Thursday, December 5, 2002


8:34 a.m.







The Inn and Conference Center

Founders Ballroom

University of Maryland University College

3501 University Boulevard East

Adelphi, Maryland  20783


     DR. BUSTA:  Good morning, everyone.  Happy holidays.

     DR. FULLER:  We may be here awhile.

     DR. BUSTA:  It's beginning to look like a holiday.  This was very fortuitous, that we had the meeting in the same place that we were staying.  We appreciate Dr. Downer getting here from her home.  She got a little excitement this morning, so her blood is rushing.  Some of the rest of us are just waking up.

     This morning, you see on our agenda, the first presentation will be by Dr. Terry Troxell, who is going to summarize the Plan and Charge, tell us what we're supposed to do from here on.

     DR. TROXELL:  Thank you.  Well, the northerners on the committee, we have come through for you with snow.  The university is closed, so maybe we should just shut down and go build a snowman and have snow fights.  They closed everything last night even before the snow happened, but that's Washington for you.

     Okay, get down to serious business: the Action Plan.  So I have 15 minutes to summarize everything everybody did yesterday.  But just briefly, let's just reup a few things.

     We talked about the analytical method yesterday, that we need to further validate the definitive methods.

     We have the need for proficiency samples so that we can assure that everyone around the world is--in this country and so on are getting the same kinds of results.

     It would really be desirable to have alternative methods.  We're looking at LCUV as a quicker, cheaper method that can be done with instrumentation that is, we believe, very prevalent.  This would be prevalent not only in companies so they can do QC or, you know, can follow the research on new products and so on, but also for developing countries where they don't have LC/MS/MS equipment and so on.

     It would have been desirable, of course, to have something simpler, like an amino assay.  But as we looked at the size of the molecule, people that advise me--leave that, it really wouldn't--we wouldn't likely get very definitive antibodies.  But if that's something the committee thinks we should explore, I suppose that would be another approach to getting something cheaper for doing some screening.

     Then the next component really gets down to incidence and levels, all the way through the exposure assessment.  We've done an exploratory survey; we need to--obviously, as we talked--expand that more comprehensively to assure that we get similar results around the country.  We need to get enough information to make it so that we can have a degree of robustness in exposure assessment.

     We are starting to analyze this as part of our Total Diet Survey, which is a survey of foods as consumed.  Therefore, the foods are baked and so on, so there's a certain degree of consumer preparation in that study.  The consumers that are preparing that, which happens to be a church group, prepare the foods according to recipe.  So there is a certain amount of the consumer-preparation angle in there.

     But the other--you know, in addition to serving to help provide data for the exposure assessment, this is going to be kind of weather-vane, as it is for the other chemicals we analyze--it's a weather vane on trends, so we'll be able to measure progress in reduction of acrylamide by using--this is one of our tools.  No one tool general is the end-all, so we look at--one always looks for a series of measures.

     Then the next component, of course, is the formation.  We have very good information at this time on a major mechanism.  Obviously, some more work needs to be done to check out other potential mechanisms in various foods.

     And when one thinks about reduction, there's probably three general strategies.  One, of course, is to remove the reactants.  So remove those precursors, asparagine and reducing sugars.  So are there ways to minimize the presence of those.  And then the second would be to stop the reaction from going, or slow the reaction--so the ways to prevent the reaction from occurring, whether one puts inhibitors in there or temperature changes or whatever.  And then finally, of course, is once it forms, is there some way that it can be destroyed after it is formed.  So that kind of maybe divides that territory.

     Then the next thing, of course, was the toxicology.  Obviously, we need to understand the toxicokinetics, particularly the comparative metabolism between animals and man.  Biomarkers are going to be very useful.  Some people look at biomarkers on the exposure side, but biomarkers are, of course, critical on the tox side, too, so we can relate the dose to the hemoglobin adducts, to the DNA adducts in the tissues, and then do comparisons between those adducts in animals and man and so on, so we can do a good risk assessment.

     And then, of course, there's the three major end points under consideration.  There's the cancer end point, there's the neurotox end point, and the germ cell mutagen end point.  The two latter, the neurotoxin and the germ cell, of course, are at much higher levels in exposures.  Of course, the animal carcinogen end point is also occurring at a much higher level than food exposures, but there is--part of the neurotox is to try to define if there's additional--well, to define that point more precisely and to look at effects, whether there might be some neuro-developmental end points or whether there's an effect from long-term exposure compared to the exposures under which the current studies were done.  And these things, then, will be fed into risk assessments, which will then feed into risk management and looking at different risk management options.

     The next component of our Action Plan is to foster those partnerships.  You know, this is a large amount of work to do when you look at the different components.  But then, on the other hand, there is also an intense interest out there, and one of our considerations is how to harness that interest so that there's a concerted, coordinated program, and we're fostering that through the JIFSAN work and through JIFSAN's running the Infonet.  And in addition, we're independently working inter-agency to coordinate our efforts, and we'll do everything we can to support or facilitate coordination not only to help the JIFSAN effort but also independently in the international and so on.

     One illustration of the need for that coordination is that the mechanism was announced independently by about five different--at least five labs, I mean, five we know of.  I think there were other people out there who discovered the mechanism at the same time.  And while it would have been nice for, say, two laboratories to do that, the other three labs could have been making progress on something else.

     There are many difficulties in the coordination in this, including the basic nature of scientists.  Their lives and their creativity depend on kind of holding things tight, not being scooped, writing papers that they can publish and not announcing them ahead of time because they won't allow them to publish.  But all that, of course, will minimize the progress and increase the level of duplication.  So we'll do everything we can to encourage people to provide the information at the earliest point.  Certainly FDA scientists, as government officials, will be releasing information as soon as it's ready.

     Then the last component was to inform and educate consumers and processors about the potential risk, provide options on how to reduce the risk as long as there's gain.  We have provided an initial consumer message.  We've also publicized our scientific agenda and what we understand about the risk in order to assure the public that we are taking the necessary steps and appropriate action to protect them.

     So that's, in a nutshell, the Action Plan.  Then turn to the Charge again.  We're asking the committee to evaluate whether the research steps outlined in the Action Plan are scientifically adequate to describe and address the public health significance of acrylamide in foods.  And based on what you heard, we would like you to provide questions, we would like to have your views and expert advice on whether the research steps are appropriate to describe and address that public health significance.  And then, are there gaps in areas that there should be increased emphasis.  And then, finally, the question of the priority of research needs--what is more important to get done early.  And also, I would suggest you think about what can practically be done early.  I mean, obviously, you can't get a bioassay done in six months.

     Anyway, so some of the presenters are here, not all of them, but I think we'll be able to answer any questions you may have during the session.  And I turn it back to you, Chair. Thank you.

     DR. BUSTA:  Don't run away.  I've got a couple of questions.  Number one, is there--you mentioned risk assessment, risk management, and then the third step is all this risk communications.  I see the educational component as risk communications, right?

     DR. TROXELL:  And risk management.  Risk communication has many components--it communicates to consumers, industry; it also communicates back to the researchers and risk assessors.  So I mean it's--basically, risk communication covers everybody's involvement throughout the process.

     DR. BUSTA:  And I see a lot of risk assessment.  I'm trying to understand the risk management component of this.

     DR. TROXELL:  We have not laid out potential risk management options at this time, but one of them--I mean, actually, our first risk management we have done is to put out a consumer message.  We'd like people to eat that balanced diet according to the pyramid and so on, and we think if they moved in that direction--and most of us don't--you know, there would be some reduction in acrylamide by that move.  So that is a risk management approach right there.

     And then, you know, there's--one can envision a series of risk management options, but we're not--I mean, that's not what we're--

     Would you like more?

     DR. BUSTA:  I just wanted to make sure it didn't go by me.

     Second question I have is, is there an indication of the amount of effort that is going to be put in on each one of these five steps, and is there an indication of budget amounts?  Or is that what you're looking for from us?  How much effort will be put in on the assay versus the other concurrent activities?

     DR. TROXELL:  I think you should address it scientifically and tell us what you think are the important things to do, whether they're critical things to do, and if you want to say, you know, this is the A list versus the B list and the C list, then we'll try to figure out how to get that money and the funding.  There is, as I said, tremendous interest out there.  I mean, Europeans are spending a lot of money on this; industry is already spending a lot of money.  There are a lot of ways to ultimately fund this work over and above federal funding.  And then, we just have to kind of check to see, you know, here's the list, are people doing it, is it credible work, and where should we fill in the gaps.  But I would not right now think--put a lot of weight on, you know, the particular cost.  You might want to comment that that's very expensive, possibly, for what we might get back, but--

     DR. BUSTA:  Okay.

     DR. TROXELL:  Other questions?

     DR. BUSTA:  As I see us proceeding--you can help if you see me going down the wrong track--but as I see us proceeding this morning, is to go through the five areas that we have on our agenda and discuss those with your questions, if we need clarification, what we see as evidence or need of evidence, discuss them as thoroughly as we feel we need to.  And if it appears to any of you that those are not--that we should not separate and try and stay in that order, we could rearrange it.  I don't have any problem with starting with the bottom one of the list or whatever.  And after we've exhausted ourselves, we will then go on to the three main questions.

     And we do not have to take the entire morning for discussion.  If we feel we've gotten the information that we need, we can move forward into discussing each of the three questions that have been posed to us and we will go around and each make comments on the questions, individual responses on each of the three questions.  We have plenty of time to discuss the various aspects.

     DR. HOTCHKISS:  I just wanted to ask Dr. Troxell kind of an umbrella kind of question, in part because he mentioned it as part of the committee's Charge.  Throughout the presentations and in your summation, the agency has gone through the same order of steps in the Action Plan.  But you haven't added the would "priority" to this or a sequence.  Have you decided or thought about a priority, or are you asking us to advise you on that?

     DR. TROXELL:  Well, I think in the Charge we do outline the various components done concurrently.  Certainly, if you see some sequence, we'd like to hear about it.  I think, you know, we have always thought that, for example, it doesn't do much good to analyze a lot of samples without a solid method, so we built that method first to our satisfaction.  And now we have probably the round-off thing of, you know, doing the inter-lab peer verification and so on.  But we're--you know, so we have that done.  Yet clearly, I think, one wants to construct a plan with the right sequence of events, and I think that's where the priority also comes in.  So I think you can help us to identify what needs to be done first and second.  I think there are also independent things, like one really needs to not wait to work on formation and find out if there's a way to reduce the amount of acrylamide in the food supply for the final word coming in from the risk assessment.  So that's why we have these things going on concurrently.

     DR. HOTCHKISS:  Thank you.

     DR. BUSTA:  Before you go, in your question, I'm interpreting in that Question 1, the sequence of--you have the first sequence, and then it says "concurrent with formation studies and toxicity studies"--and the "and" meaning a third concurrent activity, right?  If I interpret that way that's blocked, there are three concurrent activities going on?  I just want to make sure I--

     DR. TROXELL:  Right, the--yeah, there's three.  Yes.

     DR. BUSTA:  Three concurrent, okay.  That's what that "and" means.  Okay.  I just don't want to get off here.

     The alternative approach to discussing, whether we go--whether in toxicology and analytical methods, formation, et cetera, would be to go through the Action Plan that started with Testing of Foods.  Which is more comfortable?  Do we want to start off with questions and discussion about toxicology, or--Dr. Hotchkiss?

     DR. HOTCHKISS:  Because FDA has set a sequence, for my own thinking, I would think we would want to go through the sequence they have set up before discussing--it also seems like a logical sequence to me.

     DR. BUSTA:  "Sequence" being the Action Plan?

     DR. HOTCHKISS:  The Action Plan.

     DR. BUSTA:  Okay.  Is that all right with everyone who are poised to talk about toxicology right away?

     DR. HOTCHKISS:  I assume we'll get to toxicology.  I have a number of questions about that as well.

     DR. BUSTA:  And why doesn't that surprise me?  No.

     All right, well, let's look at testing.  We had a presentation on testing.  Questions, discussion on the testing of foods, which includes the methods development and approach to occurrence?

     DR. FISCHER:  You're not looking at the draft Action Plan, right, you're looking at the slides?

     DR. BUSTA:  Yes.

     DR. FISCHER:  Is that the way you're going to go through the Action Plan?

     DR. BUSTA:  Well, we can go with the draft Action Plan.  Tab 5.  Would you prefer that one?

     DR. FISCHER:  It would seem like that's the best thing to do.

     DR. BUSTA:  All right.  So that when we get to number 2--or do you want to look at the major goals or just start into the discussion?  Any comments, questions on the background?  Any clarification needed on the Major Goals?

     DR. TROXELL:  I would like to make a suggestion.  While the draft Action Plan is, you know, in more of a summary format, the presentations were intended to provide more depth, so I would use them in conjunction, at least.

     DR. BUSTA:  One comment when I look at the Major Goals is that "risk" shows up in at least three places and is inferred in others, and I think that it's obvious that the risk-assessment component is going to be the focus and I think that's been identified as we've gone through, that eventually we have to get to risk assessment.  So as we're looking at that, we can think of all the concerns that there are to try and get risk assessment.

     Number 2 on the Action Plan is Testing of Food.

     DR. FULLER:  Before we move off that, just a comment.  And perhaps I've just missed it in all the discussion, but I think the--at least as I'm trying to get to the basics of things here--the issue of looking at occurrence of acrylamide in foods, and variability, et cetera, et cetera, et cetera, I think what I haven't seen yet is on--and perhaps someone from--maybe Dr. Troxell could help on this--is at what point--has there been any consideration at what point that part's going to start and risk assessment to begin, based on information that is currently available on the tox data?  Am I making any sense?  Are you following my question?  When do you have enough of the exposure information?  And I just want--because we could do that forever.

     DR. CANADY:  We're already in risk assessment, in the sense that we're doing a--we've done a safety risk assessment, we've done evaluations like that.  We recognized early on that we needed a lot of information regarding exposure, regarding occurrence in order to do a full risk assessment.  I think you're right.  We're at the stage where we can start framing the models, start putting the models together, figuring out what questions we need to ask of the risk assessment.  And so we are doing that.  Of course, it's an iterative process, so we have to have enough information about where it occurs, obviously, before we can start understanding exposure enough.  I think we're to that point almost.  There are still a few more, you know, basic shapes to fill out, but, yeah, I think we're to that point.

