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FOOD ADVISORY COMMITTE Meeting: Acrylamide - Transcript of Proceedings February 25, 2003

February 24 - 25, 2003

Transcript of Proceedings February 25, 2003

 Transcript of Proceedings February 24, 2003
 

PARTICIPANTS

Sanford A. Miller, Ph.D., Chairman
Catherine DeRoever, Executive Secretary

PARTICIPATING FOOD ADVISORY COMMITTEE MEMBERS

Francis Fredrick Busta, Ph.D.
Annette Dickinson, Ph.D.
Johanna Dwyer, D.Sc., RD
Brandon Scholz

TEMPORARY VOTING MEMBERS

Jean Halloran
Ken Lee, Ph.D.
Harihara Mehendale, Ph.D.
Robert Russell, M.D.
Clifford W. Scherer, Ph.D.
J. Antonio Torres, Ph.D.

GUEST SPEAKERS

Robert Brown, Ph.D.
Tim Fennell, Ph.D.
Stephen S. Olin, Ph.D.
Sorell Schwartz, Ph.D.
David Zyzak, Ph.D.

CONTENTS

Call to Order:
Dr. Sanford Miller

Animal Studies and Human Health Consequences:
Dr. Sorell Schwartz

Questions of Clarification

 

Acrylamide Toxicity: Research to Address Key Data Gaps:
Dr. Stephen Olin

Questions of Clarification

Potential Implications:
Dr. David Acheson

Questions of Clarification

Summary, Charge and Questions:
Dr. Terry Troxell

Public Comment

Discussion and Committee Recommendations

PROCEEDINGS

Call to Order

DR. MILLER: We will begin the second day's program. At some point later on this morning, depending on how the discussion goes, we will determine the program that we will follow for the rest of day and see how much time we are going to need in order for our discussion and so on. We will see whether we may be able to finish early and those of you who have planes to catch will have a little more time to do that.

Our first speaker this morning is Dr. Sorell Schwartz of Georgetown who is going to talk about animal studies in relation to human health consequences.

 

Animal Studies and Human Health Consequences

[See presentation slides for Dr. Schwartz]

DR. SCHWARTZ: Thank you.

[Slide.]

It is a real privilege to be here. We never had to worry about true-type font. Now, you do because I submitted my slides to the FDA and what was a true-type font on my computer wasn't on theirs, so their computer attempted to make conversions and didn't do very well. So, this morning, we spent some time straightening it out.

However, all the errors are carried on to the printed sheets of the slides that I have. So some of them may be out of format and some of the symbols may be wrong. But welcome to the world of computers.

My presentation does not deal specifically with acrylamide. It really deals with interspecies extrapolation, the extrapolation of animal data to human data, to human use. It can take many forms. It can be rather gross such as in the default options, the false scientific assumptions that are made. If a material is a carcinogen in an animal, it is a carcinogen in a human. Why? Because we say so. That is one form of interspecies extrapolation based pretty much on what someone might say is a prudent public-health policy, or that the human is at least as sensitive as the most sensitive of animals when it comes to carcinogenicity. Again, why is that? Because we say it is based on just policy matters. But it is hardly a scientific extrapolation.

For noncancer effects, we can have also relatively gross extrapolations taking the no-observable-adverse-effect level that is observed in a rat or a mouse or whatever, dividing it by 100 or dividing it by 1000 as a safety factor, actually an uncertainty factor, again not a very sophisticated means of extrapolation but it gets the job done with respect to doing on harm, or hopefully doing no harm.

But more ambitious attempts at interspecies extrapolation involves some form of scaling the physiology of the experimental animal to the physiology of the human.

[Slide.]

The foundation of interspecies extrapolation with respect to the effects of chemicals on the biological system actually rests on two pillars; pharmacokinetics and pharmacodynamics. Pharmacokinetics, as can be seen, deals with the actions of the body on the chemical, itself. It deals with the absorption, the distribution, the metabolism and elimination, the so-called ADME, and the output that we get from it is a concentration-time relationship.

The other pillar are the pharmacodynamics which is the action of the chemical on the body. The system we are dealing with is the interaction with biological ligands. It may be a receptor. It may be an enzyme. It may be DNA. It may be some type of adduct formation. The output is, of course, the biological response.

In the interest of saving time, suffice it to say, there are no means to predictively extrapolate biological response across species other than heuristics, other than we have certain things we understand. If we are extrapolating something like some specific organ toxicity like neurotoxicity, we tend to feel that we can extrapolate from animal to man with some degree of reliability.

On the other hand, cancer as carcinogenicity is a bit more iffy, as we have learned, and teratogenicity, birth defects, are essentially extrapolatable only by guess, recognizing, for example, that the positive control in teratogenicity experiments is aspirin. So it is something that doesn't extrapolate well.

So we are left with really our heuristic understanding of what goes on in extrapolating pharmacodynamics. So that leaves is pretty much with the pharmacokinetics.

[Slide.]

Pharmacokinetic dose extrapolation from animal to man, we essentially say, let's take the area under the concentration time curve that we get for an experimental animal at a particular dose and see what it takes in man to get that same area under the curve, what dose that is.

This action is strictly empirical. There is some computation involved in estimating it, but essentially, we give the dose, we know the pharmacokinetics in man, we know the pharmacokinetics in the animal. We look at the area under the curve of the dose that has caused the effect we are looking at. What we are looking for--in this case, we have it as an LD10, which we are translating to the minimal tox dose in man, and we try to create the same area under the curve, the area under the curve and the same Cmax, so that the curves look the same.

That is essentially the goal of interspecies extrapolation but it is not as easy as one might think.

[Slide.]

We should digress a minute and look at what can we scale among species. All of us know that a rat is not a small human. Nonetheless, we continue to treat it that way. We give dose per kilogram in a rat and we say, okay, what is the dose per kilogram in a man and, somehow, we make that extrapolation.

But we know, in our heart of hearts, that a rat really isn't a small human. So, we look for some type of proportional interspecies scaling. One is isometric which means that the proportion in the rat or in the experimental animal is the same as in the human. So, across species, the proportion of the heart weight to the body weight is constant across species. The proportion of lung weight to body weight is proportional across species. And skeletal weight, and muscle weight, and GI-tract weight.

All of these are proportional across species and whatever percentage it is in a rat, you can expect within some error estimate, to be that same percentage in man.

There is one particular organ that is missing here, and that is the brain. The brain does not extrapolate across species. Actually, it does extrapolate across species except one, and that is the human. If you extrapolate across species the brain weight, it works out pretty well until you get to man because, if man is part of that extrapolation, the brain weight would be predicted to be about 275 grams. Actually, of course, it is about 1200 grams.

So this is one departure which we are going to discuss a little bit later but it is of particular importance. So isometric scaling pretty much covers for organ weight, most organ weights, and blood volume and respiratory capacity.

[Slide.]

That is isometric. Now, allometric scaling essentially says that we can extrapolate across species to some exponent of the body weight. That exponent b, in this case, is the allometric scaling component and a is a coefficient that we get from regression analysis. But is the scaling exponent that is important.

What we spoke of before, the isometric extrapolation, that scaling component is 1 so that we have a direct proportion to the body weight. There are two general categories of scaling exponents. One is at about 0.25 and heart rate, circulation time, respiratory rate, extrapolate at a scaling exponent of 0.25. The other is 0.75, or approximately 0.75.

Basic metabolic-rate blood flow, and we are going to discuss clearance in a little while, can also be extrapolated within a range of some error of that scaling component. We will discuss it in a little more detail.

Some of you who are familiar with this may say, what would have happened to two thirds, because there a two-thirds scaling component is often used. There is some disagreement with basic metabolic rates should be scaled to two-thirds or 0.75, but the two-thirds scaling is primarily used in scaling body weight to surface area.

It is used clinically in cancer chemotherapy because dose scaling in cancer drugs seems to work best by dosing per body surface area rather than per body weight.

DR. LEE: Ken Lee. Could you just explain how circulation time and blood flow are different?

DR. SCHWARTZ: Circulation time is the time it takes to get from one point to the other at a particular measurement. We know what that is. The blood flow really deals here--I understand your point. Overall, it would seem they should be the same. But it is really scaling the blood flow in a particular organ.

When you look at blood flows in particular organs, the liver blood flow, the pulmonary blood flow, the blood flow through any particular organ, scales at 0.75. The total circ time scales at 0.25.

But I understand your question and it is not clear as it is presented there.

[Slide.]

Now, pharmacokinetic factors that we have to worry about or be concerned about with respect to interspecies extrapolation, and it is the same pharmacokinetic factors we have to deal with clinically, are volume of distribution, clearance and the absorption and bioavailability.

[Slide.]

The volume of distribution is essentially defined as the volume the chemical would be distributed in if it were distributed throughout the body in the same concentration it is in the blood. So you can have, for example, a volume of distribution of 70,000 liters, certain drugs which--certain antimalarial drugs bind very strongly to all sorts of protein outside the circulation.

So it is an apparent volume, but it is important because, thermodynamically, the system actually behaves as if that apparent volume is a real volume. So it is the total mass of the chemical in the body divided by its concentration in the blood. It describes the distribution of the chemical throughout the body and, ultimately, to the biophase, the site of action.

The greater the volume of distribution, the greater the biological half life. This is scalable based on interspecies composition relationships and physical-chemical factors, what are called quantitative structural pharmacokinetic relationships. This is essentially scalable isometrically. Generally, it is scalable isometrically.

If we think about the body weights, the organ weights, being scalable isometrically, you could understand what the line of distribution might be. It is not absolute, but it is generally within 0.9 to 1.0.

[Slide.]

The clearance is the volume of blood per unit time from which the chemical is completely extracted. The higher the clearance rate, obviously the smaller the half life. It is the blood flow times the extraction ratio. The blood flow is allometrically scalable across mammalian species, as we said. It is generally to an exponent of around 0.75.

But the extraction ratio may or may not be scalable. Extraction ratio refers to just that, what fraction of the drug or the chemical is extracted by the organ. If the extraction occurs by some process such as filtration diffusion, that is a nonsaturable first-order process. Generally, it will be scalable anywhere between 0.75 and 1.0.

However, if there is metabolism involved, depending upon the saturability of the system, if it remains pretty much first order all the way through, it will be scalable. But you can also expect there will be interspecies differences in metabolism.

In the case of acrylamide, there are interspecies differences in the metabolism of acrylamide to glycidamide. Also, the acrylamide to glycidamide is saturable. In doses likely to be in contaminated foods, it is not going to be saturable, but, also, the glutathione conjugation of acrylamide and glycidamide which is a means of inactivating both of the compounds is also saturable so that extrapolation from animals can be iffy when you are looking at the metabolism of these compounds.

[Slide.]

As I said, clearance can be flow-limited, meaning we have a high extraction ratio. The clearance is really determined by the blood flow. If we have a low extraction ratio, then the clearance's capacity is limited, that would be a saturable system, what I was just speaking about. Flow-limited clearances, like I said, would be more likely to be scalable than capacity-limited clearances.

[Slide.]

Now, absorption and bioavailability are very important factors to deal with especially when you are speaking of exposures that concern food contamination. The bioavailability, which is the upper case F here, is a function of the fraction that is absorbed, the fraction that gets by GI tissue metabolism--that is why 1 minus fg is the fraction that gets by tissue metabolism--and the fraction that gets by liver metabolism. That is the same extraction ratio that we were talking about before that is equivalent to an hepatic first-pass effect where a drug is absorbed, when the drug passes from the gut into the liver through the portal vein. Before it gets into the system, it must pass through the liver. In passing through the liver, there is this first-pass effect which will metabolize the drug and reduce the systemic availability.

The problem is that you can have variations in extraction ratios, small variations in extraction ratios, which can greatly affect the bioavailability.

[Slide.]

In the interest of time, I am not going to go through some of the factors that I was going to go through, but the point that I want to bring out is that, depending upon the size of the extraction ratio, we can have small changes in the extraction ratio and large changes in the effective dose.

Conversely, we can have--this is part of the problem with the formatting. This is not complete, so I am not going to dwell on this other than to say that the extraction ratio variations can have a very profound effect across species on what is absorbed and what the absorbed dose is. It is something that I find, in reading the literature, is not often taken into account as it should be.

[Slide.]

So, for allometric extrapolation, what is likely to be reliable? GI absorption is likely to be reliable, the actual absorption, just the movement. The volume of distribution is likely to be reliably extrapolatable as blood flow, clearance, where the clearance is flow-limited and the extraction ratio is high, and bioavailability, where the extraction ratio is low.

I am not going to go into the reasons for all of this but it shows you that, in fact, you have a yin-yang between clearance and bioavailability as far as extraction ratio goes; that is, that a high extraction ratio favors the scalability of clearance but not of bioavailability and vice versa, a low extraction rate does not favor the scalability of clearance but does favor the scalability of bioavailability, which shows that life is difficult, which you probably already knew.

[Slide.]

It is less and less likely to be reliable, as I said, as we have just stated before.

[Slide.]

There are certain allometric approaches to clearance, certain variations. One is that the first approach is the one that we were just describing, just the straight equation.

Another involves the inclusion of neoteny, which is peculiar to humans. Neoteny refers to the juvenilization of humans; that is, it takes human a longer time to reach maturity than it does most mammals. Most mammals reach maturity at about 30 percent of their body weight. Humans reach maturity, puberty, at about 60 percent of body weight and it seems to have some relationship to both the life span, the maximum life-span, potential and the brain weight of humans.

There have been various approaches to include neoteny using, for example, a particular approach, the same equation of body weight to the exponent but divided by the maximum life-span potential, one involving the brain weight and the body weight. But, interestingly, as it has turned out, there is a question of whether the neoteny is as important as really doing some straight-out in vitro measurements of hepatocyte activity in the animal and in man.

[Slide.]

We can, now, get liver from humans. It seems that a way around the interspecies extrapolation for clearance, where metabolism is an important factor, is to take the clearance that is determined in animals in vivo, then take clearance determined from examination of individual human and animal hepatocytes and essentially use that as a correction factor to get the clearance.

This seems not to involve any other assumptions, brain wave or life span. It is just measuring the actual enzyme levels, themselves.

