that are safe, effective, and acceptable to various population groups, and to overcome problems of infertility.

At the NICHD, research for mothers, children and families is designed to advance knowledge of pregnancy, fetal development, and birth; to develop strategies to prevent infant and childhood mortality; to identify and promote the prerequisites of optimal physical, mental and


behavioral growth and development through infancy, childhood, and adolescence; and to contribute to the prevention and amelioration of mental retardation and developmental disabilities.

Much of this research focuses on the disciplines of cellular, molecular, and developmental biology to elucidate the mechanisms and interactions that guide a single fertilized egg through its development into a multicellular, highly organized adult organism.

The Institute's medical

rehabilitation research is designed to develop improved techniques and technologies with respect to the rehabilitation of individuals with physical

disabilities resulting from diseases, disorders, injuries, or birth defects.

The work of our Institute is done intramurally, by scientists in Bethesda, Maryland and extramurally, by scientists and clinicians throughout the United States. In Fiscal Year 1995, NICHD funded over 1000 projects (grants and contracts) involving research on fertility,


infertility, birth defects and fetal loss at a budget of over $150 million. This research involves many of the scientists and programs of the Institute, constituting over 30 percent of the NICHD budget. At the Institute, birth defects research is spread among six branches, totaling approximately $57 million in Fiscal Year 1995. The majority of this work is funded by the Mental Retardation and Developmental Disabilities Branch and the Developmental Biology, Genetics and Teratology Branch. Research on infertility and fertility amounts to approximately $98 million annually and is spread among three branches. The primary effort in this area is led by the Reproductive Sciences Branch. Research on fetal loss is done in six branches, totaling approximately $3 million annually.

The Mental Retardation and Developmental Disabilities Branch supports research and research training concerned with the prevention and/or amelioration of mental retardation and related developmental disabilities. Its activities


include the full range of biomedical, behavioral, social, and family research concerned with the etiology, pathophysiology, diagnosis, epidemiology, treatment and assessment of mental retardation and related developmental disabilities.

The Developmental Biology, Genetics, and Teratology Branch develops and supports research and research training in the etiology of congenital malformations. The Branch also examines the genetic basis of development, gene transfer, and the development of the immune system.

Birth defects account for more than 20 percent of infant deaths, making them the leading cause of infant mortality in the United States. Even if they are not lethal, birth defects impact enormously on the physical and emotional health of affected children and their families. Basic research and innovative technology provide new avenues to knowledge needed for meaningful therapy and prevention. Genes that are developmentally important and relevant to human disease are now being identified and characterized through animal


models in combination with human studies. Ongoing research is defining how genetic networks regulate cell proliferation, cell differentiation, cell interactions and cell fate. The roles of environmental agents and nutritional factors are also being investigated. Basic genetic and

molecular studies have led to a number of important and exciting findings directed at understanding normal development and the underlying mechanisms associated with birth defects. These include the identification of genes causing several birth defects, such as those associated with skeletal malformations; and the application of gene therapy to successfully treat two children with severe combined immunodeficiency.

The etiology of most birth defects, such as club foot, has not been identified. Some teratologic manifestations have been attributed primarily to inherited or chromosomal abnormalities. However, the evidence indicates that environmental agents or factors play an etiologic role in birth defects. Furthermore, recent evidence suggests that


some environmental teratogens cause developmental malformations by acting directly or indirectly on the host genome to perturb genetic expression. In the past, teratology focused primarily on congenital gross morphologic malformations and their causes. Recently, tertology has been dramatically transformed and expanded to include more subtle developmental anomalies, such as fundamental, biochemical, molecular, genetic, and behavioral deficits or aberrations, and intrauterine growth retardation. Fortunately, rapid advances in developmental biology using animal models have provided the fundamental knowledge of normal developmental processes that are essential for understanding developmental abnormalities in humans.

The program supports studies to identify teratogens and understand teratogenic mechanisms that result in congenital defects. Suspected teratogenic agents or factors currently being studied include infectious agents, maternal metabolic imbalances, nutritional deficiencies, drugs, radiation and ultrasound. Information from


these studies will serve as the basis for developing therapeutic and prevention strategies.

The Reproductive Sciences Branch supports fundamental biomedical research and research training in reproductive biology and medicine relevant to problems of human fertility and infertility.

Infertility affects 2.4 million married couples in the U.S., and its health care cost exceed $1 billion annually. Male factor infertility represents perhaps as much as 40 percent of the reported infertility cases in the U.S. Little progress has been made with respect to accurately diagnosing, alleviating, or curing male infertility. The NICHD has recently funded four new clinical projects focused on male infertility.

Other investigators funded by the

Branch have found a genetic cause for a form of male infertility. A significant number of infertile men with an absence of sperm in the semen carry genetic mutations in a small, specific region of the DNA in the Y chromosome that controls the development of


sperm. The researchers found that even men who produce low amounts of sperm may have mutations in this chromosome. Because these genetic abnormalities are carried in sperm cells, men whose sperm is used to fertilize eggs via sperm injection could pass the mutant gene on to their sons. For this reason, men with impaired sperm production might be candidates for testing and genetic counseling before beginning assisted reproductive procedures.

Female factor infertility represents at least 50 percent of the incidence of infertility in the U.S. In certain cases, a normally ovulating female fails to conceive due to what is termed a "hostile" cervix, a circumstance where sperm transport is inadequate. Very little is known about the actual cell biology of the cervix. Recently, a young NICHD-sponsored investigator devised an in vitro cervical tissue culture system that will allow the laboratory study of human cervical cell functions. This model has great promise for discovering and elucidating the functional


differences underlying the "hostile" state of the cervix associated with infertility.

The NICHD Infertility Centers program utilizes a multidisciplinary approach to coordinate a number of projects studying disorders of ovulation which account for almost half of female infertility. One immediate result from the Infertility Centers

Program has been the development of a treatment for a specific type of infertility which is a common unwanted side-effect of surgical or radiation treatments for cranial tumors in women. A procedure has been devised for replacement of the key reproductive hormone suppressed by injury to the secreting brain cells in such patients. After this treatment, ovulation occurred in 78 of the patients, and all ovulatory patients who desired fertility became pregnant.

Uterine fibroids, also known as myomas, are a very common and distressing reproductive disorder. Affected women experience pain, dysfunctional uterine bleeding, and impaired fertility. Fibroids are a major medical indication


for hysterectomy. Although it is known that fibroids are estrogen-responsive benign tumors, little is known about what causes their initiation and growth. An NICHD investigator recently found that the genes that control two specific proteins are overactive in fibroids, and that this activity is most pronounced when estrogen levels are highest. An understanding of how estrogen acts to promote growth may reveal important knowledge leading to effective new therapies that avoid or reduce the need for surgery.

The Contraceptive and Reproductive Evaluation Branch funds a national research program focusing on the epidemiology of reproductive health, including studies of contraceptive and noncontraceptive gynecological products, medical

devices, and surgical procedures. In vitro fertilization (IVF) and other forms of assisted reproductive technologies (ART) have enabled many infertile women to become pregnant. More than 200 centers in the United States offer IVF as part of their infertility services.