     And again, we need to understand variability to some degree, but then risk assessment is going to help us understand, through sensitivity analysis, for example, which are the important exposure elements, which are the important toxicity elements, and so on.  Again, though, we need to think what are the questions we're asking a risk assessment to help us with.

     DR. FISCHER:  Well, I'm confused about the exposure, after you said that you've started with risk already.  Because I thought you were doing the exposure analysis in two steps.  One is that you were going to do this--not monitoring, but this broad-picture thing, not taking time to get enough measurements or data to do a risk assessment.  Now at first, you were looking at where it is, as opposed to how much it really is in a given food group.

     DR. CANADY:  Right.

     DR. FISCHER:  And you're in this first stage now.  You're just looking things up and seeing whether it's there.  And you have some numbers, but those aren't enough data to do the exposure part of a final risk assessment with.  Am I correct?

     DR. CANADY:  I think you're both correct.  I mean, the point is we're trying to understand when a full risk assessment, when is a complete risk assessment going to be done.  And my answer is, you know, it's an iterative process, again.  I hate to keep saying that, but we're at a stage where we can use the current data to start framing the risk models that can then help us understand what further data we need.  I don't think we're to a stage where we can do a full-blown risk assessment that answers all the questions we need to answer.

     DR. TROXELL:  Let me also add that, as Dr. DiNovi said yesterday, that they're already in the process of doing an initial exposure assessment.  As you all know, exposure assessments are going to have more certainty or less, depending on the amount of data you have in there.  If we have 1 point per food, we're going to have a tremendous amount of uncertainty.  So, you know, that's part of getting the kind of critical mass of information to have a reasonable level of exposure assessment.  Also, on the tox side, you have a tremendous number of uncertainties, so if we get some of the--you know, what would be the critical quick data that would help us zero that in so we can do that next iterative step and, you know, do a risk assessment that has less uncertainty so we'd be more comfortable it would be predictive, rather than the risk assessment just saying, well, you know, these are the other research steps we should do.

     I mean, risk assessments can be used for--you know, to assist risk management, but they also can be used for determining where the gaps are so we can reduce uncertainties.

     DR. BUSTA:  Questions?

     DR. FISCHER:  Well, it seems to me the other way to do it would be to, at this point in time or at some time soon, decide where it's likely that the largest risk is going to come from--what food group, for example, or what group of foods represent the largest exposure; and then get the necessary data on those groups and do a risk assessment.  So what you're doing is looking at a worst-case situation first to get a good idea about what the risk might be, as opposed to doing an awful lot of work directed at the whole sphere of foods.  I'm suggesting to focus that on what you can determine might be the most serious problem.  There may be two or three food or food groups that you would look at.  If you want to do it quickly, it seems to me that would be a better way of doing it, more convincing, than this iterative thing--just keep going, getting more and more data, and trying to decide, okay, when should we stop and do something about risk.

     DR. HOTCHKISS:  Those groups have probably already been identified.

     DR. FISCHER:  Yeah, that's what I have in mind.

     DR. BUSTA:  Dr. Gray now, and then we'll get Dr. Canady.

     DR. GRAY:  Well, I was going to say I agree with Larry.  That would be--that's sort of the way to take an approach.  In some ways that has been done.  We have some estimate of exposure, and you can do a -- calculation that tells you this is potentially a bigger risk than almost anything we've got out there in the food supply.  That's why we have to know a whole lot better on the exposure and on the tox side how much confidence we can have in those, sort of, worst-case things that have already been done.  But those have been done, and those are the kinds of things that make people sit up and say all around the world we've got to spend some time on this.

     So I would agree with you, though, that this exposure--there are ways to think about doing out exposure, to work with, sort of, the risk-assessment approach that says where are the big sources of exposure, how can we nail those down--what are the sources of variability in exposure, how can we nail those down to understand this better.  Because part of what you're also hoping to do is to get to a place where you can learn, if it has to be managed, how to manage that risk.

     But the worst-case things have been done, and they've scared the hell out of people.

     DR. BUSTA:  Are you saying that you think there's enough data on these what you've identified are the worst-case to start doing a risk analysis with that information?

     DR. GRAY:  Yeah, I think they suggest that much more detailed work has to be done at this point.  Because using the worst-case approaches, which have been done--the WHO looked at that with exposure, we've got 20 years of regulatory experience with acrylamide in other settings--using t kind of information, it's sufficient there to say this needs more attention.  The big question is where do you put more attention to really try to do a good job of understanding those risks.

     DR. BUSTA:  Dr. Canady?

     DR. CANADY:  I think maybe part of the issue we're discussing here is sort of a formalized definition of risk assessment as the be-all and end-all and "the" document; and the process of assessment, which, as Dr. Gray has just said, is already going on, the process of risk assessment.  And what I was trying to say is that using this assessment modeling would help us understand where to look first and where to look the hardest and where we need to focus on reducing uncertainty the most, for example.

     I don't think we're disagreeing.  I think we're having a little problem with the definition of risk assessment and, you know, is there a formalized meaning.  That's all.

     DR. BUSTA:  I'm assuming that you have good statisticians that can determine when you're at a point, an asymptote of having enough data in a given sampling system to say we don't have to iterate it any longer or we change the sampling, not just keep taking more and more samples.

     DR. CANADY:  Well, the direct answer is yes, of course we do.  The indirect answer is that's something that is influenced by the framing questions and what are the countervailing risks, what decisions do you need to make.  So you know you have enough if you can make a decision that doesn't have a high cost in terms of health or in terms of other things.

     DR. BUSTA:  A very judicious answer.

     Other comments on this specific topic?  How much more sampling do you think is needed?  I mean, this has been--we've got this 700 samples.  George?

     DR. GRAY:  My thought here is, I hope that there is good communication between the folks doing the exposure assessment and the folks doing the sampling.  Because I really think that by doing this preliminary exposure assessment, where you're working with the data that are available on the kinds of foods that people consume and whatever level of aggregation you have there, you can understand from trying to do that estimation what kind of data you need that helps you understand what level of detail and aggregation you need at the sampling level.  And it may be for some foods you've already got enough sampling to adequately describe the variability in those and we don't need to go to finer levels of detail--by brand, by potato, by season or something like that; or it may be that those things are big enough that we need to do those better for certain of the categories of foods.

     So it's just sort of--it's very much in fitting with what Rick said, that you want to use the way that you're going to approach the problem, the model way you're going to try to estimate exposure from how much is in which foods that people eat how much of, to understand where you need to get more information.  So there, sort of, aren't numerical cut-offs for sampling; it's much more--I think should be related to the way in which you're going to use that information.  And I just hope that communication is going out.  I'm pretty confident it probably is.

     DR. BUSTA:  For example, my gut reaction is that the information on infant formula so far has been essentially negative.  So to continue to sample infant formula might be a waste of effort.  Is that--

     DR. GRAY:  That would probably be--sure.  And that's part of the statistical analysis that you talked about, of how many zeroes to I have to get to believe that everyone's going to be close enough to zero that I'm not going to do any more?  That has to do with what you expect for variability, though, which we've seen is kind of high.  This isn't an easy sample question.

     DR. BUSTA:  Dr. Hotchkiss?

     DR. HOTCHKISS:  That really gets to the heart of the question that I asked yesterday about comparing analytical data or inserting analytical data in the databases which calculate consumption figures, and when you do that, you begin to--you get what percentile you're covering for a given food product and so forth, and then once you have that information you can decide whether you have made a sufficient number of samples or not a sufficient number of samples relatively easily.  And that's the reason I raise that.  Dr. DiNovi assured us that--and Dr. DiNovi is an expert in this, spent his career in this, and knows what he's talking about in this, he knows the databases--assured us that that would happen, and I'm confident it will.  The agency has great expertise in that area.

     I would, though, really, to ensure--or to be more comfortable with an answer to this question, suggest in the draft document of Action Plan in 2 that the first major goal is to assess dietary exposure, and I think that is the first priority.  Under that it has a number of consequences, analysis in analytical chemistry, for example, but there are two major parts in order to assess dietary exposure, one of which is measuring levels in foods, and that's listed as how to do that, but that is in itself not sufficient.

     The other part is using the best available food consumption databases, and I would recommend that that phrase or something akin to that be added to that major goal.  When you do that, when you plug in your analytical data into a good consumption database, all of a sudden you begin to answer the question of how much confidence you have or don't have that you have covered the waterfront for that particular food.

     DR. BUSTA:  You're suggesting that goes in on goal number 1?

     DR. HOTCHKISS:  Yes, under Major Goal 1, the first bullet point under that is assess dietary exposure, and I think that's absolutely correct.  But there are two parts to that, the first of which is mentioned under that--along with that bullet, that is, measurement.  But the second part is to use that measurement in what I would call the best available consumption database.  This changes all the time, but FDA has access to these databases, as Dr. DiNovi discussed yesterday.

     DR. BUSTA:  Other comments on this specific topic?  Ken?

     DR. LEE:  I'm very interested in ways that we can solve this problem in that--you know, best-case scenario would be to reduce the level of acrylamide in foods to zero.  And I think those Industries that are most affected by this, by having the highest levels, are going to do work that will likely lead to a reduction in that level, if not ultimately reach that goal of zero.

     However, I'm also concerned by how that occurs in cooperation with the Food and Drug Administration.  We saw, for example, the posting of brand names and acrylamide contents on the World Wide Web, with, of course, the footnote that these are incomplete data sets and you shouldn't put any credence in these data.  But if I was a very litigious person, I would just be drooling at that list.  And that doesn't really serve the scientific interests or the best interests of consumers.  Because if this situation gets tied up in the courts, and if industries are afraid to come forward with forthright data or data on how their process variables affect acrylamide content of food, we're going to be set back quite significantly.

     So I would encourage any system that allows free and unencumbered exchange of acrylamide information in a way that it's blinded to brand identify.

     DR. BUSTA:  Dr. Kuzminski.

     DR. KUZMINSKI:  Thank you, Ken, for making that point.  I believe--gut feel, without any personal knowledge--I said it yesterday, and at the risk of nauseating the rest of the subcommittee, I'll say it one more time, that there's probably data out there in industry that is good, reliable, solid data in terms of occurrence in finished product, and probably data out there in terms of occurrence throughout a process to make that product.  And I think the agency, should they be able to create an environment and situation and procedures where that data is accessible, might save themselves a lot of time, a lot of effort, and probably a lot of money in terms of getting that information.  How they use that in terms of in combination with consumption data to come up with the true exposure and risk information, then can follow.

     But again, just going from experience, the way this issue suddenly bloomed last spring, there's been several months passed since that time, and the reputable companies have been all over this, just all over this issue.  It does a responsible company no good in the long run--and this is a long-run issue--to generate data that is not good, analytically not good from a sampling methodology, because their own credibility goes down the tube.

     So I would just echo your comments, Ken, that I would strongly encourage the agency to do this.

     DR. BUSTA:  Dr. Hotchkiss.

     DR. HOTCHKISS:  In a switch from several hats, and as a former FDAer and having been intimately involved in a problem or an issue very similar to this before, one has to recall that FDA is an agency based on statutory law and must ultimately answer to that statutory law.  As well, the agency has an obligation to maintain its appearance of credibility--not just its credibility, its appearance of credibility.  While the agency should take into account industry-generated data and so forth, it also must realize that it does not have control over that data, the way that data is collected, the quality of that data.  And therefore, when push comes to shove in a legal sense, the agency probably does not want to rely on that.

     In the past, particularly with the nitrosamines in beer issue, this was settled quite nicely, actually, by going to a--the industry went to a third party, a quite credible third party.  That third party did analyses for the industry, essentially sanitized that data by company name, gave that data to the agency.  The agency felt that that was a good measure of what was going on out there.  That data eventually was all published in the peer-reviewed literature and saw the light of that venue and so forth.  But in the end, when the agency set action levels, which they did--that is, they took legal regulatory steps around the issue--the data generated by industry was not used for that because it was illegal; but on the other hand, the agency took that data by going through a third party which sanitized the data.

     So there is room for compromise here, but in the end the agency has to remember that it has the force of law.

     DR. BUSTA:  Terry.

     DR. TROXELL:  Thank you.  I just wanted to point out that this data will probably be available through JIFSAN.  I mean, they're setting up this Infonet.   As Dave Lineback said yesterday, industry will be able to submit in a blinded way before it comes to JIFSAN.  We have heard at the JIFSAN workshop that there's probably 2,500 samples been analyzed out there around the U.S., and then we've heard since then that there's some 4,000 analyses in Europe that are being compiled by the U.K. in a database.  This is going to shed a lot of light on just how many zeroes do we need in some things to say, well, we don't have to worry about that.

     The other thing, of course, it's going to--I think, while there's some data on particular products, a lot of effort has gone in with many of these analyses to try to figure out what in the chain of production is contributing.  So that kind of linkage is very important.  And that doesn't necessarily fit into the database, but that also would be very valuable, again, to link into this information network in a blinded way so everybody can benefit from it.

     DR. BUSTA:  Other comments on this area?  We'll be getting back to exposure more later, right?  I have a question on exposure, but I'll wait for that one.  Some people trust NHANES more than I do.

     The next item in the Plan is the toxicology.  We had presentations as well as the development of new data on toxicology.  Comments and discussion in this area?  We had Dr. Canady up there on and on and on, and he's here smiling and ready to go again.  Dr. Hotchkiss.

     DR. HOTCHKISS:  In my view, clearly, most of the items outlined in the draft Action Plan are certainly needed and should be undertaken, particularly those that correlate some of the biomarkers with exposure--although my own view is that a fair amount of that work has been done, particularly by Tannenbaum and Farmer, through cigarette smoking.  There's actually a very good database that correlates number of cigarettes consumed per day and hemoglobin adducts and so forth, which is obviously not foods, but by a different route of exposure.  But you would assume, I think probably correctly assume, that inhalation would be the worst-case scenario compared to ingestion, and so that database seems to me to be very strong and worthy of careful attention, and may in fact be sufficient to make some conclusions.  But still, I think, biomarkers are important--biomarkers on target tumors, very important correlation between exposure and genetic adducts and genetic materials, clearly important.

