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DoD News Briefing - Bacon; Rostker; Bailey, and Golomb

Presenters: Mr. Kenneth H. Bacon, ASD PA
October 19, 1999 1:30 PM EDT

(Also participating in this briefing was Under Secretary of the Army Bernard Rostker, Assistant Secretary of Defense for Health Affairs Dr. Sue Bailey, and RAND researcher Dr. Beatrice Golomb)

MR. BACON: Good afternoon. I'm merely the lead-off act to the main attraction, which is the briefing on pyridostigmine bromide. But I'll take your questions on other issues until 2:00, when we'll have Dr. Rostker and others come on, or they can come on earlier if you want.

Charlie.

QKen, I know there's a full hearing going on on the Hill on Vieques, but where exactly does the situation stand now? I mean, what -- is the president going to make a final decision on this? Is the SECDEF going to make a recommendation to him? Has he passed along this recommendation of the commission? Where does it stand?

MR. BACON: It stands here in the secretary's office. He has not passed on the report to the president yet. He has said that he wants to try to get the sides together to talk about some of the issues raised in the report. He wants some dialogue among the representatives of Vieques, the government of Puerto Rico, and the Navy to address some of the issues raised in the report. And he has asked Rudy DeLeon, the Undersecretary for Personnel and Management, to sort of supervise the dialogue process that he hopes will lead to some resolution.

QWell, the governor testified today before the committee this is absolutely non-negotiable, that --

MR. BACON: I understand what the governor said. And the governor has testified before the commission, before the Rush panel, and I think his views have been quite clear on this. But the report does lay out a series of recommendations. And the secretary would like to try to get the sides together to discuss those recommendations and see if they can agree on a course of action. So that's the next step. And as you know, the secretary is in the Middle East now. When he gets back he'll look at the process and see where it stands. But the goal here is to try to achieve some resolution that recognizes the concerns and the needs of each side and tries to balance them out.

As you know, the report makes a fairly dramatic recommendation; and that is that the Navy prepare to stop training, live-fire training, on Vieques at the end of five years, and find alternatives. In the meantime, it would require a significant reduction in live-fire training on the island and some other protections for the people of the island. And it would also require the Navy to take certain other steps to deal with economic and environmental and other concerns.

But clearly, this is a problem that has not been resolved yet. It's an issue that demands continuing work. And the secretary's hope is that that work will be able to proceed.

QTwo more questions on the same issue:

One, has he had a chance to read the report?

And two, even though one would assume he has been briefed as the report went along, was he surprised at the recommendation to continue on for five years?

MR. BACON: I don't think he was surprised by the recommendation. He has been kept apprised of the process from beginning to end. I suspect he has read the report. It's 15 pages long, doesn't take long to read. But I don't know that for a fact. But he certainly was aware of the recommendations in the report, and certainly he has followed the process from the beginning.

Yes, Chris?

QFirst Lady Hillary Rodham Clinton yesterday called for an immediate and permanent withdrawal of U.S. troops from Vieques and said that she was disappointed in the Pentagon's view of "five years and out." Does the Pentagon have any view of the first lady's statements on the situation there?

MR. BACON: She also said that she understood the need to maintain military readiness.

QDo you have any concern with this process being politicized and the first lady being involved in this?

MR. BACON: Well, this clearly is -- no process like this can happen outside the realm of politics, and I think we all understand that. That's one of the reasons it's such a delicate and emotion-charged process.

QGiven the first lady's statements, are you concerned at all at how the report will be received by the president?

MR. BACON: No. I think the president will receive the report with an open mind, and I am not concerned.

QA substantial Puerto Rican voting bloc in New York, and the first lady's bid for office there, could affect the outcome though, could it not?

MR. BACON: Well, I'm not aware that the first lady has been elected to make a decision on this question. Right now the question has to be resolved by the secretary of Defense and by the president of the United States. And obviously, people have very strong views on this issue, and we saw a lot of those views expressed today on the Hill. And I'm sure that people will continue to express views. But right now there's a very clear decision chain as to who has to make the decision. But the timing of that is somewhat in doubt, and the reason is that Secretary Cohen hopes that the sides will be able to get together and discuss next steps following the report. So far that hasn't happened. There's only been a day since the report was released, 23 hours, to be exact, and some of that time has been taken up with testimony on the Hill.

QHow long is the secretary willing to wait for something to actually resume training there, given that there's been this long moratorium already? Isn't there some time at which it's too --

MR. BACON: Well, if you paid attention to the testimony on the Hill today, there is a deadline approaching, which is the -- around December 1st, when the Eisenhower Battle Group has to qualify to go on their next deployment. And Secretary Danzig was very clear that he hoped that in the next five or six weeks, the sides can get together and try to deal with some of these issues prior to the deployment of the Eisenhower Battle Group.

Anything else?

Okay, why don't we see if the other crew is ready. I might have to RIF your brief here or let you rush out and file on Vieques.

(Pause.)

MR. BACON: Okay. They will be in very shortly.

KEN BACON (Department spokesman): You all know Dr. Bernard Rostker, who is the special assistant for Gulf War illness. He's going to get up and make some introductory remarks about the latest of the studies that his office has been conducting looking into the possible causes or alleged causes of Gulf War illness and our continuing effort to get to the bottom of why some veterans of the Gulf are experiencing health problems. He will then introduce a larger crew of people to testify, and we will take as long as you need to answer your questions. This is a very important but complex study, and we will try to work through the questions as methodically as possible.

Dr. Rostker?

DR. ROSTKER: Thank you, Ken. It's a pleasure to be here today. This is a continuing discussion, a continuing series that we've had with you all concerning the department's activities in trying to understand the nature and causes of Gulf War illnesses among our veterans.

Today we're going to talk about a Rand report which is being released. This is one of five reports that to date the Rand Corporation has done for my office. The most important of those reports focused on stress, on oil well fires, on depleted uranium, and now on pyridostigmine bromide.

