Q: Tell me how you got involved with this issue.
A: I'm an epidemiologist. I spent 10 years at the CDC. Been here on the
faculty now for almost 15 years. I was busily working on a number of
epidemiologic projects including hepatitis C and some other fascinating new
epidemics.
And one day we got a call from Ross Perot who lives here in Dallas and he came
by the University here and said "I've been travelling around as usual talking
to veterans groups and lately I've been getting an experience that is unusual.
Groups of veterans will come up after one of my talks or will come and visit me
here at my office and their wives or their company commanders will point to
this fellow and say 'Look, before the war this guy was a strong, tough, can do
person, and now look at this poor fellow, how sick he is and this change right
after the war. And no-one's doing anything about it and they're telling him
it's due to stress and he -- that just isn't in character for this fellow' and
he says this has been happening all over. I don't know if this is real, but if
it is, we need to -- we need an independent study and if you guys at this
university will enter into such a study I will be happy to help defray the
costs."
So we went into a 50/50 partnership where we provided the faculty time for
nothing, and he chipped in and covered the out-of-pocket expenses. We started
the study and actually I was very skeptical of this idea. I thought
this was stress too. And I was collaborating with a toxicologist who had an
inkling this might be a toxic problem, so we had that hypothesis --
Q: As an epidemiologist you know that these kinds of anecdotal pieces of
evidence, they sound compelling but they often don't pan out.
A: Yes. Very frequently an epidemiologist is confronted with people who
think they've been involved in an epidemic. Two or three cases of
Hodgkin's disease at a high school reunion for example, and people say That's
just too coincidental. But in fact most of these turn out to be not epidemics,
just natural occurrences, things that would have occurred anyway, and that's
what we thought the Gulf War Syndrome was, just illnesses that would have
occurred. So we went into it really to disprove the syndrome. But then as we
actually started studying it, at each stage the data just shouted out to us
that this looked real.
Q: As an epidemiological problem this is really very hard isn't it ? You
don't have a clear case definition for Gulf War Syndrome even today, you
have dozens of possible risk factors and you don't have any good way of
assessing which vets were exposed to which risk factors, and how big were the
exposures they received. So what made you think this was an attackable
problem?
A: Very good question. This is clearly the most complex epidemic
investigation, epidemic problem that I've seen in my career, and I think it's
the hottest thing that's happened in this half of the century. The reason for
it is, not what you saw -- not the issues of risk factors and measurement of
risk factors, that's not the problem.
The problem is the definition of the disease. Most diseases, Legionnaires'
Disease, Toxic Shock Syndrome, AIDS, the big classic epidemics so far in recent
time, the disease has been obvious and so you talk to half a dozen people who
have it, and you write down a case definition and you study a population and
divide them into the ones who meet the case definition, the cases, and those
who don't, the controls, and you're off doing the study. You give the cases a
questionnaire to have them write down what their exposures have been, for
example in AIDS they would write down, they would tell you about their sexual
behaviors; Legionnaires' Disease they would tell you about where they were in
the Stratford Hotel in Philadelphia, and you gather self-reported risk factors.
In an epidemic investigation you almost then find the cause because an
epidemic is unique in that the effects, the degree of association of risk
factors with the disease is so strong that even with self-reported risk
factors, you always find it. So the problem here is not measurement of risk
factors, you can do that with self reports very satisfactorily. The problem
was the case definition. All through 1994 and up through 1996 really nobody
else would sit down and write down a case definition.
So what we did, we did a survey in order to devise a case definition from the
data. We, in fact let me step back, when we teach the students about
epidemiology there is a little saying, we say The first thing you do in an
epidemic investigation is you examine half a dozen of the cases in an epidemic
and then you write down a case definition. And if you can't do that then you
devise a case definition because failure to develop a case definition means
that you are doomed, you are -- it's a foregone conclusion that you will not
find anything in an epidemic. That's just the way it is.
And so it was quite feasible to sit down and write down eight or ten symptoms
that many of these people had in common, and so this is a case definition.
Let's do a provisional study to see if that pays off. Well, nobody did that.
Everybody said Well, these symptoms we've seen before and therefore we're
reluctant to write down a case definition.... Now the reason I think they
were reluctant to write down a case definition is to write down a case
definition may have a political implication and that it may indicate that
somebody has accepted this as a disease and to do that would have all kinds of
political ramifications, so it was never done, and that's why the investigation
never went forward.