[Slide.]

Another approach to interspecies extrapolation is physiologically based pharmacokinetic modeling. The one problem with allometry, as we have pointed out, is the fact that you can allometrically scale various individual factors in animals, but there is no way to combine all of the factors. We just pointed out, there is a probem of scaling both clearance and bioavailability when the extraction ratio is either very high or very low.

There is the other question of extrapolating various functions that, in fact, may work against each other, like we were discussing with bioavailability and clearance. In physiologically based pharmacokinetic modeling, essentially each organ is modeled by its own flow equation and we establish a model using a series of simultaneous linear and nonlinear differential equations that allow the determination, or the estimation, of concentrations in each tissue, specifically, to estimate what is in the biophase because it is not drug in blood, or chemical in blood, that is active. It is not chemical in the tissue that is active. it is chemical at the site of action that is active.

What is in the blood and what is in the tissue may not always reflect what is at the biophase of the site of action. In the case of acrylamide and its metabolite, glycidamide, dealing with adducts, potential DNA adducts, you could--now this happens to be rate model for drugs, but the pharmacodynamic side of this could be binding characteristics for adducts so that you could go all the way through and, through such a model, estimate what the binding to adducts would be in the animal compared to humans and extrapolate that and then make some assumptions about response.

[Slide.]

Just to let you know that, in this particular model, you not only can model the parent compound but you can model its metabolite essentially by running a parallel model where one model feeds the metabolite to the other and it goes through its own distribution.

[Slide.]

So physiologically based pharmacokinetic modeling to low-dose interspecies extrapolation, we develop the human physiologically based model using the tissue-blood partition coefficient that can be developed from animals because that is easily scalable, use the value for organ clearance based on human experimental data in vivo or in vitro, or by allometric extrapolation.

[Slide.]

We can use the model to identify daily intake resulting in particular target-tissue concentrations equivalent to the tissue concentration in the experimental animal, and, if there is insufficient information to develop a human PBPK model, we can extrapolate the estimated animal intake associated with an observed response to a human intake using an appropriate allometric relationship.

[Slide.]

Finally, there are a number of applications of the model, of using PBPK modeling. One is interspecies extrapolation. Another is predict the target-site concentration. The extrapolation in cases of nonlinear pharmacokinetics, or pharmacokinetics, where, for example, if you give a dose X, then you get Y blood level. If you give 2X, you expect to get two wide blood 2Y blood level. In nonlinear pharmacokinetics, that doesn't happen. Physiologically based pharmacokinetics allows you to correct for that.

It is especially good for low-dose extrapolation. It is good for route-of-exposure extrapolation. Physiologically based pharmacokinetics can allow you to take, for example, if you had a study, an animal study, that deals with inhalation of, let's say, acrylamide, or dermal absorption of acrylamide, it allows you to simulate what it would have been had it been an oral-dose experiment, a feeding experiment.

It also allows relative risk for multiple route of exposure, which doesn't apply here. So acrylamide, it does apply to such things as benzine. Finally, something here with acrylamide and hemoglobin adducts, it will allow estimations of exposure based on biological markers.

This is going through pretty fast, but to show you the various techniques that are involved in extrapolation. The most important thing that we have to know about models is that we never prove a model is correct. All we do is use it until we prove it is incorrect, which happens, so far, all of the time.

DR. MILLER: Thank you, Sorell.

Questions of Clarification

DR. MILLER: Questions or comments?

DR. BUSTA: Frank Busta. Based on this last summary, what data would you need from our question at hand?

DR. SCHWARTZ: Your question at hand being the extrapolation of acrylamide animal data to human data?

DR. BUSTA: And/or the consumption of acrylamide by humans at low doses.

DR. SCHWARTZ: My own feeling is that--first of all, I should say that acrylamide is not my field but, obviously, in preparation for this presentation, I did look to see what had been done in the modeling.

There have been some physiologically based pharmacokinetic models with acrylamide. I think from the point of view of your problem, that is the only way to go. The reason is that you have, first of all, the problem that you have a number of different routes of exposure--you have a few different routes of exposure, datasets that can be converted, if you will, by modeling to oral administration datasets which allows you to use the data.

Secondly, the concern about whether or not the amount of acrylamide likely to be taken in would saturate, or the effect it would have on glutathione conjugation. Glutathione conjugation is especially important in the inactivation of electrophiles of which, as you know, acrylamide and glycidamide are both.

I think that is pretty hard to do by straight allometric extrapolation but it can be done, it can be estimated, by physiologically based pharmacokinetic modeling. I think those are the factors.

The real question is whether or not the amount of acrylamide likely to be taken in during food exposure is going to affect how you can extrapolate from animal to man by virtue of--I guess my question is does the metabolism still remain first order. In other words, do you have enough to start saturating the metabolic systems or is it low enough that it won't saturate them and you can treat it as first order, which makes extrapolation a lot easier.

So, I would think the latter. I would think that you wouldn't saturate. You can think of all sorts of clinical situation, of someone who is taking too much tylenol or drinking too much alcohol that could have an effect on how acrylamide might respond. But that is sort of an academic exercise.

I think, from a point of view that you are interested in, PBPK modeling would show that you can deal with metabolism pretty linearly--I think. I guess the other question is whether using hemoglobin adducts as biomarkers would be of value. A PBPK model would give you some idea of that.

Does that answer your question or not?

DR. BUSTA: If I followed you, maybe.

DR. SCHWARTZ: I am sorry. I can understand the frustration that people have with pharmacokineticists, but I guess, in summary, we need to know metabolic data, we need to know physical data, tissue-distribution data. But that has already been determined for acrylamide, as far as I know. There already is a PBPK model. It hasn't worked all that well, but it is not necessarily because of lack of data.

DR. MEHENDALE: I guess one way to approach this is, partly you mentioned, the partition coefficients are generally available and the metabolic constants, kms and so on, should be available. I don't know if, for human tissue, they are available and that might be useful and suppose it can be determined from the human hepatocytes if it is not available.

But, certainly, for animals, I suspect it is available. If it is not, it can be determined. But one area that I think would be useful--generally, we look at the PBPK model as a way of dose extrapolation as you rightly emphasized. But, if there is an enzyme saturation, which, at high doses, is likely to occur--at very low realistic consumption levels, probably not.

But the issue here is that if there are animal data with high whopping doses of acrylamide, can they be used to extrapolate to humans, and if enzyme saturation is an issue.

Generally speaking, it has turned out to be an issue whether it is the glutathione pathway or the cyp 2E1 pathway. This compound is certainly showing some signs of saturating cyp 2E1 at high doses.

So my comment is whether knowing this data would be useful in trying to determine whether animal data obtained at very high doses can, in fact, be useful unless we establish those issues of saturation and so on in extrapolation with PBPK.

DR. SCHWARTZ: You have brought up what has been an age-old problem--actually, it is an age-old illusion--and that is that somehow or another, that we can get away by taking large doses, taking results of studies with large doses, and extrapolating them somehow back down to low doses without taking into account saturation.

As you know as well as I do, this has been done time after time after time. It is illusory. If you have a saturable enzyme system and you are giving large doses, it could be illusory in two directions. If your metabolite is this toxic component, you could actually be underestimating the toxicity of the substance. If your parent compound is the toxic compound, you can be overestimating the toxicity by extrapolating to low doses in these.

But you are absolutely right. It is necessary to know, and I think with the availability now of human liver and such, I think it is necessary to know what Vmax is and km for human versus the Vmax and km for whatever animal you are working with.

I think it is very fundamental data to have before you can speak about doing any extrapolation to low-dose exposure from animal experiments.

MS. HALLORAN: I am just trying to make sure I am following the discussion here. This question of extrapolation from the animal studies to the human situation is, obviously, critical. Do we, at this point, have the necessary data in terms of the pieces of the analysis you were just describing to more or less extrapolate from rat studies to human, or are there critical pieces of experiments that still need to be done to do the best possible reasonably acceptable extrapolation?

DR. SCHWARTZ: I would be deceiving you if I answered your question of how much acrylamide because it is not my area of familiarity that I have, as I said. I am discussing the methodology and I familiarized myself with some of the material that is available, but I do not know all the data available.

I think that what we are saying is that here is what data you need. Whether we have it or not--I know you don't have the human hepatocyte data, but whether you have it or not, I don't know. I do know that what data was used in the development of the physiologically based pharmacokinetic model and it didn't have human hepatocyte data.

So, actually, I can't answer your question. But we can pretty well define what it is we need and then you can decide whether or not to go after it. I do have to say some of the reviews, some of the summaries, I have seen on the ADME of acrylamide in the various reports I read and familiarized myself with, have a degree of naivete about them. I don't mean that in a pejorative sense. It is just that you really have to do exactly what you are doing right now, is say, what do we need to really model this.

So the answer to your question is, the only thing I can tell you is it is a good question. But I can't tell you the answer.

DR. DWYER: Just to follow up on Ms. Halloran's question. I think that the thing that I found a little unsettling was your comment that you can only prove that a model is incorrect and then you said that the PBPK modeling that had been done so far didn't come out very well, and then you just said the modeling was naive.

Now, would all of those things contribute to an underestimation of human risk, an overestimate of human risk or isn't it possible to even say that?

DR. SCHWARTZ: First of all, my response of modeling, it wasn't the PBPK modeling that was naive. I said the discussion of the pharmacokinetics was naive meaning that it didn't deal with the various issues such as interspecies extrapolation and the PBPK modeling was not, by any means, naive. It was very aggressive, in fact.

What is the second half of your question? I'm sorry.

DR. DWYER: I think the bottom line is whether all of this means that the modeling--are we in danger of underestimating human effects or overestimating, or is it like the three bears, just right?

DR. SCHWARTZ: I can't answer the question. We are always in danger of overestimating or understating. From a regulatory point of view, we are always in danger of overestimating, if danger is the right word, primarily because of the natural instinct to be very conservative.

But I think, from what I can see, and you have to understand, I am speaking really as a novice with respect to acrylamide. My major interest in acrylamide had been to neurotoxicity and some issues we dealt with some time ago. But, from what I see, there is a danger of overestimating the toxicity if the main toxic component is acrylamide and underestimating it if it is glycidamide. That really deals with the issue that, at a very large dose, you are getting less proportion of glycidamide than you would at a smaller dose.

DR. LEE: Ken Lee. What you just said, does that apply to the neurotoxicity as well as carcinogenicity, or are you referring to one or the other?

DR. SCHWARTZ: The neurotoxicity will occur at much larger doses than you are ever going to find in food. I can't see neurotoxicity as being a concern here.

DR. MILLER: The thresholdable phenomenon.

DR. SCHWARTZ: Right. It is not very plausible based on the dose-response data that we know that you really face with the neurotoxicity problem by the type of contamination you are talking about. The acrylamide neurotoxicity comes really from occupational exposure.

DR. MILLER: Other comments? It seems clear from Dr. Schwartz' presentation that there are substantial areas that require research. I think one of the questions that we have to determine is whether or not the modified action plan covers those areas.

Thank you, Dr. Schwartz.

Our next speaker this morning is Dr. Stephen Olin from ILSI who is going to talk specifically about acrylamide toxicity, research to address key data gaps.

 

Acrylamide Toxicity: Research to Address Key Data Gaps

[See presentation slides for Dr. Olin]

DR. OLIN: Thank you.

[Slide.]

That discussion was, hopefully, an excellent lead-in to my comments here this morning.

[Slide.]

To give you a little bit of background, where I am coming from, as you know, the Joint Institute for Food Safety and Applied Nutrition, or JIFSAN, and the National Center for Food Safety and Technology convened a workshop in late October to examine current knowledge on acrylamide and food and particularly to identify and prioritize research needs in each of five areas as shown on the slide here.

I had the privilege of co-chairing the Working Group on Technology and Metabolic Consequences with John Doull and I guess that is why I was invited to come here and talk about research needs specifically with regard to acrylamide toxicity for developing a risk assessment for acrylamide.

[Slide.]

The Working Group on Toxicity and Metabolic Consequences identified data gaps and research needs in these six focus areas. I would say, in general, that recommendations from our working group complement and build on the observations from the WHO consultation last June which, of course, is in your meeting materials.

I also would say, just to let you know, that the full report from not only our working group but the other four working groups at the JIFSAN workshop is available on the JIFSAN web site for you there, for details.

[Slide.]

I think the toxicity of acrylamide, the conclusions that came out, were really very broad and we have heard those reiterated here in various presentations and in the discussion of the committee. First, this research should accomplish these two objectives, first to assess the significance of adverse effects observed at high doses for low-level exposures in human foods, those high doses being in animal studies and, in the case of neurotoxicity, in humans and, secondly, to assess the significance for humans of effects observed in vitro and in vivo in rodents.

Dr. Schwartz and others before me have sort of laid out that challenge and our working group certainly concluded similarly.

[Slide.]

What I would like to do, then, with you in the next few minutes is to quickly run through the research needs that were identified by the working group and at least what ongoing or planned research that I am aware of that will begin to address these research needs.

As was mentioned, I think, earlier, the Acrylamide in Food website that is being managed for WHO and FAO by JIFSAN is a place where ongoing research is being posted and recorded, so that is certainly one useful resource to keep track of what is going on out there with regard to acrylamide.

First, with regard to this area that Dr. Schwartz and you talked about a bit, kinetics metabolism and modes of action or mechanisms of toxicity of acrylamide. We know that acrylamide can exhibit several kinds of toxicity in animal models, carcinogenicity, neurotoxicity, germ-cell mutations, others, but to effectively use these data in assessing risks to humans, we need to know more about the modes of action leading to these toxic effects, the critical events along the way and the dose metrics. So that is identified as one of the key research needs.

We also have quite a lot of information about metabolism and kinetics in rodents, as has been suggested here, but the working group really felt that we needed to make the link now with the metabolic fate and kinetics in humans. Those data, frankly, are lacking.

To pull all of this together, then, the group felt that we really need a good physiologically based pharmacokinetic model as discussed by Dr. Schwartz that will allow us to calculate dose to target tissue or dose to specific receptor or cellular component that may be a risk as a function of dietary intake for rodents and humans.