This is an important paper and somewhat unique, because for the first time, Rand did not reach a conclusion that the issue under study was not likely a cause of Gulf War illness. In this report they have reached the conclusion that they just don't know. They can't reject the hypothesis that exposure to taking PB may have caused chronic effects. They can't accept that conclusion either in the sense that there's just not enough information. You'll often find in scientific papers sort of the obligatory "more research is required." This is one where it's not the obligatory more research is required, but in fact we just don't know.

The paper that will be released today -- we'll ask the author to discuss that paper with you. First I'll introduce Ross Anthony, who is the project coordinator for Rand, and then he will introduce Dr. Beatrice Golomb, who is the primary author of that paper, and she'll go over those findings. She'll be prepared to take any questions you have.

Dr. Sue Bailey, who is the assistant secretary for Health Affairs, is also here and will be happy to take any questions that you also have in terms of DOD policy and the long-term effects. Now with that, I would ask Dr. Anthony to join me here and to do the introductions.

DR. ANTHONY: It's a pleasure to be here today and to release this report for you today. Just let me take a second and put this into context. When Dr. Rostker began his work as the special assistant for Gulf War illnesses, he quickly decided there was at least two pieces of information that he needed to be certain that he left no stone unturned as he sought to get to the bottom of the Gulf War illnesses. One, of course, is what happened in the Gulf and his office has spent a lot of time and effort investigating that from multiple perspectives.

A second piece of information which is important is to know what medical science says about a specific issue, if it's more important or less important depending on the particular cause we happen to be looking at. And that's what this paper does. It looks at the medical science as it deals with pyridostigmine bromide and, as Dr. Rostger told you, in this case we are not able to rule that out.

And I want to caution you that to not be able to reject a hypothesis does not necessarily mean accepting it, so as you think through these issues -- and this is a complicated subject matter -- I hope that you will keep that in mind as you think about what we have to say here today.

I am pleased to introduce to you Dr. Beatrice Golomb, who is the primary author. She is a physician. She also has a Ph.D. in biology, specializing in neurobiology. She is a RAND consultant and also a staff physician at the San Diego VA Medical Center. She is also an assistant professor of medicine at UC San Diego and also a research associate professor at USC in the psychology department. With that, let me turn it over to Dr. Golomb to discuss her findings with you.

DR. GOLOMB: Hi. As advertised, I am Dr. Beatrice Golomb and it's a pleasure to be with you here today. I've been advised that my microphone is not working, so if I turn and you can't hear me, please let me know and I'll endeavor to project more. And also, don't hesitate to signal that I need to slow down if that's the case. I do have a tendency to talk a little on the fast side.

PB, or pyridostigmine bromide, is the drug that was given to an estimated 250,000 U.S. troops in the Persian Gulf to protect them in the event of nerve agent attack. Why?

Iraq was known to have nerve agents available and militarized and had used them against Iran and Kurds. So the threat of nerve-agent use was real.

Existing treatments for nerve agent, given after nerve agent exposure, are effective against most nerve agents, including sarin, which Iraq was known to have. But they were ineffective against the nerve agent Soman. Iraq was not known to have Soman. But the Soviets had had it, and there was concern that it might have been made available to Iraq.

PB, pyridostigmine bromide, enhances the effectiveness of post-exposure treatments. For this reason, PB was given during periods of perceived high threat. To be effective, PB must be given in advance and throughout the time of threat. It is useful essentially only for Soman and is useful only if after-exposure treatments are given, as well.

PB has not been FDA-approved for nerve agent pretreatment, but it was FDA approved for decades prior to its use, for an autoimmune condition termed "myasthenia gravis" for which it is given in much higher doses, lifelong. For the lower-dose, shorter-term use, the nerve agent pretreatment was presumed to be safe.

However, myasthenia gravis is a condition in which PB is normalizing the function of a certain chemical, whereas in those without myasthenia, it's making that chemical go to abnormal levels. So the analogy is not necessarily valid.

We are going to take a minute to briefly tour some elements of how the nervous system works. And this is a little complicated, so don't hesitate to slow me down or ask questions.

Communication in the nervous system occurs by cells sending signals to one another. When a signalling cell sends a message, an electrical impulse travels down a process leading to release of neurotransmitters, nerve signaling chemicals, near the receiving cell.

In this case, the nerve-signaling chemical under question is something called acetylcholine, signified by the ACh here. Acetylcholine is known to be vitally involved in regulation of muscle action, pain, memory and other cognitive function, mood and sleep, domains that figure prominently in complaints of ill Persian Gulf War veterans.

Acetylcholine is regulated by an enzyme, acetylcholinesterase, that acts to break down excessive levels of acetylcholine, preventing abnormal excessive signaling.

Let me just review this for a minute. Acetylcholine is an important nerve signaling chemical. And there's an enzyme that acts to regulate its function by breaking down excessive amounts.

What do nerve agents do? Nerve agents bind the enzyme, blocking it from breaking down excessive amounts of acetylcholine. The consequence is excessive inappropriate signalling by this chemical leading to muscle twitching, secretions from glands, abnormalities in mood and thinking, and at higher doses paralysis, seizures and respiratory failure.

How does PB figure into this picture? PB also binds the enzyme, blocking it from breaking down excessive amounts of acetylcholine. So the potential untoward effects are similar. The difference is that PB does so temporarily, meanwhile, blocking nerve agent from permanently binding and blocking the enzyme and giving time for nerve agent to be cleared from the body. Later, after nerve agent has hopefully gone out, PB peels off the enzyme, restoring function of that enzyme toward normal.

Rand was tasked to perform a literature review to evaluate whether PB with these actions on the nervous system could plausibly be linked to illness in Gulf War veterans. Rand reviewed a wide variety of sources, including medical and pharmacological investigations, basic science research related to this nerve-signalling chemical, and also declassified government documents, including a number of documents declassified by the British late in this review. In total, thousands of abstracts and documents were read, leading ultimately to citation of over a thousand references in the report.

