GRADUATE SCHOOL

 

U.S. DEPARTMENT OF AGRICULTURE

 

 

* * *

 

FDA FOOD ADVISORY

 

COMMITTEE MEETING

 

* * *

 

 

FOOD BIOTECHNOLOGY SUBCOMMITTEE

 

OF THE FOOD ADVISORY COMMITTEE

 

 

MOLECULAR CHARACTERIZATION

 

CENTER FOR FOOD AND APPLIED NUTRITION

 

 

 

 

        Wednesday, September 24, 2003

 

        J.W. Marriott Hotel

        1331 Pennsylvania Avenue, N.W.

        Washington, D.C.

 

 

    The meeting convened, pursuant to notice

 

at 8:36 a.m., before Acting Chairman Francis F.

 

Busta.

 


MEMBERS PRESENT:

 

    JONATHAN ARIAS, Ph.D.

    Associate Research Scientist

    Department of Biological Sciences

    University of Maryland, Baltimore County

    1000 Hilltop Circle

    Baltimore, Maryland  21250

    Tel: 410-455-3470

    Fax: 410-455-3875

    Arias@umbi.umd.edu

 

 

    BOB B. BUCHANAN, Ph.D.

    Professor

    University of California

    Department of Plant and Microbial Biology

    111 Koshland Hall

    Berkeley, California  94720

    Tel: 510-642-3590

    Fax: 510-642-7356

    view@nature.berkeley.edu

 

 

    FRANCIS FREDERICK BUSTA, Ph.D.

    Emeritus Professor

    University of Minnesota

    Department of Food Science and Nutrition

    1334 Eckles Avenue

    St. Paul, Minnesota  55108-6099

    Tel: 612-624-3086

    Fax: 612-625-5272

 

 

    DOUGLAS GURIAN-SHERMAN, Ph.D.

    Science Director, Biotechnology Project

    Center for Science in the Public Interest

    1875 Connecticut Avenue, N.W.

    Suite 300

    Washington, D.C.  20009

    Tel: 202-332-9110 Ext. 377

    Fax: 202-265-4954

    dgurian-sherman@espinet.org


MEMBERS PRESENT (Continued):

 

    ANNE R. KAPUSCINSKI, Ph.D.

    Professor, University of Minnesota

    Department of Fisheries & Wildlife

    180 McNeal Hall

    1985 Buford Avenue

    St. Paul, Minnesota 55108

    Tel: 612-624-3019

    Fax: 612-625-8153

    ark@fw.umn.edu

 

 

    ABIGAIL A. SALYERS, Ph.D.

    Professor of Microbiology

    Department of Microbiology

    University of Illinois at Urban-Champaign

    B103 CLSL

    601 S. Goodwin Avenue

    Urbana, Illinois 61801

    Tel: 217-333-7378

    Fax: 217-244-8485

 

 

Temporary Voting Members:

 

    DENNIS GONSALVES, Ph.D.

    Center Director

    Pacific Basin Agricultural Research Center

    99 Apuni Street, Suite 204

    Hilo, Hawaii 96720

    Tel: 808-932-2100

    Fax: 808-969-6967

    Dgonsalkves@pbarc.ars.usda.gov

 

 

    STEPHEN BENEDICT, Ph.D.

    Department of Molecular Biosciences

    University of Kansas

    1200 Sunnyside Avenue

    Lawrence, Kansas 66045-7534

    Tel: 785-864-4007

    Fax: 785-864-5294

    sbene@ku.edu


MEMBERS PRESENT (Continued):

 

    CALVIN QUALSET, Ph.D.

    Genetic Resources Conservation Program

    DANR Building, Hopkins Road

    University of California

    Davis, California 95616

    Tel: 530-754-8502

    Fax: 530-754-8503

    coqualset@ucdavis.edu

 

 

    NINA FEDOROFF, Ph.D.

    519 Wartik Laboratory

    Huck Institute for Life Sciences

    Penn State University

    University Park, Pennsylvania 16802

    Tel: 814-863-5717

    Fax: 814-863-1357

 

 

Industry Representative:

 

    JAMES ASTWOOD, Ph.D.