Various risks have been identified, such as adverse effects of the drugs employed for ovarian stimulation, injury to the ovary and/or uterus during the retrieval or replacement phases, and the psychological impact and stress associated with this invasive and often protracted therapy. In 1988, the Branch established a five-year contract to maintain a registry of women undergoing ART. No unexpected short-term adverse effects were detected among the 3,632 participants.

While the number of women undergoing ART is growing rapidly, an even larger group uses fertility drugs without ART. In 1988, an estimated 1.9 million women aged 15 to 44 years reported having taken fertility drugs. Recent publications focused attention on the possible link between ovarian cancer and the of fertility drug clomiphene. The Branch has also initiated a contract to address this issue and to investigate other potential serious adverse effects of ovulation induction, such as breast cancer, endometrial cancer, and fetal malformations. Results are expected within five



The Demographic and Behavioral Sciences Branch supports a program of research on the processes that determine population size, growth, composition and distribution, and on the determinants and consequences of population processes. A major focus of the Branch's current program revolves around the implications of changes in U.S. family and fertility patterns for the well-being of children and families. The Branch is funding research to study factors that help or hinder the adjustment of infertile couples as they undergo extended treatment for infertility. The Branch also provides support to the National Center for Health Statistics for the National Survey of Family Growth.

A portion of the Institute's research is conducted on the NIH campus. For example, the Unit on Reproductive Medicine investigates the biochemical and physiologic mechanisms of the reproductive cycle and pregnancy, and the physiology of infertility in women. These include clinical


studies of the mechanisms underlying follicular and endometrial development, implantation, infertility, and recurrent miscarriages.

The Unite on Gynecologic

Endocrinology studies the physiology and pathophysiology of ovarian follicle development and function to develop clinical diagnostic and therapeutic interventions for women with ovulatory

disorders. The group has focused on premature ovarian failure, a condition which prematurely terminates fertility in one percent of women. The group has a particular interest in autoimmune-mediated ovarian failure, and seeks to improve understanding of this condition through clinical research and through basic immunologic research employing a mouse model of autoimmune ovarian failure.

The Pediatric Epidemiology Section conducts research on the epidemiology of birth defects. Section scientists described genetic abnormalities which explain why folic acid may prevent neural tube defects, NTDs, such as spina


bifida, anencephaly, and other serious brain and spinal cord disorders. This important advance raises the possibility of identifying women at high risk who would specifically benefit from folate supplementation before pregnancy. Earlier, the group found that women whose offspring had neural tube defects had significantly higher levels of homocysteine in their blood than women with normal offspring. An inability to eliminate homocysteine may be critical in the production of NTDs and folic acid is known to reduce homocysteine, thereby explaining its effectiveness in preventing NTDs.

Examples of NICHD research sponsored

in the Seattle area:

Two major, relevant research programs funded by NICHD are carried out here in Seattle, Washington. Research into treatment for infertility

is being conducted by Drs. William J. Bremner and colleagues at the University of Washington Population Research Center. The University of Washington, through the School of Medicine, has affiliation agreements with the Veterans Affairs


(VA) Medical Center. Dr. Bremner is Professor and Vice-Chairman of the Department of Medicine at the University of Washington; he is also Chief of the Medical Service at the VA Medical Center.

Research on birth defects is being pursued by Dr. Philip E. Mirkes, who is also at the University of Washington, in the Department of Pediatrics. And his colleague, Dr. Thomas Shepard, is here with us today. He is particularly interested in the genetic basis of birth defects. The importance of the research may be judged in the fact that 2 to 3 percent of all human newborns have clinically identifiable birth defects, defects that constitute the leading cause of infant mortality in the United States. Despite these statistics, information necessary to reduce the incidence of birth defects and related infant mortality is lacking. The studies of Dr. Mirkes are likely to contribute key information to the overall assault on the causes of birth defects.

In conclusion, I would like to thank the Presidential Advisory Committee on Gulf War


Veterans' Illnesses for the opportunity to present

the relevant portion of the research program of the National Institute of Child Health and Human Development. I would be happy to answer any questions.


MS. LASHOF: Thank you very much. Let me start the questioning, Dr.

Spirtas, by asking you about the work that you're doing in identifying reproductive hazards, toxic

chemicals, environmental hazards. How does the work you do at the National Institutes of Child and Human Development relate to the work of the National Institutes of Environmental Health Sciences and the National Toxicology Program? Is there any coordination?

MR. SPIRTAS: We have in the past had joint efforts. Dr. Richard Tosca was a consultant to NIEHS in putting together their endocrine disrupters RFA, and we have had other -- we also -we have other coordination with them. If an R01 -if a research grant comes to NIH that is in the area


of environmental exposure resulting in a birth defect, it would often get sent to NIHS with us as the dual, so that we would often have a -- have that kind of relationship.

MS. LASHOF: Would you jointly fund? Is that what you mean when you say that, or not?

MR. SPIRTAS: I don't know if we have

jointly funded projects, but I do know that -- I know that projects have come into my branch that

have been NIEHS as primary, and we've been dual. So we've been listed as the alternate agency. If NIEHS would choose not to fund, it would be possible for us to fund such a project.


MR. SPIRTAS: I don't know if we have jointly funded projects in the past.

MS. LASHOF: Have you taken on any research related to the possible environmental hazards from the Gulf War?

MR. SPIRTAS: Not that I know of. MS. LASHOF: Do you have a mechanism

for identifying and being proactive in requesting


studies around environmental toxic substances, or are you purely responding to R01 applications?

MR. SPIRTAS: There are a few mechanisms. I personally serve on one of the committees through the National Cancer Institute that advises the National Toxicology Program on chemicals to put forward for their carcinogenesis bioassay program, so that I do know -- I have a personal involvement in some committee work that is proactive. But I'm not sure that our Institute has been proactive on these specific exposures. I think NIEHS has been the lead agency on the exposure side, and we've been the lead agency on the treatment side.

Although, we would do studies where a known environmental toxicant was used in a model system, where lead, or some agent which had some known effects would be administered to animals to

elicit a certain mechanism in some kind of animal study. So there would be some studies that we funded, but it wouldn't be to discover the unknown effect of some chemical.


MS. LASHOF: Okay. Following along on that line a little bit further, are you involved in any of the epidemiologic studies of birth defects? And would you ordinarily be, or would that be CDC or NIEHS?

MR. SPIRTAS: Well, certainly. Well, Jim Mills did the neural tube defect work --


MR. SPIRTAS: -- with folate. We -and I'm trying to think about -- we would look at things like fertility drugs and birth defects. We would look at the exposures that were due to therapeutic agents or nutritional agents, but the NIEHS would be the lead agency on environmental agents.

MS. LASHOF: Okay. Thank you. Rolando?