This literature review was used first to identify theories that might link PB to illness in Gulf War veterans, and then to assess the evidence pro and con pertaining to these theories. The theories fall roughly into two categories: theories that relate to possible ways by which there could be heightened susceptibility to effects of PB in some individuals, and theories according to which PB might actually lead to chronic effects, potentially -- more commonly in individuals with heightened susceptibility. Our literature review was adequate to dismiss one of these theories and was really inadequate to really evaluate another of these. Of the remaining, we'll spend a brief amount of time discussing three as examples.

One hypothesis was that there might be individual differences in processing of PB that might lead to differential susceptibility. Indeed, our literature review found that the same dose administered of PB would lead to sevenfold differences in blood levels of PB from one individual to another.

Moreover, the same blood level of PB may lead to widely different percentages of inhibition of the enzyme acetylcholinesterase. In fact, the same dose may then lead to 15- to 25-fold differences in inhibition of that enzyme if measured at certain times after PB is administered. Furthermore, the same degree of enzyme inhibition is actually associated with widely differing degrees of clinical effects or toxicity from one individual to another. These widespread differences in individual processing of PB could lead to differences in susceptibility to effects and possibly toxic effects of PB, presuming there are any.

A second theory notes that although normally PB is largely barred from accessing the brain by something termed the blood-brain barrier, recent research largely performed since the Gulf War in animals suggests that there may be some conditions under which quite a bit of PB may pass into the brain. These conditions include stress, perhaps heat, and chemical combinations -- conditions to which some veterans may have been exposed.

In addition, one study suggests that PB itself may enable access to the brain of substances that are normally excluded, such as infectious viruses. This research suggests that if, under some conditions, PB may access the brain, then under those conditions there may be increased susceptibility to brain effects and, if present, toxic effects of PB.

The final theory we'll review and the one that really addresses the issue, Could PB be linked to chronic illness in those who perhaps have these conditions of heightened susceptibility? proposes that PB may lead to changes in regulation of the nerve signalling chemical.

Recall that PB acts by binding this enzyme, blocking it from breaking down excess acetylcholine. The consequence, again, is increased excessive abnormal action by acetylcholine in the body. The body is aware that this is not normal acetylcholine action and puts into place a variety of mechanisms to suppress acetylcholine activity. Signalling cells reduce production and release of acetylcholine and receiving cells may reduce the number of receptors to which acetylcholine can bind and through which it acts, and reduce the affinity of these receptors to bind to acetylcholine and their sensitivity to its actions. These effects at multiple levels to dampen the action of acetylcholine one would think would go away at the time that PB is withdrawn, since the body puts them into place because PB is there increasing acetylcholine action. The existing literature suggests, however, that the time courses of these various effects do not necessarily correlate with when PB is put in and taken out. Some of them are very shortlived and, in fact, go away while PB continues to be administered, while others of the effects are long-lasting or possibly permanent, lasting as long out after PB is stopped as anyone has looked.

The question is, could these long-lasting or permanent changes in regulation of this key nerve-signaling chemical be linked to illness in Gulf War veterans? And the answer right now is that we simply don't know. Many of the characteristics of these effects have yet to be delineated. And of those that are permanent, we don't actually know whether they could lead the effects described in Gulf War veterans. But we do know, again, that acetylcholine is vitally involved in regulation of sleep, mood, pain, thinking and muscle action, domains that figure prominently in complaints of ill Gulf War veterans. So it would be plausible, if there were alterations in regulation of this chemical, that symptoms of the type described by Gulf War veterans might ensue.

It's important not to misinterpret these findings. Again, as Dr. Anthony noted, just because evidence is consistent with the hypothesis or inadequate to rule it out does not mean that that hypothesis is correct or that adequate evidence is there to state that it has been proved. It does, however, suggest that the possibility can't as yet be dismissed.

In conclusion, we can't rule out pyridostigmine bromide as a contributor to health symptoms in ill Gulf War veterans. Further research is needed, and this is something that hasn't really been discussed in this briefing, to determine the effectiveness of the current dose of PB vis-a-vis the nerve agent Soman. And clearly, additional research regarding both the safety and effectiveness of PB for humans is urgently needed. The issue now is the complex one of trading off uncertain health risks, but risks now known to be biologically plausible, against possible but uncertain gains from use of PB in the warfare setting.

Thank you. And I'd be happy to take questions.

MR. BACON: I wonder if we can just have Dr. Bailey complete and then we'll take questions.

DR. BAILEY: Good morning. I am the assistant secretary of Defense, and as such, it is my responsibility to provide medical information to the department that will ensure the protection of the health of our forces.

First I want to say how much we appreciate the comprehensive efforts by Rand and by Dr. Golomb to compile this report, and in the finding solidify the need for the continued research in this area. This report is very helpful in framing the problem for future study. Dr. Golomb and I agree that further research regarding these theories is clearly necessary, that is before we are really able to draw any real conclusions.

Much of the research now being accomplished on PB is being done under the direction of the Persian Gulf Veterans Coordinating Gulf. This board is composed of representatives from the Departments of Health and Human Services, Veterans Affairs, and Defense. Right now there are 26 scientific studies, peer-reviewed or research projects underway; 23 have been directed by the Department of Defense. They specifically address the health consequences of PB as a nerve agent pretreatment. The funding for this research is approximately $20 million. These studies include evaluations of the interactions of PB with other chemicals and low-level exposure to nerve agents. Most of the ongoing studies to date reveal no definitive results to link PB to illnesses, those seen in our Persian Gulf veterans, but we must continue this very important research to really determine any causal relationship.

The IOM will also review this report with other literature that's been published on illnesses among our veterans. I've also asked a panel of independent, private-sector medical experts, the Armed Forces Epidemiologic Board, the AFEB, to advise on the priority of our research projects to ensure that we are properly focused on the issues that are addressed in Dr. Golomb's report.