So how are we doing on these research needs in terms of ongoing or planned research?

[Slide.]

We hope that FDA will be able to gather some information on critical events and dose metrics for the postulated modes of action for the various endpoints in conjunction with the NTP bioassays. I think there were some hints of that in the draft action plan that would certainly support that.

We know that NIEHS has beginning studies with this special mouse strain that has been discussed already here in which the gene for expression of the cytochrome P450 2E1 has been deleted, the so-called cyp 2E1 null mouse. These studies certainly will help to distinguish between modes of action that, in critical events involving *glycidamide and those that bypass glycidamide.

There are also some industry-sponsored studies that will contribute to our understanding here.

You heard yesterday from Dr. Fennell about the ongoing RTI work on metabolism and kinetics in humans. CDC, apparently, is planning studies of the relationship between intake and biomarkers of exposure prior to the next round of NHANES and that was discussed briefly yesterday. Several other groups are looking at this problem from various perspectives, the group at Stockholm University in Sweden, at Kaisersalutern University in Germany and others.

With regard to PBPK models, there actually was a fairly extensive PBPK model for acrylamide and glycidamide in the rat and it was published just a few weeks ago by Kirman et al. The authors of that paper note that additional data is still needed to refine model parameters for metabolism and tissue binding, particularly, in the rat and they reiterate the need for a human PBPK model for acrylamide.

I would just add that that human model also should consider variability in kinetic determinants across different life stages. We are beginning to see some models that attempt to do that and I think that would be important for acrylamide.

[Slide.]

With regard to genetic toxicity, the genotoxicity of acrylamide and, to a lesser extent, glycidamide, has been studied in a number of traditional assay systems over the years. I think the consensus at the moment is that the results for acrylamide, itself, are a bit of a mixed bag whereas, for glycidamide, we seem to have a classical DNA-reactive mutagen.

The working group identified as priority research needs in this area the identification and characterization of adducts of acrylamide and/or glycidamide with DNA and with significant nuclear proteins including the biological relevance of these adducts and their dependents on species and dose both in vivo and in vitro. You heard a little bit about ongoing planned research in that area, again, from Dr. Fennell yesterday.

The working group also pointed to the importance of the investigation of mechanisms of specific genetic effects that have already been reported such as various chromosomal effects, cell transformation et cetera.

[Slide.]

As we have seen in the draft FDA action plan, NCTR is planning DNA and protein-adduct studies including dose response in vivo to be coordinated with the rodent bioassays. Industry also is sponsoring some DNA adduct studies.

Mechanistic studies at NCTR, perhaps including in vivo mutagenicity and transgenic models such as the Big Blue rat and the thymidine-kinase heterozygous mouse as well as industry studies looking for indirect effects mediated by certain chromosomal motor proteins, kinesin-related proteins, for example, should also help to define the likely shape of the dose-response curve at lower exposures for genetic effects. So those are felt to be key research needs in that area.

[Slide.]

With regard to developmental and reproductive effects, the effects of high doses, relatively high doses, of acrylamide on reproduction in rats and mice has been well-documented. The primary effect seems to be germ-cell toxicity related to dominant lethal mutations.

The research need, however, here is for dose-response data for this germ-cell toxicity, probably in rodents, to assess the risk at lower doses for information on whether the toxicity is a direct effect of acrylamide or due to its mutagenic metabolite, glycidamide. If they had to put their money on it, they would guess glycidamide, but that does need to be defined.

The potential for developmental neurotoxicity also has not been extensively studied and the working group felt that, given the dietary exposures that we are seeing to acrylamide, more work was needed in this area.

[Slide.]

In terms of ongoing or planned research in this area, NIEHS has indicated that they will include a study of dominant lethal mutations in their work on the cyp 2E1 null mouse which will, again, test the hypothesis that glycidamide or a subsequent metabolite, perhaps, of glycidamide, is responsible for these effects.

I am not really aware of other studies on germ-cell toxicity that are planned or ongoing at the moment.

NCTR is interested in doing some work on developmental neurotoxicity under the NTP program and also the ongoing academic studies on mechanisms on neurotoxicity may shed some light on this question. So this developmental-neuro area, I guess, could go on developmental or it could go in neuro and I put it here. So now you have seen it.

It is my understanding that acrylamide and glycidamide also will be evaluated in the NCTR neonatal-mouse assay system. That certainly will be a valuable addition to our understanding of effects of early life exposure.

[Slide.]

Carcinogenicity; obviously, this has been highlighted, I guess, in much of the discussion of acrylamide that we have heard recently. The working group meeting in October was aware that the National Toxicology Program already was considering conducting a new carcinogenicity study in rats and mice at NCTR to confirm and clarify the results in previous studies.

The group noted that this could also provide an opportunity to develop enhanced data for cancer dose-response assessments, to assess the effects, if any, of perinatal exposure on carcinogenicity and, with ancillary studies, to gather useful information on the mechanisms of induction of key tumors, their modes of action, that might provide insight on their relevance to human cancer risk.

[Slide.]

So, in terms of ongoing and planned research that we are aware of, you have heard, now, the presentation of the draft action plan that plans are moving forward for the conduct of well-designed two-years studies of acrylamide in rats and mice at NCTR under the NTP program.

The neonatal-mouse studies, I believe, will require about a year or so to complete once they have been initiated and the full two-year studies in rats and mice, of course, will require several years. So another recommendation of the working group was that,in the meantime, an expert working group of pathologists be convened to look at the critical slides from the previous rodent studies all together using current diagnostic criteria with the intent of developing consensus views on some of the key neoplastic lesions.

NIEHS, as part of its efforts under the National Toxicology Program convenes these so-called pathology working groups or PWGs routinely. However, it has not been determined as yet as to whether this would be possible for acrylamide.

We also heard that FDA's draft action plan calls for mechanistic studies to complement the rodent bioassays and contribute to their utility for risk assessment and that is certainly important. Industry also has studies under way that should contribute to our understanding of the tumors that have been reported in rat thyroid, brain and the role of induced cell proliferation in various target tissues and so on. So there is quite a bit of work under way in that area.

[Slide.]

Neurotoxicity; as you all know, neurotoxicity is, in fact, the only toxic response of acrylamide that is well documented in occupationally exposed humans. The neurotoxic effects of acrylamide have been studied in the laboratory for years and years. Nevertheless, most of what we know about acrylamide's neurotoxicity is at high doses relative to our current understanding of dietary exposures in the range of tens of milligrams per kilogram body weight.

So, understanding of where our dietary exposures are, the working group concluded that we really need a better definition of the relationships between dose, duration of exposure and effect levels and the onset of neurotoxicity including a determination of the effects, if any, of low-level, long-term dietary exposures.

It is not that the group believed that we would see an effect there, but there is an information gap that may be important given the fact that we know that this can exhibit neurotoxicity in humans at high doses.

The working group further concluded that this research needs to link effects observed at the cellular or tissue level, the functional changes, to allow an assessment of the significance of the cellular responses.

It also became apparent in our meeting that several mechanisms of neurotoxicity have been proposed for acrylamide and that further work is needed including understanding the role of acrylamide versus glycidamide versus other metabolites or adducts and bridging of the studies in animals to effects observed or postulated in humans. So, where are we in that area?

[Slide.]

With regard to the area of dose duration and effect onset, there would appear to by an opportunity to gather some pertinent data in rats and mice in conjunction with the anticipated NTP studies at NCTR, although it is certainly true that the design of these studies may not be straightforward. For example, in the selection of the critical endpoints or effects to be monitored is not obvious but, perhaps, could be identified with an appropriate working group of neurotoxicologists familiar with this area. These studies also may be resource-intensive.

Mechanistic studies are continuing in academia at several universities and NIEHS will be using various approaches to look at the role of acrylamide and its metabolites and acrylamide's neurotoxic effects. Also, the proposed NIOSH study in exposed workers will examine markers of exposure and effect that should help with the animal human bridging part of that.

[Slide.]

Let's skip the next slide and just go directly on to ongoing and planned research in epidemiology.

[Slide.]

As noted before, the NIOSH study proposed to examine biomarkers of exposure and look for effects including neurobehavioral changes, also markers of reproductive effects, sperm motility, chromosomal changes, reproductive hormone levels and so on. There is also a report on the acrylamide and food website of planned industry review of the design and sensitivity of published epidemiology studies.

Finally, this was an area that was discussed some by the committee yesterday. As noted in the draft FDA action plan, there is a need to consider the feasibility and design criteria for studies in populations that are not occupationally exposed to acrylamide.

A case-control study of patients with enlarged bowel, bladder and kidney cancer and their dietary exposures to acrylamide appeared last month in the British Journal of Cancer. I believe Dr. Acheson is going to say something about that. There will undoubtedly be more such assessments of acrylamide exposures in existing populations for which health-effect ascertainment is already available.

The CDC NHANES database in the U.S., the EPIC dataset in Europe and others may be looked at prospectively over the longer term. Yesterday, we talked about the Women's Health Initiative, the Framingham study and others as possible for resources. Again, FDA has recognized the need to explore these opportunities in its action plan.

[Slide.]

So, what do we make of all of this? In conclusion, I think that it is clear that the ongoing and planned research, particularly the proposed FDA and NCTR efforts, will, indeed, address many of the most important toxicology research needs for acrylamide. Some of this work will be completed within the next few months or years, or within the next year, whereas some of it will require several years as we have seen.

It will be important to monitor the ongoing research and assemble the picture of acrylamide's risk assessment like a puzzle, as the pieces become available, perhaps modifying research priorities as we go, depending on what we are learning.

As a closing thought, though, it seems to me that, at present, our key objectives must include creating a robust PBPK model for acrylamide in humans and developing an understanding of the significance of high-dose carcinogenic effects in rodents and neurotoxic effects in humans and experimental systems for low-level exposures to acrylamide in foods. That, I think, is our principal research challenge.

Thank you.

DR. MILLER: Thank you.

Questions for Clarification

DR. MILLER: Comments or questions?

DR. RUSSELL: Thank you very much. I had a question about cancer sites. In the rat, I gather there is--you mentioned thyroid and brain and some mesotheliomas, I think, that are reported but, in the epidemiology studies, you just mention the sites. I haven't seen that report, but you mentioned large bowel and kidney in the human.

So is there some evidence that the site specificity is different in the animals versus humans?

DR. OLIN: No. The Mucci et al. study that appeared last month in the British Journal of Cancer was using an already existing cohort of patients with large-bowel, kidney and whatever the third cancer site was and then going back and looking at what could be ascertained with regard to dietary sources of acrylamide. So it wasn't specifically selecting those as likely sites, but those sites were actually available.

DR. MILLER: For clarification; is it true that the tumor types that were found in the animal studies were relatively rare types in humans?

DR. OLIN: Well, you know, that begs the question of site importance.

DR. MILLER: I am trying to clarify that.

DR. OLIN: There are some that are relatively rare. For example, the testicular tumors of the tunica vaginalis is not a common tumor in humans. The astrocytomas, we do see brain tumors, occasionally, in humans. The thyroid follicular-cell tumors, the question there, really, with the rat being the model, is are we looking at a rat-specific phenomenon that has been well-documented. That can be examined and I think that is being examined now to find out whether that is a relevant endpoint for human risk assessment.

DR. MILLER: The reason I asked the question is not because it is necessary for the same tumor site to be the endpoint in the species but to emphasize the possibility of important species differences not only in the site specific for the carcinogen but also in terms of metabolism.

We already know that rats and mice metabolize differently, so we already know there are species differences.

DR. MILLER: Dr. Mehendale?

DR. MEHENDALE: I know NIEHS is planning, I guess, this cyp 2E1 knockout, studies with knockouts. I wonder if anyone has considered some studies with mice that overexpress cyp 2E1. There may be some populations that would overexpress cyp 2E1 even if they drink alcohol or not. There may be other conditions for overexpressing cyp 2E1. Just a question to see if someone is considering those studies.

DR. OLIN: I am not aware of any such studies that are planned at the moment. The studies in the knockout mouse, of course, are really to try to sort out acrylamide versus glycidamide as the active intermediate.

DR. BUSTA: Frank Busta. I fully agree with your last conclusion there that the key objectives include those of developing a PBPK model, et cetera. When I listen to the research proposals that you put forward, it sounded like we wanted to really learn how to develop and care for rats. I know we know rat nutrition very well, so we have got that better than in humans.

It seems like a tremendous amount of work on high dose and on rat metabolism and not very much on low-dose exposures in food even though the whole workshop was titled Acrylamide in Foods.

DR. OLIN: If that impression came through from my presentation, that certainly was not the impression I wanted to give. The focus of all of this research, really, is trying to take what we already know at very high doses and assess the relevance of that for low-dose human exposures. That is, as you well know, easier said than done. But that is where we need to go with all of this.

DR. MILLER: Towards that same end, was there much discussion concerning dose selection?

DR. OLIN: Not really, other than the fact that it is the low-dose region that we need to understand better. But, in terms of the details of what specific dose-level studies need to be done, no. The neurotoxic rodent studies and, actually, a primate study as well, the carcinogenicity studies, and so on, generally have shown effects down to the level of around 1 milligram per kilogram body weight per day.

DR. MILLER: What kinds of effects? Carcinogenicity?

DR. OLIN: Carcinogenicity. I think for neurotoxicity, the WHO consultation, if I am not mistaken, estimated that the no-observed-adverse-effect level would be around 0.5 milligrams per kilogram body weight per day. So that is kind of where the animal studies have gone so far.

DR. MILLER: That would be the quasi-MTD?

DR. OLIN: The NOAEL, the no-observed-adverse-effect level. So the question, then, is how do we assess the shape of the various dose-response curves, and there are a lot of them, at levels below that down to the 1.0 microgram per kilogram body-weight level where we are seeing dietary exposures in humans. That is a long distance from a milligram to a microgram.

DR. MILLER: Right.

DR. DWYER: Now that you have seen the draft FDA plan, I wondered if you could give us your observations on areas where it might be further strengthened.

DR. OLIN: I think it is good. I really do. I am not being paid to say that. I mentioned a couple of areas along the way. This area of trying to gather neurotoxic data in conjunction with the bioassay studies may be a challenge. Those studies certainly haven't been designed. I don't have proposed designs, but I think that would be useful.