MR. RIOS: Dr. Chandra, have there been any studies in other countries on whether or not there's been a change in infertility rates?

MS. CHANDRA: Yeah, I think there

have been, but overall the general population rate


has remained comparable in other industrialized

countries. I think in recent times there have been

some concerns about changes in sort of semen analysis, sperm counts. I'm sure you may be familiar with some of those. But they've been debated, still, to my knowledge. In countries -- I think Sweden has some studies, Norway had some studies. But their overall population rate of infertility has not changed, and it's in the ballpark of our figures in the U.S. of about 8 percent among married couples. They generally use a two-year timeframe, so they get slightly different figures for that reason.

MR. RIOS: And in the study here in the U.S., were there any differences in subcategories like socioeconomic, race?

MS. CHANDRA: Well, when you look at the measure that we call just straight infertility which, as I mentioned, was limited to married couples, you see no difference by race. You see a clear difference by age, as you would expect. It goes up with age. But you see no difference based


upon any socioeconomic status. Where the differences lie are in the service-seeking for it.

Our measure of impaired fecundity,

however, which is not limited to married women, and it also encompasses trouble carrying to term and not just trouble conceiving, there we do see -- in a couple of the analyses we've done, we've seen some differences by race. And those disappear when you can control in a multivariant way for risk factors such as pelvic inflammatory disease and so on. So

they are not differences -- true differences by race or socioeconomic group, but differences in the risk factors associated with them.

MS. LASHOF: Other questions? Kathi?

MS. HANNA: Dr. Chandra, you said when you began your description of your survey that you do it in civilian populations only. Is there any administrative or legal reason why you cannot survey military populations?

MS. CHANDRA: I believe there are both of those.


MS. HANNA: Both.

MS. CHANDRA: I'm not sure what -- I couldn't go into all of them. I'm not that familiar with it. But I think largely monetary. I mean, just the logistics of -- we have a big problem just tracing the people we have to trace, to get them to respond to our survey. And if we had to deal with tracking down people on bases, and so forth, that may need to be relocated, and so forth, it would be -- we just couldn't do it.

MS. HANNA: Are you aware of any existing surveys similar to yours in the military population? Is there any systematic type of survey?

MS. CHANDRA: Nothing that's

systematic. I think that there may be some smaller-scale things happening on -- and I'm not even familiar with those, particularly. But there are just some methodologic differences that would need to be considered for looking at that.

MS. HANNA: In terms of data collection.

MS. CHANDRA: In terms of data


collection, for sure, and in terms of our measurement. The kinds of questions that we're asking sort of presuppose that the two spouses or the couple live together, and our measurement would need to be different, perhaps, with the military population.

MS. HANNA: I just had one last question. Would you expect that there would be any differences between the civilian and a military population in terms of these data? Would the civilian population be a good case control for a military population if you were collecting the same data?

MS. CHANDRA: I don't know about that, but what I was about to suggest is that I think we would have sort of a healthy worker, healthy soldier situation to look at when you were designing studies for -- and I think that was on your agenda for tomorrow -- so you know, sort of looking at the reproductive health needs of specific populations.

But I think that in some respects you


could argue that you might see a lower prevalence of

some these. The military population may be younger

and healthier on the grand scale. Obviously, there

are exceptions, but those kinds of issues would need to be considered to generalize this methodology.

MS. HANNA: Thank you.

MS. LASHOF: Other questions? Joe? Marguerite?

Thank you very much, Dr. Chandra, Dr. Spirtas.

Let me ask our last panel for today to come forward. The last panel is discussing the evaluating rates of congenital anomalies in the children of Gulf War veterans.

Okay, thank you very much. Dr. Araneta, I think you're going to kick off the presentation, and then Dr. Olney, and Dr. Cowan.

And I gather Dr. Edmonds is going to

answer -- be available for answering questions today, but will be talking tomorrow. Is that correct?



MS. LASHOF: Very good. Okay.

Dr. Araneta.



MS. ARANETA: Good afternoon. My

name is --

MS. LASHOF: Sorry we're so late, but you can have until we adjourn.

MS. ARANETA: That's all right.

My name is Happy Maria Rosario

Araneta. I'm a perinatal epidemiologist at the Naval Health Research Center in San Diego, and I'm responsible for evaluating -- for conducting epidemiologic studies to evaluate the prevalence of birth defects among Gulf War veterans.

I'm going to describe two studies today. One is our measurement of the prevalence of major congenital anomalies in states which conduct active surveillance for birth defects, and the second is an ongoing investigation of Goldenhar syndrome among Gulf War veterans and non-deployed



The first study began in March. That's when the protocol was developed. We started data collection in October, so I'm going to describe the background objectives and methodology, and very limited preliminary results.

The other investigators from NHRC are listed, and Larry Edmonds of the Birth Defects and Genetic Diseases Branch of CDC has, and continues to provide guidance in study design, data collection, and analysis. And of course we'd like to acknowledge the participation of the seven states.

Previous studies have reported no

difference in the overall rates of birth defects in infants born to Gulf War and non-deployed veterans in military hospitals. Birth defect rates among infants born in an Army reserve unit in Mississippi and newborns in Army hospitals between 1992 and 1993 did not differ from those reported to the Metropolitan Atlanta Major Congenital Defects


These studies, however, have some


limitations. In some studies, birth defects were based on conditions recognized at the time of birth. Birth defects diagnosed after delivery were not included, but account for 30 to 40 percent of all major birth defects.

Secondly, infants of separated military personnel are not represented. At the end of September of 1993 approximately 44 percent of Gulf War veterans had left the military. Some of these studies were based on very small sample sizes because birth defects are a rare event, and comparisons with the Atlanta rates may not have been appropriate because of exposures unique to the military or to certain geographic locations.

Unlike most infectious diseases,

birth defects is not a reportable condition in the United States. Mandatory reporting of birth defects to the local or state health department is not required nationally. In the absence of a national active birth surveillance program, we proposed to measure the prevalence of birth defects among infants of military personnel in seven of the eight


states which conduct active surveillance for major congenital anomalies. These states are outlined in red. Active surveillance began recently in Texas; however, they do not have the data required of our

study. These seven states are geographically diverse, and account for approximately 18 percent of all births in the United States.

Active surveillance is population based, and is conducted for each child from birth through twelve months of age, thus enabling identification of approximately 95 percent of all major birth defects. Data are abstracted from a variety of sources including medical records at hospitals, cytogenetic clinics' chromosome laboratories. These active surveillance methods provide more complete ascertainment and accurate morphologic classification of birth defects than self-reports by parent, passive surveillance reports by physicians, or hospital discharge records.

The objective of the study is to determine if the prevalence and types of major birth defects among infants born to Gulf War veterans


between 1989 through 1993 differ from children of non-deployed veterans in these seven states. Other objectives include to compare the frequency and types of birth defects among infants of three populations, Gulf War veterans, non-deployed veterans, and non-military populations in these seven states. We will also be able to compare the prevalence of birth defects among active duty and separated veterans.