It is my responsibility as assistant secretary of Defense to advise the secretary on all the matters pertaining to the health of our forces. We know that the nerve agent soman is among the chemical agents in the arsenal of our enemies. Soman is a lethal nerve agent and there is no antidote without the pretreatment of PB.

Given the deadliness of soman and the lack of other treatments available, we certainly cannot rule out using PB to protect our forces in the future. However, our leadership would be very judicious in deciding to use PB in the future. The decision would involve weighing concerns about possible long-term health effects with a threat-risk assessment of how likely it is that soman would used against our troops.

Thank you.

QMadame Secretary, can I ask, the report says that two -- it provided for 250,000 troops. Did all of them take it, and was it mandatory for them to take it, or were they given the option of taking it?

DR. BAILEY: If an order was given by a commander to take PB, then it was mandatory, as any order is. We've assessed that about 250,000 were ordered to begin taking PB, given the threat. But we have, unfortunately, not the record-keeping that we would like from that experience to assure us exactly how many took it.

QIs there any estimate of the veterans who are claiming some symptom, who say they are ill? Is there any percentage, any guess of how many of those claim to have taken PB?

DR. BAILEY: Well, I can tell you that that's one of the queries. And I think it clearly points us in future deployments to record-keeping that will let us know what environmental or medical exposures there may have been.

Specifically, we have many people, as you know, who have registered -- over 100,000 with our registry -- following that war. There is a percentage of those, about 20 percent, with at this point undiagnosed illnesses and many others with illnesses much like we expect in the general population. What I'm not seeing is a real correlation between those who were exposed to all kinds of environmental or wartime exposures -- the oil well fires, some of the insecticides that we needed to employ -- and specifically pyridostigmine so that we don't see a direct correlation. I see no direct correlation between those who are ill and those who may have taken it. Granted there are many who report the kind of chronic illnesses we've seen who have self-reported having taken the PB.

QBut even -- wait a minute. Even those who are self-reporting, of the hundred thousand who are in your registry, is it roughly half that say they took PB? Is it only 20 percent who say they took PB?

DR. BAILEY: I would need to get back to you with a specific percentage on that.

QDo you -- do you know for --

DR. BAILEY: It's very difficult because not only do we not know who began taking it. It is our estimate that most only took a small amount of the PB.

QAnd I take it there's no way to determine through testing, blood testing or tissue samples or anything, whether someone was exposed to PB at one point or another.

DR. BAILEY: Not at this time.

DR. ROSTKER: The VA is engaged in a random survey of the health status of veterans, and I think this is one of the issues we would like to ensure that comes out from that. But I think there is some British work that features cites in her report.

DR. GOLOMB: There's really only one relatively systematic report that has addressed the epidemiology of whether self-reported PB is linked to illness in Gulf War veterans, and that comes from Britain. In that study, among the different exposures and risk factors examined, the one that had the strongest and statistically significant relationship to development of Gulf War illness defined by the CDC, who developed a case definition, was PB. However, many other exposures also appear to show a relationship with illness. There is a study from the U.S. also by Dr. Robert Haley (sp) in Texas that appeared to indicate of three factor-analysis derived syndromes in Gulf War veterans that an adverse response to having taken PB was associated with two of those three. But --

QI'm sorry. Even though there's no so-called smoking gun here, and even though scientists don't like to do this, what's your gut feeling? If there is further research -- and I'm sure there will be -- do you think you're close to finding an answer, a definitive answer here?

And then, to Bernie, if I may, are you guys reaching? Are you just grabbing PB because you couldn't find anything else? Or do you think you've really got something here?

DR. GOLOMB: Which question?

Let me say that I think I have slightly more hope than many others do that there is a possibility that we'll learn the answer. We won't probably learn it by epidemiology because of the problems with self-report. But there are two strategies that can become currently undertaken that might help to answer this question. One is additional research regarding the time courses and effects in animal studies of these acetylcholine-affecting actions of PB and related drugs. And the other is investigations, some of which are currently ongoing, looking for objective markers of illness in Gulf War veterans such as abnormalities in eye movements that can't be faked -- for example, when one eye moves a little bit before another, but not discernibly so -- or changes in blood flow in different regions of the brain. Once we can find objective markers, then we can look for those markers in animals after applying different ones of the possible exposures to which Gulf War veterans were exposed.

So that might help to sort out whether PB, or pesticides or these other agents, might have a role. And it is conceivable that, ultimately, we would have an answer.

DR. ROSTKER: When we started, we promised in the vernacular of "no stone unturned." And one of the early considerations was PB. It's highlighted in reports from the Senate Veterans Committee. It's an area that has been suspect. It was a substance that got a clean bill of health, if you would, from the IOM and from the President's Advisory Committee, the PAC.

We commissioned this work some time ago because at the time, there was not a definitive treatment of PB. If you go to the IOM or you go to the PAC report, you'll find about two paragraphs.

This report has been in the works for some period of time. We have shared the results of this with decision-makers, as we have had need to. When we had Desert Fox, for example, and there was a concern about possibly sending U.S. troops back to the Gulf, the research wasn't finished, but we made sure that the decision-makers in the department were aware of this so that this would have a weight in that decision.

We have been very careful in bringing this study forward because it does break new ground and we wanted to make sure that people who had concerns about it, had a chance to voice those concerns and that Dr. Golomb had a chance to respond to that.

The study was available this summer. It was printed. We got copies in September, and we arranged for the release now.

So this has been an important inquiry all along. It's just that it is ripe now to bring it forward.

QBernie, can I ask you, was this -- is this -- to fill in the -- (inaudible) -- so to speak, is this a tablet or a pill or a capsule? And how often does it have to be taken --

DR. ROSTKER: Well, Bill --

Q-- to remain effective once one starts?