    Director, Food and Feed Safety Policy

    Monsanto

    800 North Lindbergh Boulevard

    St. Louis, Missouri 63167

    Tel: 314-694-8396

    Fax: 314-694-8562

    james.d.astwood@monsanto.com

 

 

ALSO PRESENT:

 

    MR. BOB LAKE

    MS. JEANETTE GLOVER GLEW, CFSAN

    MR. MICHAEL HANSON (Public Comment)

    DR. JAMES MARYANSKI, CFSAN

    DR. THOMAS CEBULA, CFSAN


C O N T E N T S

 

AGENDA ITEM                                 PAGE

 

Welcome and Introductions                     6

Acting FBS Chair

 

Conflict of Interest Statement                9

 

Welcome from FDA                             13

 

Charge and Questions                         23

Acting FBS Chair

 

FDA's Biotech Food Safety Assessment         29

Ms. Jeanette Glover Glew, CFSAN

 

Questions of Clarification                   43

FBS Members

 

Codex Approach                               74

Dr. James Maryanski, CFSAN

 

Questions of Clarification                   92

FBS Members

 

FDA's Discussion Paper — Molecular

Characterization                            103

Dr. Thomas Cebula, CFSAN

 

Questions of Clarification                  122

FBS Members

 

Public Comment                              153

 

Summary and Review of Charge and

Questions                                   172

FDA

 

Discussion                                  179

FBS Members

 

Response to Questions                       194

FBS Members

 

Concluding Comments                         334

Acting FBS Chair


P R O C E E D I N G S

    CHAIRMAN BUSTA:  The meeting is called to order.  And welcome, all of the committee members, guests, and the members of FDA to the--this Biotechnology Subcommittee meeting of the Food Advisory Committee.

    My name is Frank Busta.  I'm a professor emeritus at the University of Minnesota.  I'm a member of the, let's see, the term is full committee.  I'm--that is not implied that I'm full of it, but some people would say it.  And I've been asked to chair this meeting as an acting chair.

    In front of you, you have an agenda, and, as you see, in addition to welcoming you, we'd like to have our introductions so that everybody knows who everyone is, and we have it on the record.

    I believe that we're asked always to talk into the microphones because it is being recorded, and that gives us a record, as well as someone taking notes.

    So, if we could start with introductions, telling us basically who you are and your--the

committee.  Douglas, would you start?

    DR. GURIAN-SHERMAN:  Doug Gurian-Sherman.  I'm with Center for Science in the Public Interest.

    CHAIRMAN BUSTA:  And you are a member of the--the regular member?

    DR. GURIAN-SHERMAN:  Yes, I'm a member of the subcommittee.

    DR. QUALSET:  I'm Cal Qualset, professor emeritus, University of California at Davis.  I'm a member--a temporary member of the subcommittee.

    DR. BENEDICT:  Steve Benedict, University of Kansas, and I'm a temporary member.

    DR. ARIAS:  Jonathan Arias, University of Maryland.  I'm a subcommittee member.

    DR. FEDOROFF:  Nina Fedoroff, Penn State University.  I guess I'm a temporary member.

    CHAIRMAN BUSTA:  Abigail?

    DR. SALYERS:  Abigail Salyers, University of Illinois, and former President of the American Society for Microbiology.  And I'm not sure what kind of member I am.

    CHAIRMAN BUSTA:  You are a member of the

subcommittee.

    DR. SALYERS:  Oh, okay.

    DR. BUCHANAN:  Bob Buchanan, University of California at Berkeley, and I believe I'm member.

    DR. GONSALVES:  Dennis Gonsalves.  I'm at Pacific Basin and Agriculture Research Center, and I'm a temporary member.

    DR. ASTWOOD:  I'm Jim Astwood.  I'm with Monsanto, and, I'm the industry liaison.

    CHAIRMAN BUSTA:  And Mike?

    DR. WATSON:  Mike Watson, the Food and Drug Administration.

    CHAIRMAN BUSTA:  And Mike does all the work.

    All right.  To get this organized and straight, I would like you to refer to our agenda.  You see estimated times to accomplish what we need to do today on the agenda.

    We hope that we can stay fairly close to that.  I will try to be as firm a chair as possible so that we do not diminish our opportunities for discussion and summaries in the afternoon.

    Mike, we're five minutes ahead of time, but I'd like--I don't mind that at all.

    DR. WATSON:  That's fine.

    CHAIRMAN BUSTA:  I will turn over the conflict of interest statement, et cetera, to Mike Watson.

    DR. WATSON:  Good morning, again.  I'm Mike Watson.  I'm the Acting Executive Secretary for the Biotechnology Subcommittee of the FDA Food Advisory Committee.

    First, I would like to read the temporary voting member appointment and conflict of interest statements into the record.

    By the authority granted under the Food Advisory Charter of July 2002, the following individuals have been appointed as temporary voting members by Joseph A. Levitt, Director of the Center for Food Safety and Applied Nutrition:

    Dr. Steven Benedict;

    Dr. Nina Fedoroff;

    Dr. Dennis Gonsalves; and

    Dr. Calvin Qualset.