Q: What was the hypothesis you were testing --
A: The hypothesis we were testing was that what we thought to be vague,
non-specific symptoms were in fact a real syndrome. The syndrome was due to
brain dysfunction, and that that was caused by exposure to combinations of
organophosphates that would work together synergistically. Whereas people who
were exposed to just one, would probably not be sick, but those exposed to two
or three would be the ones who were sick. That was the hypothesis that we put
out ahead of time.
Q: And these organophosphates would produce what's called a neuropathy?
A: Organophosphates are known to produce two syndromes. The failure to
recognize these two syndromes has been another thing that stood in the way of
understanding this problem. Everybody, every doctor knows, and the military is
well aware, that exposure to organophosphates can produce an acute, immediate,
very serious reaction that can kill you. And that's due to the paralysis or
binding of an enzyme in your body called cholinesterase, and it causes you to
have trouble breathing, to have diarrhea and tearing and finally you stop
breathing and you can die. If you get over it however you're supposed to --
you have -- you're totally ??... because the enzyme regenerates and you're back
functioning normally. And that was what people had in mind.
It was unknown to almost every doctor and to most people in the Defense
Department and throughout the country, that there is another syndrome, that is
being exposed to some organophosphates, but not all -- whether or not you have
that initial syndrome, you can have a delayed reaction where several weeks or
months later you can develop a spectra of neurological dysfunctions, which can
be permanent. And these are on a spectrum from a very florid peripheral
neuropathy where your nerves in your hands and feet stop working, and you can
even become somewhat paralyzed. Also involvement of the spinal chord when you
develop spasticity, and in some people, particularly where the exposure is long
term, periodic and long term and low level, they might not get these peripheral
manifestations but they might only get a disorder of the lower part of the
brain in the brain stem which produces just psychiatric-like symptoms, vague
symptoms like dizziness, difficulty concentrating, and the sorts of things that
we see in the Gulf War veterans.
Q: As far as I can tell, the Presidential Advisory Committee and the other
panels know abut this work. They just don't think of it as very relevant or in
some cases very good. There's a value judgment being made about what this work
means. They have considered it and dismissed it. I don't think it's just
ignorance.
A: No. I don't think it's ignorance. But I couldn't comment on what it is.
Q: Let's move on to discuss your study and some of the comments scientists have
made. One criticism that has been made by a number of epidemiologists is that
you had sample bias.
A: Yes. It's been written. The criticism that our study contained a selection
bias because not all of the members of the battalion participated is an invalid
criticism and has been shown so in our responses to those comments.
What we did in the study is, 41 percent of the members of this battalion
participated in the study. You'd like to have 100% and you know if fewer than
100% participate then the ones who didn't participate might be different from
the ones that did participate. This is very common in epidemiologic studies to
have less than 100% participation and so what we typically do is do a secondary
study, a background study, to study the participants and the non-participants
and compare them to see if they are different. We did that and published that
in the paper, and found that in fact they're identical on age, race, sex,
educational levels, jobs that they performed in the Gulf War, various risk
factors. The only way they differed was on the probability that they had a
serious illness, some kind of illness after the war. But it was not like night
and day. It was 70% in the participants and 40% in the non-participants. What
that means is that there is going to be a bias in our estimates of the
prevalence, but since the risk factors were balanced, that means there's not
going to be a bias in our estimation of the relative risks, looking at the risk
factors, or in identifying the syndromes. It's only in estimates of the
prevalence of the syndromes.
So, in the paper we correct our estimates of the prevalence for the fact that
there was a disparity in the degree of illness. Those were corrected in the
paper, but they were not noticed by the critics. Once we pointed that out
there I think all the scientists that reviewed it felt that answered the
question and there was not a selection bias.
Q: Let me go on to the risk factor issue. This is another thing you've been
criticised for is the way you assessed exposure. Basically, the way you
assessed exposure was asking people whether they thought they were exposed to
various chemicals. Now, the critics argue as follows:-- it's one thing to rely
on self reporting for somebody's sexual history for an AIDS patient, or a
Legionnaires' Disease case, it's another thing to rely on self-reporting as a
way of getting exposure data in an area like this where, especially in a
political area where these things have such volatility, where strong
suggestions have already appeared in the media.