And the reason why we're interested in births as early as 1989 is to enable comparisons in the rates among pre-deployment and

post-deployment conceptions; secondly, to describe the pathologic patterns of major birth defects by subpopulation; and third, since conceptions with chromosomal defects often result in fetal demise, to compare rates of reported fetal deaths, and also to enable comparisons of pre-term deliveries and low birth weight.

In addition to enabling comparison of the prevalence rates, examination of patterns of birth defects coupled with information about


exposures in selected occupations or geographic locations during the war may be useful in developing hypotheses about genetically or environmentally induced defects for future investigations.

Registry matches will be performed

between data sets from the Department of Defense, the Defense Manpower Data Center in Monterey, and the DEARS data set, which has information about the spouses and the children. And these personal identifiers from the military data sets will be matched against the birth certificate records of these seven states to identify children of military personnel born in that five-year period in these seven states.

The same procedure will be applied for the fetal death records, and once children common to the military and the birth certificate records are identified, they will then be matched against the birth defect registries of these states.

Data on major congenital anomalies

are collected in all seven states. Minor anomalies

and syndromes are collected in some states, but not


others; therefore, the rates of syndromes and minor congenital anomalies will be calculated separately from the major birth defects.

Rates of major birth defects will be calculated as a live birth -- diagnosed with birth defects per thousand live births. Concordance rates will be calculated within twin pairs, recurrence rates will be evaluated among siblings, and univariant and multivariant analyses will be performed to compare overall and diagnostic-specific rates to identify covariants associated with these defects, and identify inner relations among selected anomalies in subpopulations.

Our sample size estimates identified that we need at least 1,100 live births to Gulf War veterans. Data from military hospitals in 1992 indicated that there are approximately 8,700 births to active duty and separated Gulf War veterans in these seven states, exceeding our minimum sample size criteria.

This table illustrates the proportion of the general population in the military in these


states. They range from a low of .02 in Iowa to a high of almost 4 percent in Hawaii.

In October 1995, we initiated a pilot study in Honolulu to test our ability to conduct electronic registry matches. And Hawaii was

selected for the following reasons. First of all, they have all the data we need. They only have 20,000 births a year, and are able to follow each child for a twelve-month period within a year and a half. California has 600,000 births per year, 30 times the size of Hawaii.

Okay. Very quickly, we matched identifiers with military data, obtained identifying information from their spouses and their children, made sure that we were able to distinguish biological parents from adoptive parents, matched them to the 100,000 births reported in Hawaii between '89 and '83, identified 17,000 births to military personnel, and we matched those to the Hawaii birth defect monitoring program, and so far have identified approximately 900 children with birth defects born to Gulf War and non-deployed



Another important feature about Hawaii is that although only 4 percent of Hawaii's population are active duty military personnel, 17 percent of the births occur among military personnel in Hawaii.

This study has several limitations. One is the issue of generalizability, particularly in states such as California and Georgia where active surveillance is restricted to selected counties and access to military hospitals is limited. We will be able to capture the births of separated veterans, however. Secondly, we cannot

infer causality since the linked data sets cannot identify etiologic factors associated with birth defects. Third, data are limited to births which are healthy enough to survive to term.

Approximately 22 to 50 percent of all

conceptions are spontaneously terminated, and of these, a third to two-thirds are chromosomally aberrant, and as such, may have a congenital anomaly. So the effect of Persian Gulf War exposure


on birth defects among fetal losses cannot be measured.

Induced abortions, including those which were terminated due to prenatal diagnosis of a malformation are not available through these data sets, and therefore not represented.

Confounders such as family history of birth defects and other recognized risk factors are not uniformly available from all states.

And finally, diagnostic bias may occur if case ascertainment differs geographically or temporally as populations' exposures and diagnostic instruments differ.

Would you like me to proceed to the Goldenhar investigation, or should I address questions at this time?


MS. LASHOF: Why don't we take questions on this first presentation, and then proceed to the Goldenhar?


MS. LASHOF: I understand you have to


leave early.


MS. LASHOF: And I'm sorry to have kept you so long, and I apologize for interrupting your vacation, as well.

So are there questions the panel has? I have one, Dr. Araneta. I didn't

catch how many birth defects you said you had found in Hawaii.

MS. ARANETA: Exactly 882 so far. MS. LASHOF: Among both --

MS. ARANETA: Among Gulf War and nondeployed.

MS. LASHOF: Okay. Have you made a calculation of how much greater the risk would have to be among Gulf Wars as compared to non-Gulf War for you to get a statistically significant result, if you were going to end up with a positive result, that is?

MS. ARANETA: Well, it would -- our sample size calculations were based on a two-fold risk, or an odds ratio of 2 among the children of


Gulf War veterans, with a power of 90 and an alpha of 5 percent. And we calculated at least 1,100 births to Gulf War veterans on an annual basis, so about 5 -- 5,500. And that's for overall rates. Certainly the sample sizes, as you start to look at specific birth defects, will have to be larger, and

we haven't -- we haven't accounted for that. Certainly the minimum sample size criteria we need is about an eighth of what we expect to get. Does that answer your question?

MS. LASHOF: Oh. Okay. Yeah. MS. ARANETA: Our sample size

calculations were determined based on calculating differences in the overall rates of birth defects among Gulf War and non-deployed veterans. It was not based on specific defects.

MS. LASHOF: Right.

MS. ARANETA: And as you deal with more infrequent occurrences, certainly your sample sizes have to be larger.

MS. LASHOF: Yeah. But you're satisfied the sample size is big enough so that you


would -- if there were a two-fold increase, you would be able to identify it overall?


MS. LASHOF: Okay. Thank you. No other questions? Then go ahead with your Goldenhar.


MS. ARANETA: Okay. On October 12th, 1985 the Office of Health Affairs of the Department of Defense instructed NHRC to identify cases of Goldenhar syndrome or oculoauriculovertebral spectrum among children of Persian Gulf War veterans. The investigation was precipitated by public concern and press reports about a possible excess of Goldenhar syndrome among infants born to

Gulf War veterans. On October 13th we requested assistance from CDC.

I'm going to describe the background and objectives. Dr. Richard Olney of the CDC will describe the etiology and clinical characteristics of Goldenhar syndrome, the methodology and criteria for case ascertainment, and preliminary results. And then I will return and report the preliminary


rates by parental Gulf War status.

As indicated previously, in the absence of a national birth defect registry, the prevalence rate of Goldenhar syndrome in the United States is not available. The rates are available in states which conduct active surveillance for major birth defects, some of which, however, do not collect data from military hospitals. The Department of Defense also does not maintain a birth defects registry in which affected children or a cluster of specific defects can be identified immediately.

Medical records for inpatient admissions in military hospitals are available for military personnel and their dependent, and were used for this hospital-based surveillance of Goldenhar syndrome. The objectives of this investigation are to ascertain cases of Goldenhar syndrome among infants born or admitted in military hospitals between September 1, 1991 through September 30th of 1993, and to measure the prevalence rates by parental Gulf War service.