    With regard to the issue of conflict of interest, committee members, both permanent and temporary, were screened for interest in bioengineered food developers.  As a result of this review, in accordance with 18 U.S.C., Section 208 (b)(3), Dr. Robert Buchanan and Dr. Dennis Gonsalves have been granted a particular matter of general applicability waiver that permits them to participate fully in matters at issue.

    Copies of their waiver statements may be obtained by submitting a written request to the Agency's Freedom of Information Office, Room 12A-30 of the Parklawn Building.

    We would also like to note that Dr. James Astwood is participating in this meeting as the acting industry representative, and is a non-voting participant.

    With respect to all other participants, we ask that, in the interest of fairness, that they address any current or previous financial involvement with any firm that develops or sells bioengineered food crops.

    Finally, FDA received a letter on Monday this week, September 22, 2003, from the Center for Science in the Public Interest, CSPI, related to the work of this subcommittee.  This letter was signed by Dr. Gurian-Sherman, a consumer representative on this subcommittee, on behalf of himself and two other subcommittee members, Drs. Arias and Kapucinski.

    The letter expresses concern about FDA's management of the subcommittee, selection of agenda topics, and other issues.  FDA has provided copies of this letter to the subcommittee members, and copies are available to the public.

    FDA appreciates receiving suggestions for enhancing the work of the subcommittee.  Since this letter was submitted too late for FDA to fully consider its contents and suggestions for changes for this meeting, we intend to examine the letter carefully and respond following this meeting.

    For today, we intend to focus on the agenda that we have prepared.  Mr. Chairman, we note that one of the issues raised in the CSPI

letter dealt with future agenda items for the subcommittee.

    We leave it to your discretion; but, if time permits, FDA will be interested to hear any suggestions that subcommittee members may have on future agenda items.

    I'll turn it back over to Dr. Busta.

    CHAIRMAN BUSTA:  Well, thank you, Mike.

    I'm not sure if we got a copy of that letter by e-mail before this meeting.  I'm not sure how many of you are in a position to see your

e-mail en route.  The--we'll have an opportunity to look at that in case you hadn't seen it earlier; and, as Mike indicated, we will do our best to get through the agenda.  And we will place that at the end of the agenda for comment, and we can expand that for other comments beyond the letter as for future agenda items.

    All right.  Now, we're going to have a welcome from FDA.  And I assume that's Bob Lake?

    MR. LAKE:  Yes.

    CHAIRMAN BUSTA:  They're really neglecting

you this morning, Bob.  They didn't give you a name card.

    MR. LAKE:  Well, that's all right.

    Let me--well, again, I am Bob Lake.  I'm the Director of Regulations and Policy at the Center for Food Safety and Applied Nutrition.  I report directly to Joe Levitt, and one of the things in my portfolio is policy issues relating to bioengineered foods.  Jim Maryanski, Dr. Maryanski, who will be talking to you later, and who I think is--most of you know very well--has been my technical advisor for probably 15 years.

    He is the biotech coordinator, but we established that position back in the late '80s; and his title and mine have changed a little bit over the years.  But we have worked very closely together throughout that time.

    I want to officially, on behalf of SISAM management, welcome you here to this meeting.  I know everyone has very busy schedules, and it's certainly hard to find a time where we can get everyone.

    But we very much appreciate all of you being here.  You are important to us.  We very much appreciate your time, your consideration; and will value whatever advice we get from you.

    I thought I would take a little bit of a moment to just sort of update you on sort of what's been going on, or, in some cases, not going on.  Just to give you a little bit of a backdrop, I'm going to try to do this very quickly.

    As you all I think know, FDA is only one of the agencies in the Federal Government that is involved in issues that relate to bioengineered foods.  The Department of Agriculture, most notably.  The Animal, Plant, Health and Inspection Service has responsibility for, you know, the planning of bioengineered plants.  EPA has responsibility for genetically engineered pesticides that are genetically engineered into new plant varieties.  And then FDA, of course, has the responsibility for the safety of foods, and, you know, again, that's--we're talking about what happens to the person who eats the food.

    Also, we have the responsibility for animal feeds, and so we have a concern about that, as well.

    Since the StarLink episode of a few years ago, there's been a sense across the agencies that there has been a need for greater interaction.  And, indeed, there have been numerous meetings among the agencies, these agencies, also others, from time to time, to deal with a couple of sort of cross-cutting issues.  These, by the way, have generally been held under the auspices of the Office of Science and Technology Policy, OSTP.

    One of these issues that we have grappled with in an interagency context has related to the potential for new plant varieties that are still in the developmental stage perhaps inadvertently contaminating traditional food crops.  And the OSTP, after numerous interagency discussions, published a document setting out some tentative thoughts about that and invited public comment.