DR. BAILEY: The troops were given a blister pack.

And these are the pyridostigmine pills. These pills are given at 30 milligram doses every eight hours. So each pill is 30 milligrams and is taken three times a day. That would only be given during the high-threat time so that you may take it for a short time. And if we assess that the threat is reduced, then it would be discontinued.

It's also important to note that PB only works with the follow-up of what's called a mark-two kit, which is the autoinjectable -- self-injected drugs that also then protect our troops and allow them to survive what would have otherwise been a lethal attack of a nerve agent like Soman.

QThat looks like a week's supply -- 21 --

DR. BAILEY: Dates 21 days, and that would be extended if the threat were maintained.

QNo, no, no. That's one week -- 21 pills would be one week, right?

DR.: That's right.

QThree pills a day.

DR. BAILEY: Three pills a day. It would be 21, yes.

QDr. Golomb, if I could just ask you quickly, you indicated that it was plausible --

DR. GOLOMB: Yes.

Q-- that pyridostigmine bromide might cause some of these symptoms. From a scientific perspective, what would get you to make the leap from "plausible" to "probable"? In other words, you indicated you can't really do an epidemiologic study, at least not totally satisfactorily, but there are steps that would probably convince you.

DR. GOLOMB: Right, and I think the two steps that I articulated previously would really be those. If we could again look more carefully at the time courses of the effects on regulation of this nerve-signalling chemical, acetylcholine, and look at what the consequences of those are in animal studies, which are limited because animals can't report the kinds of symptoms Gulf War veterans have and if, in addition, we find objective markers of illness in Gulf War veterans and then find we can reproduce those in animals with drugs like PB, perhaps in conjunction with stress or some of these other exposures, that would be substantially more persuasive evidence.

QJust a quick follow-up. You looked at lots of literature. Were you surprised by the findings, given the fact that there were warnings about PB before the Gulf War, there were concerns raised that this agent might cause symptoms in soldiers.

DR. GOLOMB: I would have to say that I went in with a totally open mind about what I would find, and so neither direction would surprise me more or less.

QGiven what we know now, or what -- from your research, has the bar been raised as far as the Defense Department using this drug in extremis?

DR. BAILEY: Well, clearly, we are concerned about the possible ill effects from any of the medications we may give, specifically PB here. And I might mention that the work that's been reviewed in this report, the majority of that work is Department of Defense-directed research that's been ongoing for some time. Approximately five of the -- in fact, five of the research efforts have already been completed and another 21 are underway. So we have been looking at this for some time and, of course, are very concerned.

For that reason, yes, the bar has been raised. We will be very specific about looking at medical information, battlefield conditions, and what our intelligence provides us in terms of understanding the real threat of an attack or an imminent attack before we would direct the troops to take PB.

QProfessor Bailey --

QBut it would be tougher to administer this drug today than it was at the beginning of the Gulf War? Is that what you're saying?

DR. ROSTKER: No. The decision to use this drug would be carefully considered on the basis of the threat, the nature of the threat, the status of our understanding of the health effects. It would not be an automatic thing. We'd have to consider the environment we're in. We are at this point now the most conservative of nations in terms of considering the possible future use of PB. Other nations who are involved in research on chemical weapons who have PB in their stockpile have indicated to us that upon any indication of chemicals on the battlefield their policies are to continue to use PB.

QI mean, what about the persistence and the toxicity? Let's say someone took 21 of those over a week period, and then the threat diminished and they stopped taking them. Had the damage been done?

DR. ROSTKER: I think that gets to the first set of hypotheses that Dr. Golomb talked about. And --

Do you want to respond?

DR. GOLOMB: I think --

Dr. Bailey, why don't you reply first?

DR. BAILEY: (Inaudible) -- first on that one.

It's a fairly short half-life, which means most of it's cleared out of the body very quickly. And as you saw from Dr. Golomb's charts, PB only temporarily binds. Unfortunately, the nerve agent binds permanently, immediately. We don't have the kind of golden hour to do our medical combat casualty work. We don't have a golden minute. It is very lethal, and it's very rapid because it permanently binds. However, PB does not, so that within a very short number of hours, in fact, it begins to clear the body and theoretically should be cleared. And I say "theoretically", and I think Dr. Golomb will, therefore, express more of the concern that we have about the theory that there may be some long-term effect.

QWell, that was my concern for the follow-up, not necessarily the short term, but about the persistence over the long term. How much, or did any of your research show you how much would have to be taken to possibly cause problems?

DR. GOLOMB: No. There are some studies using comparatively modest doses. Most of the animals studied use higher doses than are used in humans. On the other hand, higher doses are often needed to gain the same level of enzyme inhibition. But those studies do suggest that it's not the problem with PB persisting in the body, but the consequences of the body's response to PB that may be persistent. And again, some of those consequences appear to be long-term, and possibly permanent. As to whether those would occur in humans at the doses given, there simply aren't data to say.

QHave the -- the troops that have been in Kuwait since the war, what are you finding? Is there some environmental factor that --

DR. ROSTKER: Nope. No troops since the war have been given PB.

QOkay.

DR. ROSTKER: PB was given when there was a threat of Iraq using nerve agents, when there was concern that soman might have been in the inventory. PB has not been administered to troops since the Gulf War.

QBut are troops that have been in the gulf since showing any kinds of symptoms that parallel the Gulf War Illness?

DR. ROSTKER: We don't see that. We do keep health records on the health status of troops who have been deployed, and we don't see these kinds of things.

Now, technically a soldier or serviceman can still join the health registries, and we do have some of those who have been in service. But the technical, the -- there was no cut-off as to when a serviceman could come into the health registry. So we talk about 700,000 people being deployed to the gulf during the Gulf War, and we talk about 110,000 or 120,000 in the health registry. Some of those are soldiers who went to the gulf after the Gulf War. They still have the right to come into the health registry.