Hospitalization data for infants born in DOD hospitals were provided by DMDC in Monterey, and this data set contains all hospital discharge diagnostic information reported by the International Classification of Disease for the ICD-9 codes.

Gulf War status was also obtained

from the service personnel records and recorded in DMDC databases. Data were limited to conceptions after the Gulf War and births through September of '93 since hospitalization data are presently available through that time.

The hospitalization database represents 86 percent of all Gulf War veterans, specifically 580,000 members of the Army, Navy, Marine Corps, and Air Force. Fourteen percent of the Gulf War veterans were members of the reserves of National Guard forces, and were not represented in our investigation.

A comparison group consisting of 700,000 active duty military personnel who were not deployed to the Gulf was randomly selected by DMDC, and they comprise a 50 percent sample of all 1.4


million non-deployed veterans.

Hospitalization data for all children with subsequent pediatric admissions are going to be obtained from the standardized inpatient data records at Fort Dietrich's data processing center. I'm going to -- we're going to discuss just the investigation concerning diagnoses among newborns.

Hospital discharge diagnostic codes were evaluated for over 75,000 infants born in all U.S. military hospitals in the United States, Europe, and Asia between September '91 through September '93. Medical records were reviewed for newborns diagnosed with specific defects which might be morphologically related to Goldenhar syndrome. Medical records were obtained from the hospital of birth or from the National Personnel Records Center in St. Louis, Missouri. And when indicated, they were also acquired from referral facilities including genetic clinics and civilian hospitals, with parental permission.

Medical records were requested from eighty-one DOD hospitals. Personal identifiers were


removed at NHRC and case ascertainment was made at CDC by two pediatricians. Records were reviewed independently, and the reviewers were blinded to the parental Gulf War status of each infant. Linkage information which enabled identification was kept in a locked file at NHRC.

At this time I'd like to introduce Dr. Richard Olney of the CDC, and I will return after his presentation.

MS. LASHOF: Dr. Olney.



MR. OLNEY: Good afternoon. I'm Richard Olney, and I'm a pediatrician and medical

epidemiologist at the Birth Defects and Genetic Diseases Branch at CDC. And I'd like to thank the Committee for inviting us at CDC to testify about the design of this collaborative study.

We know that many veterans and active duty soldiers and their families have had questions about their pregnancies following the Gulf War, and


we appreciate the opportunity to use our experience in the science of genetics and birth defects epidemiology to help answer these questions.

As Dr. Araneta mentioned, in 1995 the Naval Health Research Center asked us to identify records of infants with a congenital condition known as Goldenhar syndrome. I participated in this study along with Mr. Larry Edmonds, who is sitting here, and Dr. Cynthia Moore, a board-certified clinical geneticist, pediatrician, and dysmorphologist, also at the CDC.

The objective of this study, as Dr. Araneta mentioned, was to classify the records of the 75,414 infants born to active duty personnel from September 1991 through September 1993. The CDC role was to define criteria for computer searches of newborn records by the Defense Manpower Data Center, and to determine whether written medical records of selected newborns supported a diagnosis of Goldenhar syndrome. Dr. Moore made the final decisions about case classification, but she is unfortunately unable to attend today.


In our review, we identified eight infants with Goldenhar syndrome. This testimony describes the methods we used to identify those eight infants.

Goldenhar syndrome is a disorder characterized by abnormal prenatal development of facial structures derived from a part of the embryo called the branchial arches. Although the cause of Goldenhar is usually unknown, chromosomal and other genetic conditions have occasionally been implicated, and specific maternal conditions or exposures such as diabetes and certain acne drugs can produce similar features.

We were aware from our experience in the medical literature that Goldenhar syndrome is included under a broader diagnostic category known as the oculoauriculovertebral spectrum, or OAV. Although the term "OAV" is more precise, and describes the type of conditions we were searching for, I'll be using the term "Goldenhar" since that's been more widely discussed.

Using a long list of congenital


anomalies or conditions that could potentially be used to describe infants with Goldenhar, we selected medical records with any mention of these conditions in order to find all infants who could possibly fit our case definition. We have outlined the details of this process in a flowchart provided as an appendix to my written testimony.

The selection criteria were designed

so that as many relevant records as possible would be retrieved from the more than 75,000 computerized newborn records from the data center. As Dr. Araneta mentioned, we were unaware of the Gulf War deployment status of the parents of the children whose records we were considering, and names and other personal identifiers were removed from the records. In other words, we performed a blind objective classification of infants in respect to whether they were born with Goldenhar.

There's no single blood test, X-ray, or other form of diagnostic testing currently available for Goldenhar syndrome. Diagnosis is made when clinicians identify particular combinations of


physical features and internal abnormalities. There are also no universally agreed-upon minimal diagnostic criteria in either research or clinical settings for Goldenhar or OAV, but most experts consider a necessary feature to be an ear anomaly such as a missing earlobe or skin tags in front of the ear. Other supporting components commonly discussed in the Goldenhar literature include asymmetry or hypoplasia of the face or jaw, and specific anomalies of the eye, vertebrae, mouth, or palate.

After discussion among our group and with other practicing dysmorphologists and experts, we set two minimal criteria for our Goldenhar classification. The first was the presence of a specific ear anomaly. The second was the presence

of either asymmetry or hypoplasia of the face or jaw, or one of a limited number of physical features rarely seen with without Goldenhar such as specific anomalies of the eyes or eyelids.

The discharge diagnoses were the key items we used to select records for review.


Diagnoses from newborn records are computerized with a standard coding system, ICD-9 CM. Identifying cases of Goldenhar syndrome from ICD-9 CM codes in newborn records is complex for multiple reasons.

One of the most important problems is

that newborn physical exams were usually done with a checklist, and often had limited descriptive information. Abnormalities identified in newborns' first physical exams were not described uniformly by different health care providers, and even when described, were sometimes not subsequently listed as discharge diagnoses.

Another problem in classification is that although Goldenhar is listed in the ICD-9 CM code books, the code assigned to it is not unique and includes many other common conditions. In addition, even when the diagnosis was made at the birth hospital and was written in the newborn record, it may not have been listed as a discharge diagnosis.

Another obvious limitation of our approach is that we had to rely on correct and


specific coding at the hospital level.

The last potential limitation is that the facial features of Goldenhar evolve over time. An infant's jaw may not appear asymmetric in the newborn period, but this feature may be more obvious by the first birthday, and we did not examine the newborns personally, review postnatal records, or follow these infants over time as a clinician would.

To address these limitations, we cast

a wide net to identify infants with anomalies compatible with our case definition that may or may not have been diagnosed with Goldenhar at the birth hospital. We used a list of all overlapping ICD-9 CM codes that could possibly relate to the specific components of Goldenhar and selected records with these codes for more in-depth review.