    Following that, the--there was a recognition that there's a growing concern about

the use of food crop plants to produce pharmaceutical, industrial chemicals.  We generally refer to these as pharm plants, spelled P-H-A-R-M, as a convenient shorthand for talking about these kinds of crops.

    As some of you know, we did have an episode last year.  Nothing got into food.  But it sort of heightened the concerns within the government about the potential for contamination of food with non-food producing crops, such as corn used to produce pharmaceuticals.

    Those discussions are ongoing.  They have not come to closure yet. When they do, I expect that there will be something similar coming out of that to the OSTP publication that I mentioned a moment ago.

    Of course, throughout all of these discussions, FDA is going to the meetings, participating in the meetings, with the recognition that our primary responsibility really is about the safety of the food; and we try to stay focused on that as we go through these discussions,

recognizing there are many other issues.

    But the one that is primary importance to FDA, and that we like to stay primarily focused on is the safety of the food itself.

    We--as you all know, we published a proposal to make our current consultation process mandatory.  We have not taken final action on that.  Any of you who read the proposal will know that we raised in that proposal an issue about whether we actually had the legal authority to make the process mandatory.  That has continued to be an issue.

    The other thing that has come along is the events of September 11th of 2001, and a need to focus a lot of attention on bioterrorism.  I can tell you personally that that issue has largely taken over my life since I head the office that is responsible for developing FDA's regulations to implement that new law that was passed by Congress and signed President Bush June a year ago.

    The other thing, of course, that we always face is that there are a large number of very

important issues before the agency at any given time, and we can't deal with all of them all at once.

    When our Center Director, Joe Levitt, came back in 1998, one of the practices he instituted was a process, a priority-setting process, that results in something that we normally refer to as the Yellow Book, that articulates the Center's priorities.

    And the A-list things are things we are going to do within the current, you know, fiscal year.  B-list are things that are being worked on, and anything that's not on either of those two lists is not going to be done for a while.

    We have--again, one of the other things that Mr. Levitt instituted was a process of seeking public input on what these priorities are.  And we can't make everybody happy.  We can't deal at any instant with anything--with everything that is deemed by even us to be important; but we do try to have this orderly process for setting priorities. And one of the things you will note is that the

mandatory proposal is not an A-list item.

    The other thing that we are continuing to work on, but have not come to completion on yet, is allergenicity.  This subcommittee considered some of those issues at your first meeting.  We still intend to come back to the subcommittee with allergenicity issues, but we have not, you know, we were not ready to do that for this meeting.

    We generally are trying to keep up with the science, though, we certainly see this subcommittee as helping us in that process.  And, as you will hear more about a little later, we have, over the last four years, participated actively in the Codex Alimentarias effort at the international level to develop principles and guidelines for the assessment of bioengineered plants and also bioengineered microorganisms used in food production.  And Dr. Maryanski will talk about some of that as it relates to the agenda before you today.

    In the meantime, FDA is still following the guidance that we issued in 1992.  We--it

continues to be our belief that all of the foods that are in the marketplace in the United States today have gone through that process; and, also, so far as we know, none of the foods that have successfully completed that consultation process is presenting any kind of public health problems to American citizens.

    Nonetheless, we recognize that science changes.  We want to assure that our guidance remains current.  And that is one reason why

this--in fact the primary reason--why this subcommittee was created.

    We want to use the very best science in all of the work we do, but I think particularly in this area where there's so much noise that is not about science.  We want to be sure, and we understand people disagreeing on matters of policy et cetera.  But we want to be sure that we are following the best science possible.

    And with that in mind, we will be seeking your advice at this meeting, and in future meetings.  And today, we're asking you to look at

some things on molecular biology--I can't even pronounce it, and I can assure you I know nothing about it, so I'm not going to say anything more about that other than to return the meeting back to the Chair, who will explain what it is we are asking for advice on today.

    So with that, I will close.

    Thank you very much.  We are looking forward to your deliberations today, and to the advice you give us at the end of the day.  And, if there's anything we can do to help, let us know.  Thank you.

    CHAIRMAN BUSTA:  Thank you, Bob.

    I know there--you have a busy schedule, and you'll be with us for--until the break at least?

    MR. LAKE:  Yes.  I'll be here through the break; though, again, the other BT, that is, bioterrorism, as opposed to biotechnology, it causes to me leave at the break to go to some other meeting.

    CHAIRMAN BUSTA:  Okay.  So, if we have

some questions or clarification for Bob before--

    MR. LAKE:  Yeah, and, in fact, I can stay through the break if anyone has anything they want to ask me privately; though, I will take any questions other than anybody might have now.