We need to get a better understanding of potential effects of chronic low-level exposures in rodents and we just don't have that data yet. I think continuing work in bringing all the pieces together for a human physiologically based pharmacokinetic model is an important goal.

DR. MILLER: Jean?

MS. HALLORAN: Hearing all this, I am impressed by the degree to which science has progressed in this area in the last year or so. It seems as though the questions have been fairly well defined and there are approaches to getting answers to them. I wonder if you could say how long--I know you can't always predict science, but here we have got very specific questions we are trying to get answers to.

How long will it take before the work has been done and the answers are in place to have a pretty good idea of whether you can extrapolate from high-dose rats to low-dose humans, or have the data in place to assess the risk to the low-dose humans?

DR. OLIN: I wish I could answer that. I can't say that I really know. I think there is some low-hanging fruit, as they say, that we can get answers to in a fairly short term. I think a lot of the answer to that really will depend on what data become available from some of this low-hanging fruit over the next six months to a year. I think we will have a better idea of what the critical issues really will need to be, what additional data might be needed for an appropriate risk assessment.

So that is why I think it is really important for the community at large to have in mind a framework for a risk assessment for acrylamide and to monitor the pieces as they fall in place so we can see how it is developing.

DR. MILLER: Again, as a matter of curiosity, was much thought given to the endpoints for the neurotoxicity studies, the functional endpoints that are going to be used, any suggestions that were made, because you get terrific differences depending on which model you use.

DR. OLIN: No; there was not a lot of detail given there. I think what was recommended was that the neurotox community come together and look at that and provide some consensus recommendations on what these studies should be. There has been some work on that. Dr. Canady cochaired a meeting at the neurotox meeting in Little Rock in November and there was some discussion of that issue then.

DR. MILLER: Any other questions or comments?

We are going to take a break now. If you would all be back by 10:20.

[Break.]

DR. MILLER: Our next speaker is Dr. David Acheson of CFSAN. He is going to talk about implications of this work.

 

Potential Implications

[See presentation slides for Dr. Acheson]

DR. ACHESON: Thank you, Dr. Miller.

[Slide.]

What I want to do in the next fifteen minutes is just to talk about some of the implications of a lot of the science that we have heard about in the last day and a half.

[Slide.]

I am going to divide the talk into three main parts. The first part is just to go over some of these current areas of scientific interest that we have been hearing about and then really to try to address this issue of what we know about these scientific areas in relation to the current impact on health risks, which I think is a critical question, and then finally to at least bring up the issue of whether the consumer message should be altered based on the current state of knowledge. I want to emphasize the word "current."

[Slide.]

To begin, I just want to repeat the overall goal that we have in this regard, "Through scientific investigation and risk-management decision-making, prevent and/or reduce potential risk of acrylamide in foods to the greatest possible extent."

Dr. Troxell already went over this, but a subgoal of that in relation to consumers is to, "Inform and educate consumers and processors about potential risks throughout this process as we go through it and as knowledge is gained.

[Slide.]

Consumers who are having to deal with this are having to address a multitude of questions and many of them are not easy to answer. I just put some of them on this slide which, from a consumer perspective, may raise questions such as will eating certain types of food cause cancer. What is safe to eat? Should I stop eating certain types of food in this context? Should I be cooking foods differently? What should I be doing differently to protect myself and family?

Although these are not particularly put in a scientific perspective, I think these are the sorts of questions that our goal is to try to come up with answers for.

[Slide.]

So our current consumer message is to eat a balanced diet that heeds the advice in dietary guidelines. I think one of the questions on the table is should this be any different based on current knowledge.

[Slide.]

So, where are we in terms of the science? You have heard a lot in the last day and a half about a whole variety of issues that relate to our action plan and the science that goes around it. I just want to go through some of these in a little bit of detail.

First of all, the whole question of the formation of acrylamide. We have heard a lot about that and with two great presentations yesterday in relation to looking at ways to diminish formation. Obviously, understanding the way in which the acrylamide is formed, what its components are, asparagine and reducing sugars, we will begin to open pathways to allow us to develop mitigation strategies.

So, formation is an important and ongoing area of scientific interest. There is ongoing work looking at the levels of acrylamide in food. Ever since this problem developed from last April, there has been an increasing number of publications related to the levels of acrylamide in food.

But this is ongoing. We already have generated a lot of information but there are more questions in terms of variability. You heard, through the talks yesterday in relation to using dietary intakes of various foods, and there was some discussion around that, of the limitations of intake data, two days, three days, fourteen days, when we are really dealing with the need to understand chronic exposure.

The exposure assessment, about which I will say a little bit more about in a subsequent slide, you heard about that yesterday and how that will also evolve. Then, finally, the epidemiology. The critical question, which I believe is what is the impact of all of this exposure at various levels, at various ages, on human health.

[Slide.]

So, understanding formation and developing mitigation strategies could certainly lead to a reduction of levels in food. Some of the preliminary data that you heard yesterday is very exciting and very encouraging.

But there is still a key need to understand the health implications from these levels. I keep coming back to this because I think this is a key issue.

[Slide.]

The exposure assessment that we heard about yesterday was based really on a relatively small number of foods, but the data clearly showed that a small number contribute most to the total daily acrylamide exposure. Yet, there was no single food that contributed the majority. As Dr. Robie pointed out, there were seven or eight foods that accounted for more than 5 percent of the intake, so we are talking about a fairly large spectrum of food, but no single food that was a primary culprit.

The overall mean acrylamide exposure is generally in the range of 0.3 to 0.5 micrograms per kilogram per day and those numbers seem to be becoming more solid in relation to what we have found and what others have shown.

[Slide.]

But there was a wide range of exposure and this clearly depended on the diet. Generally, diet that is high in certain types of foods such as fries, chips, et cetera, will have higher acrylamide intakes than diets of equivalent caloric intake that are lower in those types of food.

To me, I am essentially stating the obvious, but I think it is an important point, is that diet does have an impact. For example, 100 calories of raw apple is clearly going to have less acrylamide than 100 calories of overbaked fries. We already know that.

But, again, coming back to this issue and the mean levels and exposure assessment, what is the impact on human health?

[Slide.]

This is a key need. In the last two talks, you have heard a lot about the ongoing research, the planned research, in relation to trying to understand this issue of the human consequences as it relates to neurological issues, whether they be developmental or whatever, the effects on germ cells and acrylamide's role as a potential carcinogen.

[Slide.]

So where are we in terms of trying to put this in place and to look at the evidence that indicates that these levels of exposure are, indeed, harmful to health. Well, I think, as we have already determined, there is still work to be done. But you heard a lot this morning in relation to animal studies and the complexities of translating studies using doses in the milligram per kilogram range, 0.5 to 2.0 milligrams per kilogram, down to the microgram per kilogram range that we are seeing from human exposure and the complexities of making that extrapolation which are clearly considerable.

In terms of human dosing studies, there are some single-dose kinetic studies that are under way but, as yet, that data is not yet available but will clearly play a key role in helping us understand these issues.

Turning now to the epidemiological studies which, again, we have heard are an important part of this endeavor to try to understand the human health risk, but are clearly very complex and very cumbersome. There are data out there on occupational exposure which has been already discussed which are linked with neurological consequences as, as far as I am aware, there have been no links with cancer in relation to occupational exposure but it is clearly an area that could be examined.

The key question, what about exposure via food. As has been discussed during the course of the last couple of days, there is one study that has been done to look at that.

[Slide.]

In relation to trying to make these links and looking at human epidemiological studies, there are a number of factors to consider. Dose is one of them. The length of exposure, the age at which exposure begins and the levels in relation to age, whether there is some genetic susceptibility. I am just throwing that out there as a possibility.

We certainly heard about issues in relation to cytochrome P450 and whether there is some genetic susceptibility in relation to that. Maybe there are synergistic factors in terms of the metabolism of acrylamide, and, certainly, as was mentioned by the previous speaker, variation in the types of tumors that we should be looking for.

[Slide.]

In the next two slides, I am going to summarize the data from this study that was published in the British Journal of Cancer just about a month ago by Mucci, et al. First, to state the purpose of this study, and that was to analyze data from a population-based control study in Sweden to investigate whether higher intakes of certain food items with a higher acrylamide content increases the risk of large-bowel, bladder or kidney cancer.

They only looked at three types of tumor in this study. Again, as was mentioned before, this was because they already had the dataset available.

[Slide.]

In summary of the study design, they have 538 controls, 591 cases of large-bowel cancer, 263 cases of bladder cancers and 133 cases of kidney cancer. They ascertained dietary consumption through questionnaires and they went back five years prior to the submission of the questionnaire focusing on the foods that were high in acrylamide.

Most high acrylamide foods were included in the questions. I want to just underline the word "most" because one of the issues with this study, acknowledged by the authors, is that it did not necessarily cover all foods which may have contained acrylamide but certainly most.

[Slide.]

Based on the data that they received, they then stratified the acrylamide exposure into quartiles and then looked for associations. The conclusion of the study was that there was no positive association between dietary exposure to acrylamide and the risks of bowel, bladder or kidney cancer.

[Slide.]

These are limitations as acknowledged by the authors. There was a limited sample size. This was a cohort of patients that they already had and I think the authors should be congratulated on at least looking at this and raising the questions. But it was a limited sample size.

As I have already mentioned, not all acrylamide-containing foods were captured in the questionnaire and I think, importantly, they only looked at selected cancers. So it is critical not to extrapolate these data too far.

[Slide.]

So this brings us back to the current implications. Again, we are coming back with this question of the strength of the link between the animal-tox studies in the milligram-per-kilogram range with human exposures in the microgram-per-kilogram range and what exactly does that mean and how do we extrapolate that. A lot of effort is going in to understand that.

Human data indicating that this level of exposure poses a significant health risk I believe is currently lacking. There is a lot of work ongoing to try to fill that gap but, as far as we can determine, that direct link is not there. That clearly needs to play into the consumer message.

We also know that consumptions of certain types of food will increase exposure to acrylamide. But, in view of all of this, what should the advice be to consumers?

[Slide.]

This is clearly a complicated risk-management problem and we certainly do not want to create one problem by solving another. Where I am going there is specifically the issues in relation to cooking, and this was mentioned yesterday by Dr. Troxell, and the dangers of getting an inappropriate consumer message over of "cook food less" could certainly raise problems in terms of undercooking certain types of food that do need adequate cooking to kill pathogens.

A second issue is in relation to nutrition. We do not want to get out a message that could have nutritional consequences if people stopped eating certain types of food. One of the observations in the Mucci study was that, in the large-bowel-cancer group, there was a trend towards protection against cancer in those in the higher quartile with acrylamide.

Now, I say a trend. This was not statistically significant. But it simply raises the question of what were these people getting in their diet potentially that was protected. There are certainly data out there to say high fibers are protected against large-bowel cancers. So I think all it is just illustrative of simply reducing the foods containing high acrylamide could have unforeseen consequences. This needs to be thought through very carefully.

Really, what I am coming to is that maintaining objectivity and a balance is a critical part of managing this risk.

[Slide.]

Currently, our advice is to follow dietary guidelines which I have listed here and I am not going to read through all of these. They are on your handouts. These essentially are the federal guidelines for diet.

[Slide.]

So where are we going in the future? I think it is important to emphasize that we are going to review our consumer messages as new information is obtained during implementation of the action plan. The message that we have right now is good for February, 2003. As new data comes in, we are constantly looking at it and attempting to integrate the science into the message and should we change it.

We are very interested in the methods that will be involved in reducing levels as I have already discussed whether these be related to industry and at home, and there is a lot of ongoing work in relation to the action plan of trying to understand the formation and methods to mitigate acrylamide formation.

I think the bottom line of all of this is the key need to better understand the risk to human health with the doses that we are now beginning to understand people are being exposed to.

With that, I will finish and will be happy to take any questions.

DR. MILLER: Thank you, David.

Questions of Clarification

DR. MILLER: Comments or questions?

DR. DWYER: David, I wonder if you could comment on the Nurses Health Study and that analysis that has been in all of the newspapers I have been reading?

DR. ACHESON: I am not familiar with that one. Which one?

DR. DWYER: I thought that they had done a study in the Nurses Health Study that suggested the risks were not large.

DR. ACHESON: Is that the same study I am talking about, the one from Sweden, the Mucci?

DR. DWYER: No. I thought it was the Nurses Health Study. Am I wrong?

DR. RUSSELL: Yes. I think that was one that was mentioned as the possibility of planning it. But it has not been carried out. The one that was was the Swedish--

DR. DWYER: Oh; I mistook it.

DR. TORRES: Antonio Torres. One question I have, yesterday we saw some estimate of what would be the reduction in the exposure if we brought down to zero certain foods. That is just a guessing game of trying to look at what would be the impact of doing some measures.

The question is has there been some effort, since this is such a broad-spectrum exposure, at looking at the way we prepare certain foods in terms to see what would be reasonable reductions without getting into any risk situation; for example, we know that if we cook too much potato chips, then we will have higher acrylamide concentrations. Could we think about what would be reasonable levels and see how much the exposure would be reduced?

DR. ACHESON: Yes. I mean, part of understanding that is to understand the formation, how much cooking leads to how much acrylamide. Only by knowing that, can you come up with advice in terms of don't overcook something. But the obvious question is, how much should I not overcook. That is complicated.

Linked in with that is obviously gaining an understanding of what the health consequence is of reducing the level from X to Y. Without that, it is difficult to know where to pitch that. So I think the answer to your question is that we are looking at the ways to reduce it. Then the question is going to be is that enough, does that get us to the point where we are having an impact on human health?

So it is evolving. But, yes; those kinds of deliberations and discussions occur.

DR. DICKINSON: Annette Dickinson. We have been focusing, as we should, on extrapolating the animal data to the human situation. I wonder if you, or perhaps some others of our speakers who are still here, would characterize what, in your view, is the strength of the evidence on the animal carcinogenicity of acrylamide as compared to other things that you might have looked at. Is it weak? Is it strong? How specific is it?

