Maureen, what is epidemiology?

Well, epidemiology is actually an attempt to identify the causes of disease, but carrying out studies in human populations as opposed to under controlled circumstances in a laboratory.

You know, you should just look at Dick.

Look at Dick. Okay, I'll try to. Sorry. I'll try it again.

Forget the camera as well.

Okay.

Just talking to me.

Okay. Fine. Begin again? Um, epidemiology is the study of the causes of disease in human populations as opposed to in the laboratory.

Why is the best chance of studying the effects of Agent Orange through the techniques of epidemiology?

Well, we can be aided or perhaps even guided by studies in laboratory animals, but because of the rather extreme variations in species sensitivity we'll never really know the answer to the question of what effects there are in humans except from studies in man. Particularly, by the way, with dioxin. There seems to be a really wide range of variation from species to species. It's very striking.

Uh, what are the dimensions of the inquiry that is trying, that is being launched and that people are trying to get launched into the effects of Agent Orange? Is it only dioxin? Is it more than that?

Well, part of the confusion is that at least to date, the evidence that we have to draw on are really from studies of different agents at different doses and in different settings.

So that in trying to talk about effects of Agent Orange or dioxin we're really culling information from studies of people exposed to different herbicides, a mixture of herbicides, perhaps in some cases workers who were working strictly with chlorinated dioxins, always at different levels, sometimes inside, sometimes outside, sometimes repeated doses, sometimes single doses. All of this makes it much more difficult to, to form a cohesive body of knowledge about...

Where do the studies stand now, those that are underway or being planned? Can you sort of give us an overview?

As I understand, I'm going to talk now about studies of Agent Orange effects particularly. There is one study being carried out by CDC, in the Atlanta region, which examines the question of whether or not there is a relationship of Vietnam service or dioxin or rather Agent Orange exposure to neural tube defects in offspring. This is a particular type of defect that has been of some concern in this connection.

The Air Force study of the ranch handers, who were the men who flew the C-123 missions that uh spray the herbicide, they are beginning to report their data now, and have in fact given us some of the initial results in the mortality study.

The Atlanta study, I think it's just coming in from the field. It should be due next year. And now the Centers for Disease Control has agreed to sort of take on a whole set of studies originally assigned to the Veteran's Administration and obviously that would be a very big job but they are really just beginning. They are just beginning to hire and I think they are just beginning to plan, and that is as much as I know about the status.

Any, any, could one predict how long that set of studies will take?

Oh, it's going to take years I think. The protocols for the Air Force study, also for the old veteran's administration studies went through lots of review procedures and one can expect the same thing to happen, happen now. And then, of course, any epidemiologic study takes time. There is no question. Somewhere between three to five years per study, I would think.

Uh. you recently were in Vietnam and attended a conference that addressed a number of these issues. Could you just briefly describe that and your impression of the state of Vietnamese studies in these areas?

Yes, I was recently at a conference, an international symposium held in Vietnam in January of 1983 in which the Vietnamese had a chance to present some of the research that they have been doing since the time of herbicide spraying.

Um, I particularly worked with the group that concerned itself with reviewing studies of reproductive effects. The particular types of outcomes that were considered in these studies were miscarriages and stillbirths, um birth defects to offspring, and an entity known as a molar pregnancy, or a hydatidiform mole. Do you want me to go on? This is a very unusual...nobody is going to know what that is. That's why I think if you don't mind I better give you a definition.

Yeah.

Okay? A molar pregnancy actually refers to a conception that lacks an embryo, but which involves hyperplasia of the chorionic villae, so you get something that looks like a collection of grapes. It's very unusual genetically. It's what is known as androgenetic.

That means that although it has the normal chromosome constitution, the entire genetic contribution is from the mother. There are no paternal chromosomes involved at all.

And what seems to have been established about how this occurs is that a normal haploid sperm fertilizes an egg, an ovum that either lacks a nucleus, or in which the nucleus has been inactivated. So that there is some kind of error, some damage to the maternal germ cell that underlies these pregnancies.

Another unfortunate consequence. Of course, the pregnancy naturally always aborts. But another unfortunate consequence is that frequently these women go on to develop coriocarcenoma.

And you say that this was the area that, of the group that you were...?

That's right. The group I was in considered seven different Vietnamese studies, which concerned themselves with one or more of these kinds of reproductive outcomes. Really two types of studies were done. There were studies that were carried out in the south of Vietnam. And in the south women, um, had the potential for herbicide exposure as well as their mates.

There were also three studies that were carried out in the north of Vietnam using a rather ingenious study design. In the north, so far as we know, women were not at risk of exposure. But northern men, who served in the military, may have been posted to the south where they were of course at risk of exposure.

So these studies could compare the reproductive histories of couples, veterans always, where the father either did or did not serve in the south.

Would, do you consider these studies conclusive in any way?

No, I would say that they were conclusive. They certainly are...they are credible efforts. They were carried out by people who appear to have good credentials. That is they are medical people. At least they certainly attempt to use current methodologies and so forth. No single epidemiologic study is ever conclusive.