    DR. GURIAN-SHERMAN:  Dr. Gurian-Sherman.  Bob, maybe you could clarify a couple of things: one is I think you mentioned that the mandatory process is not on the A-list.  Is it on the B-list?  You mentioned that things that are not on the

A-or B-list are probably not going to get looked at very closely.

    The other is, do you have any kind of timeline, or rough timeline, on your progress on the allergenicity issue, as well?

    MR. LAKE:  Yes.  Yeah, I guess I should have clarified.  It not only is not on the A-list, but I've been--okay.

    DR. WATSON:  It's on the B-list for '03.

    MR. LAKE:  Okay.  Well, it is still on the B-list.  The '04 is still I think not finalized.

    The--but there's a good chance that simply

because of everything going on, that it may not even be on the B-list for the next issue, though we have not yet issued the '04 plan.

    With regard to the allergenicity, I don't know that I can give you a specific time frame, other than to note that that continues to be something that we consider to be very important; and we do, indeed, intent to come back to this subcommittee.  But I'm not prepared to give you a time frame for that.  I just don't know.

    CHAIRMAN BUSTA:  Thank you.  We'll I'm on line now to talk about our charge, and questions that we have for today.

    You all should have received in the mail a discussion paper and a draft guidelines of Codex; and this morning, in front of you, you have the charge and questions.

    I'd like to go through this slowly and try and paraphrase it somewhat, but as you've heard this is an area that is of interest and activity with FDA.

    And, as it states in the introduction, FDA

believes that it's important to the developers of products to characterize the genetic modifications introduced in those food plants.

    Developers using molecular biological data to assess whether these new substances, intended or unintended, are likely to be expressed as a consequence of the inserted genetic material.  There have been many advances in the field, as you've heard many times and are well aware.  And FDA is seeking to determine whether any of these new advances would enhance FDA's food--FDA's safety assessment of bioengineered food plants.

    So, our charge, specific charge for today is to consider the current FDA approach for the molecular characterization of bioengineered food plants, and to provide suggestions regarding additional information the FDA subcommittee believes would enhance the safety assessment.  This is an assessment of the science.

    Now, there's three items, issues that are listed below, and these are some. Our discussion and questions and issues are not limited to those,

but they are questions that have been put forth with our charge from FDA.

    Number one:  the molecular biology data provide information that assists in identifying new substances.  Techniques like Northern or Western Blot have been useful in identifying newly expressed substances.

    The question here is: to what extent does sequencing information contribute to the identification of newly expressed substances?  And if sequencing information is important for the purpose of FDA's safety assessment, what sequence information should be reviewed?  For example, the entire sequence of inserted genetic material or the sequence of the surrounding region of the plant genome et cetera.

    If so, how does this information contribute to the safety assessment?  The science behind that, and we've got a lot of experts here that should be able to give us some insight into that after we hear what FDA is doing.

    Number two: current approaches to safety

assessment recommend certain kinds of molecular biology data.  There are four that are listed

here--the number of insertion sites, number of gene copies inserted into each insertion site, the information on the organization of the DNA within the inserts, and the potential reading frames that could express unintended proteins.

    The question here is: are there other data that would be useful to safety assessment?  And, if so, what data, and how would safety assessment be enhanced?

    The third item on the issues is: there have been many advances.  Are there new advances that could be used to enhance the safety assessment?  And, if so, what and how?

    I'll open end, as we said, as I said at the beginning, these are some of the items.  It's not limited to these, but these are considerations.  From my vantage point, it seems like there's--that could keep us here for a week and a half.  It's plenty open-ended.  So, that is our charge.

    The approach that I hope that we'll be

able to do is we will listen to the presentations on FDA's current food safety assessment and the Codex approach, and the discussion paper; and we'll have questions for clarification at the--after each of those presentations, but not significant debate at that point, or extensive discussion; but questions of clarification.

    And then, we will have an opportunity for public comment.  Has any public comment been submitted?  One?  Okay.

    And then, we will, again, look at this issue and have some real opportunity for discussion and evaluation, getting into greater depth that need from the participants of the experts that are here.  And then, in the middle of the afternoon, I would like to see us go round, one by one, and succinctly--I love that word--succinctly summarize our thoughts in response to the charge and the issues.

    At that point, and, hopefully, we're on time or even a little ahead of time, we then--there is a little bit of agenda on the back--concluding

remarks.  But then I would like to address the letter and future guidance, future agenda items, at that point.

    But we will have addressed our charge, and then we can move on to the future.

    That's all right?  We'll move on.

    Well, I'm quite proud that we're running about 10 minutes ahead of time, and since no one else has his timing agenda, no one else is sort of coming 10 minutes late, so I'm very pleased.