A: Right.
Q: So, is asking somebody whether they've been exposed to chemical weapons
remotely comparable to asking whether somebody had intercourse without a
condom. How do the vets know whether they've been exposed to chemical
weapons?
A: Okay, the questions about chemical weapon exposures referred to were there
incidents in which the chemical weapon or arms that were supposed to infect
sarin -- organophosphates-- alarms sounded -- the marines went around yelling
this is not a drill, this is not a drill, put on your MOP4 protective suits,
and then people had symptoms of gastroenteritis for the next 24 hours. I mean
--if I ask you, did you have an experience like that, you would know whether
you had experience like that. And so -- what our study is saying is that
veterans who have experiences like that are much more likely to be the most
severely ill of the veterans.
Q: Are you implying though an experience like that means you've been exposed to
chemicals?
A: If that experience-- is highly associated with having the illness, it is a
clue to the etiology. Now then to take the next step and say what that
actually means, that's a much more complex issue getting into laboratory animal
studies and collateral evidence of what chemical weapons were on the
battlefield if they were, what clouds went over and so forth, and that's not
really our area of ex-expertise and as you know that's well -- highly disputed
at this point.
Let me say, it's not my expertise to evaluate evidence on chemical uses in the
war, and military evidence, intelligence evidence, that's not my expertise, so
I can't comment on that. Other than to say that I find very frustrating all
the confusion and I'm not sure that we're ever going to have documentation of
what actually happened in the war. But I don't think that's necessarily very
important. I think what is important is to focus on the ills of war veterans.
What I think is going to solve this is a systematic population study of the
700,000 deployed veterans and the 1.4 million non-deployed veterans at the same
time, who didn't go over to the war. Random sample surveys of those in which
we test further our neurotoxic hypothesis. And we are actually planning such a
study and the Defense Department is contributing funding to it. So we will
actually pick a random sample of these two groups, survey them with our
instruments and repeat ??... cases and controls back to Dallas, do intensive
testing neurologically of the same kind of blinded conditions as before, look
at those factors and try to repeat the study in a representative sample of the
population. I think if that were to come out with something similar to what we
found before I think it would be very convincing.
Q: Now to generalize from the few Seabees you studied to the tens of thousands
of vets who have registered with symptoms you have to overcome a problem, don't
you: for 80.000 vets to be suffering from organophosphate (OP) induced
neuropathy there has to be sufficient quantities of OP in the field.
A: Quantities of what?
Q: Organophosphates.
A: Right.
Q: Right. Now the pesticides that were used out there are the ones that you
buy in hardware stores. They are the ones which we use here. As for the
chemical weapons, How do you get exposure a little bit of exposure to so many
Gulf War troops scattered all over the Gulf--a huge area--without anybody
having an acute attack? That seems to me a very telling argument against
chemical weapons.
A: No. Absolutely not. The hypothesis put forward is that many of these, that
not nobody was exposed to levels of any of these organophosphates that, by
themselves, would produce acute symptoms. Let me start over. Our theory is
that people were exposed to residue low levels of these that would not have
injured them, would not have produced acute symptoms, and we know that is true.
Nobody was overcome by organophosphates, and so to posit that there were very
high levels would make no sense.
Q: But how do you distribute over a large area --
A: It's a problem of, -- it's a good point. -- Take for example the use of
pesticides. We know that there were several uses of pesticides. And because
the military was very rightly concerned with protecting the troops from
insects, because they had -- carry lethal diseases. So therefore they very
carefully sprayed the camps with chlorpheriphos, with Dosman(ph) which is a
pesticide which we have fought with here in Dallas county and many other
counties in the city -- in the state and in the nation. They're in common
practice. But low levels get around, everyone is exposed-- many people are
exposed to low levels, particularly people who are outside at night, would be
exposed to high levels, but not enough to injure anyone by itself. However,
that is a little bit of pesticide exposure. You wouldn't expect anybody to be
injured by that by itself. People put on DEET. After putting on 10% DEET, an
insect repellent, typical OFF or also using Avon Skin So Soft, obvious get no
DEET? However, a number of the troops were using the military issue that was
75% DEET and ethanol, thought to be harmless. But now we know that, by itself,
will not injure an adult, but it will get high blood levels. Also, the people
who were taking perlostigmine, thought(?) they were taking a dose that was know
wouldn't hurt people, because we give 10 times that much to patients with
thyastin nergravis so nobody should have been injured by perlistigmine by
itself.