DR. ACHESON: I think that is a hard one to answer. It is what we have. I do not profess to be a toxicologist. If there is somebody who wants to--maybe Dr. Canady can specifically address that, if that is all right with the chair.

DR. MILLER: Yes; it is okay.

DR. CANADY: There are two rat studies, two chronic rat studies, that have clearly shown increased tumors with exposure to acrylamide. So the evidence, at least in the rats, is fairly clear and widely accepted.

DR. DICKINSON: Are they benign or otherwise?

DR. CANADY: It is a mixture. Perhaps Dr. Olin will want to speak more specifically to that. But it is a mixture. That is really all I am going to say. The doses that showed tumor went down as low as, I think, 0.5 milligrams per kilogram per day in the rat studies. The route of exposure was drinking water, not food.

MS. HALLORAN: I have two questions about your consumer message and whether you have considered alternatives. One was to have a message to follow the dietary guidelines is really not a message. We are constantly told to follow dietary guidelines. It seems like a non-answer or possibly even an evasive answer.

Has FDA considered an alternative message which would be, to my mind, more direct like, "The FDA does not yet feel it has enough scientific data to answer the question on whether there should be any special dietary advice as a result of knowledge about acrylamide." Have you considered that sort of message?

DR. ACHESON: Reviewing of the consumer message is an ongoing process. I think that the feel was to try to say something positive about diet. What you are proposing is certainly something that we should think about as making that statement.

But, in effect, without stating it, it is implicit in what I am saying here is that the science is not yet at a point where we can make any other determination. But it is not explicitly said.

MS. HALLORAN: I actually think it is not implicit. It is certainly not obvious, I think, to the average consumer. I think, to the average consumer, they see a bee-hive of activity. They are aware in the press that there is tremendous research going on this and then, when you go to FDA for advice, they say, "Follow the dietary guidelines." It seems nonresponsive.

DR. ACHESON: We can certainly consider that; yes.

DR. MILLER: That is one of the questions we are going to have to deal with in our discussion in our advice to the agency.

DR. LEE: Ken Lee. I just wanted to follow up a little bit about the message and behavior. If you came out with a very direct message, hypothetically--I know we are not going to do this--and said people should avoid foods with acrylamide, what, in your opinion, would be the actual behavior? Would people change the way they eat? Would it spike for a few weeks and then go back to the way it was? What is our track record in that regard?

DR. ACHESON: I think, like dealing with any nutritional issue, the general population does not necessarily follow advice. That pertains not just to this but many, many other significant problems. I think our goal would be to give the best scientific advice that we can and couch it in such a way as a consumer message that it was not complicated and easy to understand.

I think those two things, to me, are critical. Whether people heed it, I don't know. That is somewhat beyond my control, but our goal would be, certainly, to try to get a simple message that was clear.

DR. LEE: Certainly, that has been studied. There must be some data on how dietary recommendations are actually affecting consumption patterns.

DR. ACHESON: I'm sure there are. I am not personally familiar with those, but there will be. Obviously, we would need to try to get that right.

DR. DWYER: I think it is like the Ten Commandments. There is quite a bit of slippage. Two questions. One is have you done any focus groups to see if consumers do feel it is a slippery statement or whether they feel that it does answer their concerns. Secondly, would your message be the same if the Mucci study had come out with relative risks of 1.3 or 1.5 for one of those various cancers?

DR. ACHESON: The answer to your first question is not yet. I think, obviously, with any consumer message, couching it, developing it and then going out with it to test it is a critical part of determining whether it is going to be successful and whether it hits the target.

The Mucci study? You are right. What if? Clearly, that would have played into the science and the message. It may well have been a little different but you would have to look at the science. If they had come out with an odds ratio that was significant, then you are starting to say what is the power of the study, is it enough, do we believe it, et cetera, in terms of moving forward with that.

DR. DWYER: The reason I ask you that is because the agency, yesterday, I guess it was, made available a larger database. Scientists tend to look at what they can look at and now you have a large database. I would suspect, in the next several months, there will be ten or fifteen case-control studies. Everybody who possibly can look at it will.

So one of those studies, even if there are a hundred studies, even if there is nothing there, you would have three or four or five that are going to be significant; right, just by the law of odds?

DR. ACHESON: Yes. I think that that would play into it. Right now, we have one. The second one may be negative or it may be positive. I think you are building it up as you go along and each one would need to be looked at in terms of its scientific merit, its design, its power, in terms of making consumer messages which, I think, could have a big impact.

That was another part of where I was trying to go is that, even though we are focusing on acrylamide, dietary messages have impacts on many other things in terms of telling people to eat and not to eat certain things.

DR. DWYER: Did you consider telling people not to smoke? Isn't there acrylamide in smoke?

DR. ACHESON: I think that message is already out there.

DR. DWYER: It seems like it might be tied into the dietary guidelines, too.

DR. MILLER: Smoking?

DR. DWYER: Say, "If you are going to follow the dietary guidelines, don't smoke."

MS. HALLORAN: I know the new FDA Commissioner and others in FDA are interested in reevaluating health claims on food with the thought that the use of health claims on food could promote beneficial consumption patterns. Are you considering how to integrate that effort with any message you might have on acrylamide or concerns about acrylamide? For instance, I suppose french-fry makers could promote potatoes as a source of Vitamin C.

DR. ACHESON: I think that would all have to be looked at in the context of what the message was and what the health claim was.

MS. HALLORAN: Do you have a mechanism for integrating your work with the health-claim work at FDA?

DR. ACHESON: Yes. That is all part of CFSAN is to look at the big picture.

MS. HALLORAN: I have one more question. In the FDA action plan, it says, "As messages are developed and refined, FDA will consider working with diet, nutrition and home-economics organizations and the Ag Extension Service to get its message out to consumers."

Is there any reason for not including consumer organizations and the general media?

DR. ACHESON: Absolutely not. I think that was one of the points that was made yesterday when Dr. Troxell gave his talk was that the potential there was a little narrow.

DR. TORRES: If I could learn a little bit more about the message impact, could you tell me a little bit about what is the difference between when you say a specific message like, "Don't smoke," which is under my control versus, "Eat more vegetables," which is--well, maybe not that. Let me think about it. "Don't eat food that has too much cholesterol." If I am going to eat meat, or I am going to eat stuff like that, I have no control over how much cholesterol that food has. So it is harder for me to become a vegetarian, which I don't want to be.

The difference between things that are much more under my control than things over which I have no control. What is the response of consumers when they say, "Don't eat food because it has acrylamide," but you look and every darned food has some acrylamide. So what do I do then?

DR. ACHESON: I think you have just put your finger on the problem. It is very complicated as to how do you deal with that? The smoking message is clear. You can say, "Don't smoke." This is much more complex because, as you just pointed out, acrylamide is present in a lot of foods. It is present in foods that are important for nutrition, for fiber. So how do you couch that in terms of education and a message?

That is part of where we are trying to go here is to get a really good handle on the science so that whatever message we come out with is going to have a significant health impact in a positive direction.

DR. DICKINSON: It sounds to me like a great deal of what you are saying and what many of our other speakers have said is that the evidence is really not strong enough at this point to recommend that anybody avoid any particular food or class of foods and that you are going to try to refine that evidence in case something would actually emerge from it.

But, if I am reading Dr. Robie's presentation from yesterday, and also other presentations, that indicated that potatoes, because of their amino-acid content and because of their sugar content, may have a unique propensity to form acrylamides when they are exposed to excessive heat or to drying heat, and if I look at Dr. Robie's tables, it seems to me that between 34 percent and 40 percent of the cumulative exposure in her tables is accounted for by french fries and potato chips, while I think it is certainly scientifically correct if the decision is to say, "We don't know enough about the risk to say that you should restrict anything," at the same time, if you were to decide there is a risk that would suggest restricting something, it does seem to me that the intake projections, and I realize they are models and not real-life samples, do suggest that there may be a limited number of foods which a person might choose to restrict which would not likely have a negative impact on nutritional content or on other cooking practices.

DR. ACHESON: Yes. We are not at a point where I think we can make that statement. As you have pointed out, those data are being developed. Part of the reason for stating that the best advice is to follow guidelines is that, if you do follow the guidelines, you will limit intake of some of those high-fat, fried goods that have been--that come out repeatedly on the list.

Obviously, it doesn't cover everything. But, to some extent, it does address that in terms of if you follow the dietary guidelines. But, your final point is that as data is developed, then I think the strength to go with more force down a certain track will, hopefully, develop or you will learn, "No; it is not worth it." It is all couched in the context of the human health risk.

I think if the advice were, "Don't eat potatoes," then there could be some significant consequences of that that have got nothing to do with acrylamide that need to be considered.

DR. DICKINSON: But there are potatoes and potatoes.

DR. ACHESON: Right. So, again, complex consumer message. But, before you even go down that road, you really need to know what is it going to be, what is the health benefit from that message and what is the science behind it.

DR. MILLER: I think the issue is, partly, from a communications point of view and Cliff can comment on this better than I can, the difference between a positive message and a negative message. There is a story this morning on the news concerning acrylamide. The reporter went and interviewed some people at a local diner. Uniformly, the people he talked to just pooh-poohed this negative message about avoiding things. They said, "They are always telling us not to eat something."

The differences in terms of the dietary guidelines, for all its problems, is that it is a positive statement, in a sense. As you said, if you follow the guidelines, you are going to reduce some of the high acrylamide products but it is a much more complex analysis, if you will, about what you are talking about.

It seems to me, and this is something we will have to talk about later, that, if it comes to Draconian measures that have to be taken, they better have the data to support it. Short of that, it is going to be a much trickier situation to deal with. It seems so easy to say, "Don't eat french-fried potatoes." It may turn out to be not only french-fried potatoes. It may turn out to be asparagus.

MS. HALLORAN: We are obviously starting to get into the discussion about policy. I had one more question about--you have said a couple of times that you have a concern that somehow, if there was a message about cooking, that the result would be that people would undercook things with pathogens, which is basically meat.

I wonder if you have any data or focus groups that would suggest that people would get confused in that way. To me, it is not necessarily apparent that a message about cooking potatoes and grains would be confused with a message about cooking meat. After all, people routinely thoroughly cook chicken and pork but eat rare beef.

DR. ACHESON: The specific answer to your question is no, we do not have data on that. It is simply an area that I think needs to be taken under consideration of ensuring, maybe through focus groups, that, if a message goes out, don't overcook one product, that it is not interpreted as, don't overcook, or adequately cook, everything else.

But it is just simply another concern that needs to be considered in a broader picture.

DR. DICKINSON: To go back to the flip side of the same point that we were just discussing a moment ago, I have been somewhat concerned in these couple of days to hear it continually mentioned that one of the reasons we don't want to give specific food advice, even if we got to the point that you thought specific food advice was necessary, is that it is ubiquitous in the food supply.

The other side of my comment about the cumulative effect of specific foods is that I am concerned that people get the idea that it is ubiquitous, that it is in virtually everything, the implication being that it is in approximately equal amounts in virtually everything and that, therefore, I am doomed, there is nothing I can do about it when, in fact, the evidence would appear to suggest that there may be some things that could be adjusted without an impact on the overall consumption of a variety of foods if, indeed, the evidence suggested that that was reasonable advice.

DR. ACHESON: I think that is a very good point. Part of the dilemma here is trying to come up with consumer advice based on inadequate data, that this is where we are now. This is what our consumer advice is now based on what we know now. But, within that context, as we develop more information about types of cooking, types of potato, which just isn't there yet, then, yes, I think you are right, a focused message, because don't also want to give over the notion that it is hopeless and that there is nothing you can do if, indeed, it turns out to be a significant health risk.

I think that is part of the problem, in the midst of trying to understand all this.

DR. DWYER: Back to Annette's point. I think it is important, in your plans, to plan for worst-case as well as a best-case scenarios and to begin to think of what the message would be if, in fact, this did prove to be a major problem. So you can't wait until the day you get on television, or wherever, to have a message that hasn't been thought out very carefully ahead of time.

The other thing is this whole climate that we are in right now where we have a lot of people saying all sorts of sometimes true and sometimes not true things about foods and supplements and whether there is an equivalence here among the messages that consumers are receiving. I leave that to my betters, but it is rather a vague message at this point. Maybe it needs to be that vague, but I agree with Annette that I think we know a little more than that.

MR. SCHOLZ: We are not ready to give advice, or you say we are not ready to give advice, on food and how we are going to cook it and what products but, yet, we are listing a lot of products here. Aren't we, in a sense, implying some of these are bad just by the amount in the parts per billion that they have. We kind of joked yesterday there was at least one brand of potato chips we might have a problem eating when we kind of checked to see what the amount was.

Aren't we implicating some of these products now and is that the right thing? Is that what we intend to do?

DR. ACHESON: I think my take on that is that one is struggling with the need to be transparent and keep the public informed of progress, and, with just that, we are not overinterpreting the data. The assumption that the high levels are bad, and what does that mean in the context, that the levels are higher in one product versus another product.

But, again, back to what I was trying to get over is what is the impact of that as a health consequence? That is where we are trying to take this.

MS. SCHOLZ: Are you doing enough, though, to say we are listing these products, because you are listing them by name. It is not just generic categories. So we are listing it by name. We are implicating that when one has a much higher incidence, we are, in effect, saying we think it is bad, we just don't know it is bad.

Take that, then, into a consumer warning. If we are going to show this and we are going to list this, should you, in fact, be doing a consumer warning now before you know?

DR. ACHESON: I think, right from the beginning, we have been saying that this is pilot, preliminary, exploratory. The action plan, by its very nature, is saying that there is more to come. Comparing one brand versus another brand, the n's are just not there yet, I think, to make those statements.

DR. TORRES: I had two questions. One was, looking at the data and to kind of follow up with the same question, is why wasn't--since we know there is so much variability between lot-to-lot and batch-to-batch within the same food, et cetera, why wasn't there more effort and time to keep the data to generic rather than very specific brand names.

I find it a little bit concerning that we may be sending messages on data we really don't know. We are saying, Product XXX has so much, and we really don't know whether the product effect. So, I am sure that the food industry must be very concerned.