    So, if our next presenter, Jeanette Glover Glew is ready to go, we will--oh, Mike Watson has a statement.

    DR. WATSON:  I'd just like to ask if there's any questions for Mr. Lake, please do them before the break so they can be part of the record?

    CHAIRMAN BUSTA:  Oh.  All right.  So we have it on--

    DR. WATSON:  On the public record.

    CHAIRMAN BUSTA:  All right.  You have copies of the presentation, PowerPoint, so that you only have to take notes and not write what's on the

slides.

    MS. GLOVER GLEW:  I'm going to give a little caveat up front, as they showed me how to work this device, but I was not very successful in the rehearsal earlier.  So, we'll see how we do right now.

    Good morning.  As I said, I'm Jeanette Glover-Glew.  I work in the Office of Food Additive Safety in the Center for Food Safety and Applied Nutrition; and I'm going to be talking to you, in general terms, about our policy for evaluating bioengineered foods.  I will also touch on parts of our molecular biology review for these types of foods.  However, I'll just do a little foreshadowing here, and let you know that Dr. Tom Cebula will be going into some more detail about the type of molecular biology evaluation we do, a little bit later this morning.

    Do I have to point to that?  To give you a quick outline of what I'm going to cover in my presentation, I'll start out talking about the Federal Government's regulatory framework, then

talk specifically about FDA's policies and procedures.  And I'll wrap up talking about some recent initiatives we've made in light of public input we've received.

    In 1986, the Federal Government proposed a coordinated framework for regulating genetically engineered foods.  There were three primary players: the U.S. Department of Agriculture, the Environmental Protection Agency, and the Food and Drug Administration.

    Two of the primary principles based on this coordinated framework were that it would be the product that would be evaluated, not the process of its development; and that the products would be evaluated under existing frameworks.  The United States Department of Agriculture evaluates agricultural food safety, doing field trials; and EPA evaluates the food safety and environmental safety of products that have, well,

pesticidal--insecticides inserted; in other words, if BT proteins have been inserted into a crop that is EPA's responsibility to evaluate.

    That brings us to FDA.  Our statutory authority derives primarily from the Federal Food, Drug, and Cosmetic Act.  I'll be calling that the "Act" through the rest of my talk.

    Under the Act, we're responsible for the food safety and proper labeling of all foods and food substances, except for meat and poultry products, which are evaluated by USDA.

    That means that we have oversight over cereals, fruits, vegetables, plant by-products, such as starch and oil, milk, seafood, and other substances added to food, such as flavorings and preservatives.

    There are two provisions of the Act that are particularly important in ensuring food safety.  One of them is our post-market adulteration provision in Section 402.  This is our primary legal tool for regulating the safety of whole foods.  It means that if a food enters the marketplace, and we find it to be adulterated, for example, if it had a level of toxicant that was outside of the normal range, or if it had an

unlabeled food allergen, then we could take action to remove that product from the market using our post-market adulteration authority.

    We also have the Section 409 authority, which means that an additive that is going to be added to food must undergo pre-market review and approval by FDA before it can enter the marketplace, that is, unless the product has been demonstrated to be generally recognized as safe.

    If we see a product that is not substantially similar to products that have been consumed in food, then we could ask that it come in under our pre-marked approval authority.

    I'll next talk to you about FDA's policies and procedures.

    In 1992, FDA published a policy stating how we believed the foods derived from new plant varieties should be regulated.  It was developed for genetically engineered foods, but it described how we would apply our authority under the Act to ensure the safety of all foods under our authority.

    It was, as I said, derived primarily for

developers who, at that time, were using recombinant DNA technology in crop production.  And those are primarily the users that have operated under that policy statement.

    Let me go over some of the basic principles in the policy statement.

    First, we consider the nature of the food, not primarily the method of development.  Any food, including genetically engineered foods that enter the market place, must meet the same stringent safety standards as convention foods.  And those traditional counterparts are the foods that we compare the bioengineered food to.

    Some other basic principles in the policy statement.  We recommended guidance on particular scientific and regulatory issues, and we also recommended a voluntary consultation with FDA.  The purpose of that consultation was to make sure that any questions that might arise of a scientific or regulatory nature would be resolved before the developer went to market.

    The core of the guidance document was a

series of flow charts related to the safety and the nutritional values of genetically engineered foods.  You could see if you were a developer, you would walk yourself through this flow chart, and you would--could end up eventually in one of two boxes.  The box at the bottom says no concerns, and the boxes off to the side say consultant FDA.  There is also in the flow charts a third box that says basically don't even think about going in that direction; but that's not on this particular slide.