QAre there any factors --

DR. BAILEY: Let me add to that, because I think that's an area for further research. And, in fact, that's one of the things that I have been looking at in health affairs that we compare, because it is very ripe for research.

We have people in the gulf today. I was out there with them last year in the gulf. And I, too, would like to look at the fact that the formula has changed, or we know that people are there in that same environment with many of the same conditions. So if we drop out pyridostigmine, if, in fact, we are not -- if it is not needed in the future, then we know that that's not in the equation. The equation will shift, but much of the equation remains the same. So it is ripe for research.

Let me just also add about tracking, that we are doing something very different today in our tracking. We do know we need to apply the lessons learned from the Gulf and, frankly, every other war before that to get medical records that will allow us to look to the future for possible long-term effects and give better continuity of care. To that end, we are doing predeployment questionnaires for all who are deployed, whether that's in Kosovo or in the gulf. We're looking at deployment records and computerizing that while they're in theater, and then post-deployment questionnaires. And I think when we look to the future we'll have better understanding of environmental and medical concerns.

QWell, Dr. Golomb, did you put any weight on the fact that the French were the only troops who did not take PB and that they are not experiencing any symptoms?

DR. GOLOMB: I don't if -- Bernie probably wants to --

DR. ROSTKER: Let me first say as we speak today I have a team that's in the gulf working with the Saudi National Guard reviewing their health records from periods before the Gulf War to periods after the Gulf War. So we're very interested in this issue.

That was the -- John, the common perception was the French didn't do that. When we went to France and we asked them that question, they said that was not true. They did not give the order to use PB. But when they went to collect the PB tablets, they did not get all back. In fact, the briefer said, he said that PB, it was a very good thing, he took it all the time. So that control, if you -- (laughter) -- and he did it in a wonderful French accent that they -- will kill me if I try to repeat. (Laughter.)

QWhat's next, Bernie? Where do we go from here?

DR. ROSTKER: You know, a great frustration is we haven't found a single cause for Gulf War illnesses. I'm not sure we will ever find a single cause for Gulf War illnesses. We have made commitments to the president's oversight board to try to end this episode with the special assistant for Gulf War Illness. We're trying to bring to closure the various pieces of research that we have outstanding. We will be republishing much of what we've done before to bring it up to date. And then I think the issue becomes where do we go in the future with the whole question of deployment and the outstanding work that's been done on medical force protection over the last decade. But your question is well taken. We certainly have gotten to the point where we know there are still sick individuals. But our unique contribution in this is probably coming to an end.

QBernie? If I could come back --

DR. ROSTKER: One second. I think that --

DR. GOLOMB (?): I just want to comment that there two people who have had their hands up kind of hoping -- (laughter).

QJust to come back to one point you were making with just hopefully a little more clarity one more time. If you had to send U.S. troops back to the Persian Gulf today, facing the same threats in area you faced before, what would your recommendation be on PB?

DR. ROSTKER: I think if -- we would look for more of a confirmation for soman in the arsenal of the adversary. If that was clear, that soman was prevalent in that arsenal and where we stand in terms of the health work today, understanding the threat of soman, my recommendation would be to use it. But that's only my recommendation, and I think others would be in this discussion also.

Sue, do you want to -- ?

QGiven that, may I ask then do you feel that this opens up either the Department of Defense or the Veterans Administration any additional I guess medical liability for veterans that took PB and say that they're ill, now that you're saying you would not use it in the same scenario that you did?

DR. BAILEY: Well, first of all, anyone who is ill with a service-related disability is compensated and treated. Furthermore -- and Bernie may want to add to this -- clearly we are providing for any who are ill after the Gulf War or any of our deployments, and we are looking to provide diagnosis and treatment for any symptomatology. So that is covered.

Clearly, I think we're going to be very careful, as Dr. Rostker says, about what it is that we are able to do in terms of intelligence to assure that we are under threat of imminent attack. At the same time, much as we protect our soldiers in every possible way, whether it's through the medical effects of vaccines and pretreatments or whether it is with flack jackets and helmets, this is an era where we're not just protecting against bullets and bombs, we're protecting against one deep breath which can kill.

QAre there any other medical treatments that you're now re-thinking that you would put in the same category, you'd need more intelligence before you would use them again?

DR. ROSTKER: I mean, this was always a judgment call in terms of soman. The standard worldwide is to use PB at the first indication of any chemical weapon. I think it's prudent to now look at a heightened awareness of soman. But then my recommendation would be to use it. So I don't think we've really broken in that regard much with the past.

Let me clarify the veterans' status. Veterans of the Gulf War uniquely operate under a provision called presumption of service connection. If a veteran has unexplained illnesses, he does -- he or she does not have to demonstrate that that is service-connected. The presumption is service connection, and he or she are entitled to medical treatment, and if they are disabled, to what we call compensation or disability payments. This doesn't change the exposure of the Department of Veterans Affairs or the Department in one way or the other.

QAre there any other medical --

DR. BAILEY: (Inaudible) -- to answer your question, there's an example that might be helpful.

When we went into Kosovo, we had a team there. I was in Albania and then in Camp Bondsteel. We had to assess the risk against tick-borne encephalitis. We have an investigational new drug, a vaccine for TBE. The question was, what was the level of the threat, given the many concerns about any drug that has not been approved by the FDA or fully licensed? It is investigational often because we know it has merit. We know that it appears to be safe and efficacious and has not gone through the entire process.

So the debate was, do we use tick-borne encephalitis, the vaccine? And we assessed that given as best we could our assessment of that particular vector and the endemic concerns there about the level of the tick vector, and that we had something else we could use. If all the troops followed the recommendations about the wearing of their clothing, keeping their sleeves rolled down, pants tucked in, and also used, appropriately, DEET or reapplied DEET and permethrin (sp), we could lower the risk from any vector -- specifically, in this case, ticks. That's the kind of decision we're making all the time; what is the safest way that we can use a chemical or a medicine or protective gear to assure that our troops have the safest possible deployment?