     The one area of the Plan that's a little hazy to me--and maybe it could be further clarified for me--is the chronic tumorigenicity study.  Apparently FDA four years ago or so found the data of sufficient quality to actually--and formally concluded, through the Cancer Risk Assessment Committee, that the data was robust enough to actually set what amounts to an ADI kind of number and so forth.  I just wonder, by spending all that time and money in a chronic rodent assay what would be expected to be learned that's not already known?  And what would the--I mean, I think I'd bet the mortgage that--it's not much of a mortgage, but I'd bet the mortgage anyway that you're going to find out in fact it is a carcinogen in the rat, and you may get a little bit different answer than the previous studies, but it's probably going to be well within an order of magnitude of the answer you already have.

     The rest of the toxicology I think is great, the one about spending millions of dollars to do that kind of study.

     DR. BUSTA:  Dr. Canady.

     DR. CANADY:  Thank you for that comment.  I think your two comments, or the two areas you commented on, are actually related, though, in the sense that one of the reasons we're very interested in doing an NTP bioassay is that we can fold in biomarker data, DNA adduct data and those sorts of things with the end points that would be considered under a chronic assay.  So that's one point.  The second point is that early information from the bioassay will also be very useful to us, dose-ranging studies, corollary studies, and so on.

     So, while I understand that going into a multi-year process to get to an answer that may not be substantially different from what we already have in hand is something you might question.  I would make the point that the information we could get by bringing more advanced technologies--or rather, bringing a fuller suite of technologies to bear on the problem may give us a better understanding of the extrapolation from the rat to the human than we currently have.  Having it all in one package with the same animals is going to help us make that low-dose extrapolation a lot more confidently.

     And that's that argument I would make for having the bioassay.  The other thing is that we talked about zero as a goal.  We're not going to get to zero for quite a long time.  This is not going to be an issue that's going to go away.

     DR. HOTCHKISS:  If I could just follow that up.  I'm sorry, I don't want to sound too lawyerly--I'd rather sound human than lawyerly.  As I read what actually was available to the agency and considered in depth by the agency in '97, and I believe before that, was--I don't want to give you the quote, but it's something like the agency considers the data robust or sufficient to make this kind of--in other words, none of the issues that you raised were raised apparently three or four years ago when acrylamide toxicity, as it relates to potential migration from food contact materials, was an issue at the agency.  But now you feel that at that time the agency felt that it was sufficient, but now it doesn't.  Is that the deal?

     DR. CANADY:  Decision context is always something that I think you need to consider in these situations.  And at that time the decision was that food contact exposure--which was, if I remember correctly, three orders of magnitude below what we're considering now, perhaps more--in that context the dose-response information was clearly adequate.  It was clearly sufficient for us to make a decision that that use was one that did not present an unacceptable risk.

     When you consider in contrast the broad exposure that we're currently considering, you have to ask the question, I feel, do we have sufficient information, again, for this new decision context.  And that's the question that we'd like to have the committee address, really.

     DR. BUSTA:  Could I just ask the question--yesterday, someone said it was a flat extrapolation.

     DR. HOTCHKISS:  It comes from FDA's document.

     DR. BUSTA:  Yeah.  Flat--could you explain "flat," to make sure that I'm not misinterpreting?  Does this mean that at low concentrations it's potentially more hazardous or less hazardous?

     DR. GRAY:  Can I just--I mean, from my read of this document, when FDA reviewed this, it simply says that the dose-response information in the range at which it was tested, which is still very, very high, was relatively flat, meaning that between controls and dose groups the tumor rate didn't go up like this; it went up--it was a very flat dose response curve.

     DR. HOTCHKISS:  Yeah.

     DR. GRAY:  That's all I was saying.  And that's in the range of doses that are thousands of--well, hundreds of times higher than what we're talking about today.

     DR. CANADY:  Actually thousands is right.

     DR. GRAY:  Yeah.

     DR. FISCHER:  I still don't understand that.  Meaning--

     DR. HOTCHKISS:  What it says is the response is not tightly correlated to dose.  In other words, if I go up in dose, I would expect a number of tumors, number of animals and so forth to in some way proportionally go up.  But those curves were relatively flat.  That doesn't mean that the chemical is not a carcinogen; it just raises a flag, I think, for many toxicologists that there is more to the story that's not understood, that it--in most cases, "more" produces more response; in this case, for some reason, maybe it's saturating some kind of system that--a system that converts it into the penultimate or the actual carcinogen.  Maybe it's saturating that system, so when you double the dose you don't get double the response.  Something like that.  There's more to the thing.  It raises a flag that we don't know everything there is to know about it.

     DR. BUSTA:  But in reverse, does this mean that when it's flat it means you could get--you know where I'm going.  If it's flat enough, then you could go very down, very low doses and still get a response.

     DR. HOTCHKISS:  Your operative would of "could" is right--a lot of things could happen.

     DR. GRAY:  But if you look at these data, what most of them say is that things--the low-dose groups have very little going on.  They're flat with the controls, too.  So I mean it's--this all depends on ultimately what sort of choices of models and such are used to extend those data.  So that's--you know, that dose-response data is moderately interesting in that high-dose range.

     In fact, if I could make a comment, I mean, I think one of the problems we have here is that this particular issue is a challenge to the traditional ways that these risks have been assessed.  Either the reliance on high-dose rodent cancer bioassays--do we believe that a rodent carcinogen is always a human carcinogen?  Or the models that are used, the linear no-threshold model that's used to extend the dose response from animal data to human--is that correct or is it not correct?  And also, what levels we think are important levels to manage risk.  Are hazard quotients of 1 something we get worried about when we compare it to the ADI?

     So this is a tough one.  And one of the things that I'd actually like to perhaps see a little bit more of in the Action Plan is, I agree that these research data-gathering goals that are set out here are very good and very appropriate.  But what I'd like to see is--think a little bit more about is how those data are going to be used.  And I think one of the most important things that we could recommend very early on is to use things like the toxicokinetic data and things like that that are going to come.  Put them into some kind of physiologically based pharmacokinetic models, things that are going to let us look at the assumptions that are based--that are in the traditional approach.

     And with those kinds of things, we can look at the difference between routes or food matrices and we could say pretty quickly--and I think Dr. Hotchkiss is probably right, by the time we get to the right doses and another rodent bioassay, we're going to get about the same response.  We can look at the different routes of exposure, the inhalation data from Epi, which is probably equivalent to a considerably higher oral dose.  If we had good pharmacokinetic data, we could relate that--and we might be getting closer to doses that people are getting--and have maybe more confidence in what the Epi is telling us compared to the animal bioassays.

     So I guess I'd like to see a little more discussion about how these data are then going to feed back into the process and be used.  And some of them will be much more useful in the shorter term than the time that it will take to get a new rodent bioassay done, which, under any circumstances, won't be sooner than three years from today and will probably be longer than that.

     I'd also, sort of along the same lines--and this is echoing remarks we've had from others--is urge the FDA to use some of those data that are coming from industry, especially some of that really impressive stuff we saw that's being done by the chemical industry around acrylamide.  Those human studies will be extremely helpful in trying to do a good job with PB PK.  I was at the Chicago meeting, and the head of the company was there offering to allow all of the medical monitoring data and all of their plants to be used for Epi studies.  That seems like something that should at least be investigated and potentially used.  It's another opportunity, again, if we're going to question this use of the high-dose rodent bioassay as the basis, let's get in there and get some more and some better Epi data to help us have some comfort with what we're going to do.

     So I guess the thing I'd like to see is, in addition to the science that's laid out--and I think it is the right science that answers a lot of the questions that need to be answered--is think about how that's going to be used, both in the short term, when it can help us answer questions today, and in the longer term, when it comes to ultimately making decisions.

     DR. BUSTA:  Dr. Fischer.

     DR. FISHER:  I would like to know whether--I can't recall whether there was going to be a mouse component.  Are mice going to be used as well as--okay.  Because they're supposed to be somewhat more sensitive.  So I suggest that the mouse--it's a good idea.

     I think it's worth--I never am sure whether it's worth to do the rodent bioassay the way it's usually done, with high doses, to do risk assessment with.  Clearly, I think what we know already from the bioassay is that it's a carcinogen.  I mean, there's a lot of evidence to back that up.  But what we don't know is whether it causes an increased risk of cancer at very low doses.  And the only way we're going to know that is, I guess, repeating the assay with lower doses, trying to see a better dose-response relationship than we've got now.  We know at high doses we can see this, but how about at lower doses in between the NOAEL and the doses that produce tumors?

     But in repeating the bioassay, I certainly think it ought to be a mechanistically oriented exercise.  And I think Dr. Gray has already talked about that, I think.  We need to--certainly in its plan to measure biomarkers and so on, that's definitely something that should be done.  But I think they ought to think carefully about other information that they might be able to get, toxicokinetic information, from these animals that are used in the assay.  This is being done for other compounds by the EPA to do a very mechanistically based bioassay.  And I think here we have a good chance to get a lot of information from these animals, who are going to be dosed for a long period of time, in terms of toxicokinetics and mechanisms if we make the right measurements.

     So having said that, I think it wouldn't be a bad idea to get the National Cancer Institute and NIEHS interested in acrylamide research based upon the mechanistic aspects of the outcomes that are expected, or not expected.  Couldn't NCI put some money into mechanistic research, maybe even tying it in to the cancer bioassay; and couldn't NIEHS look for mechanisms, or examine mechanisms which may be active in these animals that are getting dosed for two years, and so on?

     So--and perhaps they could do this by putting out RFAs for research on acrylamide-induced toxicity, cancer and other things--reproduction and so on.  Neurotoxicity.  I think it's worth a try to get these funding agencies interested in helping with the mechanistic data that we need to understand a toxicity, cancer and others.  I don't know what the FDA thinks about that, whether that's possible.  But I certainly suggest that that be done.

     DR. HOTCHKISS:  Let me point out that the IARC Monograph, Vol. 60 of the IARC Monograph, which details a great deal of toxicology--as you're all aware IARC monographs do--points out that acrylamide has been tested in both mouse and rat.  Its probable route of metabolism to the ultimate carcinogen has been studied in some detail, but -- never proved these things.  But given the history of epoxides, beginning with aflatoxin metabolism and going through cyclopropenes and a whole variety of epoxides, I think that most cancer toxicologists would feel--would, again, bet mortgages larger than mine that that is the proper route.  In other words, much of what we're discussing is, I think, reported in the IARC Monograph, which is in fact a very detailed and--I haven't counted the references, but probably a hundred or more references on the toxicology of this compound.  This compound has been known to be a carcinogen for more than two decades, its metabolism widely studied, its epidemiology studied in occupational environments and so forth.  This is a little bit of an unusual thing from the standpoint of food contaminants in that we have all this history to it, and I don't think the agency should spend a lot of time reinventing the wheel, but rather trying to decide what to do about the wheel.

     DR. BUSTA:  Dr. Lee.

     DR. LEE:  Yeah, there's a lot of talk about animal studies.  I'm not a toxicologist, so I'm really speaking out of a quest for more information.  It appears to me that the relevance to the human is the most important thing when it comes to food exposure, particularly from the Food and Drug Administration's point of view.  So I would just underscore what Dr. Gray alluded to.

     We heard briefly yesterday from, I think, Dr. Friedman about a Covane study in Madison, Wisconsin, where 24 sterile males were being fed three-dose levels of acrylamide, and--I mean, I think this was a casual mention, but to what extent is this going on with human studies?  And I don't have that information in front of me.  So I need to know, is there a lot of feeding going on of human beings with acrylamide, and what useful information could come out of these studies?

     DR. BUSTA:  Sterile males?

     DR. LEE:  Yeah.

     DR. BUSTA:  Dr. Whitaker.  I presume it was voluntary.

     DR. WHITAKER:  I would just like to amplify on what Dr. Lee said.  My thought my process is as I sat here and listened--I'm not a toxicologist, so I feel like I'm on the outside looking in.  But I've had many years of exposure to aflatoxin, through the Codex system, of trying to set limits and understand what the consequences of aflatoxin was in humans.  And nobody could every agree on the rat studies.  And the definitive studies that seemed to break the ice dam was the Chinese study.  And so it--I don't know whether the analogy still holds here with acrylamide, but maybe the emphasis should be headed more towards the human effects if indeed that data is out there.  I've heard you mention--Dr. Lee mention, Dr. Gray mention--so maybe those studies are the ones that should be emphasized, because we may head down the same road that we did for 25 years with aflatoxin and its effects on humans.

     DR. BUSTA:  And we don't want to do that.

     DR. LEE:  I can add that they used sterile males because the concern was -- reproductive effects.

     DR. BUSTA:  Dr. Fuller.

     DR. FULLER:  Thank you.  I'm pretty comfortable as well with FDA's action plan on all of this, and I'd like to reiterate, I guess, a couple of the points that Dr. Gray.  And also, just to--back to FDA, to ensure that they are looking at and in consultation with the chemical industry on the studies and aren't repeating any of the studies that--and I didn't have a good sense of how familiar FDA was with the work that Dr. Friedman was telling us about at the end of the day yesterday.

     DR. CANADY:  I think the best way to share that information is through the Acrylamide Infonet, to make people aware of studies, what their protocols are, when the results are expected.  And then the point was made earlier that we're constrained by what we can use in regulatory purposes, so it needs to be peer-reviewed and published, obviously, as well, before we can ultimately use it to make regulatory action.  That would be my understanding.

     DR. FULLER:  Is there no mechanism under which you can review at this stage, if it's made available to you, the conduct of the studies, et cetera, to provide some reassurance?  And I'm just thinking of let's don't duplicate if it's not necessary.  And I appreciate that the constraints being a regulatory body and needing to maintain integrity, et cetera, et cetera, et cetera.  At the same time, I hate to see a lot of resources spent if there are some--if there are good data that are being generated that would either prevent the necessity of doing a particular study or, more importantly, change the emphasis or what you're looking at in a particular study.

     DR. CANADY:  Yeah, I think this underscores the fifth component of the Action Plan, and that is collaborations are an essential part of collecting information, making sure there isn't replication and those sorts of things--or actually, making sure the replication is knowingly done, to the degree that you can.

     So, yeah, I think, again, this is part of the Plan that we've laid out, that we would look to all sources and collect information where it's available and avoid unnecessary duplication where we can.

     DR. FULLER:  Has--and I'm sorry, I just--maybe you are answering the question, I'm just not hearing it.  Is that happening now, in the planning stages, based on--and have you had that collaboration, or is there something about to happen with that?  I just didn't hear that in the presentation.