The theory we raised though is-- What if you are exposed to three innocent
levels that won't produce acute symptoms, but if all three of those
chemicals, or two of them, we've the symptoms? Moreover, you put each of
those chemicals in groups of animals and they didn't injure the animals. The
animals had no symptoms. But when you put in the animals two of those, they
got brain damage. (reference to AbuDhonia study)
Q: So let's move on to the group you did the neurological testing on. Now this
was a subset of the original --
A: That's correct --
Q: This is the 23 worst cases.
A: No. To determine whether these clustered syndromes were actually due to a
neurological condition or not, we selected 23 of the veterans with the
syndromes who were the most typical of those with the syndromes and then 20
controls who were not ill.
Now what do I mean by most typical and this gets in, unfortunately, into the
math, but I will go ahead and do it. In the factor analysis for each of the
syndromes you get what's called a factor score. It's a score that goes from
minus-one to plus-one with a variance of one, okay, a standard deviation of one
and the ones that are the highest on that scale are not the most severely ill
-- and this has been misunderstood by some of the critics, these are the ones
who are the most typical of syndrome 1 or syndrome 2. They're most like
syndrome 2. And so we picked the ones who are highest on the scale because
they were most typical of the syndrome. It says nothing about the severity of
their illness, only about how typical they are of this cluster you see. So
that's what we picked. Then we brought them in and showed in fact that they
had more severe brain dysfunction than the controls.
Q: Now when neurologists tested these selected 23 individuals that you found,
they couldn't find anything abnormal. Right?
A: That's correct. Right.
Q: And if you took the group of 23 as a whole, the results of these tests were
not that different from normative data, but were different from a control
group.
A: That's correct. By -- the answer to that is, you have to ask what is
normative data. What is normative data? Normative data is a control group, but
it's a control group of a cross-section of the population. So it's a very
general control group and they set the normal limits against that control group
very broadly -- in order to detect tumors, strokes, multiple sclerosis and very
obvious, very dramatic neurological damage or neurological diseases you see
because that's why these tests were invented, to detect tumors, strokes and
multiple sclerosis, similar things.
They were not developed to detect neuro toxicity because neuro toxicity has
very subtle differences from controls because, think about this, a tumor would
take a big bite out of your side of your brain or a stroke would damage a large
part and so therefore every part of your body that's controlled by that part of
your brain would just stop functioning and so these tests would be very
abnormal and that's why they set the control -- the normal limits to be very
broad so that only people with those things stick out. See? Well, that's not
applicable in neurotoxicity because in neurotoxicity the damage is a random
neuron here and a random axon there throughout the nervous system -- or
throughout certain parts of the nervous system and so no test is going to be
dramatically abnormal. So if you set up confident -- if you use c- normal
limits that only detect very dramatic things, you gotta conclude there's
nothing here and that's the that's the problem we're facing in trying to
diagnose this in the usual medical setting. See, we're applying normal limits
that were set for more -- much more dramatic diseases. So, how do you solve
that problem? What you do is you have to establish much tighter normal limits
in people -- in controls that are exactly like the cases.
So what we do instead of picking the general population to set our normal
limits as has been done for the tests in general, we pick a control group that
are the same age, sex, race and even educational level to the cases, fairly
similar people who even do the same jobs, they're in the same military unit,
then ... do the tests at the same time and the variance you see in that normal
control group is the normal limits --
Q: The other thing which has been voiced by your critics in the pages of JAMA
is they say you used the wrong neurological tests for your hypothesis. The
wrong tests for OPIDN
A: Yes. Some critics have suggested that the neurological tests we used were
not the ones that they would prefer for this Organophosphate Induced Delayed
Neuropathy. Unfortunately that comment comes from misunderstanding of the
spectrum of the Organophosphate Induced Syndromes. The assumed is that the
only type of illness you get from organophosphates is a severe neuro --
peripheral neuropathy. That is dysfunction or malfunction of the nerves
in the arms and the legs. In fact, the truth about OPIDN, or organophosphate
induced delayed neuropathy, is there's a spectrum from, if you take a very big
dose of poisoning of one of these compounds, all at once in one dose, typically
about 10 days later you get paralysis of the -- tingling or paralysis in the
arms and legs, but over a year or so that tends to go away, leaving, in its
place, severe dysfunction, or mild dysfunction of the spinal chord and the
lower bone stem. So, critics say, Well you should have done studies of the
peripheral neuropathy. Well, see, we were studying this 3 and 4 years later.