    What happened, practically speaking, is most developers, when they go through the flow charts, end up in the no concerns box.  However, because of our desire to encourage the voluntary consultation process, we believe that all of the people have come in to us to demonstrate what they think are the issues that, once they go through our flow charts, and to make sure we agree that they fall into the no-concerns box.

    The frequency and level of consultation that we carry on with the developers is really dependent upon the complexity and the novelty of

the crop and the insert.

    We encourage them to come in early and often.  This is an iterative process.  We believe that, by coming in early, it benefits both the developer and FDA.  We're aware of what's being done in terms of the research, and they're aware of the kinds of issues that we might find of concern.

    We--in our 1990 policy, we did not publish a suite of testing regimes that people could go and say, okay, I've got a tomato or I've got this type of insert, therefore, I need to do these types of testing.

    We wanted this to be done on a

case-by-case basis.  And so what happens is the company comes in.  They say, okay, this is the information we've developed in the lab or in the greenhouse or in our field trials.  And, we say, okay, well, based upon what you're demonstrating to us, we have these kinds of questions.  And the company will use the input FDA gives them to go back to their lab or the greenhouse or the field trial, and develop the data to answer those

questions.

    So we have an iterative process, where FDA has credible input about the kind of testing regime.  It's done on a case-by-case basis.

    Prior to commercialization, the notifier will come in to us with a final data package that summarizes the information they've developed, and FDA will respond to them with a letter saying either we have--still have remaining questions or we have no further questions.

    The approach in these consultations is multidisciplinary.  We have teams of individuals who review these submissions.  They include molecular biologists, several of which are here today, microbiologists, chemists, nutritionists, food scientists of various kinds; and we cover a broad spectrum that's provided, everything from the agronomic characteristics to the compositional characteristics of the crop.

    In this next slide, I've just presented the information in this way to emphasize that we look at both at the intended changes and the

unintended changes to the crop.  In the intended changes, of course, we're going to be looking at information about the trait--desired trait that was inserted and to the kinds of alterations that might make.  And we look at information about the background of the crop, and the exposure.

    However, we're also looking for unintended changes, because this tells us whether or not cryptic pathways have been turned on.  We'll look and see whether or not there's been changes in known toxicants or nutrients to see if there's something that lets us know that a genetic pathway has been interrupted by the insertion, and that there's something that we need to be paying special attention to.  And another way that we do that is to look at the genetic stability over time.

    I've added these next four slides just to go over real quickly because it gives you the elements of the safety evaluation, including what we look at in terms of the molecular biology evaluation.  But Dr. Cebula is going to be going into some more detail later on; so this is a just a

skim to prepare your minds for what we're going to be talking about.

    In the host plant, we'll look at the taxonomy, history of safe use, the presence of any naturally occurring harmful constituents, and important nutrients.  If we were going to be looking at an orange, we'd expect Vitamin C to be there.

    In the donor organism, we're going to be looking at similar characteristics, but we're also going to be looking through--whether or not any baggage has been picked up due to passage through microbial host.  And, of course, most importantly for the donor organism, we're going to want to know about the identity and function of the introduced material.

    For that introduced material, we're going to look at concentration, so we know what dietary exposure is.

    We're going to look at the potential for it to be an allergen or a toxin.  I already mentioned that we're going to be looking at

similarity to other substances in the food supply.  Talked about looking for changes in metabolic pathways.

    We're going to find out if there's

post-relational modification, such as glycosylation of a protein.  And something that I'll throw out here.  Other countries have been concerned about the presence of antibiotic resistance marker genes.  And we also evaluate those.

    And this comes to the information that is more the basis of what we're going to be talking about and getting input from you on today is the inserted genetic material.  And here, we're going to look at the method of transformation, what the regulatory sequences are, the promoters, the terminators, how those are working, whether there's the chance of open reading frames that might read through into the indigenous genome, how many inserts they are, where they are, if they, you know, flipped or they inserted into a site that may create problems; and then we're going to be looking at Mendelian inheritance, so whether or not it's

genetically stable.

    I'm going to switch gears here, and just for a few minutes talk about some of the recent initiatives that we've taken as a result of a public outreach.

    We know that the biotechnology field is rapidly changing.  That's why you're here.  That's why we want your advice.  But also, in 1999, we decided to hold a series of three public meetings.  And we said, we're going to look at our 1992 policy to see if it needs to be modified in any way.  And, as a result of soliciting that input, we received over 50,000 comments.  Excuse me a moment.

    We were pleased to find that, as a result of those comments, that we really hadn't received new data to question the safety of bioengineered foods that are on the market today.  However, we heard concern from public, academics, public policy groups about the future, of whether or not the products that were going to be coming down the research pipeline were such that we had either the regulatory or scientific framework and background

to address the safety of these products.