     DR. CANADY:  Yeah, I think the first time that I heard about the studies that were mentioned yesterday was at the June consultation at Geneva.  And at that time, we asked for the protocols.  We've again asked for the protocols, I think it was at the Chicago meeting.  And we heard the same offer; it was made by SNF.  So we're willing to look at them, receive them and so on.

     DR. FULLER:  Thank you.

     DR. TROXELL:  So again, we're fully aware what they're doing; and secondly, you know, as with food additives, we review any studies that are submitted, and we'll use them to the fullest extent.  We obviously want to minimize duplication.  We're very interested in seeing what the results are of their human exposures so we can learn what we can about the adducts.

     DR. FULLER:  Thank you.

     DR. ACHOLONU:  The material given us here says there are uncertainties about the impact of acrylamide on public health.  There are uncertainties.  Yes, tests have been done on rats, on mice.  We have tested food to find out the content of acrylamide in food.  Until we find a way to connect it to human beings, it will be causing unnecessary alarm to the public.  If we no get out information saying that acrylamide is carcinogenic, yes, it is carcinogenic to rats.  The genetic makeup of rats and human beings are quite different.  Of course, we have got mammals.  But we have to be aware of that and be apprised of it.  But to connect this with human nature, we cannot say that we have gone far in making people aware of the dangers of acrylamide.

     And this is the point I want to make.  Whatever we do, whatever study we conduct, should lead us to connecting it to human beings.  That is the comment I wanted to make.

     DR. BUSTA:  I don't want to change the topic here, but there's a fair amount of mention about glycidamide, and yet we just talk about acrylamide.  If that is the mode of action, or apparent mode of action, why aren't we doing more testing on glycidamide?

     DR. CANADY:  I'm not sure I heard your question right.  Did you mean in the last case to say "acrylamide"?  Could you restate the question?  I'm sorry.  I didn't quite understand it.

     DR. BUSTA:  Well, you know, it's my understanding that glycidamide is the step of the toxicity.  Is that right?

     DR. CANADY:  It's one of the proposed mechanisms.  There's some debate for neurotoxicity and for the reproductive effects, for that matter, as to what the active moiety is.  And that's one reason to do the mechanistic work that has been underscored several times and that we have a lot of interest in doing.  And that is to understand what happens between the higher doses we have information for animals and humans in and the lower doses that we see in foods--understand that relationship.  One of the steps in there is figuring out which chemical actually causes the damage in the body, which converted chemical or which parent chemical causes the damage, so that we can make that extrapolation and understand how rats or mice differ from humans and what we would expect to happen in humans compared to what we see in rats and mice.

     DR. BUSTA:  And the glycidamide, is that the adduct?

     DR. CANADY:  It is one of the two adducts that forms with hemoglobin.  Acrylamide and glycidamide both form adducts.  The argument has been made that direct interaction with DNA only occurs for glycidamide.  The argument has been made both ways with regard to neurotoxicity whether acrylamide or glycidamide is the active agent.  I'm trying to state this neutrally.  I mean, this is the way the arguments have been laid out.

     DR. BUSTA:  But I hear very little--it's mentioned, but I hear very little about research on glycidamide.

     DR. CANADY:  I'm sorry.  The nomination to the NTP was for both glycidamide and acrylamide.  And that was, again, recognizing the need to understand the mechanism for low-dose toxicity.  And again, one of the main reasons for doing the NTP studies is to understand this transition from high-dose animal to low-dose human.  I mean, that's a very important part of why we nominated acrylamide and glycidamide, so that we could do the mechanistic work, essentially.

     DR. BUSTA:  Other questions around this point?

     As I look at--we're working through here, toxicology moves on to methodologies.

     DR. GRAY:  Could I just ask, what tab are you on?  I'd like to be following along.

     DR. BUSTA:  Well, tab 5 is the general one, and then I keep flipping back to the presentations.  Formation would be the next item in the draft plan, and we have presentations on formation by Lauren Jackson, who's here.  She got here--that's impressive.

     Questions and comments on formation?

     DR. FISCHER:  Well, I would like to see--there's two ways to look at this.  I think I mentioned this the other day.  We need information for the person who's doing the cooking at home on ways to prevent the formation of acrylamide.  And of course industry needs to know the same kind of information so that can put out products that have less acrylamide, if it's needed.

     So who should do the research?  Should the government do the research for the homeowner who is producing acrylamide at home, and industry do research to reduce acrylamide in their products, and not have the two talk to one another?  That seems--I imagine that could actually happen, but it seems crazy to have it happen.

     So I think the two groups, those doing research with federal money and those doing research with their own money on their own products, ought to be talking to one another and sharing information.  And I know the FDA says that they have good collaborations with industry, but I would question whether they really have the way to get the information that they need from industry.  For example, we just heard that they have not yet gotten the protocols from the studies being done by the chemical industry on acrylamide, after having asked for them.  So I wonder whether there really is this good collaboration going on.

     So who should--I think there should be not only a communication, but there should be some way that the information that industry knows about the formation of acrylamide be passed along to others so that it can be widely distributed.  And I'm not confident at this time, after just listening this short amount of time, that this is going to happen as smoothly as one would hope.

     DR. BUSTA:  Well, I've heard on several occasions now that JIFSAN will be the potential route of that.  Dave's not here.  Do we have any idea how much information is moving in that route now?  Has that been well adopted?  Does anybody--

     DR. CANADY:  It's just started.

     DR. BUSTA:  It's just started.  So it's hard to know what--not everyone has raced to put their data in there immediately.

     DR. CANADY:  It's hard to really respond to that.  It's just a few weeks old.

     DR. LEE:  As I understood from Dave Lineback, the Infonet is a worldwide linkage--it's a World Wide Web site that will link to data that you have either posted on your own website, your company's website, your scientific website or wherever.  So in that way, it is already in the public domain.  But I did ask Dave yesterday what is going to motivate me if I have a company and I have a product that has acrylamide that's a thousandfold higher than everyone else's; am I going to put that on the Web?  Okay?  I don't think I will.  And I think Dave agreed that a company is not motivated to do that.

     DR. BUSTA:  But we heard NFPA, I think, offered to sanitize data?  Is that an appropriate interpretation?  It's blind data--nice word.  Blind data.  Is NFPA involved in JIFSAN?  Were they-- Okay.  So that-- okay, Henry just said that I've got to get this on the record.  Can I interpret the shaking of a head?

     DR. JARMAN:  Yes.  That's a yes.

     DR. BUSTA:  Rick Jarman, NFPA, indicated that NFPA would blind information through them and put it onto JIFSAN if there was a concern about that.  So that's at least one mechanism.  Will JIFSAN accept blinded data?  Terry?

     DR. TROXELL:  Yes.  They're willing.  As Dave Lineback said yesterday with respect to the sampling data, that they expect companies to blind the data either through associations or lawyers and so on to put it in.  And I think the same kind of mechanism would work for research on formation.  I think more of the hindrances are that scientists or even companies may not want to give up initially what they have learned until they can, you know, see further that it's going to work or that they can publish a paper.  I think that's where the FDA is going to keep working to encourage and jaw-bone everybody to, you know, do the right thing so we can get to the answers as quickly and efficiently as possible.

     Let me mention also that in addition to the JIFSAN mechanism, I mean, we do have our consortium, the National Center for Food Safety and Technology, that is a very mature organization.  And that's where--really, that's where our food processing research is conducted.  We have a full division out there.  And they have a very strong relationship with the industry and IIT, and they have a very strong program of food processing work.  And this is clearly one of the priorities now for the NCFST, and I think that, you know, through Lauren and the staff out there, Dr. Sadler and IIT, there's going to be a--there'll be a strength of focus to really get to that formation research.  And we'll keep checking in with various--whether it be industry and Europe and so on--various people that are doing research.  We'll--I mean, you're right.  We have to keep pushing to make sure we're gathering the information that people are developing.

     DR. ACHOLONU:  I have a question.  Yesterday, when we were discussing this formation of acrylamide, I made some statements with respect to each connection, the chemical process.  And I read some materials where they talk about migration of acrylamide into food from plastic.  And then, when you talk about formation of a chemical material, you have to come up with a simple equation that says from this--if you add this to this, you get this.  I think we should pay more attention to finding out how acrylamide is formed chemically, and go from there.  Maybe the chemists or the biochemists should go into this.  We have given it a name.

     I have read the material given.  There are lots of--some equations here, and they talk about acrylamide from Maillard reaction products.  Still, that doesn't give what we are looking for when we talk about the chemistry of the material, the substance.  Could we go more into this aspect?  Because it said formation chemical mechanisms governing the production of acrylamide is unclear.  I think FDA should spend some time trying to make this clear.

     This is the comment I want to make.  When you say you're forming something, the public, the scientific world has to know how this material is formed chemically.  Thank you.

     DR. BUSTA:  Dr. Downer?

     DR. DOWNER:  I wanted to just respond to Dr. Fischer's comment about the groups who should disseminate this information.  And I think it should go beyond just the FDA and the industry, but look at some of the professional organizations like the American Dietetic Association, like the American College of Nutrition, and other home economics groups that would be a good conduit for this information to get to John Public, who's actually cooking at home.

     DR. BUSTA:  Dr. Gray.

     DR. GRAY:  Well, the first thing I want to say is that I do--I think the formation research is very important.  And I think even there, there are these opportunities perhaps to do some kind of mechanistic or empirical work, and would suggest, as I think others have, that, for example, trying to correlate levels of free asparagine in foods to levels of acrylamide is the kind of thing that can help build a link to understanding both formation and perhaps control.

     But I'm using this as an opportunity because it's mentioned in this particular bullet point.  It's the first place communication comes up.  I want to follow on Dr. Downer's points.  And I think this is a place where we really do need to be making some effort.

     I think one of the themes--I participated in the Chicago meeting on acrylamide and risk communication.  One of the themes there was an important fact that even follows from this Action Plan is we're going to be having information coming out continually over the next probably five years, and much of it is going to be led by exposure information.  We're going to learn what foods it's in.  It's already now on the World Wide Web.  You can look and see if it's in your favorite breakfast cereal.  And we're just going to have more and more of that.  We're going to have the NHANES data finding the material in blood, of you, me, our kids.  These are going to be communication challenges that, if we think about them now, we'll do a better job of dealing with them.

     And for that, I want to suggest that FDA take advantage of its own strength in consumer research, that it work with these industries--these food industries do an awful lot of consumer research as well; there's a lot of knowledge there.  How can we the message that is appropriate?  And I would suggest that FDA's message so far has been very, very good, including--I want to recognize their recognition of the potential for tradeoffs here, that there are no simple solutions to this.  How can we get that message to people, whether it's leveraging the professional organizations, physicians, people who interact with people and have some moral--not moral, authoritative--an authoritative voice with them.  Don't attribute too much.  Or if these are things that have to be done directly.  If we're working with the news media, how do we make sure that these messages are well done?

     And I think one of the things we have to think about is there's a big world out there that studies risk communication.  When we've got a strong consumer component, including the fact that you and I are making acrylamide at home when we make toast and we make bread, we have to think very carefully about how we're going to communicate those things.

     And then finally, I guess, but along those same lines, one thing that I've found, I didn't--well, it didn't sit quite right with me in the Action Plan--is a fundamental assertion right off the bat that what we want to do is reduce acrylamide levels.  I think there is still--we're recognizing that there is scientific uncertainty; we're not sure the levels at which this is a problem.  And I think even if the Action Plan recognizes it, there's some uncertainty.  We've got to learn something before we even think it's good to do that--that helps with communication.  If we have an Action Plan that says get as much of it out as we can today, and then say don't worry, eat your regular balanced diet, those mixed messages make it a lot harder to communicate.

     DR. BUSTA:  Dr. Lee.

     DR. LEE:  I'm glad that Dr. Gray and Dr. Downer introduced the idea of communication.  And I think it might be appropriate, certainly not today, but perhaps FDA or some other body would like to make a determination whether or not acrylamide is a natural substance or it is a manmade substance, or perhaps it's both.  Because that, of course, has a lot of implications when it comes to communication and it also has a lot of implications when it comes to litigation.

     DR. DOWNER:  That was going to be my point.

     DR. ACHOLONU:  What is this idea of its migration?  Why are some documents, some publications making reference to acrylamide migrating into food?  Could somebody please explain that to me?  Because in the biological sense, things that migrate are under their own locomotion.  Is the migration by active transport or by passive transport?  How is it occurring?  How does it migrate from plastic into the food?  Would somebody please explain that to me?

     DR. BUSTA:  Dr. Canady, do you want to--

     DR. CANADY:  I think the reference is being made to prior FDA decisions about food contact materials--the wrappings, the packagings for foods.  The situation we're talking about today refers to incurred acrylamide through cooking.  In other words, you cook the food--it doesn't migrate to the food during the cooking process, rather it's created during the normal cooking process.  So the issue of migration affects our current situation in the sense that it talks about how acrylamide might move out of the food that's been caused to have the acrylamide in it through the normal cooking process.

     DR. ACHOLONU:  But you know it's in the literature, right?  Apart from what you gave us, check in on acrylamide.  I see it used constantly, "migrating into food."

     DR. BUSTA:  I have a question on formation.  Some of that data are really straight--I mean they're just so obvious, they really hit you in the face with the presence of glucose and asparagine, I mean, produce all kinds of acrylamide.  When I look at that, I sort of say all we have to do is apply that.  Is there still--am I simplifying that too much?  I look at some of the materials that Dr. Jackson presented, and it's sort of, well, if you've got a free reducing sugar and asparagine and you heat it up, you're going to get acrylamide.  I mean, it seems just right there, and I don't--what are the big questions on formation?

     DR. FULLER:  You're asking him how much more work is needed.

     DR. BUSTA:  Yeah, it seems I--or is it--are we going to look into food systems or whatever, but, I mean, it seems like it's answered; it's there.

     DR. DOWNER:  But is it just glucose and asparagine in the absence of the temperature and the exposure?

     DR. BUSTA:  My understanding is it's a reducing sugar and asparagine, maybe cystine, and heat.  And we get acrylamide.  Is that--

     DR. FISCHER:  I don't think that's true, is it?  I don't think this is true, because they say--they've told us that if you microwave the products, you don't get it.  So that's heat and temperature--

     DR. BUSTA:  It's not hot.