Also, talking about the industry point of view, consumers, when they see this kind of information to specific brand names, they would like to know what are you telling the food industry to do. So one message is the message to the consumer and the other message is what FDA is going to tell industry to do.

DR. ACHESON: In answer to your first question, that is essentially a policy of FDA to give that level of detail. In terms of what the FDA tells industry to do is, as you have heard, there are a variety of industry groups that are trying to understand formation and mitigation strategies.

Again, it is a point of really trying to understand the science behind this problem before anybody is capable of saying this is what you should do, either to the consumer or industry, and I am using the word "should." I think it is very encouraging that there are so many groups who are taking this seriously to try to understand it.

MS. HALLORAN: This is following-up on Brandon's comments and the earlier comments. You are obviously working towards a risk assessment. What is happening, though, is you have got one endpoint message which is "Follow the dietary guidelines," and then this huge mass and growing mass of information which is coming out in literature, on the FDA website and so forth, without any interpretation by FDA, really, for the public because you are limiting yourself to this one endpoint of one sentence or two sentences of message to consumer.

So I was wondering if you had given any consideration to say a three-page status report which could be updated on a regular basis which would give the public the essentials of what you are looking into and the status of that work, you are looking into the levels in food, whether it causes problems in animals, whether you can extrapolate from animals to humans, what the human data is, sort of what we have gotten here today.

"Here is what we know. Here is what we don't know. Because we don't know about how you extrapolate to humans, and we have got conflicting data on what happens in humans, we can't make a definitive discussion, but here is where we stand."

I think you could do that in a quick--I mean, it might be sort of difficult to arrive at consensus of all parties as to the exact wording of such a statement, but I was wondering if you had considered that possibility?

DR. ACHESON: That is a useful suggestion. Thank you. We will look into that.

DR. SCHERER: In fact, I guess building on what Jean is saying, it seems to me that that is exactly the issue because you are talking about an environment of transparency, of putting information out there and making it available and, at the same time, not wanting to overinterpret the data.

But the problem that I see is that the consumers are liable to overinterpret the data. I would rather you interpret the data than have a lot of the media and consumers interpret the data and not really understand what it is saying. I think that is the real issue.

DR. DWYER: I was just concerned--this is already public domain, isn't it?

DR. ACHESON: What are you referring to?

DR. DWYER: This sheet that says, Exploratory Data on Acrylamide in Foods.

DR. ACHESON: Yes; I believe it is.

DR. DWYER: I am concerned that it doesn't have standard errors or anything on it. I guess they are fairly small, are they? Or are they? It gives a precision that, perhaps, is not warranted.

DR. ACHESON: You are talking about the analyses, themselves?

DR. DWYER: Correct. Again, they are small numbers, like 10 or 2 or 6. What is it?

DR. ACHESON: Dr. Troxell can address that, if that is okay with the Chair.

DR. TROXELL: The problem with the survey, the exploratory survey, is the within-lot or between-lot variability and the sampling kinds of problems. The analytical error is very small. Generally, those levels are at least two analyses that are clustered very close together. So the analytical precision is quite good.

DR. DWYER: So, on this thing that says, Home Pride Butter Top Wheat Bread, that is a sample of two pieces of bread from two different supermarkets?

DR. TROXELL: No; it is a sample of one product and I think they probably use, like, 100 grams. I think they were using portion size for preparing the sample. So, yes; there can even be some within-sample variability. But, as far as the analysis goes of the analytical result, it is an accurate analytical result. There can be sample-preparation errors and there can be errors, of course, between one loaf of bread versus another which would be variations between loaves or lots and so on.

DR. MILLER: I don't think that they looked at a hundred different loaves, different brands of loaves of bread, to get the variation.

DR. DWYER: What I am after is whether Mayer's Butter Top Wheat Bread and the Home Pride Butter Top Wheat Bread are really different. One is 52 and one is 96.

DR. TROXELL: We agree that there can be variations in one run versus another of a product as well as one day's production versus this next, maybe the beginning of the day's production versus the end and, clearly, between lots. We just simply don't have thousands of datapoints to explore those variations.

We have done some of that exploring of variation to show that there is a lot of variation by doing that small chip study we did on Lay's Potato Chips. We saw--I will go into this now. I was going to mention this later--that we saw some clustering when we looked at a particular bag lot from a particular production.

But even from one day-code to the next, we could see some very distinct shifts in the levels. Those potato chips were produced on the same line in the same plant from potatoes harvested from the same farm, from the same cultivar but the potatoes may have been stored an extra week or whatever. So, again, that gets to this issue that Dr. Zyzak was talking about, the variation in the glucose levels could vary depending on storage conditions and so on.

So these levels were extremely sensitive to conditions. And, yes, we have tried to reflect in our disclaimer in the beginning of the exploratory survey, how these levels can vary between lots and so on. We certainly haven't explored the full distribution on these products.

DR. TORRES: I think my question has been answered. Basically, you have convinced me that you have very good analytical methods but, also, you have convinced me that we have a lot of variability between batches and samples. So, when I look at these tables now, they don't tell me anything. I get more lost than helped by having more products listed.

Unless I really know what is the variability for a given product, I really can't make any sense out of it.

DR. LEE: Somewhat of a follow up for Terry or anyone. Is FDA getting any feedback from industry on the analyses that are being published on the web? Are the numbers being generated by the private sector consistent, too high, too low, relative to the FDA or is it too early to tell that.

DR. ACHESON: I don't know whether Dr. Troxell wants to address that, but my understanding is that essentially the numbers we are generating are pretty much matching up with what others have found. We are not finding anything exceptional. I think that is probably an international story, too.

DR. MILLER: It just seems to me that we ought not to make too much of the specificity of these numbers. They give you an order of magnitude. That is, I think, just what you need. You know that there are certain products that have higher concentrations of acrylamide than other kinds of products and that there can be variation within that but it is certainly going to produce greater exposure than some other products that are much lower. So that ought to be looked at.

DR. LEE: Actually, where I was going with that question is is there any reaction to these numbers? Are they being used for any purpose other than saying, "Oh; this is interesting. We need to study this further." Is there anyone actually proposing to do something on the basis of high content or low content?

DR. ACHESON: I can't speak specifically to what is industry's reaction to those numbers. I am not privy to those internal discussions. But, clearly, industry are taking this serious, hence the presentations that we had yesterday where they are looking at the science behind formation and potential mitigation strategies.

So, yes; I think people are reacting to numbers, both ones that we have generated, ones that they have generated and other countries have generated.

DR. LEE: What about states like California? Are they going to label products on the basis of these numbers?

DR. ACHESON: I have no idea.

DR. MILLER: But, Ken, California, the presence of a genetic carcinogen alone in any concentration is sufficient to have a label.

DR. LEE: That's right. What numbers are they going to use?

DR. MILLER: They don't have to have any numbers. It is a genetic carcinogen. Therefore, at any level, it is unsafe.

DR. LEE: So what you are saying is the difference between 0 and 1.

DR. MILLER: The difference between 0 and 1; yes.

DR. LEE: Whose 1 and whose 0 are we using?

DR. MILLER: That is up to the--I don't know what they are going to use.

Terry, do you want to comment?

DR. TROXELL: I believe what you are referring to, Dr. Lee, is California's Prop 65 where they have a specific law relating to carcinogens known to the Governor, reproductive toxicants known to the Governor. It is my understanding that the trigger level there would be 0.2 micrograms exposure.

If they move forward with that level, then there would be, as far as that probably comes out in a consumer portion from a package. I think, from the portion sizes that we have given you yesterday, you can see that there would be a large number of foods which would require some kind of labeling. But that is a law specific to California, specific to Prop 65. The FDA and the federal government do not have any relationship to that.

DR. MILLER: Where did they get the 0.2 micrograms? Is that the limits of detection?

DR. TROXELL: No; that is based on a risk assessment, I believe, that they use. I think they use 10-6 risk. No? 10-5 risk. I am being corrected. They use 10-5 risk and they derive 0.2 micrograms from a portion of food from a particular product. Therefore, with respect to your point, though, if a particular lot would rise to that level, I suppose they would have to label that lot.

MR. SCHOLZ: I just have one quick question back to the exploratory data and the discussion of how many samples. Have you considered, or would you consider, reporting on here the number of samples that you used to make the test?

DR. ACHESON: Yes; we could certainly look into that. I think it is important to emphasize that this is ongoing. This gets added to every week. It is current data. It is up to date, but--

MR. SCHOLZ: I understand that.

DR. ACHESON: You are asking what is the n value on any particular--

MR. SCHOLZ: Yes.

DR. MILLER: Unless there are any other burning issues, we have gotten into part of our discussion already. We will come back to this.

Thank you.

Finally, Terry Troxell is going to summarize the charge and the questions.

Summary, Charge and Questions

DR. TROXELL: I am not going to go into detail because that would be reinventing everything we have just done. What we tried to do was cover the events that led to the development of our action plan and the events in the intervening five minutes that we have used in revising the action plan including the subcommittee meeting and the recommendations therefrom.

Then I summarized the action plan and you have detailed copies there.

Then we provided a series of presentations to provide the current status of the work to assist the committee in commenting on the action plan. Those, of course, included the mechanism of formation, reduction strategies, our exposure assessment, adduct levels, the animal to human extrapolation, tox studies and the implications.

What we didn't do at this meeting, and, actually, we covered this in more depth at the subcommittee meetings, we did not go in depth into the analytical method. We have a solid method at this point and we are encouraging development of other methods and also proficiency examples need to be used among everybody so the results are accurate.

The other thing we didn't do is we didn't go over the data and talk about this within-lot variability and show some of the relationships and so on. I just mentioned a point I was going to bring up, how some subtle differences c can lead to distinct within-lot variations.

But the other thing, of course, was that the data was limited. In some categories, that seemed to contribute to the exposures, like we have only seven datapoints on cookies at this point and we had very few datapoints on toast. Of course, how was that toasted? How does that represent consumers' practices.

So there are those limitations. But, nevertheless, our exposure assessment did come in within the range. But the total population exposure assessment probably won't change all that much even though we get much richer data. It is going to be those individual components that contribute to the exposure. They are going to move around some.

So, anyway, we have provided you a pretty good snapshot, we hope, on which to base your discussions of the action plan and give us the input.

So, then, I want to turn to the charge, again, and that is we are asking the committee to evaluate the revised action plan as tool for providing the scientific basis from which to assess the significance of acrylamide in foods and the potential public-health consequences.

The first question is; does the revised action plan meet its intended goal of serving as a tool for this purpose. The next question is; the new data on acrylamide levels, exposure and potential interventions have become available in recent months. Does the action plan accommodate these new data? Please comment on the new data including exposure assessment of potential interventions.

The last question; does FDA's consumer message stresses the importance of eating a balanced diet. Given the uncertainties associated with the current state of scientific knowledge, FDA has concluded that there is not sufficient data to revise this message. Please comment.

So I think, hopefully, we are at the point where you can move into your discussion.

Thank you.

DR. MILLER: Terry, before you go, could you clarify in the second question, the last sentence, "Please comment on the new data including exposure assessment of potential interventions." What, exactly, do you want this committee to do in that regard?

DR. TROXELL: You have heard new information that hasn't been presented before the exposure assessment, some of the intervention work. Certainly, there is this Mucci study on epidemiology. We are looking for any comments the committee may have relating to that and then, of course, how that might relate to further work on the action plan. So we are giving the committee a chance to comment on this new information.

DR. MILLER: I am not sure the committee can comment on that. We have already had some extensive discussion already concerning the exposure, the question of numbers and variation and so on.

Are there any questions for Dr. Troxell before we begin our discussions?

Thank you.

Public Comment

DR. MILLER: Since no one has registered for public comment, we are going to move right on, then, to the discussion of the questions.

Discussion and Committee Recommendations

DR. MILLER: I would propose, if you would all agree, that, in order to get the discussion going on the first question, that we ought to begin by--I think we ought to compliment the agency and the subcommittee that worked with the agency on the action plan for what I think is a very comprehensive document.

If anyone disagrees with that, let's comment on that now. Then we can go on to any recommendations we want to make concerning further modification of the thing.

Are there any objections to making that part of the record? Okay.

DR. BUSTA: May I add to that? I think that, being the chair of the subcommittee, I was impressed at the responsiveness to the recommendations of the subcommittee and the integration of those recommendations into the revised plan. I think the parallel nature of the plan, multiple research activities going on simultaneously, is a very positive approach to an unknown situation so that you are not required to wait for one system to complete before you move on to the next one.

DR. MILLER: Any further comments? There were several issues that came up during our discussion, meaning from generic, general types of things to specific recommendations that we really ought to determine whether we want to include as part of our recommendations to the agency.

It seems to me one of the most important procedural issues in this whole process is the need for coordination and integration of the data. There are increasing numbers of laboratories that are getting involved in this activity. Clearly, what is needed is integration of a lot of data. Dr. Schwartz, this morning, indicated the complexity of the physiologically based pharmacodynamic model.

That data comes from a lot of different points and a lot of places. I think that that portion of the action plan that talks about how this is going to be coordinated, should be more specific and recommendations should be made about who is going to be responsible for coordinating the activities and so on.

It is really a vital issue because this is an extremely complex subject. I think that this is one of the more difficult ones that FDA has dealt with. It is not a simple matter and there is obviously difference in metabolism among species and the kinetics are different among species.

There ought to be some attempt made to have some uniformity in doses and so on and there needs to be these coordinating mechanisms which are not really spelled out very well or in much detail, I should say, in the action plan.

Does anybody want to comment on that?

DR. RUSSELL: I would just say another area where that coordination needs to be spelled out is in the food-matrix issue because if everybody starts using different food matrices, we are going to come up with very different results, both kinetic and dynamic and end results, biomarkers or tumors, for example.

DR. MILLER: I think that is a good example of what needs to be done.

Let me remind the members of committee, under the rules of the Chairman, unless you specifically say so, you will be recorded as agreeing. I discovered that is a much better way of doing it than trying to get everybody to say yes or no. It saves time.

DR. DICKINSON: I would like to add just one more example of another area that needs to be coordinated that Johanna mentioned several yesterday, several other agencies that are looking at food composition; for example, the USDA, obviously, has a very large food-composition database group that I don't think specifically got mentioned yesterday and should have some information to contribute.