These studies, these were preliminary reports to us. We had a chance to discuss them at some length with the investigators but of course although they had been translated into English, um there was something...something I'm sure was lost in translation, and in some cases there was more work to be done on the studies. Um...

Would it be better in your view if, if, if uh more American scientists or western scientists could be working directly with the Vietnamese in studies of this kind, or doesn't it matter?

I think that in terms of the acceptance of the results in the international community, it would be a good idea if there could be some kind of collaboration, some kind of international collaboration in the data gathering and in data analysis. And in fact I know of at least one case where that is ongoing.

The data are being analyzed both here in the US by scientists at Stony Brook and by Vietnamese investigators. And they also worked together to design the study and items in the questionnaire and so forth.

Um, what...what lessons do you think we should learn, should have learned, ought to consider trying to draw from this whole episode of the use of these herbicides, these potential side effects, and with all of these fears and questions that that has raised in the minds of so many people?

Well, those are hard question. No, I shouldn't say that because I'm not supposed to hear your question...Um, give me a minute. I'd like also, can I step back? Can we go back for a minute? I want to be able to tell the results of the studies. I want to at least give my impressions of what I think that the evidence is worth taking account of in the Vietnamese studies.

Um, I think that although they aren't conclusive that there are at least two points that are worth our consideration in terms of future research here, and perhaps some kind of collaborative research or support of future Vietnamese studies. And those are the possibility that exposure to Vietnamese women may have increased their risk of hydatidiform mole which is already for us, reasons that are not understood a more common occurrence in Asian populations.

And also, and of course this is of great concern to the US veterans, on the basis of the Vietnamese research I don't think we can be complacent about the possibility that paternal exposure, exposure by the male to herbicides has not caused birth defects in the offspring. I think we have to continue to consider that as a possibility although studies don't um make this a definite certainty. Um. In terms of lessons that could be learned by the experience, it's hard, and I think some of the government...

Before you...we just ran out of film.

What lessons would you draw?

I think if there is a lesson to be learned from this it is that we have to learn to move a little bit more expeditiously. We already have some animal evidence suggesting human risk or that there might be reproductive risk and then we begin to get reports from humans of clinical effects, we need to be prepared to mount studies more expeditiously.

Ah...epidemiology is difficult enough, but when we are trying to measure effects of exposures that occurred at a minimum of ten to fifteen years in the past, we, we throw up maybe even insuperable obstacles.

Cut. But, is that all right?

The lessons.

I think one of the lessons we need to learn from this is that we need to be prepared to act more quickly. If we get the first inklings from laboratory research that a particular compound may pose reproductive risks, as soon as we begin to hear complaints from humans that there may be in fact clinical effects, we need to begin to be prepared to do epidemiologic investigations. If we wait as we have in this case fifteen years after the time of exposure we complicate what is already a very difficult task.

Cut. Very good.

Why has it been relatively easy apparently to identify chloracne as ah, as an effect of dioxin exposure?

Granted that there is always some difficulty in drawing firm inferences about associations between a particular agent and disease in epidemiologic studies, um I think the reason why we feel that we can say with some certainty that chloracne is a consequence of dioxin exposure is that it is a very specific and even unusual type of effect and one that does not have a large number of other known causes.

Some of the other clinical problems that have been proposed as effects of herbicide or Agent Orange dioxin exposure are much more general. These kinds of central nervous system effects can have many other types of causes. The same is true of birth defects and certainly of miscarriages which are a very heterogeneous type of disorder.

Is chloracne very serious? Does it go away? Does it persist? One hears about veterans who still have it all these years after exposure.

Um, although I've not, myself, I don't do work on chloracne, I've uh, know people at Mt. Sinai who do. And they certainly can point to cases and quite serious cases, and certainly if it is a skin rash it certainly is one of the more serious skin rashes, which after some time did appea—did disappear. But it certainly does seem in many instances to be quite persistent. It's hardly a trivial, uh trivial affair.

Cut.

I think part of the problem that's arisen in connection with the veterans' concerns that their exposure may have caused an increase in birth defects in their offspring is two fold. One is that they are talking about defects occurring in pregnancies many years after exposure.

It means... it's a little unusual. It means that the substance has to be in the body for some period and able to operate at the time of the conception. The other problem is that we don't yet know of a situation, either, certainly not in humans and rarely in laboratory animals where exposure to the male parent can affect a conception that has already occurred except by genetic means. And the defects that we are talking about are generally not genetic defects.

Okay.

No good? You try, we try again, it's a real, it's a real, I mean it's, it...

A problem, um, I think, in trying to deal with the veterans' concerns that their exposure has caused an increase in birth defects, defects like cleft palate and neural tube problems in their offspring is that it's not a biologic mechanism that is well known or established at all in humans. In general if we think about the male parent we think that there's damage to the germ cells.

This could give rise to a gene mutation or to a chromosome anomaly like Downs' Syndrome. But when we talk about neural tube defects or cleft palate, these have their origins after conception, and in the past have at any rate been associated with exposures to the mother during pregnancy.

Cut, I think...

Is that better or can you come up with something?