     DR. FISCHER:  Sure it's hot.

     DR. BUSTA:  Not hot enough.

     DR. FISHER:  It's hot.  Put your finger in a piece of bread--

     DR. DOWNER:  It's exposure time.

     DR. BUSTA:  It's only 100 C.

     DR. HOTCHKISS:  Never above 100 C.

     DR. FISCHER:  Never above 100 C?

     DR. HOTCHKISS:  Only at the surface.  You can't raise the temperature until you get rid of the water.

     DR. LEE:  Well, you can pop popcorn at a lot higher temperature.

     DR. FISCHER:  It seems to me there was something with the browning reaction.

     DR. LEE:  Those data are incomplete.  I don't know if microwave popcorn has acrylamide or not.

     DR. FISCHER:  It think it's in the list.

     DR. LEE:  All right, let me look at the list.

     DR. BUSTA:  Dr. Troxell?

     DR. TROXELL:  Thank you.  Well, if it--maybe you should, if it's obvious, and professor emeritus, I would go back and figure out how we can do it.  We're all stumped.

     You know, this is you got components of living food materials, potatoes and so on, how do you--you know, you could eliminate this if you could eliminate the sugar and the free asparagine.  Well, I'm not sure we have food by eliminating those things, or I'm not sure we have tasty food by eliminating sugar.  So the question is, is how to maybe reduce the levels in key things so we're--and then--or how to target inhibition of a reaction.  Because there's an extremely complex series of reactions.

     So it's one thing to say we understand the mechanism, and it's another thing to--a totally different world to try to capitalize on that which everybody is feverishly working on now.  They're feverishly working on capitalizing this, to prevent the formation or reduce the formation in foods.  And as far as the temperature, it doesn't form below about 120 C, so you need to get at least the surface temperature of the food above 120 and probably substantially above that to really start pushing the reaction along.

     DR. BUSTA:  In regard to microwaves, that's one of the problems that's one of the problems.  It doesn't brown.  And so you--

     But what I'm trying to get to is we're fairly knowledgeable about the formation mechanisms, and it's the control of the formation and modification of formation that is the research interest.  Is that--I mean, Stadler published this one graph that seems so dramatic that it seems like we have a pretty good idea about mechanisms.

     DR. FISCHER:  I saw there's some question marks in the scheme.  I don't understand, and apparently no one else does either, why there's such variability in the formation of acrylamide, that we've seen the data that nobody understands.  That tells me, anyway, that there is some factor, or factors, involved that we don't know about that's causing this variability.  Sometimes in the same batch of products you've got pieces that are much higher than others.  So there's something unknown.

     DR. BUSTA:  Dr. Jackson, then Dr. Lee.

     DR. JACKSON:  I think when you look at the data, you're seeing the variability.  There are two sources of variation there, one with the processing, the other with the raw material.  If you look at a batch of potatoes--and I haven't tested this myself, but from when I've talked to the people in the potato industry, you grab one potato out of a bag, they're going to be very different even though they're stored the same.  They're a living plant.  And you're going to have variation in the free asparagine and the sugar levels.

     And I don't know how you're going to eliminate this problem--I mean, Ken Lee talked about this--I don't think you're going to be able to eliminate the acrylamide levels to zero, because you can't eliminate asparagine from foods.  I mean, that's an amino acid required for the structure and the plant.

     So I think what's going on, at least from when I've talked to the people that are doing the potato--you know, the fries--what they're trying to do is look into storage of potatoes and trying to reduce levels by storing the potatoes and testing, you know, different conditions where they can store and lower the levels of free asparagine and sugars that way.  Another way that they're looking into this also is looking into different variety of potatoes that might have lower free asparagine as well or free reducing sugars.

     But processing, I think, is the only controllable way, I think, that we can look at this problem as an agency.  I don't know how we can do it any other way.

     DR. BUSTA:  And that's--we have a fairly good idea of the formation; it's the control and the variability and the other things influencing that formation that are the real questions.

     DR. JACKSON:  I think one of the areas that we're going to research is to separate and determine where the variability is, if it's in the process and in the raw material, because--I didn't include the data in the presentation yesterday, but when we did fry three different batches of potatoes, same temperature--they were all stored the same--the three batches, no matter how well I tried to control the temperature in that oil, we got very different levels.  Especially when you got to the higher temperatures, where you got probably more browning and things going on, it was very difficult to control the acrylamide.  You'd get tight--you know, the replicates were very different.

     So there's something going on.  And that's why I--it points to using model systems, because you can control the raw material going in and then you can see if there's variability in the process.  And that's what we intend to do as well.

     DR. BUSTA:  Dr. Lee.

     DR. LEE:  Thanks, Lauren, for the comment.  You know I have very high confidence in you as a scientist as well as your colleagues in Argo-Summit.

     And formation and control, I think, are the same argument, because if you know how it forms, you know how to control it.  But I would venture a guess, just speculate, that the industry is going to be the first people on the block to understand how to control this.  Because they have far greater vested interest in controlling it, and they also have a much more controllable process.  The consistency of manufacture is such that you're in control of almost everything you can possibly measure.

     So again, I would just put in a plug here that we make it easy and in industry's best interest to share both their data on occurrence and process variables that control.  Now, when you're sharing process variables, you're sharing brand identify, so this has to be done in a double-blind fashion, if at all possible.

     And then a quick segue--two people have mentioned microwave.  You know, if we have data on our website now, 157-181 micrograms per milligram to microwave popcorn.  So, you know, it's not supported that microwaving is going to give you an acrylamide-free product.

     DR. BUSTA:  Dr. Kuzminski.

     DR. KUZMINSKI:  Just an observation just to follow up on some of the discussion.

     I think that this problem creates a number of opportunities and challenges, challenges for the trade associations, if you will.  When a company--just from experience, when a company is asked to share processing information, my experience is--in terms of process variables, my experience is that that's proprietary information.  It's part of the formulation to produce that finished product.

     So the challenge, as I see it, to--and yet we have a situation here where we know that it exists in finished products, we know that there's variability in the raw materials going into that finished product, yet we know that that process to produce that finished product creates conditions that produces acrylamide.  So the challenge, I think, to industry is to--and to the trade associations that represent them, is to figure out a way whereby valid information can come forward that would help with the levels in finished product.  And I suspect it will be a very gut-wrenching exercise for that body of society to come up with a way to come forward with process variables.

     The conundrum for a company, as I look at it, is that they have a product that's out there with an established market share, whatever that share is.  And that product is achieving that share through a number of means and also because it has a certain product image to the consumer.  And that image to the consumer is responsible for some of its success.  Changing the process to change that image is the big challenge to a company, to the industry.

     So it's not an easy problem for them to solve.  I'd like the committee to fully realize that, in terms of coming to grips with sharing that kind of process information.  Not an easy problem at all.  But it's a challenge to the trade associations and to industry to come to grips with it.

     DR. BUSTA:  Dr. Whitaker.

     DR. WHITAKER:  Lauren, I would just like to comment that there is another source of uncertainty, and that's in the acrylamide test procedure.  And this is what I was trying to get to yesterday with Steve Musser.

     I suspect the greatest variability would be from potato to potato, but your sample preparation and your analytical components of your test procedure also contribute to the uncertainty.  But my guess is those lower two components, the sample preparation and the analytical, are small compared to potato-to-potato.  But I think it has to be acknowledged or understood that that's also there and characterized.

     DR. BUSTA:  Are there any other points?

     DR. JACKSON:  Actually, I wanted to add something.  We talked about potatoes and grain products where the asparagine-sugar mechanism's probably the main mechanism.  Coffee we didn't talk about very much.  Coffee--there might be some other mechanisms going on, mainly because you go to very high temperatures, you know, over 500 Fahrenheit, 250 degrees C.  So there might be some other mechanisms going on there, and that needs to be fleshed out as well.

     DR. BUSTA:  Dr. Lee.

     DR. LEE:  Lauren, it was you that showed data that at very high temperatures acrylamide contents were lower.

     DR. JACKSON:  That's right.

     DR. LEE:  So you're speculating that there's another mechanism there?  Or do you have any clues as to what's going on?

     DR. JACKSON:  We don't really know.  I know from what the Nestle people--we had this meeting out in Chicago.  Stadler from Nestle was talking about coffee.  And what they do, is they measure the different roasts of coffee from the light roasts all the way to the dark roasts.  So they measured the acrylamide levels from light roasts to dark roasts, and they didn't find any differences.  Which suggests, maybe, there's some type of degradation going on as well as formation.  You know, you--we don't really know.

     So that needs to be understood, too.  The formation as well as degradation.  I showed there was a dip in the graph there.  That really needs to be understood as well.

     DR. ACHOLONU:  This glucose and asparagine reaction, are you using it as an example of a way acrylamide can be formed, or is it the general way it is formed every time, every time?

     DR. JACKSON:  According to the research we've seen so far, that is the main mechanism.  I mean, if you look at the yields of acrylamide--if you look at the yield of acrylamide in a model system, Moltram and his colleagues, when he did his reactions, .3 percent of the asparagine actually became converted to acrylamide.  If you look in a food that's fried, you get roughly the same percent conversion.  So they kind of match up there.  But if you look at other amino acids--methionine, the other ones, cystine--the amounts, the yields you get from those amino acids just don't compare.  They just don't--couldn't account for all the acrylamide that you do form in food.

     DR. ACHOLONU:  So if you fry french fries, you are assuming that you have asparagine there and you have glucose--of course we know that french fries has glucose--and that any kind of combination that comes up, and we say acrylamide is in this food after it was fried or baked, that this is the very process that took place chemically?  Is this what you're saying.

     DR. JACKSON:  I understood your question.  If the french fry, the raw material, has asparagine and glucose, you can pretty much bet, if you get the temperature to the right temperature, you're going to have acrylamide in that food.  You saw that one piece in one of the slides, the Procter & Gamble people depleted all of the asparagine, or most of the asparagine in the potato, fried it, and then didn't form acrylamide.  So that--I think that's pretty good evidence there that asparagine is the key amino acid in acrylamide formation, at least in the potato, and in grain probably as well.

     DR. ACHOLONU:  Would you assume that there are other ways that we don't know at this present time?

     DR. JACKSON:  There could--yeah, there very well could be.  There very well could be.

     DR. BUSTA:  If you notice, there's an asterisk that says the Chairman has the "perogative" of calling a break.

     DR. LEE:  PRE-rogative.

     DR. BUSTA:  Whatever.  I would just like to make one comment--again, taking my opportunity--and reiterate what Dr. Gray said earlier.  We've just been discussing about getting rid of the acrylamide, controlling acrylamide, it being there, et cetera, and we're really not sure that it's a problem yet.  I mean, we really don't know if it's a problem in food.  And I think--I have to keep reminding myself of that.  We're so enthusiastic to reduce it, measure it, check it, get rid of it, and even talk zero levels and we have no idea if it's a problem.

     Now, if none of you wish to attack me on that statement, we will take a 15-minute break.

     DR. FISCHER:  I do want to ask you whether you're saying that we shouldn't do any research on formation until we know there's a problem.

     DR. BUSTA:  No, no.  I just--I think we should not declare it a problem--

     DR. LEE:  Not a human health hazard, right.

     DR. BUSTA:  --a human health hazard until we've got a little better information.

     DR. LEE:  It is a problem, it's just not--

     DR. FISCHER:  It is a hazard, I think.  The definition of a hazard is it's something that causes a--that has a potential for harm.

     DR. LEE:  Right.

     DR. FISCHER:  And this is a hazard.  It may not be a--

     DR. BUSTA:  May not be a risk?

     DR. FISCHER:  Yeah, may not be a risk, but it's a potential.

     DR. LEE:  Okay.

     DR. BUSTA:  With that, we need a break.


     DR. BUSTA:  If there's no more comment about formation--

     DR. FULLER:  One.

     DR. BUSTA:  Okay, we've got a comment on formation here.

     DR. FULLER:  Thank you.  I just want to sort of go back to a point we were talking as we ended just a minute ago, about message and the point that Dr. Gray brought up about issues concerning--perhaps the group looking at the message that we want to say or comment back to FDA on, and that was getting to the point on reducing the amount of acrylamide prior to clear knowledge of a risk or a significant hazard, significant risk.

     And I think, personally, I did not--I don't think you were, Dr. Gray--and correct me--I don't think you were saying to ignore this as a potential risk, but just to, in that message, clarify; or at least I would suggest that the committee just clarify that the significance of a risk is unknown at this point, not--and there is some concern about stressing too greatly reducing a risk with an assumption that--or reducing, excuse me, reducing exposure based on an assumption that there is significant risk when, indeed, we A) don't know that there is a significant risk.  There is certainly calculable or theoretical--there's potential for it.  I'm not saying this very well.

     But I think we want to--does the committee want to address that issue and more clearly--or clarify that issue?

     I'm getting a bunch of blanks.

     DR. FISCHER:  Well, I think you're talking about the last bullet here, Information--develop/foster public-private partnership, gather scientific information for assessing a human--  No, you're not.  Excuse me.  Educate Consumers.

     DR. BUSTA:  The second-to-last one.

     DR. FISCHER:  Yeah, second-to-last one.

     DR. FULLER:  Yeah, it came up at the end of our discussion just a moment ago.  And I don't think--I think we need to be careful, and maybe we should just hold this off till that bullet, but I just think we need to be careful about the message that we send to the consumer.  And we can address it at that point, if that would be more appropriate.  I'll leave it to our Chair to--

     DR. BUSTA:  Well, we'll be there shortly.

     DR. FULLER:  Okay.  We'll do it then.

     DR. BUSTA:  It's my thought that some of you may get antsy before 3 o'clock.  So if we can sort of look at moving reasonably fast and maybe even having a relatively short lunch and come back, if that's all right with you.  If it's all right with you, we'll get back to the education component, as I see it, on the next page.  If there's no other urgency on formation, or discussion--and we're all going to be talking about this one more time, when we make our statements.

     Methodologies is basically the next item.  Is there any comment about methods, current methods, evaluating the screening?  Any discussion or need for clarification?

     DR. FISCHER:  Well, I can say we discussed a little bit, maybe it was at dinner, about how difficult it might be--and I think it was mentioned here this morning--how difficult it might be to develop an immunoassay-based screening effort.