QDoes your FDA waiver still apply for the use of PB?

DR. ROSTKER: Let me just say one thing. Dr. Bailey was very careful in using the word "investigative new drug." She did not use the word "experimental drug." You will find some of your colleagues sometimes use that word. There is a vast difference between these words. We are not experimenting on our soldiers. We are providing them with the best -- the best protection we possibly can. Sometimes that protection comes in a way that has not fully been licensed by the FDA. In the case of PB during the Gulf War, there were concerns about the efficacy of PB, its effectiveness. At that time there were no concerns about its health in that application.

Dr. Golomb's work raises now for the first time in a scientific way questions about the safety, and that will have to be considered by the department, by the FDA. We've asked the Institute of Medicine, which has a charge to, again, look at symptoms and possible causes of Gulf War illness, we've asked them to concentrate, to focus on PB and to consider the work here as they move forward in their considerations. These were not experimental; these were appropriately investigative.

QSo is PB still an investigational new drug or has it lost that status?

DR. BAILEY: It is still under an IND.

QBut you have the FDA's permission to continue to use it. In other words, they gave you a waiver.

DR. BAILEY: As an investigational new drug using all of -- we are required to meet all of the requirements set forth by the FDA for an IND. And indeed those are being met.

QWhat's the difference between soman and sarin? And why would it be preferable to use soman for some country today?

DR. ROSTKER: Both are nerve agents, but soman is particular fast-acting. And wherein a sarin attack -- first of all, you would always want to go into battle in your MOPP gear. And we have improved alarms from the Gulf. We have MOPP gear that's much more comfortable than we had in the Gulf. So we provide the first level of protection in the overgarments and in the gas mask and an improved set of alarms.

If you were exposed to soman at a lethal dose, it would take a reaction so fast that you would not have the chance to inject yourself with atropine (sic) and 2-PAM. And so you need that hedge of protection, which we believe would be provided by PB.

That's not true in terms of sarin. If the alarm went off, you mask; you would have adequate time to inject yourself. You would have that protection.

So it's the unique speed of which soman acts that requires a pretreatment, and the pretreatment at this point is pyridostigmine bromide.

QCould you explain to me why, in very simple terms, the chemical reaction that you explained that PB does with the ACh, it seemed to be the same thing that the nerve agent does.

DR. GOLOMB: Yes.

QSo why is it that when you take PB, you experience the same symptoms that you would be experiencing with the nerve agent, just not permanent?

DR. GOLOMB: Right. The answer is that the symptoms that are experienced as side effects from PB are similar to what would be experienced by a very low level of nerve agent. There is potentially increased running of the nose, increased running of the eyes; contractions of the abdomen, which can lead to abdominal pain; contractions of the ureter, which can lead to the need to urinate very quickly; sweating and other side effects of that kind.

But the level is low. And the effects are presumed to be reversible.

QAnd the other thing I just want to be clear on: The order was given for 250,000 people to take this, but you don't know how many of them actually did. And you certainly don't know how many of the people that are now suffering from Persian Gulf War, did?

DR. GOLOMB: We don't actually know that the order was given for 250,000 because the orders were given at a unit level.

QOkay.

DR. GOLOMB: The estimate of 250,000 was based on the number of pills that were sent over, the number of pills that were sent back, and queries with medical personnel at the scene in terms of their estimates of how much might have been thrown out at site.

QAnd a question for Dr. Golomb --

DR. BAILEY: Let me just add, because I wasn't sure about the 20 to 40 percent --

DR. GOLOMB: Oh -- right. That's --

DR. BAILEY: Let me just add that when you take pyridostigmine, it's not blocking all of your capability at the nervous system synapse. It's only blocking estimated 20 to 40 percent. Now, that's what we're going for in doing 30 milligrams every eight hours. That's one of the areas for research in the future, and I think Dr. Golomb's report certainly indicates that.

QCan you tell me why that's significant?

DR. BAILEY: It's significant because you are left able to function. You need that synapse to work and those chemical messengers to go. So we're taking 20 to 40 percent, and the real answer there is that buys the time for you then to auto-inject the other drugs that will then protect. It will pull off the nerve agent, actually take it off of the receptor, so you then can do the same thing you can do with sarin and the other nerve agents -- you can auto-inject and survive the attack.

QIs it something I could reasonably compare to, like, chemotherapy for cancer patients where you are poisoning to kill the cancer and you also end up killing --

DR. BAILEY: No. No, that analogy won't work.

QBut you're depressing normal action and --

DR. GOLOMB: Actually -- it's actually the opposite, because what PB is doing, to clarify a little bit what Dr. Bailey said, is blocking the enzyme that breaks down the activity, so the consequence is that you are heightening the activity, you're reducing by 20 to 40 percent the enzyme's ability to break down excessive acetylcholine at the synapse.

QDr. Golomb, your last words in your summary were "uncertain gains in a wartime setting." Does that refer to the exacerbating effect that PB has on exposure to sarin?

DR. GOLOMB: It refers really to a combination of factors. The studies on efficacy against sonan have been done in monkeys at doses three to 10 times as high as those that are used in humans. We have reasons to think that those extrapolate to the doses used in humans, but we don't actually have the sort of confirmatory evidence to close that loop. It also referred to the fact that you never know, even if soman is in the battlefield, with any certainty whether it will be used or whether you'll be the one exposed to more than a lethal dose but still within the amount that PB protects against.

And as regards to your comment, animal studies suggest a small reduction in protection against the nerve agent sarin with pretreatment with PB. Existing studies, which are mostly done on rodents, suggest that this reduction in protection in small and not significant from a military perspective. The remaining degree of uncertainty there is that there's not much of it in some primates about the side, if any, effect reduction, and certainly none in humans.