The approach of searching for multiple codes should have minimized the possibility of missing cases. For example, if an ear anomaly was miscoded or not coded at all, we could still capture the records of a child with Goldenhar with our search for the associated eye or jaw



Although this method could theoretically miss some children with Goldenhar syndrome, particularly those with less severe presentations, we would expect that these limitations would have applied equally to the children of Gulf War veterans and to the children of other military personnel born before 1994. The limitations should therefore not bias estimates of

the relative frequency of infants with Goldenhar born to parents with or without a history of Gulf War deployment.

Searching the ICD-9 codes, we identified 396 birth records with discharge diagnoses potentially related to Goldenhar syndrome. At this point we've reviewed 393 of these 396 written medical records, individually and in depth, and we found eight infants whose records listed conditions meeting our criteria for Goldenhar syndrome. The Naval Health Research Center is still attempting to obtain the three records that we have not yet reviewed.


The medical records of all eight infants listed some type of major ear anomaly, and specific jaw or eye anomalies. Seven of the eight infants were examined by clinical geneticists, who confirmed the diagnoses. The Naval Health Research Center is investigating pediatric records for the child with no mention of genetic evaluation.

No known environmental or genetic causes for these conditions were mentioned, although the record of one child indicated a chromosome abnormality that was not yet fully characterized in the record. The relationship of this chromosome abnormality to Goldenhar for this child is unclear.

As I mentioned at the outset, we were

unaware of the Gulf War status of the parents of these children, and we provided the Naval Health Research Center a list of code numbers for these


We also identified four infants that had single or multiple anomalies that have been associated with Goldenhar, but were not specific enough to meet our Goldenhar case definition. We


recommended to the Naval Health Research Center that they not include these potential cases in calculations of Goldenhar rates in the two groups, because the infants may not have Goldenhar syndrome. Follow-up information is also needed for these children.

We intend to continue to work with the Naval Health Research Center on these questions.

And I'll turn it back over to Dr.

Araneta, who will discuss their analysis of the rate data for these infants.


MS. ARANETA: Before I proceed with the rate data, I'd like to add to some of the limitations Dr. Olney identified, and emphasize again that the data presented today is limited to newborns who were born in military hospitals only. We have not begun to review medical records for children who were not born in military hospitals, but subsequently admitted in the OD hospital. We also have not looked at pediatric admissions for children who were born in military hospitals, but


whose defects evolved over time and were recognized

and diagnosed after delivery.

The data does not include births to active-duty personnel in CHAMPUS facilities, and such births consist of approximately 38 percent of all births to active-duty personnel. Also, infants born to separated personnel are not included, so it is in unclear if the preliminary prevalence rates measured in our investigation are generalizable to infants born in civilian hospitals. Okay.

I'd like to first of all present the prevalence rates of Goldenhar syndrome in three states with birth defect monitoring programs. In a small state such as Hawaii, based on approximately 150,000 births, the rate of Gold- -- there were six cases of Goldenhar syndrome in a six-year period. And the prevalence rate ranged from 4.1 per 100,000 live births, but the 95 percent confidence intervals were high, and they ranged from 1.6 -- from 1.6 to 9.3 percent in Hawaii. This means that there is a 95 percent chance that the true rate will be contained within these limits.


When you compare it to a large population like California, which had about 1.8 million births and 146 cases of Goldenhar syndrome between 1987 and 1992, the confidence intervals are narrow. The rates are 8.3 per 100,000, but the confidence intervals range from 7 to 9.7 percent.

So when reporting and interpreting

the prevalence rates of a rare condition such as Goldenhar syndrome, the confidence intervals around the rate must be considered.

CDC provided the study numbers of the eight infants which fulfilled the case guide criteria. Of the eight cases identified, five were infants of Gulf War veterans, and three to nondeployed veterans. And during this two-year period there were 34,000 live births to Gulf War veterans, 41,000 to non-deployed veterans, and the Gulf War status was not available on the DMDC data set for 127.

The prevalence rates were calculated by dividing the number of Goldenhar cases by the number of live births and multiplying that by


100,000. So the preliminary rate of Goldenhar syndrome among Gulf War veterans is 14.7 per 100,000 births. And the confidence intervals range from 5.4 to 36.4, so that the true rate lies between 5.4 to 36.4. In non-deployed veterans the preliminary rate is 7.3 per 100,000, and the confidence intervals range from 1.8 to 23.2.

When you compare the confidence intervals of the military data to the state data, you'll see that the confidence intervals are wider among both military cohorts, and are likely a consequence of fewer births sampled. This group had five cases of Goldenhar syndrome. Hawaii had six, but Hawaii had five times the number of births. And that's why you see the narrow -- narrower confidence intervals.

And what does that mean? It means that a rate like California's or Georgia's will

probably be sufficiently precise. However, these rates are likely to fluctuate with the inclusion of one or two cases, and as we continue, as we extend surveillance to other populations.


A test of association was performed to determine if these preliminary rates differed in a statistically significant manner by parental Gulf War status. And statistical significance was defined as p-values less than .05 and an odds ratio with 95 percent confidence intervals, which excluded one.

High score analysis was unable to detect a statistical significant difference in the rates of Goldenhar syndrome. The p-value was greater than .05. And the inability to detect a difference in the rates among both groups was due to insufficient power. "Power" is defined at the probability to effect -- to detect a statistically significant association of a particular magnitude. And it's a common limitation in epidemiologic studies of rare disease. Low power is often a consequence of few affected cases, small denominators, or small live births in this case, and a low odds ratio between the exposed and the unexposed cohorts.

Ideally, a power of about 80 percent


is preferred to detect meaningful rate differences

between populations. If the -- if there is -- to

detect a twofold risk of Goldenhar syndrome among the Gulf War non-deployed groups with a power of 80 percent at an alpha level of .05, and assuming that the rate in the non-deployed group remains stable at 7.3 per 100,000, this is an example of the calculation.

You just asked, Dr. Lashof, earlier, what would our -- are our sample sizes sufficient for selected birth defects. And in this case, with such a rare condition, it is not. We would need 281,000 births to Gulf War veterans alone. We had 34,000 births to Gulf War veterans in a two-year period, and we would need eight times that size, or about sixteen years' worth of live-birth data to Gulf War veterans, if the number of births remained constant.


MS. LASHOF: Can I be very difficult and ask why you did this study, knowing that this was the kind of size sample you would need?


MS. ARANETA: We did not --

MS. LASHOF: You would know that in advance, wouldn't you, just from what we know about Goldenhar, the incidence?

MS. ARANETA: We were not sure what the prevalence rate was, because there is no national rate. Some studies in genetic textbooks reported a prevalence of one per 3,000 to one per 5,000 births. Other states, like Georgia, reported one in 25,000. We also did not know the -- whether it was going to be a twofold risk or a threefold

risk. Certainly if the odds ratio changes, the power and the sample size requirements will also change. The power will increase and the -

MS. LASHOF: Yeah; if you were

looking for more than twofold risk --


MS. LASHOF: -- you would be able to do that. And so you really needed to define at the beginning what-fold risk you were going to be hunting for. And you did have some better figures, I think, as you showed from California, that there


were enough births and enough cases of Goldenhar to have a fairly narrow confidence limit. And the confidence limit for the others are so far -- so wide as to not be really helpful.