     DR. BUSTA:  Yeah, that was mentioned this morning.

     DR. FISCHER:  It would be great to be able to do that because it would be so fast and so on.  But I'm wondering whether we really know we have the information to eliminate that possibility altogether.  For example, you can use an assay based on antibodies or you can use an assay based on a receptor for acrylamide in cells.  I don't know whether we know whether there is a receptor that's involved for causing neurotoxicity or whatever else, but if you had the receptor, then you could base an assay on that receptor.

     We don't know whether acrylamide is actively transported across membranes, or at least I haven't read of that.  I may have missed it.  But if it's actively transported, there's another receptor and possibility for a specific binding for an assay.

     So I guess what I'm saying is that I wouldn't throw away the possibility of going the routes of that type of an assay.  It's worth investigating to see whether it's possible.

     DR. BUSTA:  It's my understanding that FDA will be evaluating screening methodologies, not necessarily developing them.  Is that correct?  Are you developing rapid, quick, and fast, easy methods?

     DR. TROXELL:  One of our groups is at this point looking into an LCUV method.  And if the committee thinks that we should looking into other quick assays such as--see if there's a possibility for immunoassay or something, then we would carry that advice back and see, you know, if we should look into that further.

     DR. BUSTA:  Dr. Hotchkiss?

     DR. HOTCHKISS:  In the past history of these kinds of contaminants, the agency and others have, I think, very logically developed two levels, if you will, of analysis.  One is a screening or presumptive analysis; the other is a confirmatory analysis typically used more in a regulatory sense.  The agency, I think, has to date developed a first-rate confirmatory analysis for which I think there will be no argument with other than the cost.

     My reading of the literature, however, is that there already is a what appears to be a relatively quick and nice screening method based on bromination and electron capture or gas chromatography.  And I suppose I've, given what I read, urged the agency to round-robin, maybe through AOAC, that procedure because EC detection, because of the pesticide issues in food, is very widely available, routinely done by hundreds and hundreds of labs around the world and thousands of samples per day.  It seems to me that this method would give a very quick screening method that could be in place in probably a matter of weeks if people really wanted to do it.

     DR. BUSTA:  Any other comments on methods?  Let's move forward, then, to Meetings and Collaborative Projects in the draft Action Plan.  There are a number of bullets on here.  Are there any comments on that area?  That's on page 4 and 5 of the draft Action Plan, under tab 5.

     DR. DOWNER:  I'd just like to see we include the nutrition professional and academic groups included in this, and home economics groups, particularly for the consumer's interest.

     DR. BUSTA:  Okay.  I would think when you include academics, you'd include, for example, the extension service that, hopefully, still has a connection with the consumer.

     Any other comments on the meetings, public meetings, subcommittee meetings of this committee?

     DR. HOTCHKISS:  Just to congratulate FDA, who, as these issues have unfolded in the past, has not always been so cognizant of the importance of bringing a variety of stake-holders into the picture.  This seems to be a very good trend, very good move.

     DR. BUSTA:  Well, let's move on to Consumer Messages.  And we had a presentation by Dr. Acheson.  And we have these consumer messages that we're--Dr. Downer and then Dr. Fuller.

     DR. DOWNER:  My major concern with the consumer message as it's outlined, and particularly in our presentation yesterday, was it gave the impression that eating a balanced diet may have a protective factor against acrylamide.  And we don't know this.  Because he kept saying eat a balanced diet, one with fruits and vegetables.  And so what I quickly got from it was if I'm eating a balanced--whatever "balanced" is--I'd really put it as the term "healthful," healthful diet.  We need to make that clear, because it's quite confounding.

     As I said before, it appears to me that if we're eating a balanced or healthful diet that it gives a person--that's a protective factor against acrylamide or what may come with it.  If we're going to put this and couch this in a message for the consumer, I hope that it will be clear, with something--for example, saying "In addition to eating a healthful diet and handling food safely," make sure that you do so-and-so.  I don't want to see one message replacing the other or causing additional confusion.

     DR. BUSTA:  Dr. Fuller.

     DR. FULLER:  Let me come back to that.  I want to compose my thoughts a little bit more coherently, particularly in light of that comment.  So let me come back to that in just a minute.  I think Dr. Gray is interested in a comment.

     DR. GRAY:  Well, actually my comment is slightly different, but it's sort of a communication idea that goes to Dr. Downer's comment as well.  I wonder if we could, or whether FDA could, using its exposure-assessment models and such, compare sort of a total-diet survey, what-do-people-really-eat diet to a food-pyramid healthful diet, in terms of acrylamide content, just as another way to show people that if you follow this advice that says eat a balanced, healthful diet with a variety of foods, in addition to all the other good things it does, your acrylamide exposure will be lower as well.

     DR. DOWNER:  May I respond?  The problem with that is we recommend that you eat six to 11 servings from the breads and cereal group.  That's the big group.  And that's the group where acrylamide is most contained in meal preparation.  So again, you see how the message has--

     DR. GRAY:  Well, it may well be that I'm wrong that doing that would make a difference.  But it also--part of it is which choices are made even within those groups.  And I'm sure that the American Dietetic Association or someone like that has particular recommendations within those groups that may be different than what people are actually doing.

     DR. DOWNER:  Well, the government actually--the FDA and USDA, they're the ones who put out the food guide pyramid.  And I think my--it's not the food so much alone, but how it's prepared, is what we're hearing now.  And so that--the message will be meal preparation rather than the food guide pyramid.  I think if we put the food guide pyramid and put it in place with the acrylamide message, we may end up having a hornet's nest.  So that's--we have to be careful as well.

     DR. BUSTA:  Dr. Lee?

     DR. LEE:  This is kind of a segue from the prior discussion of meetings.  You know, every time you call a meeting or have some kind of action, the media watches.  So each one of these meetings represents some opportunity to communicate to the consumer.  The release of the information on the website triggered something on the CBS News this morning about acrylamide, which--unfortunately "eat a balanced diet" is not news.  We know that.  If it bleeds, it leads, okay.  Usually news is negative, it's bad.  So the news, of course, is, "Oh, my God, did you know this stuff was in baby food" or whatever.  So I don't know if there's a conscious effort on anybody's part to work with media or to control the net impression that people get from all this news on acrylamide.

     But I'm kind of uncomfortable going forward to the consumer with a message when we sit here and say, look, we really don't even know if this stuff is a human risk, we don't know how to control it, there's a lot of unknowns.  So, yes, one should always be cognizant of the consumer message, but I just don't know what that message needs to be at this point.

     DR. BUSTA:  Dr. Fuller.

     DR. FULLER:  Well, that does help.  And I guess I--my personal feeling is that the message does need to be couched carefully.  We have information this is a rodent carcinogen, we don't know perhaps the significance of the rodent data to human exposure and human risk.  But we also can't say that there is not--that we can go la-di-da along our merry way and forget it.

     I do have more confidence, perhaps, than some in a carefully crafted message to the public that says very clearly here's what we do know, here's what we don't know, here are the areas of uncertainty.  And yes, I realize that this is a complicated message, but I disagree that your message always has to be a sound bite.  And I think you can carefully craft that message and give information to the consumer, or at least information that will point the consumer to where they can get good, reliable information in a form they can understand, and point to, okay, yeah, there's something here; no, I don't need to give up potatoes from my diet, but perhaps I should consider not having as--maybe I should not go with the french fries every day for lunch, but perhaps I should go with something different--potato salad rather than french fries.

     So I think we can carefully craft that message, and I actually think FDA is doing a pretty good job in that thus far.  I don't think they have given the message that says stop, halt, you've got something in the diet that is of immense risk.  They are saying that we are looking at ways to reduce this exposure.  The only part that I haven't heard is--perhaps that I might emphasize a little bit stronger--is the uncertainty of the information to date.  But I don't find tremendous fault with the message thus far.

     DR. BUSTA:  Dr. Hotchkiss.

     DR. HOTCHKISS:  Yes, I have a question for Dr. Acheson or whoever may know about this.  Has the agency put together any communications, for example with the consumer safety officers in the regional offices, or is there anything to be done in the FDA Consumer or other agency-controlled public vehicles for providing information on this topic?

     DR. ACHESON:  What we're currently doing is developing a talk paper to try to address some of those issues to get that message out.

     DR. HOTCHKISS:  Let me tell you the reason I ask that question.  I presume all of you have seen this morning's USDA--Freudian slip--USA Today.  You haven't seen it?  There's a relatively significant article that names brands and products and so forth based on yesterday's discussion in this meeting--quotes agency officials by name and so forth in this morning's paper.  What that does, as you all well know, is leaves the agency in a position of responding, of reacting to the media and others.  And if you read that article, as we did this morning, I think you'll find it not to be a very good representation of what went on in this room yesterday--at least in my view it wasn't.

     We in New York State have a very efficient system of getting consumer responses back through our county agents.  And I know what's going to happen when I get back--assuming I do sometime in the future.  When I do get back, we are going to have--we have a system for every consumer inquiry to a county cooperative extension agent gets back to the university, and very specific.  I know, based on what's in that article, we will have a series of them, questions, for which we'll quickly put something together and put it back.  The problem with that is that this puts us, and more importantly the agency, on the defense, rather than being proactive to say this is what we know, this is what we don't know, the kinds of things you're going to do in putting it out.

     I think the major consumer concern as we get these back through the county agencies is not specifically Frito Lay potato chips versus other things--it is when they read it in the paper--but what they really want to know is, is anybody at home on the issue, what are they doing about it, what is the game plan, are they looking at this, what do we know, what do we don't know?  They're interested just in knowing that somebody's there taking care of us and trying to straighten it out.  And that means that then the press response to FDA or other authorities rather than FDA responding reactively.

     DR. BUSTA:  Dr. Troxell.

     DR. TROXELL:  Thank you, Terry.  The talk points have gone to a public affairs officers, so when they see the questions they'll be able to address them.  And secondly, there is an article in draft for the FDA Consumer, so there'll be something in that venue also.

     DR. BUSTA:  You said what kind of paper is being prepared?

     DR. TROXELL:  There's a talk paper to give the public affairs specialists a basis to field questions on this issue and the survey.  That has gone out.  And there's also an article that is, you know, close to final that is going to be published our FDA Consumer in the next month or two on acrylamide and the actions we're taking, that we're addressing the research needs, and also will have the consumer message in.

     DR. HOTCHKISS:  Will that talk paper go out to the regional consumer affairs officers?

     DR. TROXELL:  Yes--our public affairs officers is what they're called now.

     DR. BUSTA:  Dr. Acholonu.

     DR. ACHOLONU:  I just want to amplify what Dr. Fuller said.  I remember the last person I spoke to yesterday, Mr. Stier.  He took time to emphasize the fact that we must be careful about what we put out to the public, that there has been no correlation so far between acrylamide and human beings.  I do know that an ounce of prevention is better than a pound of cure.  The FDA is doing the right thing to make the public know about its concern about acrylamide.  So every effort should be made to publicize this as widely as possible, possibly by radio and TV and any other means.

     But the message must contain the fact very clearly that so far there is no connection known between the effect of acrylamide on mice and rats and the effect of acrylamide on human beings, that study is still going on, and maybe in the due course of time we will find out if it is carcinogenic to man.

     So that's the point I wanted to make.  As you put out the information, the message to people, make it clear that it is still in the realm of probability, of possibility, that it is not a foregone conclusion that acrylamide is carcinogenic to man.

     DR. BUSTA:  Dr. Lee.

     DR. LEE:  I'd like to agree very much with Dr. Hotchkiss in that the message that somebody's at home, somebody's watching the issue, we're taking care of it, we're on top of it can very well be the message here with acrylamide.  Because I think the agency's doing a great job of being very proactive in looking at this from every possible angle.

     And therein also lies an opportunity.  Joe mentioned the county and the extension apparatus.  Every state in the nation has extension capability, and I would think that there's an opportunity here as a generic template to extend the FDA's reach by interfacing effectively with land grant university campuses that have extension.

     DR. BUSTA:  Even if those are USDA.  Dr. Kuzminski.

     DR. LEE:  Agency rivalries aside.

     DR. KUZMINSKI:  The tab 5 that we're looking at, it's a draft Action Plan.  And I think personally that the agency has done a very good job of trying to manage the scientific information from around the world and trying to funnel it through vehicles that exist to make that information available.  And because it's a draft action plan, it's a plan in process, I guess.  I think number 7, as it reads--Consumer Messages as it now reads in our binders, to me sounds a little weak, a little wishy-washy.  And it could be embellished by some of the comments that have been made today in terms of more specifics of we're doing this talk paper, whatever they want to call it, articles will be published in the FDA Consumer and other documents.

     Because sometimes in reading this kind of material and listening to the amount of work that's going on, maybe this was your point, Marion--I know we talked about it yesterday--how much knowledge is enough knowledge before you come out with some sort of proclamation or a position or a preliminary risk assessment?  I know this is a difficult area for the agency to deal with, a preliminary kind of basis, but in order to continue the fine managerial leadership they shown on the scientific and technical basis, I think that same kind of leadership should be exercised on the consumer-communication basis.

     DR. FULLER:  I'll add just one more comment, and that is perhaps part of the message needs to be that the message--acknowledge up front that the message is going to change as more information comes in.  And I think we sometimes fail to say that up front.  It's always an underlying assumption, but having been through some shorter-term, high-profile incidents in which the message was having to change on a fairly short-term basis, my personal experience has just been if you are very up-front with what you know, what you don't know, you can say "this is what we think at this point in time, there are problems with what we think, here are the problem areas, and this will change as these studies come in."  And it may go "our concern may increase or in fact may decrease, depending on the data that are generated."  And you said it very well.  Thank you.

     DR. BUSTA:  All right.  The only other item on the draft document that we haven't discussed is Regulatory Options.  Does somebody have some burning feeling on that?  To me, that's policy and--

     Oh, Kenny pointed out, thank you, we went running quickly past Exposure.  And we discussed that and it's not highly identified as a heading.  Are there any points or discussion on exposure that you wish to talk about before we go into the questions?  We've been alluding to exposure a lot, as I see many of these comments on education, et cetera.  And earlier, I think, Dr. Gray--well, a number of the individuals have commented on real-diet intakes and things of that type on exposure.  Are there any other discussions on exposure, or questions about exposure?