After which you would have expected the peripheral neuropathy to have resolved
and gone away leaving only the bone stem and the spinal chord. So why did we
do studies of the peripheral neuropathy when in fact all we would
predict that only the brain stem damage would be left. So see it reflects just
a misunderstanding of the progression of this illness.
Q: But I thought that there was no evidence of large doses, acute symptoms in
the field, or any of these typical --
A: I didn't make myself clear. If you're exposed only to small doses, for
example a pesticide sprayer gets exposed, they don't have peripheral
neuropathies. And our critics were saying, You should have tested for
peripheral neuropathies. People who were exposed to small doses over periods
of time and in combinations, they only get central problems. In fact they are
often mistaken for psychiatric disorders, depression, schizophrenia, and so
forth. So, Why did you test for peripheral neuropathy, when small doses should
produce central problems. Central nervous system problems? The criticism
doesn't make any sense based on what we know about the disease and what we
expect occurred in the Gulf. Low doses, combinations, perhaps over a period of
time, only cognitive, possibly psychiatric type changes in the brain, and very
few symptoms related to neuropathy, why did we want to test for neuropathy and
not test for central nervous system findings?
Q: I think that's a confusion. The hypothesis you're testing for is
organophosphate induced delayed polyneuropathy, right?
A: Right, and organophosphate induced delayed polyneuropathy has a spectrum of
symptoms. With a one time large dose you expect peripheral neuropathy. With
repetitive small doses and combinations of things you expect central nervous
things to -- abnormalities to predominate. We proposed that it was small doses
over a short -- over a period of time and perhaps in combinations that would
produce central neuropathic findings, the symptoms that the veterans have are
of the central nervous system nature and we did tests, neurological tests to
brain stem and central nervous system and spinal chord disorders. Our critics
have said, You should have tested for peripheral nerve disorders. But that
only occurs when you have severe one-time exposures, and even gets well after a
year or two, and this was three or four years later, so it doesn't make any
sense at all to test only for peripheral neuropathy and to avoid testing for
central neuropathy as our critics have suggested. What we did was exactly what
you would want to do.
Q: The other thing the critics say is that you have these 23 patients, which
are then divided between three.
A: Right, the syndromes, right.
Q: Fairly small numbers, and then you run a lot of tests on them and therefore
you run into the what is sometimes called the Texas Sharpshooter Problem, or
the multiple comparison problem. How do you answer that? Don't you, in these
things, have to be really specific up front about your hypothesis? Otherwise
you're bound to find some sort of match.
A: Right. The Texas sharpshooter problem is a very good criticism. We
anticipated it and in the articles we answered that criticism. We did an
analysis of the number of tests that we performed on the 23 cases and 23
controls. We analyzed all of the total numbers of tests we did, how many
showed that the ones with the syndromes may have merely been the controls.
And, vice versa, how many of the tests came out the other way. The controls
more sick than the cases. And then we did a statistical test on that to see if
that difference of that pattern could have occurred by chance. And you know
what the probability of that could have occurred be the sharpshooter effect?
Less than one in 10,000.
Q: What do you say to the argument of the scientific panels that stress is a
likely exacerbating factor for the symptoms--much more likely in fact than low
levels of chemicals.
A: Right. Some of the critics have said that the Gulf War veterans' physical
symptoms that they're having are due to stress. Now what does that argument
really entail? The only illness we know of in the list of medical diseases
and psychiatric diseases, that's caused by stress, is post traumatic stress
disorder.
Listen, I've been in stressful conditions for three and a half years doing
study and I don't have post traumatic stress disorder, and I don't have
physiological affects. -- Business executives are all the time under stress.
People who are forced to be on welfare or on -- have terrible stress. And
no-one's ever connected these types of stresses to the types of symptoms these
Gulf War veterans are having. That's just completely specious.
