ATDEPARTMENT OF HEALTH AND HUMAN SERVICES

> FOOD AND DRUG ADMINISTRATION
>
> CENTER FOR FOOD SAFETY AND APPLIED NUTRITION
>
> FOOD ADVISORY COMMITTEE
>
> ACRYLAMIDE
>
> Tuesday, February 25, 2003
>
> 8:30 a.m.
>
> Sheraton College Park Hotel
>
> 4095 Powder Mill Road
>
> Beltsville, Maryland 20705
>
> 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.
>
> [C O N T E N T S]{.underline}
>
> Call to Order:
>
> Dr. Sanford Miller 4
>
> Animal Studies and Human Health Consequences:
>
> Dr. Sorell Schwartz 4
>
> Questions of Clarification 26
>
> Acrylamide Toxicity: Research to Address Key Data Gaps:
>
> Dr. Stephen Olin 36
>
> Questions of Clarification 54
>
> Potential Implications:
>
> Dr. David Acheson 63
>
> Questions of Clarification 77
>
> Summary, Charge and Questions:
>
> Dr. Terry Troxell 111
>
> Public Comment 116
>
> Discussion and Committee Recommendations 144
>
> [P]{.underline} [R]{.underline} [O]{.underline} [C]{.underline}
> [E]{.underline} [E]{.underline} [D]{.underline} [I]{.underline}
> [N]{.underline} [G]{.underline} [S]{.underline}
>
> **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**
>
> 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 LD~10~, 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 f~g~ 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**
>
> 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**
>
> 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.
>
> \[Whereupon, at 12:00 p.m., the proceedings were recessed to be
> resumed at 1:00 p.m.\]
>
> [A F T E R N O O N P R O C E E D I N G S]{.underline}
>
> \[1:00 p.m.\]
>
> **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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