     DR. LEE:  Where is Exposure in this outline?

     DR. BUSTA:  It's in--some in Toxicology and in Testing, Total Diet Study, and--

     DR. FISCHER:  There's a section called Testing of Food.

     DR. BUSTA:  In Testing.  Under Testing of Food, under Actions, there's Total Diet Study in that.

     DR. HOTCHKISS:  Dr. Busta?

     DR. BUSTA:  Yes.

     DR. HOTCHKISS:  Yesterday, during the--before I got here, then yesterday during the presentations, I thought, well, gee, maybe Exposure should be taken out as a major goal, as a section unto itself.  But I think that's really in some ways redundant, they're not going to do all these other things unless they do exposure; really is a matter of choice of how you want to emphasize it.  Obviously--at least, I think, to virtually everybody in this room--it's obvious that exposure is a key element here.  If you want to make it obvious to those who it might not otherwise be obvious, then you could put it out.  But it is under Major Goals.  It is the first bullet under Major Goals, and so--and when the analytical discussion occurred yesterday, I think right at the front it was said that the reason for doing this analytical work is so that we can accurately assess exposure.  So certainly this has not escaped the notice of the agency that this is primary.  On the other hand, if this is a public document and someone were going to make it more obvious, you could put a bullet or a number in here to bring out exposure.

     The technical issues, in my view, around exposure are not analytical.  As I said yesterday, FDA is a first-rate organization in that.  The technical issue is connecting the analytical data with best available consumption data, which FDA is also first-rate on doing, and I'm sure they were doing--it's just not very obvious in the document.  And that's why this morning I recommended using--some mention of using the best available database should be put into the document.

     DR. BUSTA:  Dr. Lee?

     DR. LEE:  I don't know where to put this, so I mention it under Exposure.  I still don't know for sure whether or not you have de novo synthesis of acrylamide or have some in vivo formation of it.  There's really no human population that I know that does not eat cooked foods, so the only populations I can think of that don't eat cooked foods are wild animals and--it was just mentioned casually that acrylamide's been detected in those creatures.  So there are some things that I have yet to understand about exposure.

     DR. BUSTA:  Other comments?  Is the subcommittee ready to start addressing questions?

     DR. HOTCHKISS:  I am.

     DR. BUSTA:  All right, I'll start off with Question No. 1.  You have that in your Charge and Questions.

     Given what we know about acrylamide's toxicology, occurrence, formation, exposure, and risk, are the following research steps appropriate to describe and address the public health significance of acrylamide in food?  There are three items below that.  Number one, the following sequence of a current study -- variability, exposure evaluation, concurrent with formation studies and concurrent with toxicity studies.  Are those appropriate to describe and address the public health significance of acrylamide in food?

     I thought we would rotate around the room, unless someone has a burning desire to be first.  Is Dr. Downer ready to respond?

     DR. DOWNER:  Are the research steps appropriate?  I think that they are.  I think the preliminary steps are fine, but that more research is needed on information regarding absorption, metabolism, distribution, and excretion of acrylamide in humans so that we can estimate the risk, relay the risk to humans that can be made.

     DR. BUSTA:  Okay.  Dr. Hotchkiss.

     DR. HOTCHKISS:  In general, the research steps and plan put forth by FDA, in my view, are quite appropriate, logical, and will serve the public interest of public health.  My only caveat or disagreement is that I don't see the benefit of the long-term cancer bioassay surveys per southeast.  I do see a considerable need for much of the pharmaco- and toxicokinetic work, much of the biomarker work, the germ cell genotoxicity, all of those kinds of things, but I don't believe that the long-term carcinogenicity assay is required to gather information from those.

     Other than that one part of that, I think that FDA has, as I said before, put forth a comprehensive and logical plan.  I think that, and I think it will be addressed in our Question 3, I think priority of work is important in this, and I want to reserve comment for that.

     DR. ACHOLONU:  It is my opinion that FDA has done well so far.  But we're expecting more in the future.  Thank you.

     DR. GRAY:  Well, I'd like to echo the others who say that this is a very well thought out action plan and I think that it covers, at this point, all the bases for developing--most of the bases for developing information to describe the risks.  The one thing I don't see here, and it may be implicit, is discussion of the tools and the approaches and potential research that needs to be done for methods of using this information to describe the risk.  And here I'm thinking particularly about evaluating particular risk assessment approaches that can be used in this setting.

     And the one other thing I would suggest that isn't here that may be appropriate, and this has to do with both resource and timing considerations that I'm not very good at estimating, is a question of whether further epidemiologic work would be helpful.  It's not currently in the plan, and given that a large part of our concern is the potential relevance of the animal data to humans, more data on humans may help to resolve that.

     DR. BUSTA:  Dr. Kuzminski is not a voting member, but you can make a comment if you wish.

     DR. KUZMINSKI:  Oh, thank you.  I think the elements that are contained in bullet one are--it's a good plan.  We've heard discussion.  I think there are a couple of things that could be in different order in the written material here, like validation of method ahead of survey, but we've heard discussion that that indeed was the priority.  Somewhere in there, the need for work on and use of risk assessment as knowledge is generated needs to be included.

     I guess my other comments will be addressed by bullets two and three.

     DR. BUSTA:  Dr. Whitaker.

     DR. WHITAKER:  I do think that the steps as outlined here are appropriate.  I think it shows FDA spent a lot of time thinking through the process, and the steps seem to be logical.

     I think that there's not much said in Question 1 about priority, but I assume that, from what we've said here yesterday and today, that those priorities are probably understood, such as analytical validation should be done before anything else.

     And this is a lot of research.  And I don't know that FDA necessarily will do it all itself, and it should try to make use of industry and academics to attack these goals in terms of a research process.

     DR. BUSTA:  Dr. Fischer.

     DR. FISCHER:  I agree with everyone regarding the completeness and applicability of the plan to what needs to be done to understand acrylamide's potential role in causing harm from the food supply.  I think it's a well thought out, good plan.

     I agree with Dr. Gray that what it lacks is specific statements of intended research, or research needs in humans.  I think in the end we always like to see the human data.  We've already, I think, talked about the inadequacy of the present data in that these were worker studies, in the main.  And I would say, from what I can see in my experience, that worker studies are never looked upon as being sufficient when you're looking at a low-dose situation like we're looking at now, particularly with food being the matrix in which exposure occurs.

     So there's a--any chance to increase the information in humans, I think, ought to be taken.  That includes toxicokinetic studies as well as some way to get some epidemiological information.  It seems to me we've kind of ruled out the possibility of doing any epidemiology, either on exposure or exposure and outcomes.  And maybe there is a way to do it.  Maybe somebody's got a creative way of getting a population that we could look at who is more highly exposed than other populations.

     So I would agree that we need to consider more information in humans.

     DR. BUSTA:  Dr. Fuller.

     DR. FULLER:  Like everyone else, I applaud the efforts and the plan, I think, is also very carefully thought out.  I have some ambivalent feelings, like Dr. Hotchkiss, on long-term studies.  I do think, though, that they're--I don't know that it would be--that I would agree or suggest that they should not be done.  I think there is potential there for those to be further enlightening, although how much more so and how much bang for that buck, I'm not as certain there.  But I don't know that my uncertainty is such that I'd say don't do it.

     Otherwise, I think--the points that have been made I won't reiterate, and I just think it's a pretty thorough plan.

     DR. BUSTA:  Dr. Lee.

     DR. LEE:  Being near the end risks redundancy, but I'll leave the ultimate redundancy to our chairman, Frank Busta.

     Yes, the steps are appropriate and are in the interests of the public good, and I agree with prior comments.  The occurrence survey requires good cooperation now underway both with international organizations and the food industry.  But more importantly, to understand the mechanism and means to minimize the chemical, the cooperation of the total research community is needed.

     In particular, understanding process variables will require active participation by industry in a way that does not disclose proprietary information or single out a particular brand or product as a target.  The JIFSAN Infonet appears to be a good start, but there needs to be some active management of that.

     DR. BUSTA:  Ken always has described me very well--the ultimate redundancy.

     DR. LEE:  Put that on record, will you?

     DR. BUSTA:  Put that on record.

     I am impressed by the unanimity of the entire committee, in that there is extensive support, strong support for the research steps.  I think the concurrent activities, of three activities going on at the same time, are very appropriate and a very logical approach to the research needs.

     I believe that the role of food in not only the formation of acrylamide but its occurrence and the toxicity are all valid and important research activities.  So that I know we talk about model systems, and I know we look at mechanistic approaches and we measure the occurrence of acrylamide, but I think there's a need to factor in the specific food matrix systems and the processing in those considerations and try and link them across all three of the areas.  Because there may be a dramatic variation between what we've seen so far in other products and maybe the food matrices will give us an answer to that.

     I concur with all the individuals who've commented about the cooperative research activities, and would like to emphasize that the academic opportunities are here as well.  Unfortunately, frequently academic research is terribly slow, especially with graduate students.  It takes time.  And the information is not terribly readily available until they've concluded their effort.  But I think there are opportunities, at least in the long run, for academic participation in some of the fundamental work here, as well as industry and the government agency.

     I also concur with the need for the human consideration all the way through, including exposure and the kind of eating patterns.  I think that a 13-year-old young man eating a variety of different foods is a consideration that may not fit in a lot of the other databases and needs to be thought through.  I think that it relates to the home cooking activity and it relates to the toxicity problems, at least in concentration.

     And when I look at the toxicity studies, I see the order of priority just the way they're listed on the Charge.  I think mechanistic studies to support low-dose concentration is probably the most pertinent because of that low-dose extrapolation, and then going down through the rest; because the long-term cancer studies may not serve us as well, at least for our immediate research needs.

     Finally--and two people have mentioned it, and I would like to say it again, as long as I'm being totally redundant--the epidemiology seems to have more promise than I've heard put forth here.  It just seems to me that we could find a population somewhere in this world that doesn't like or eat browned foods--maybe a North Alaskan Inuit population or some population somewhere that does not consume highly browned foods; and in some way try and get a matched population to do the epidemiology to see if that--and that may be based on a lot of markers that are still not proven as well.  But it seems to me that that would address some of the questions that Ken has mentioned about endogenous generation of acrylamide, et cetera.

     A long and windy answer, but I had to, you know-- It's nearly 12 o'clock, so we can take a break and come back for Questions 2 and 3.  And we'll try and have a reasonably quick lunch and be back between 12:30 and quarter to 1:00.

     DR. FISCHER:  You don't want to finish up?  I mean, we're so close to finishing.

     DR. BUSTA:  Okay.  Is that what I'm hearing, let's keep it on a roll?

     DR. HOTCHKISS:  I would like to finish because--I agree we are quite close and I think we could finish this up and lunch will be about the same temperature.

     DR. BUSTA:  It really is--from my experience, it takes somewhere between two and four hours before you're really up at the hazard realm.  Unless it's been there since 10 o'clock.

     DR. LEE:  So it's not just temperature, it's time too.

     DR. BUSTA:  All right.  If that's the--

     DR. HOTCHKISS:  Go for it.

     DR. BUSTA:  Now I will do a reverse and start with Dr. Lee on the second question.

     Are there gaps in the research plan or areas where emphasis should be increased?

     DR. LEE:  You fooled me by doing that.

     Are there gaps in the research plan?  I think toxicity studies should take full advantage of any information developed by the acrylamide and related manufacturing industries, because industry cooperation, again, is needed to solve this problem if the problem truly is significant.

     The best interests of consumers is preempted, perhaps, by legal actions, and the means to minimize this hazard will dissipate if data is sequestered by the courts and made unavailable by industries who seek self-protection.

     There is questionable value in posting incomplete data sets and brand names on the World Wide Web, as was recently done.

     And to the extent positions, a system for free and unencumbered exchange of data must exist.  Industry data on acrylamide contents of foods and process variables that favor or inhibit its formation are critical parts to this puzzle.  A blind system that protects brand or process identify is essential, and this represents a potential gap in the plan.

     DR. BUSTA:  Dr. Fuller.

     DR. FULLER:  I didn't see any overt gaps.  And I would just stress the issues that we talked about a little earlier on the use of data in risk assessment and communication.  I won't go into long, lengthy comment on that, but--because I think we've addressed it previously.

     DR. BUSTA:  Dr. Fischer.

     DR. FISCHER:  As far as gaps goes, I think we addressed--in my last comment, we addressed a gap, and that is a human angle.  And I think that's there.

     The other thing I think I don't see is--another way to get a better idea of whether the human might be susceptible to a particular toxicity if you don't have any human data is to have good information on species differences.  And I don't think I see that stressed much in the plan.  So if we could have--if we could find a reasonable species that is much less sensitive, for example, or much more sensitive, it would give us a good idea of whether we can extrapolate to the human.  If all the species we study look about the same, then we have a good idea that the human might be susceptible.  So a little more attention to species differences might be helpful in the end.

     DR. BUSTA:  Dr. Whitaker.

     DR. WHITAKER:  I know we all have our own ideas as to what is important and what is not so important, but I only listed two things that I thought were--that I felt strongly about, and one is the human studies, which has already been mentioned.

     The other has to do with variability.  And I'm talking about variability now at the bottom of the pyramid.  We've heard about variability from food to food and variability from brand to brand.  But I know that eventually somebody in FDA is going to want to know how accurately and how precisely are we measuring acrylamide in a lot.  So I would like FDA to also take it one step lower in their thought processes, and that is to understand the variability that's associated with sampling, sample preparation, and analysis.

     DR. BUSTA:  Dr. Gray.

     DR. GRAY:  The only comment I would make here is that I do think that area that could benefit from some increased emphasis here is simply the notion of communication, that we think very hard about how to communicate with people over the entire period of execution of this plan and into the future after that.

     DR. BUSTA:  Dr. Acholonu.

     DR. ACHOLONU:  I'm impressed with what has been done so far.  But I want to reiterate what I said about connecting whatever they do with human beings.  I want to say that rats, mice are rodents.  They don't come close to human beings.  I'd like to recommend to FDA to consider carrying out some experiments with monkeys or apes, then eventually to man.  So that's my recommendation.

     DR. BUSTA:  Dr. Hotchkiss.