Q: People have fund the notion of chemical weapons terribly exciting. Much
more exciting that DEET or other pesticides, right? But you are saying, am I
getting you right? Your theory doesn't need chemical weapons?
A: Our findings show that our first syndrome, syndrome one, is associated with
what appears to be pesticide exposure. Syndrome three is associated very
strongly with DEET and pyridigstigmine bromide exposure, and probably a
synergistic effect of the two. Our syndrome two, which is the most severe,
most of the veterans who have it, unemployable very very handicapped with these
neurological, very severe neurological deficits. This was most strongly
associated with risk factors that strongly suggest low level chemical nerve
agent exposure and toxicity from peritostigmine and a synergistic effect
between the two. Does our theory need chemical weapon exposure to explain it?
I don't think theories need anything. I think the problem is, that's what the
risk factors suggest.
Others will, hopefully, duplicate this study and see that they find the same
effect. We're going to do the same study in a large representative sample of
veterans, and maybe we won't find the same thing the next time. That's
certainly possible. Then we would have to adjust to that and our
theories would have to change. But right now, on the table, that's one of the
risk factors that -- and there's no counter evidence in veterans, epidemiologic
evidence, that would suggest that's not right. It's just there's no other
evidence. No-one else has done a study.
Q: I want to come back to the exposure question. For chemical agents to explain
Gulf War illnesses, there has to be exposure that gets to masses of US troops
all over the Gulf. Even if the doses are very very small, there still has to be
a way to distribute it very widely. I mean the chemicals have got to come from
somewhere. Now one popular theory is aerial bombings. But UNSCOM (the UN
special commission on chemical and biological weapons who have been to all of
Sadam's bunkers to find and destroy the weapons) told me that in their view
allied bombings destroyed hardly any of Sadam's chemical weapons duing the war.
And I pressed them on this, I said, "do you mean that Saddam, ended the war
with about the same amount of chemical weapons than he started" -- they said,
"Yes. A very small fraction was destroyed".
Now, I have problem from just the point of view of basic physics of how you
get this stuff to so many troops if not much of it was blown up. Isn't that a
problem that has to be addressed...you can't just say, Oh the epidemiology says
otherwise.
A: I'm just an epidemiologist. I'm not qualified to talk about aerial bombing
and intelligence information and so forth. That's so far out of my area I just
couldn't comment on it.
Q: So-- it doesn't follow that there was any widespread chemical exposure from
what you've found, from chemical weapons?
A: Our evidence pretty strongly suggests that chemical weapon, the perception
of chemical weapon exposure and interaction, synergistic interaction with
pyridigstigmine bromide is a serious risk factor that needs to be explored.
Whether there were actual exposures on the battlefield, the evaluation of all
the evidence, the political evidence and the intelligence evidence is just so
far beyond my expertise I really just couldn't comment on it.
Q: But isn't that the point. There's a difference between perception of a
toxic exposure and the toxic exposure?
A: We have a very high relative risk, which is a number indicating how strong
the association is, with the perception of chemical exposure, synergistic
effect with pyridigstigmine bromide which is a very dramatic finding
epidemiologically. How that squares with intelligence information is somebody
else's call.
Q: But perception of a toxic exposure is not the same as actual toxic exposure.
Correct?
A: That's correct. Yes. But what you do have to worry is the plausibility of
an eye witness testimony versus the plausibility of intelligence information,
and again, that's just out of my area of expertise.
Q: To establish the ideas we've been talking about, you have to convince your
scientific colleagues, it's not a question of being popular with veterans or
with politicians. You have to establish in the scientific community. Is that
going to be a hard job?
A: No. Very easy. That's the easiest part of the job. Where they,
scientists, become convinced is, they read scientific papers and they go to
scientific meetings and hear scientific presentations given on those data. And
that's it. And then they form their opinions, or they don't.
-------------------
Note: Dr. Haley's 1997 articles in Journal of the American Medical
Association can be accessed at JAMA's web site.
Haley's articles elicited many letters in JAMA criticizing his studies. For
example, read Dr. Philip J. Landrigan's editorial "Illness in Gulf War
Veterans" Access this by going to JAMA's web site
. Type in Landrigan's name and title of his editorial on the search page.
| 