At this point, I gather, you're not going to be able to go any further with the Goldenhar. This is about where you are now.

MS. ARANETA: What we're going to do is, we're going to follow up on the one case Dr. Olney mentioned wherein there was no documentation of a genetic evaluation. There are also the four potential cases he identified, and the three records which are missing.

MS. LASHOF: Are these records enough that it will make a difference? If you pursue all of that, will it really give you enough to have a better confidence level?

MS. ARANETA: I think it would depend on the case status of the -- it may not narrow the

confidence intervals around the rate substantially. But if these -- these four missing records turn out to be cases, or half of them turn out to be cases,


what it will change is the odds ratio and our power estimates. But it will not change the confidence intervals substantially around the rates. Only -

MS. LASHOF: So you still will have

grave difficulty drawing any solid conclusion from this.

MS. ARANETA: Yes. The goal was to calculate a prevalence rate, with no background or no base line rate of Goldenhar syndrome in a military population, and guessing that it ranged from one in 3,000, as reported in the literature, to as high as one per 25,000.

MS. LASHOF: Okay. Thank you. Other questions? Mark?

MR. BROWN: Yeah. Did -- the confidence limits for the odds ratio is reported at 2.02 or something. It looked like the confidence limits for the odds ratio went as high as 10.8 or something. I forget. Just to help me understand what that means, does that mean that you can't say that the -- at 10.6, that you can't -- that the odds ratio could be -- there's a 95 percent possibility


-- that within the 95 percent confidence limits, that the odds ratio could be nearly 11?

MS. ARANETA: Right; that the risk of

having Goldenhar syndrome in the Gulf War in the non-deployed veterans is not a twofold risk, but can range anywhere.

MR. BROWN: Yeah. And the other question I have is, when you showed all those confidence limits for different state registries and the --


MR. BROWN: There you go. It looks to me, if you did some kind of appropriate test analysis, a variance or something, you'd find that really none of those are distinguishable. Is that -- is that a fair statement, do you think, or -

MS. ARANETA: Do you mean from each

other or --

MR. BROWN: From each other, yeah. MS. ARANETA: I don't know. I

haven't attempted that.

MS. LASHOF: Sorry; what was your


question again?

MR. BROWN: That if you did some type of analysis of variance or some appropriate statistical test, that what you'd find is, none of those means are statistically distinguishable, was my question, that they all could come from the same population.

MS. ARANETA: I haven't calculated it, but I'll be glad to.

MS. LASHOF: Well, clearly -- I mean, I think this is a chart that clearly shows you, of course, that the larger the number of the births you

have, the narrower your range is, and you have a pretty good confidence limit. And California is a very --

MR. BROWN: Well, it seems like it would be --

MS. LASHOF: That's it. And if we added them all up, threw them all together, you ought to come up with that.

MR. BROWN: Yes. That was my impression. I think if you checked that they


weren't distinguishable statistically, that that would bolster that conclusion, it seems to me.

MS. LASHOF: Okay. More questions? MS. ARANETA: I think what

complicates that comparison is that there seems to be no agreement in the minimal criteria used to diagnose Goldenhar syndrome. The rates that we used in our investigation were identical to those reported by Georgia. And it is not clear to me, at least, how the criteria differed for Hawaii and California.

In closing, I'd also like to mention that the Department of Defense is considering several options. One is the possibility of establishing a DOD birth defects registry so that we will be able to easily identify affected children and clusters of birth defects.

And the other is, we also considered -- considering continued surveillance for other cohorts, including the postnatal admissions in

military hospitals, since we have easy access to

those records.


MS. LASHOF: And one other question, and then we really should let you go.

The -- what do we know about the difference between the veterans who are still on active duty and those who have been discharged?

MS. ARANETA: Differences in -- in

terms of --

MS. LASHOF: Their health, their age, any of the factors that might influence any of this data.

MS. ARANETA: I'm not familiar with that. Do you have that?

MR. COWAN: We know very little. MS. LASHOF: We know very little

about who elects to stay in and who elects to be discharged. Okay.


MS. HANNA: One quick question. In the -- in the medical record, you're just using the ICD codes. Is that correct? And then -- do you have any data whatsoever on pregnancy history or -

MR. OLNEY: We used the ICD-9 codes


to select records to review. Within the medical records there was some information about pregnancy history, although it tends to be limited in newborn physical exams.

MS. HANNA: Yeah. And so you don't have very extensive data on the history of that particular pregnancy, in terms of --

MR. OLNEY: No, usually not, unless there was something remarkable that happened to be mentioned.

MS. HANNA: And it was in the record. MR. OLNEY: It wasn't -- it wasn't

done systematically. In other words, the family histories weren't taken systematically, and specific questions about exposures were not listed in those records.

MS. ARANETA: It was just the live birth record, and it did not include prenatal -prenatal care.

Also, this group is a very mobile population, and may have gone to several facilities for prenatal care and prenatal screening for


possible congenital anomalies.

MS. LASHOF: Thank you very much. Dr. Cowan?



MR. COWAN: Yes, ma'am. If someone

here could handle the overheads -- Mr. Edmonds can. Thank you very much. I appreciate

the opportunity to address the panel again. My name is David Cowan. I'm a research epidemiologist employed by SRA Technologies of Falls Church, Virginia. I've been consulting with the Naval

Health Research Center for nearly two years now, and continue to work with them, and I'm also working with the Deployment Surveillance Team in Falls Church, Virginia.

At a previous meeting of the PAC held in San Francisco last year, I presented preliminary data from my analyses of birth defects among military personnel. Since then we have had an additional year of birth data, bringing the total


number of live births studied to over 75,000. Furthermore, working with scientists from the CDC, most notably Mr. Edmonds, we have conducted additional analyses based on different definitions of "birth defects." The data I'm presenting today have not been presented elsewhere, and analyses are not yet complete.

Next. Thank you. The concept of this study is that we are conducting a historical cohort study of all Gulf War veterans, approximately 579,000, and a random sample of 700,000 service members who did not serve in the war. We are identifying all live births to both groups which occurred in military hospitals. We have examined inpatient data records to identify those which had a birth defect coded. We are attempting to determine if there is a generalized increase in risk of birth defects among Gulf War veterans, compared to nonveterans. And we're not attempting to evaluate the risk of specific birth defects. In addition, we're not attempting to assess specific exposures which

may have occurred in theater; rather, we're merely


comparing the experiences of those who were deployed to those who were not deployed.

Next. I'll be presenting analyses which consider two definitions of "birth defects." The first is a sensitive coding which included all ICD-9 codes for congenital anomalies, 740 to 759, plus neoplasms and hereditary diseases. I want to point out that this is a very sensitive coding which captures everything, and it's likely to have a high proportion of false positives included.