DR. MILLER: Do we know if USDA is doing acrylamide and glycidamide? Terry, do you know that analysis?

DR. TROXELL: They certainly are fully aware of the problem and, as far as I know, they are not looking at it. There is some data on the products they regulate and pretty much they are either nondetects or extremely low levels.

DR. MILLER: It would seem to me that, given the nature of the potential public-health hazard associated with this material, or these materials is a better way to say it, that it seems to me that everybody who has capability ought to be involved to one extent or another.

So that is a recommendation.

DR. DWYER: Sandy, just going a little further, I think what you expressed was the need for coordination and integration of the data especially for developing models but also for other purposes. It seems to me that the action plan needs to designated who--that is, which agency within the government will take the lead or will be given the lead to coordinate.

These steps need to be spelled out, it seems to me, not only with respect to the plan but the time frame and not only for reporting and keeping everyone within government marching to the same drummer but also Ms. Halloran pointed out some kind of updating on a periodic basis of the consumer's needs to be thought of.

This, it seems to me, requires action at the highest levels of the agency; that is, at the Commissioner level or perhaps, even, the Secretary level within the department because it is going to involve collaboration between different cabinet-level agencies.

DR. MILLER: Right. We will come back to that last point about the consumer issue. There is another issue concerning funding which I want to raise to the committee's consideration after we get through some of this.

DR. MEHENDALE: I think we discussed yesterday that one area that was not addressed sufficiently is the coverage of stressed populations.

DR. MILLER: That is what I was going to bring up next.

DR. MEHENDALE: Okay. If I may just go on, one other point is we also had some discussion on perhaps trying to set a workable timetable to identify the low dose versus the high dose, in fact, so that what we learn from those things may have global impact on many other studies. So that might be quite desirable to do that.

DR. MILLER: This stress issue is important, and there are multiple stresses that could be look at, but it seems to me that is one of the things that ought to be coordinated, again, is which stress population you may look at. As a model, if you are looking for a model, you may want to use nutritional stress. If you look at the human population, you may want to use any stress that could conceivably cause entry inoculative enzyme.

Another issue which is implied, I think, in the action plan but isn't discussed and I think is extremely important, given the potential difference in metabolism at different dose levels, is dose selection. I would really suggest that the action plan have an explicit process for selecting the doses and that this also be coordinated.

If there are no comments about that, another issue was neurotoxicology. I think we have opportunity to read with some great concentration the action plan in the sense that I don't think that that was emphasized to any great extent in the action plan, unless I missed something.

It seems to me it is one of the issues that keeps coming up. The reason I think it is important to be mentioned is, again, this issue of coordination and integration and the utilization of resources. This is an expensive activity. If neurotoxicology is not going to be considered, and there is a potential toxicological endpoint, then that ought to be specified and explained. But it certainly ought to be discussed in the action plan, which has come up several times in our discussion.

DR. TORRES: I was a little bit convinced that the neurotoxicity for food exposure was not such a hot issue. Given the always financial constraints, I feel comfortable with having it not so much emphasized in the action plan.

DR. MILLER: I agree. I am not arguing that point. What I am saying, though, is that, given the fact that it has come up several times means it is being considered. I think that if the FDA is not going to look at it as an important component of the acrylamide story, they ought to specify in the action plan why they didn't.

DR. MILLER: When we are talking about stressed populations, I also wanted, again, to emphasize age as a variable in this thing, is there a difference between infants and children and the elderly population. The older I get, I become much more interested in this. So I think age needs to be emphasized as one of the variables in the studies.

DR. TORRES: Along the same lines, I don't know if we have information about the consumption patterns of different ethnic groups, if that will affect, in terms of the estimation of how much they are consuming of acrylamide.

DR. MILLER: That is actually an interesting question because it is not only ethnic groups but also geographic location, cultural patterns. I don't think that is something that could be done right away, but something for long-term consideration.

Also, again, we talk about stress, we can talk about nutritional stress, caloric limitations and so on. That may be an important consideration.

DR. BUSTA: Is Dr. Robie here? How easily can you adjust your system to take into consideration different populations and different groups in different areas and different regions? It seemed like, listening to you, that wouldn't be very difficult.

DR. ROBIE: To do that, the data are available. The CSFII survey data indicate ethnic group, socioeconomic group, things like that. The way that we have the data right now is in the database that allows us very easily to do the age. So when we do the two years and older population, two to five, we could do teen-age boys or lactating mothers, women of child-bearing age, things like that.

It is not trivial to do ethnic group or geographical location, but it can be done. It wouldn't be as easy as just changing the age group, is what I am trying to say, with the database as we have it. We would have to go to the raw data and do it. But it could be done.

DR. MILLER: My own feeling is that is something that needs to be done but not, certainly, one of the highest priorities. It seems to me that you first need to have a better idea of what the risks are and then, from that, you can determine whether what you are looking at is of significance or not.

Terry, can I ask you a question? Has any thought been given to how these models are going to be developed when all the data is collected? Is this going to be left to chance that somebody is going to sit down and write a paper by collecting all the models so that you have a PBPK that comes out of it? Has thought been given to that?

DR. TROXELL: I think Dr. Canady has to comment on the PBPK. Certainly, we have Dr. Bolger's group and Dr. Carrington, are kind of leaders in quantitative risk-assessment approaches so they can build the quantitative risk assessment model. But I don't know about the actual plans for the PBPK.

By the way, while I am here, it did slip my mind that--you asked a question earlier about USDA and I mentioned FSIS. But we have involvement from other components of USDA, ARS, Dr. Lahote has been in methods. We have been getting ARS involved and actually Rick also reminded me that FSIS was at our interagency meeting and participated.

So we really have tried to go out to a wide range of groups to bring to bear as great a power of energy as we could.

DR. CANADY: Our thinking with regard to using toxicokinetic information was to use the available information including physiologically based pharmacokinetic modeling to inform dose selection, species-to-species extrapolation within the NTP-NCTR studies. The thought to use a specific human PBPK model is something that we need to consider in more detail based, in part, on the recommendations we have heard so far and that is something we need to take forward.

But, again, the thought was to use the PBPK models that were in existence to help inform dose selection. The ones that are in existence are animal-based models, rat models, essentially.

Does that answer your question?

DR. MILLER: Yes. You propose to do this all in-house?

DR. CANADY: The idea to develop a human PBPK model is something that we are just hearing from the committee as a recommendation. It is not something we had decided to undertake prior to this meeting. We were considering using animal PBPK models to help inform dose selection and low-dose extrapolation and species-to-species extrapolation, to use the full dataset.

DR. MILLER: You would have to do a human PBPK to do that. You would have to do a human model to do that, to look at species difference including, I assume, humans.

DR. CANADY: Right. You can use the animal-based models to include more previous studies in your evaluation of the overall dose response. But then you are right. Extrapolating to humans, obviously, you do need to do some sort of modeling, whether it is PBPK or allometric, as Dr. Schwartz was talking about earlier, is a decision that needs to be made.

What I am hearing is that the recommendation to use a full model, a human model, is--

DR. MILLER: Right. You already know that you have a material that has species differences in so many different areas, it would seem to me worthwhile.

Let me make just one more comment about funding. This is clearly an expensive activity. It isn't clear to me where all the funding is going to be taking place. The industry is doing a substantial amount of work and some of the other federal agencies are proposing, or are considering--I think the report says, the action plan says, they are considering.

It seems to me the agency has to look for a designated source of funds in order to pay for much of this research. Also, it is noticeable that there is not a lot of academic activity going on in this area. If we look at the people who are doing the work, at least here in the United States, it is either industry or federal agencies and so on.

I would suggest that it might be worthwhile for the Commissioner and the NIH Director to get together and develop an extramural program that could be funded. NIH ought to get involved. This is a public-health matter of some importance and it seems to me that this committee ought to recommend that kind of interaction to look for funds that could underwrite these very expensive and very important modeling studies that we have been talking about.

Let's move on. If some thought comes to your mind, we will have an opportunity, when we finish, to go around and if anybody has anything additional to add.

DR. LEE: Just to clarify your last comment, Sandy, about academic activity. Are you thinking primarily on the toxicological and pharmacokinetic side? What about the formation prevention? Is that something you were thinking about?

DR. MILLER: That is not usually something that is in the NIH mandate. It seems to me that is something that USDA--there is an area that I think either USDA or RAS could play an important role in which they do fund studies of this kind.

DR. DWYER: What kinds of studies?

DR. MILLER: Formation and intervention studies. Basically, we are talking about processing modifications.

DR. LEE: Right; and, for that matter, recurrence.

DR. MILLER: The dietary composition studies that USDA does, acrylamide and developing methods for acrylamide, would be appropriate.

DR. LEE: But I think you are quite correct in that a coordinated approach towards funding the essential elements of this plan is--

DR. MILLER: Right.

DR. DWYER: That would probably also include CSRAS, not just ARS which is mostly intramural.

DR. MILLER: Okay, good. Let's move on to the second question about whether or not the action plan accommodates the new data on exposure and possible interventions and so on. Does anybody have any comment to make about that as far as the action plan? We are focusing on the action plan.

DR. BUSTA: This is Frank Busta. I thought that, in a number of places in the action plan, there were statements about building on the data, working with the data. I took it for granted when I said that the parallel approaches were appropriate, but, to me, that would be very important is to build in data from one area while you are investigating another area simultaneously, whether it is formation or methodology or toxicology. That interchange really needs to be constantly exchanged. That was also covered in your coordination.

DR. MILLER: I think another way of putting the question, and I think what you are are saying it does, is that the program is sufficiently flexible to make changes as the data change. As I read it, it seems to me that it is. Would you all agree?

[Agreement.]

DR. DWYER: I wondered--it seems to me, and maybe I am reading the wrong part of the action plan--I think it is Page 2 and onward--if it could specify a little more precisely. What I am concerned about is is there a "there" there? In other words, are these effects--can we somehow specify, or encourage by whatever means, whether it is extramural activities of other agencies or whatever, that a number of different epidemiology studies be done to base, or to put all the eggs in the basket of one study that was done in Europe, so far, seems unwise, and to base everything on just one cohort study when there are many, many around, would seem to be unwise, too.

So it seems to me we need a lot of different studies of that and that we should specify them.

DR. MILLER: I am not sure exactly what you are--because, I thought that they did mention--they have a whole section on epidemiology and they talk about--

DR. DWYER: Maybe I have got the wrong page. The pages are not numbered. What page would you say?

DR. MILLER: I would strongly advise that, in the future--I am talking to the staff, now--that, in the future, when documents are given to the committees, the pages ought to be numbered.

DR. BUSTA: It is the fifth action item.

DR. MILLER: There is a whole section on epidemiology. Do you see it?

DR. DWYER: Yes. I am not sure it is as detailed as it needs to be.

DR. MILLER: Down in the second bullet, it talks about monitor large numbers of individuals, et cetera. They are asking that.

Dr. Torres?

DR. TORRES: One area that I find that is too little in the report is research on formation. Since we see so much variability in the products that we are measuring, I think we are relying a lot on the industry research and not enough on public research, and even the size.

DR. MILLER: That is what we were talking about before with USDA. That is the kind of research they fund. And they do. I think that our recommendation is that they be brought into this consortium, if you will, with the specific mandate of operating, trying to look for methods of mitigation and also exposure, and calculating the concentration.

DR. TORRES: Before, we were talking about the integration question but here I am talking about what should be targeted, that there should be more emphasis on formation than what we see.

DR. MILLER: Right; that is what we were talking about before. We have got to make sure we make a note of that.

What did you specifically want, Johanna? What did you specifically want in terms of the epidemiology? What ares you suggesting?

DR. DWYER: Specifically, the Framingham studies, the Women's Health Initiative, any other large-scale studies that are funded by the federal government, not just one or two but they should all be looked at. I realize this is a huge task, but there are a lot of big studies that the NIH and other groups in the federal government have large investments in already. There us one in Hawaii, too. I don't know if that is useful, if you are talking about stress groups, Dr. Kolonel's study.

DR. LEE: I hate to jump around like this, but going back to what Dr. Torres' comments were about the database and developing information on formation and occurrence, there are really four sources of that information. There is what we are talking about with USDA or otherwise federally funded HIH, NSF, wherever you can get that done. There is the academic world which, of course, could be funded by that way.

We are talking about the international community which is feeding into the JIFSAN and the WHO websites. We are also talking about the private industry that has, of course, a vested interest in monitoring these levels.

So, just for the sake of completeness, we need to recognize that industry is going to develop a fair-sized database on acrylamide formation, content and prevention. To the extent possible, FDA needs to make it possible for that industry to share those data without jeopardizing their own brand. Maybe a third-party intervention can occur so that, if a manufacturer discovers a very high level of acrylamide, that does get published to the website with the brand name on it and they can enhance the scientific advance by having that cooperative arrangement.

DR. MILLER: Perhaps we ought to say that we need to develop a method that encourages the sharing of data from both the public and the private sector.

DR. LEE: Yes; that would help.

DR. MILLER: Because it is not only the concentration and exposure but it is also methods of communication. What I was thinking was that we need to mobilize the academic community and that depends on grants and so on in order to expand the population of researchers that can come up with new ideas about how to deal with this issue, because the companies, correctly so, concentrate on their own products. We need to have it somewhere else where maybe broader approaches to the problem can be reached.

DR. TORRES: I think, also, we should come up with some recommendation also on the structure of the data. Having just a number, without having the number of samples, what temperature was the process, a little more specificity. Otherwise, it is really difficult to make any conclusion about what does the number tell me.

DR. MILLER: You anticipate, again. In the second question, there is a comment about the new data, including exposure assessment and potential interventions. I think the committee would generally agree that we need to continue collecting more information on exposure, increasing sample sizes and the distribution samples and so on and so forth. That is a vital part of the ultimate risk assessment that is going to determine that.

So that needs to continue. There needs to be some agreement on how this data is reported and what part of the data is concerned. It is very important, as we pointed out, that we know what the source of variation is in this data. Is it lot-to-lot? Is it day-to-day in the processing? Is it the age of the oil in the frying? Whatever it is.