QDr. Golomb --

QWas this the first one that was used in -- by our military in this -- ?

DR. ROSTKER: I don't know of any other time when we've used it.

QThank you.

QDr. Golomb.

DR. GOLOMB: Yes.

QJust a question about the process. How long did you spend working on this, putting together this report? When did you submit it to the Pentagon, if I could? And did the Pentagon vet this before its public release, or was it released in the form that you submitted it?

DR. GOLOMB: The process began in early 1997. And the first draft was sent out for peer review to scientists that had been vetted not by this group, but by the head of the Institute of Medicine to assure that they were adequately credentialed scientists. And it came back for a round of revisions in response to their suggestions. And at that point it did go out to individuals in the VA, DOD and other places for their comments and suggestions.

QWhen was that?

DR. GOLOMB: I actually don't recall. Sometime in 1998 --

DR. BAILEY: (Inaudible) -- Anthony might answer.

MR. ANTHONY (sp): I mean, I'll try to answer it, because I'm the one who ended up coordinating most of this stuff.

DR. ROSTKER: You can step to the microphone.

MR. ANTHONY (sp): Yeah. Excuse me. Really, as a person that stands between peer reviewers and the authors so that, in essence, if somebody really has something that they really want to get in the process and they don't want to communicate directly with the author, we traditionally do that.

The process took some time, and I'm -- without looking back at the dates I won't remember them exactly. But there were two rounds. There were -- the peer review process. And that began around the beginning of 1998. Once we got that back, that took about, oh, three or four months to respond and get their sign-off. And then it went into a process both within the OSAGWY (ph) and the VA and some of the -- and Health Affairs I think saw a copy also. We received back their comments. I received them back, and I passed them on to the author, and they were considered. And you know, we took those comments, as we do anybody's; we consider them. But as an independent body, we certainly didn't take them all. And they were primarily comments that we looked at to enhance the quality of the paper.

QSo the report, after having been peer-reviewed, was submitted to your office, Dr. Rostker, in the last year, you said?

DR. ROSTKER: The process that we have established was: First of all, we asked Rand to -- Rand normally has a peer-review process; it's an internal peer-review process -- we asked them to go outside of the organization to get reviewers.

And so they did that. So that went through their internal process.

We then asked for comments from interested governmental organizations. And these were technical comments.

QThat's where it went through your office and --

DR. ROSTKER: It went through my office, and we farmed --

Q-- the VA?

DR. ROSTKER: -- it out.

MR. ANTHONY (sp) (?): Are you asking a question about the timing or --

QWell, I am asking how it was vetted and --

DR. ROSTKER: Right.

Q-- what -- you know, essentially --

DR. ROSTKER: And then those comments came back, were considered by the author. I made it very plain to all involved that these reports are Rand, and not ours. We want the best report we possibly can. And so we are eager to get comments from people who are knowledgeable.

We have had a similar discussion in concerns of depleted uranium, where the peer-review process, and this process, has been reviewed by the President's Oversight Panel and reviewed by the General Accounting Office. So this is a very standard process that we have gone through.

QCould I ask the doctor then whether the final product, which we have here today, is -- how close that is to what you submitted -- (inaudible)?

DR. GOLOMB: I think in all essential elements, I would have to say there is no difference: The hypotheses are the same, the conclusions are the same, the details of the writing vary to small degree.

QIs there anything in particular left out or taken out during the vetting process that you were left uncomfortable with?

DR. GOLOMB: Nothing that comes to mind.

DR. ROSTKER: One of the things, for example, we asked Dr. Golomb to consider is, fairly late in the process, the British made a wealth of data available, declassified it, and we asked her to consider that. That probably took, well, a considerable amount of time to go through that, or else we would have been here six months -- at least six months ago.

QAnd the final product was then submitted back to the Pentagon when?

DR. ROSTKER: In September for release, which came immediately, and then we scheduled this process to bring it to you.

QAll right. So you got the finished product in September.

QCould I ask you, what would be the most likely, the most likely problems caused by this, the PB? I know Gulf illness is a wide variety of complaints. What would be the most likely that this would cause?

DR. GOLOMB: Well, to sort of go back to the hypothesis, my answer would deviate from the direction of your question by suggesting that perhaps the most likely mechanism of chronic illness would be through change in regulation of this chemical. And change in regulation of that chemical would be likely to affect anything from sleep, muscle action, all those different domains because all of those are regulated by acetylcholine.

QAnd if you were put in a situation where you were asked to take this drug at this point, would you have problems in taking this drug?

DR. GOLOMB: What I'd have to say is I think the full force of considerations is never felt when one answers a hypothetical question, and hypothetical questions are notoriously unreliable for -- (laughter) -- having any bearing on one's answer in a real situation. So I would actually decline to answer that question.

QYou're more a politician than you are a scientist. (Laughter.)

QHow much time do you spend in Ken Bacon's office? (Laughter.)

DR. GOLOMB: No, actually, that's based on my scientist response. I am aware of the literature on hypothetical responses. (Laughter.)

DR. BAILEY: Let me just add that I, as a physician and a scientist, for myself, having been out with our troops in the Gulf and on aircraft carriers and most recently in Kosovo, you get into a situation like that and the situation becomes not so hypothetical. And so I would say without a doubt, even given concerns -- and I think these are valid concerns about possible long-term effects, we're going to look to every avenue of research to answer the questions that have been raised; at the same time, were I to know that we were under threat of imminent attack and I know I would not survive because there is no antidote that will work without it, I would take PB.

QThank you.

QDr. Rostker, or anyone who wants to answer this. (Inaudible) -- people concerned about anthrax. Do you think that news of this could by some be used as ammunition for that? And how do you plan to educate them?

DR. ROSTKER: I think the substances are totally different. They work on different parts of the body. There is a different literature in terms of experience. But I would just say that we've been very forthcoming. I personally have taken the anthrax shots. I'm comfortable with it.

Thank you.

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