     DR. HOTCHKISS:  Yes, the question are there gaps in the research plan?  At least explicitly, perhaps.  Let me give you, or in my view, some specifics.  The first recommendation I would have relates to the issue of human epidemiology.  This acrylamide is an unusual substance in that, as I've said before, there is substantial occupational exposure, and a number of epidemiological studies have been conducted on that.  The question is whether or not those epidemiological studies are applicable to a different route of exposure, a different level of exposure, which is probably considerably lower but also over a very longer period of time.  It seems to me those are important questions.  I would recommend to the agency that they, either in-house or externally, contract a group to address those specific issues around epidemiology and to advise them whether or not they feel that the current epidemiology is applicable or not applicable and to what degree.

     The second area is, I guess, implicit in the plan but not specifically mentioned or addressed in terms of methodology, and that is really risk assessment.  I think that that is the absolute key thing here.  We're dancing around this issue because there is no credible risk assessment conducted, at least for this exposure.  There is a--risk assessment has been conducted by the agency itself on acrylamide as a migrant, but not in the context of a food contaminant.  And I think if we had that risk assessment--of course, I understand there are lots of things implied in that in terms of analytical methodology and the quality of sampling and so forth.  But still, it seems to me that's a key piece of information, is what's the risk and how do we compare that risk to other risks.

     In the toxicology studies, perhaps again implicit, but I think there are two issues that seem to me to be fairly straightforward to address in the right toxicology study, and that's germ cell toxicity and neurotoxicity.

     Neurotoxicity is typically most sensitive during fetal development, and there are a number of protocols for assessing neurotoxicity in animal models during fetal development.  If you don't see toxicity in that, it's unlikely you, at those doses, will see toxicity elsewhere.  Those are the most sensitive systems.  Those are relatively well established and straightforward.

     The other is germ cell threshold, and it's again a similar kind of thing.  Probably, or it's possible that there is a threshold for germ cell toxicity, and again those protocols for those kinds of assays are fairly well developed, again, in young animals during maturation.  There are certain stages of the maturation process that the germ cells are very susceptible to toxicants.

     Those kinds of studies probably would put this issue to rest, again assuming it has not already been put to rest because of the occupational exposures.  But in general, it is those kind of specific things that I think perhaps could be included in the draft plan.

     DR. BUSTA:  Dr. Downer.

     DR. DOWNER:  Thank you.  I concur with my colleagues that we need some information on human subjects.  However, I also think that biomarkers to include both short-term and long-term exposure should be investigated further.  Bioavailability of acrylamide, or its metabolite glyceride [ph], from food needs to be looked at also.  And I'd also like us to look at the food consumption data and compartmentalize it into not just what general Americans eat, but look at the different ethnic groups, look at the different age group categories, and also look at some of the socioeconomic data to get a better picture of what's going on.  Because we know that these different groups have different health issues that go along with it, and I suspect we may find some correlation there.

     DR. BUSTA:  Dr. Kuzminski.

     DR. KUZMINSKI:  Thank you, Frank.  I think there are two gaps that are areas where emphasis should be increased.  One is the use of risk assessment at an appropriate point in time--and there's big quotes around that would "appropriate."  And I don't know the answer that, and I don't think a lot of people in this room know the answer to that, but some decision needs to be made in terms of managing this entire process both from a technical information-gathering viewpoint and from a communication to consumer viewpoint.  So that's one.

     The other gap and area where emphasis should be increased is on the role of data that could be obtained not just from government agencies but external data, industrial data, if you will.  I must be frank; I didn't hear much passion on either side of the coin, by either industry or by the agency, in terms of talking about that's a source of data that we're working on through JIFSAN.  I think it's a huge area that could be exploited, exploited to benefit in terms of helping to solve the problem and helping to define further the problem and then solve it, if there indeed is one.

     DR. BUSTA:  Joe?

     DR. HOTCHKISS:  I just wanted to make a comment about the epidemiology that perhaps not everyone is aware of.  But the epidemiology around fried foods would be extraordinarily difficult if not impossible to do for a variety of reasons, one of which is that the general conditions, at least as we know it now, in which acrylamide is formed in foods happens to be exactly the same conditions that a whole variety of other, I think on an equal basis, more toxic compounds--the heterocyclic amines and a whole variety of those kinds of compounds--are formed.  So if you compare a population that is a fried-potato eater against a non-fried-potato eater, you're going to face the question of acrylamide versus heterocyclic amine versus a variety of other issues as well.  So recommending to the agency to do something like a fried-food epidemiology is rather a difficult if not impossible task.

     DR. BUSTA:  I think that was aimed at me.

     DR. FULLER:  Perhaps.

     DR. BUSTA:  Just confirming the difficulty.

     I won't be as redundant this time as I was last time, or at least go on as long.  I concur.  I haven't heard any of these comments that I disagree with.  The gaps that were identified, I think, are significant and important--by the other members of the committee.  I feel that the emphasis that was stated earlier in just running what I said, where I thought mechanistic studies could be emphasized initially and that exposure information and the role of food, I think, are indications of my opinion of where emphasis can be increase, or at least placed.

     Any other gaps stirring anyone else?  All right.

     Number 3.  Now, I started this way--I'm trying to spread this around.  Number 3, I'll start:  Priority research needs that should be addressed first.

     I'll just be redundant on what I just said, and that is that I think we need to look at the--on Consumption, I think we need to look at exposure levels with the emphasis, in addition to analyzing some of the foods.  And I have heard of the design of these food studies, and the combination of information from around the world, as being significant in achieving the first of the concurrent research activities that are stated here.

     I think that the role of food, again, is very important both in toxicity studies and in formation and control studies.  And that's why I think the emphasis should be placed first.

     Let's start with Dr. Kuzminski.  We'll come up this way.

     DR. KUZMINSKI:  Thank you, Frank.  I must defer to the toxicologists in terms of the time that it takes, just in the time that it takes to come up with the research answers to some of these topics that are proposed.  My sense is that it takes a longer time than it takes to do some of the others, just based on some very limited experience in some toxicity tests that I have been involved in.

     So I think the methodology, the occurrence, and the formation and the exposure mechanisms, that mix of investigative pathways as outlined in their sequence here is taking priority, has taken priority over the last several months and should be maintained.  But the others should be clicking in pretty promptly.

     DR. BUSTA:  Dr. Whitaker.

     DR. WHITAKER:  I wasn't sure how to address this question, because in my way of thinking FDA has already started the process as they should have; and to be commended for that, not to wait on us.

     If I laid out the priorities, and I look at what FDA has done or has started to do already, I would agree with it.  I think the first thing you have to do is make sure the analytical method is giving you correct answers, and they've done that and they should continue.  And I would have gone into occurrence, exposure, and risk.  And I think that--at least what I've gotten out of this--is the way they have gone, along with some other areas also.

     So I think, based upon the way they have started and what way I would look at it, that they're on a turn.

     DR. BUSTA:  Dr. Fischer.

     DR. FISCHER:  Well, I find this a difficult one as well.  Certainly, exposure is an important factor and should be among the first things done.  It's already under way, so I don't have any worry that we're not going to have exposure data probably first.

     The toxicity studies and mechanistic studies do take a longer time, and for that reason I guess one way to look at it is why put them off?  If in fact they're going to take a long time, maybe you ought to get them started.  And I think that that's being done as well.  So I agree to that.

     I would say, if I had--what I would start almost right away is thinking about risk communication--not a research need, but maybe you could call it research.  I'd start thinking about scenarios where you're going to have to respond to the public's concern and crafting the kind of response that you may need to make.  And maybe already some is needed.  So I wouldn't put off communicating with the public about this issue.

     DR. BUSTA:  Dr. Fuller.

     DR. FULLER:  I'll be honest; I don't think I have anything meaningful to say, so I won't.

     DR. BUSTA:  Dr. Lee?

     DR. LEE:  I wish I had faculty like you.

     DR. BUSTA:  You wish you had faculty.

     DR. LEE:  Yeah, right.

     Are there priority research needs?  I believe there is no shortcut to determining if acrylamide is a significant health hazard or a food compound that has negligible toxicological effects.  Nonetheless, the FDA will be doing its job by first placing its finite and often meager resources where consumer interests are best served.  This could include rapid, inexpensive tests for the compound, means to reduce the total dietary exposure, and an informed public that has science-based information on which to make dietary choices.

     It may be useful to determine if acrylamide is a natural product, a man-made product, or both.  It would be helpful if research could provide a basis for the answer to this question.

     And in the context of total food risk--that includes issues such as security, food counterfeiting, diversion, food-borne pathogens or prions in chronic wasting disease--acrylamide appears to be a lesser immediate threat to the human condition and thus a lesser priority.

     DR. BUSTA:  Dr. Gray.

     DR. GRAY:  Thanks.  Recognizing the timing difficulties involved with much of the toxicological research, the main suggestion I would make in the way of priorities is, to the greatest extent possible, moving along the toxicologic data and the tox analysis and risk analysis in order to provide context for the exposure information that we know is going to be coming soon, both in the forms of specific foods with acrylamide contents and things like adduct levels in the population.

     So this is just, as soon as we can, even as uncertain as it might be, to be able to provide some context to these exposure levels that are going to be coming first.

     DR. BUSTA:  Dr. Acholonu.

     DR. ACHOLONU:  I think that FDA could spend more time working on the kinds of food prepared.  To what extent is the level of acrylamide found in fried food, in broiled food, in baked food, and in roasted food?  It may be good to do some work, and grade them.  Find out where the level is found to be highest.

     The next thing I feel we should go into is work on safe limits of acrylamide in food.  To what extent can you take in acrylamide, to make sure that it is safe for health, that it will not be carcinogenic?

     Next, I don't know if we addressed the issue of cumulative action.  Can acrylamide, when it gets into you, be metabolized and taken out or excreted; or does it accumulate?  As you get exposed to it and as you eat, does it keep on increasing to the level then causing cancer in a human being?  So we need to go into that aspect.

     And as I've said before, priority.  We are making this study assuming that it can do something to man.  So emphasis, anything we can do, any research we carry out should bring us closer to confirming that it is carcinogenic to man--not just say it is probable, it is assumed.  Everything we have said so far, what has been written so far has been speculative as far as human beings are concerned.  So any research, any work we do should point towards confirming that acrylamide is carcinogenic to man.  Thank you.

     DR. BUSTA:  Dr. Hotchkiss.

     DR. HOTCHKISS:  The question as framed is are there priority research needs that should be addressed first?  In my view, the answer to that is emphatically yes.  Is FDA doing that?  It seems by de facto, yes.  As we see the FDA ongoing and planned work in this area, it seems to be a logical sequence.  Have FDA prioritized their work?  It seems certainly not.  I've seen nothing in here to really prioritize it.  They've done it in kind of a de facto way.  My recommendation is that FDA say, yes, this is our priority, this is the sequence of events we're going to unfold.  There is a timing frame back in here that actually puts timing -- that implies priority but does not state so.

     My own priority would be a post haste risk assessment, and not necessarily waiting for all data.  You never get all data for risk assessment.  You'll refine your risk assessment.  And as a matter fact, as I've painfully pointed out to the FDA, they've already conducted a risk assessment for acrylamide and have published that risk assessment.  With the available current data, they should either conduct a subsequent risk assessment or say why that cannot be done, because it really is the key element here, is risk.

     If we knew the risk assessment--and, of course, implied in "risk assessment" is a lot of things.  Exposure, you can't do a risk assessment without exposure, and you can't do exposure without all the analytical kinds of things and those things that FDA is doing.  But if we had our best current guess on risk now, then that would certainly guide us better in the future.  So that would be my first priority.

     Along with that, clearly the major risk is going to be carcinogenicity.  It virtually always is.  But along with that, the short-term, oral-dose neurotoxicity and germ cell experiments, I think, should also be a priority because that will either take those issues off of the table or bring them to the forefront on the table, depending on how those specific outcomes are seen.  My guess is what's going to happen is the tumorigenicity risk assessment--tumorigenicities at low dose is going to be the primary thing--but until that works, then you don't know that--and then a risk assessment.

     Other than that, I think, in a practical sense, FDA is prioritizing these things in a de facto sense very well.

     DR. BUSTA:  Dr. Downer.

     DR. DOWNER:  I think the FDA has already started on the priorities, and my recommendation that I'm going to make is simply adjunctive rather than a priority.  I think one of the things to look for would be whether or not acrylamide, at the levels found in food, is of any toxicological significance.  I would also want to look to see, if we make changes or recommendations with regard to food preparation, what are some of the tradeoffs to ensure microbial safety and definitely to maintain organoleptic properties.

     DR. BUSTA:  There's time for a last statement if any of you feel that you have anything further to add to the record.  Dr. Downer.

     DR. DOWNER:  I just want to thank you all for the opportunity to be on this committee and for the white papers and the presentations that were made.  I certainly came here, after reading the documents, with one perception, and was able to be swayed and educated further to make some of the decisions I made today.  So thank you.

     DR. BUSTA:  Dr. Lee.

     DR. LEE:  Well, I don't want to roll credits, but I want to thank Dr. Henry Kim for being very comprehensive in preparing everyone for this meeting, and his e-mails were very helpful.

     DR. BUSTA:  Dr. Kuzminski.

     DR. KUZMINSKI:  I would just like to thank our Chair for the job he's done.

     DR. DOWNER:  Ditto.

     DR. KUZMINSKI:  You've done a good job.

     DR. LEE:  I appreciate the Chair for his redundancy.

     DR. BUSTA:  I think this has been a very excellent experience.  The committee is so compatible, they took over my last statement.  I'd like to, of course, thank FDA for all their efforts and Henry for sitting here watching me closely to make sure that I really don't get myself into trouble.  And this entire subcommittee, I think we've had a good day and a half.  And I think we'll have another opportunity to experience some of this again when we have the full committee.

     Thank you, and for those of you that can make it home tonight, good luck.

     DR. DOWNER:  You'll have to come to my house.

     DR. BUSTA:  Those of you that can't, good luck.  Terry?

     DR. TROXELL:  I'd like to have the last word.

     DR. BUSTA:  You're on.

     DR. TROXELL:  I want to thank the committee, for the FDA, for CFSAN, for myself, for the tremendous amount of work you have done and the advice you have given us; for braving the weather, braving the trip home.  We wish you a safe and speedy trip home, and hope the folks heading to Florida can get to the sunshine.

     Thank you again, everyone.

     [Whereupon, at 12:23 p.m., the meeting was concluded.]

- - -