The data that were collected now in the rush for everybody simply to collect more data to determine what the actual exposure is, there has been a tendency to do a lot of samples of small lot size rather than concentrating on doing a more detailed analysis in a particular lot to get some idea what the variation is in things like lots, and so on.

DR. DWYER: What I am terribly concerned about is that we don't get off on something like--remember, back in the '80's the business of coffee? Do you remember that, Dr. Miller? Caffeine and the business of the rats that had the intraperitoneal infusions and how everybody was talking about not drinking more than a couple of cups of coffee a day.

DR. MILLER: We were talking about this before, with caffeine and spinal birth defects. They weren't infused. They were actually fed it. But the issue there is the same issue that we are dealing with here is that caffeine is metabolized differently in people than it is rats and in dogs and so on.

The result was that the results that were observed in rats simply didn't apply to people because the active component was not produced in humans. It was only produced in rats. I think that was the point why the toxicology and the multispecies analysis of the data, or the ultimate component of the design of the experiments is so important because we already know that there are species differences in metabolism and kinetics in this material.

I think that is what we have talked about when we talked about Question 1. I think the action plan needs to reflect the importance of doing the multispecies thing. It talks about it, but it doesn't emphasize the importance of it.

DR. BUSTA: Could I ask a question. Is it implicit when we are looking at new data that, somewhere along the line, if we decide--is there a way of deciding that it is not a problem and that we stop or, because we have got an action plan, do we keep looking and looking and looking because we have got all this stuff to do?

DR. MILLER: I think there is another way of putting that. That is a policy decision and it is an issue that I think that is not part of the mandate of the committee to discuss. But, nevertheless, I think there is another way of putting it, that the action plan needs to have built into it periodic reviews. It has got to be reviewed periodically.

I would suggest that it needs to be reviewed at least by the subcommittee of this Food Advisory Committee on a regular basis.

DR. BUSTA: Trying to prove something is not is very difficult.

DR. MILLER: That is in the negative, and that is not possible. But I would strongly advise that the action plan, itself, have built into it these periodic reassessments by an outside group and I think that the subcommittee of the Food Advisory Committee could serve that role. That is a good point.

Are there any comments concerning the potential interventions? I am not sure exactly whether we are competent to determine whether or not the work that is going on looking at dimensions is sufficient, but I think that, until the committee comes up with something, it is never sufficient. It looks like what is available now is not reasonable or feasible to be implemented.

Are there any other comments on Question 2? We can come back to this later. Let me propose that we break for lunch and be back in an hour, and then we will try to finish up. That means you should be back at 1 o'clock.

[Whereupon, at 12:00 p.m., the proceedings were recessed to be resumed at 1:00 p.m.]

AFTERNOON PROCEEDINGS

[1:00 p.m.]

Committee Recommendations

DR. MILLER: Let's reconvene and move on to the last question concerning the consumer message. The question has been asked for comment is, given the uncertainty of the scientific database, FDA is not, for the moment, going to change its recommendation to people to continue eating a balanced diet.

I think there, in listening to discussions, we had a good part of this discussion already. It isn't clear what a balanced diet really is, although, in the draft action plan, it defines a balanced diet as a variety of foods that are low in transfat and saturated fat and rich in high fiber, grains, fruits and vegetables, which is better than just saying a balanced diet.

But the question is what else can FDA do that we could recommend as part of the action plan that would develop into a more useful consumer message. Jean Halloran recommended that the agency publish a two- or three-page interpretive paper for consumers that explains the difficulties of looking into this explaining what the problems are, the lack of scientific data and what needs to be done.

Jean pointed out that FDA has published in the FDA consumer magazine an article on acrylamide which we have distributed to everybody. The question is is this the kind of thing we are talking about or are there further things that could be done that would be useful for this.

MS. HALLORAN: I think the FDA consumer piece is very good and a very good start. But I would recommend creating something that is a little bit more formal in its format that explains what the agency is doing, that it has got an effort to put together a risk assessment in progress and that it is investigating the various things that you need to know in order to know whether there is a risk here, that might summarize the status of what it has found out and what is known that is relevant to that.

A lot of it would be the same as what is in here. It would be just, I think, a slightly different approach. I think what is interesting about this is that it shows that, in a couple of pages, you can really present the gist of the issues and the material and the state of uncertainty and what you know and what you don't know in consumer-friendly language, pretty concisely.

So I think that is what is good about what is a model here. I would especially hope that FDA could create something that could be updated on, perhaps, a monthly or quarterly basis as new information emerges. I think that addresses the point you brought up of what happens when new studies are published, how are they put in the context of the whole and not just interpreted as one datapoint that could set people off in the wrong direction.

DR. MILLER: I think maybe we could put it this way; FDA should explore the possibility of developing a document for the website. Let me put it this way; if FDA is going to publish data that it collects in terms of exposure and toxicology and so on, it ought to also publish some kind of interpretive document so people understand the strengths and weaknesses of the data.

That ought to go on the website the same way.

MS. HALLORAN: And put it in the context of current risk-assessment efforts and framework.

DR. MILLER: You are talking about something aimed specifically for consumers.

MS. HALLORAN: Yes.

DR. MILLER: So that they understand what they can use the data for and what they can't use it for.

MS. HALLORAN: Exactly.

DR. MILLER: Cliff?

MR. SCHERER: Just to add to that thought, it seems to me that it needs to be also targeted to organizations that are on the firing line of consumers answering these kinds of questions. They need to be notified and included in the process because there are sensitive health people out there that react to any kind of information coming out.

I had a couple of other thoughts.

DR. MILLER: Please.

DR. SCHERER: As I look at the plan, it seems to me that there are a number of elements that I think are very positive. I really like the idea of transparency. I think the organization is to be congratulated on that. But, as we indicated earlier, that also brings up some problems that need to be addressed.

I think the plan, as it is there, is a sound start but it is simply incomplete, as Jean has pointed out. It is on target in the sense that I think the message can't be changed. It is right to say maintain good health, diet and so forth. But the part that is really missing is this idea of helping consumers interpret what is happening at the agency.

You don't want to cry wolf because credibility, in the long run, can be damaged seriously and then the effectiveness of being able to communicate with consumers is hurt. At the same time, with all of the wolf-hunting activity going on, you have to explain what that is. I think that is the real essence of one of my concerns.

The idea that you just brought up, the idea that, in fact, studies are going to be coming out that some of them are likely to show that there may be a problem. There needs to be a mechanism in place in terms of thinking through a strategy, how are we going to begin addressing those. Do we have things in place that we know how to get out to other organizations to the extension service, to diet groups and so forth, that, if something happens and the media pick it up, you need things in place to be able to quickly get information out to those groups so they can address the concerns of the consumer.

It seems to me that the other issue that you need to think about in terms of the plan is that a lot of research activity is taking place. This is an incredibly complex message, even now, and it has the potential of getting more complex as more data comes in.

It seems to me that we know a lot about risk communication and how to tailor messages, how consumers react to messages, in a variety of contexts but it may very well be that some small amount of resources need to be devoted to trying to study this particular issue and help design a strategy based on the best research that we have. That may involve expanding some of the ideas of focus groups, for example, to find out how people are going to react to these kinds of messages, just to have the plan in place in the long run but be sure that it is based on the best research that we have in terms of social science and risk communication because that is a critical part of what you are doing.

Then it seems to me that there is another area that needs to be incorporated in the plan and that is addressing, what shall I say, some of the off-the-wall concerns that may arise as a result of this. I am aware, for example, of a blizzard of e-mails attributing--you know, truth doesn't matter. It is perception that matters--the blizzard of e-mails coming from one segment of a discussion going on attributing to acrylamides in food to pesticide residues.

It seems to me that that is an example of a case that, whether it is true or not, there needs to be some way of trying to address that issue. Again, I would point out, the truth doesn't matter. We still have to try to address the concerns because it may very well be that, if that concern would continue to grow and the media pick it up, that could become the focus or the framing of this entire issue.

I don't think we want that to happen in the long run. You want it to stay on the science and what the science is saying, but you need to address that.

The other part, and I guess my last thought is that, in looking at past media coverage of the acrylamide issue, it is very apparent that, worldwide, there was a lot of media coverage in the international newspapers following the Swedish announcement and so forth.

U.S. coverage is just little blips. That is understandable because the media are focused on terrorism, the war. Eventually, that will go away and they will be looking for--they will get tired of it. Whether it goes away, they will get tired of it. So the pattern of the media will be that they will start looking for other kinds of things to cover.

If studies come out on this particular issue that shows there might be a risk, there could be, in fact, a blow-up of misinterpretation of the data. Again, I am simply emphasizing that there needs to be a strategy in place long-term that tries to address some of these things so that you have information essentially ready to go based on what happens in the media.

You simply don't want it to get out of control.

DR. MILLER: Let me see if I got your points. One is that part of the action plan should incorporate research in how to deliver a complex message on a complex subject.

DR. SCHERER: And consumer understanding; right.

DR. MILLER: Consumer understanding. That is what we are talking about. Secondly, the action plan should also cover the possibility of developing a strategy of how to deal with consumer concerns, true or not, and, similarly, use that kind of information to develop a strategy of providing appropriate fact-based responses to the press and to the media as their concerns arise, or different strategies to then use for the consumer.

Did I miss something? I think there was another one.

DR. SCHERER: Preparation of release of studies as research becomes available, preparing for how to address that in the media.

DR. MILLER: That is an issue that is important that the agency continually update these materials. It has got to be uniform. You can't wait too long because, as the data becomes available, the modification of whatever material the agency is providing has to be simultaneous.

DR. SCHERER: I think it was brought up from a research point of view, it is almost a question of what is the trigger point, what will we need to know before you start really expressing concern that this is a human health risk. What if one study comes in next week that addresses certain issues? Does that raise the concern level of the research and scientific community and what is, then, the message that needs to go out to the media?

I don't see it as an and/or. It is stages. How do we begin addressing that without crying wolf prematurely, because we can only cry wolf so many times. Already, I think you reported that the media, this morning, were interviewing people and they were saying, "Ah; I don't pay any attention to that anyway."

DR. MILLER: That's right. Any comments? Any more comments on this issue of consumer messages and so on?

DR. DWYER: Just to reiterate. I think what Cliff and Jean have already said so very well, the point that I think you both raised a little on the various professional consumer-related organizations. I don't think I have heard too much on this in the professional meetings I go to. This is a chance, I think, for the fine scientists within the agency to show their stuff.

There us nobody better than some of the scientists we have heard today talking about the models and about the human assessments that they are doing in terms of possible exposures keeping it rather simple, I would hope. But I think that is an important part of the plan, too. This is an issue where the agency has excellent people. You need to be sent around, more than five of them at the same time, to meetings. Perhaps this needs to be incorporated directly into the action plan. Keeping the FDA people here in Washington is not helping the agency's face out in the field.

DR. SCHERER: Just as follow-on on that. I don't want to get into picky language, but the plan says, "will consider recruiting." I would hope that that would be changed to, "will recruit and seek the aid of home-economics organizations, diet and nutrition and extension services," because I think those are very important organizations to multiply the message that FDA has.

DR. BUSTA: I think we earlier mentioned the expansion of that group beyond what was listed.

DR. MILLER: Consumer organizations, without mentioning anybody by name.

DR. BUSTA: But the Institute of Food Technologists.

DR. MILLER: Just to reiterate, I think one of the important issues of the action plan is that there is substantial research also required in this area. This is not just applying some kind of formula approach to the problem and delivering a consumer message but just as research in toxicology or in chemistry or whatever is necessary, research on how to deliver this complex message is equally important and should be provided for. Whether it is being done in the agency or being done outside the agency, you need to know how to deal with this.

DR. DWYER: Just one additional suggestion that might be considered in the action plan. I think it says it but it doesn't really say it explicitly that the Cooperative Extension Program is quite good at doing this. It is a nice example of two cabinet-level departments working together. Maybe there are some opportunities for that that should be specifically explored.

DR. MILLER: Let me just ask one more time if anybody has any comments they want to make, recommendations concerning modification of the action plan in any area.

MS. HALLORAN: I am not sure exactly where this falls, but I want to come back to the point that Annette made earlier that it does seem like not all foods are equally risky in this area. While FDA is not ready to give specific advice, still, if people are thinking about reducing their risk in advance of FDA's having a decision, there are some things that are more worrisome than others.

I don't know whether that can be incorporated in the consumer message, but I think that would be useful if it were.

DR. MILLER: Comments?

DR. DICKINSON: I noted, when we came back from lunch, we had this FDA consumer piece. It does highlight certain foods that are high in carbohydrates and mentions that cooking at high temperatures is related, so at least that is a step in that direction.

DR. MILLER: Any other comments? The process from here on out remains as it has in the past. The staff will produce a summary of the meeting and outline the recommendations that have been made by this group, recommendations to the agency.

We will distribute this to the members of the committee. It will also be published on the website. You are apt to get it quicker from the website. Nothing personal. As I said, unless you have some really specific problems with the document, we will take it that you have endorsed the report with having actually do it. We just did it and will make it part of the record, unless you have a specific comment that you need to have.

DR. DWYER: Dr. Miller, I don't check that website often, if ever. Therefore, I don't know if things are up there. I wondered if there is a blanket e-mail that you could send out when you post it to the website. You have my e-mail address.

DR. MILLER: One thing Cathy has is more information on us than we would like for her to have. She will track us down no matter where.

If that is all, unless someone has something to add, we have completed our work. Let me thank you all for your attention and your hard work on this. It is an important area and certainly one of the more complex public-health questions that I think the agency has faced. I hope and I believe we have made some important contributions to this.

I also want to thank the FDA staff people and others who have contributed to this meeting. This is the most important part of these meetings, briefing the committee.

Terry, do you want to make a comment?

DR. TROXELL: Yes. I just want to express our sincere thanks for your listening to our couple of days of presentations and for your deliberations, coming from such warm places as Boston and so on to sunny Washington. Thank you so much and have a good journey back.

DR. MILLER: We are adjourned.

[Whereupon, at 1:30 p.m., the meeting was adjourned.]

 

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