We then conducted specific analyses on specific coding, of forty-seven codes identified by the Centers for Disease Control, as being of sufficient severity and frequency to be considered as a public health concern.

Next. We don't need to dwell on these, but these are the specific codes provided to me by the Centers for Disease Control.

Go to the next one, please, and the next one. These have been provided to the panel in hard copy.

We have now identified over 62,000


live births born to male service members and over 12,000 live births identified for women service members. These represent over 60 percent of all live births to active-duty service members during this period.

Next. May I have the pointer, please?

This slide presents the risk of birth defect among the male service members. The dark bars are for the very sensitive indicators, and the light bars are for the specific indicators. I'd like to note that comparing Gulf War vets to the non-deployed men, there is no difference between the risk of the sensitive birth defects, the sensitive measure. And when we look at the more specific categorization, the rates are also very similar. There are -- excuse me; back up. There are no statistically significant differences between these two comparisons.

Next. This slide presents the findings for the female service members, children of female service members. There is approximately a 13


percent increase in risk for birth defects, using the very sensitive measure, among children born to women. This is a statistically significant difference, marginally so, with the lower confidence bound being 1.01. When we consider the more specific indicator of birth defects, there are no differences between these two groups.

Next. We then went into logistic regression modeling to estimate relative risk of birth defects for Gulf War veterans to non-veterans. Now, we found that the sensitive definition was confounded -- that is, mixed up by other factors such as branch of service, rank of the sponsor, race/ethnicity of the sponsor, and the age of the

mother. In our initial analyses, it looks as though the specific definition does not appear to be confounded. But I want to point out that the analyses are not yet complete.

Now, an odds ratio estimate the risk of birth defects among Gulf War veterans to nondeployed veterans, and that's an estimate of the relative risk. An odds ratio or relative risk of


1.0 indicates no association between Gulf War service and risk of birth defects. If the 95 percent confidence interval includes the value of 1.0, then the odds ratio is not significantly -statistically significantly elevated. An adjusted odds ratio takes into account factors which may confound the association.

Next. When we consider the sensitive definition and the calculated adjusted odds ratios, for the male Gulf War veterans the odds ratio is 0.97, with a confidence level interval of .91 to 1.03, indicating no association between Gulf War service and risk of birth defects.

For the female Gulf war veterans, the odds ratio is 1.07, indicating approximately a 7

percent increase in risk. But note that the confidence interval is well over the value of 1.0, indicating that this is not a statistically significant increase in risk -- that is, we cannot differentiate it, between it and it being no risk at all. These models included the race/ethnicity of the sponsor, maternal age, the branch of service,


and rank of the sponsor.

Next, please. Oh, back up again, please.

I want to point out that we found no association for the sensitive measure with duration of service in the theater of operations. That is, the risk did not increase with increased time in service. And also, there was no change in the risk by -- with the interval between return from the theater and the estimated date of conception. That is, the risk did not change for those born closer -those conceived closer to when the mother or the father returned from the theater, as opposed to those who were conceived a year or more afterwards.

Next. When we considered the

specific definition -- and this is univariate analysis; we've not yet conducted multivariate analysis -- we find a relative risk of 1.03 for the males, a confidence interval of 0.92 to 1.15, and for the female veterans, 0.92; 0.71 to 1.20. Again, no significant association between Gulf War service and these very specific definitions of "birth



Next, please. From our study, we found that for both a sensitive definition and a more restrictive definition of "birth defects," we found no significant associations between Gulf War service and the overall risk of birth defects for

children of men or women in our cohorts.

The data are not shown, but we found no significant dose-response relationship between duration of Gulf War service and the overall risk of birth defects, for the sensitive definition, for children of women or men in our cohorts; furthermore, no difference in risk for conceptions, regardless of the interval between return from theater and conception.

Next, please. There are important limitations which we acknowledge. Our data included only live-born children of active-duty members born in military hospitals. It includes only the ICD-9 information from the birth hospitalization. We have no information about birth defects which may have been diagnosed after the initial hospitalization.


There may be limited generalizability beyond the comparison groups, and comparison with civilian data may not be appropriate. However, I am now less concerned that this is a problem since I've been working with Mr. Edmonds, and he has done some analyses of civilian data using our definitions, and we find that they are indeed quite comparable. He can speak on that much more than I can. And we also acknowledge that our study will not detect rare occurrences of specific birth defects. However -

Next, please. Our study also has

important strengths which I'd like to acknowledge, and that is that we include data from over 75,000 births. It includes both paternal and material exposure groups. Births occurring shortly after the

war were evaluated. Multivariate analyses controlled for potential confounding variables, at least in the sensitive definition. Although the data were not shown, attrition were similar in deployed and non-deployed cohorts. And very important, the same source of data for deployed and non-cohort -- non-deployed cohorts was used for


outcome information.

That concludes my presentation. Thank you very much.


MS. LASHOF: Questions?

Again help me with my statistics. How big a difference between Gulf War deployed and non-deployed would there have to have been for you to be able to find it, and with the 75,000 births?

MR. COWAN: Using the sensitive

definition, we could detect approximately a 12 percent difference. I haven't calculated for using the specific definitions, but it would be -- it would not be as powerful, because they're substantially rarer.

MS. HANNA: Yes. The overhead that you put up of the risk of birth defects among female service members where, when you used the sensitive definition you had the difference, and then when you used the other definition, it dropped -- could you speculate on what might have dropped out when you used the less sensitive definition? Because you


also tied it to the confounders. Can you give an example of one or two ICDs that dropped out when you went to the less sensitive definition?

MR. COWAN: I can't give you specific information. But for example, skin tags and polydactyly are associated with race and ethnicity. Indeed, we found that race was a very important predictor of the sensitive definition; therefore, it was confounded by race, as race was also associated with Gulf War service. However, race was not a predictor of the more specific definition. So -excuse me -- so we are losing many of these minor defects that are associated, for example, with race and ethnicity.

MS. HANNA: Thanks.


MR. CASSELLS: Just one clarification -- you mentioned attrition was similar in both groups. I assume that "attrition" means the drop from sensitive to specific was the same in both groups, approximately.

MR. COWAN: Oh, I'm sorry. The -- by


"attrition" I'm meaning loss from service, losing -losing follow-up of the sponsors as they left active duty. The rate of attrition at two times periods, September 30, 1992 and September 30, 1993, was very similar for Gulf War veterans and for the nondeployed service members. I'm sorry I wasn't clear on that.

MS. LASHOF: Any other questions? If not, thank you very much. Thank

you for your patience. I apologize for our running late, but appreciate all your time and effort.

We're adjourned. We'll recess for

the day, and we resume at -- we're resuming at 8:30 tomorrow morning.

(Whereupon, at 5:15 p.m. the meeting was adjourned.)



We hereby certify that this is the transcript of the meeting of the



held on Monday, June 17, 1996 in Seattle, Washington, and that this is a full and correct transcription of the proceedings.

Karl Fuss, Reporter

William Wagner, Transcriber