    So, as a result of that solicited input, we have taken several initiatives.  One of them is you guys.  That's why we're here today.  We established the Food Biotech Subcommittee, and we hope to be using you for this purpose quite a bit in the near future.

    We have committed to support research on allergenicity, and we have combined with USDA and EPA to support a study by the National Academy of Science on potential unintended effects in bioengineered foods.

    Before I wind up, I'm just going to give you a snapshot of the types of products we've seen.  The corn, cotton, and soybean are the primary commodities that we've seen in.  We've seen other minor crops.  The kinds of traits that have been introduced have been primarily agronomic traits that are of interest to the farmer, either pest resistance or herbicide tolerance.  Though we expect, in the second and third generation of crops, to see more complex physical traits, such as

salinity, tolerance, or drought resistance; and also traits that would be of interest to the consumer, such as increased nutritional value.

    The goal of us at CFSAN and here today in talking with you is to make sure that we're prepared to meet our scientific and regulatory responsibilities in the future.  So we're really looking forward to you looking at the charge and the questions and advising us as to where we can to specifically in the arena of molecular biology techniques.

    And I just wanted to let you know that I've given you our website.  If you want to look at any of the documents that I've mentioned today, either our 1992 policy statement or the proposed rule that Mr. Lake mentioned, or a list of the products we've developed, including our scientific memos evaluating those products, you can go to the website and find that information.

    But I think we're running ahead of schedule, so I have time to answer any questions you might have before we go on to the next speaker

at the break I guess.

    DR. GURIAN-SHERMAN:  Jeanette, I had two questions, clarification.  One is concerning the website.  That doesn't have, as far as I know, any of the more detailed aspects of the consultations, in other words, the data summaries, which I found very useful to look at to kind to get a better idea of what is actually submitted and what you're actually doing with it.

    MS. GLOVER GLEW:  That.  That's a--

    DR. GURIAN-SHERMAN:  So one question is: if committee members want to see any of those, could they be made available and how could that be done?

    And the second question is: If you could clarify a little bit kind of the case-by-case approach.  How do you determine kind of what the baseline minimum assessment should be?  And to put that in context, for instance, when I looked at some of those studies, just as one example, two of the BT crops, looked at whether phytate levels and known anti-nutrient in the corn had changed, two

did not.  You know, so how do you determine what's enough?  Which anti-nutrient should be looked at?  Which allergens, you know, et cetera, under the current system?

    MS. GLOVER GLEW:  Okay.  Try and remove the first question before I get to the second.

    The first question has to do with the fact that I mentioned that at the end of the consultation process, we receive a data package that summarizes the material, and this is what we use when we are completing our evaluation.

    That information is not currently available on our website.  It is available by Freedom of Information Act request, which is how Dr. Gurian-Sherman got it.

    We--I did not go into all of the efforts that we have committed to make as a result of the public meetings.  I wanted to focus primarily on the scientific nature of some of the concerns that were expressed, particularly the ones that you can address today in the molecular biology discussion.

    However, we have made some commitments to

try and have increased transparency.  Those are something that we have to balance with our obligations to protect confidential business information.  But we have--our ongoing discussions.  I honestly don't know, Doug, whether or not the Food Advisory Committee can get copies of those documents outside the FOI process, and perhaps one of the people on the FAC Committee can help us with that a little bit later.

    The second question: how do we get a baseline?  That's a good question, and the thing is it's like mini-targets as it moves.  And I'll use your phytate example; is that when some of the earlier consultations, we would talk about the areas of concern--the nutrients, or the toxicants, or the anti-nutrients--and the company would go away; and they would develop that information.  And, this is in addition to general principles, which we outlined in the 1992 policy, about looking for allergenicity, examining whether it's a potential for it to be a toxin.

    So we have the general principles, and

then we have some of the more specific give and take on the case-by-case basis.  And the answer about the phytate is that it does--the target moves.

    As we've been involved with Codex, as we've been involved with our European counterparts, particularly Dr. William Price, who is in the audience today, has been participating in committees that are laying out some of the known important nutrients, anti-nutrients, and toxicants; and we're able to now use these kinds of materials to give clearer, better, more particular information.

    So, you can look at earlier submissions, and you'll find that they're missing information that perhaps are in more current submissions.  And that's because, as the science advances, as we are more aware of the types of information that are important for us to look at, we would be

giving--tailoring our information.

    Does that answer your question?

    DR. GURIAN-SHERMAN:  Yeah, I guess the only follow up I would have is, if you're

developing some of this internal guidance or guidelines, is there any plan on making them publicly available?  Are they just still in the development stage?

    I think in 2000, NAS recommended that you do that with, you know, come up with a database of known toxicants and anti-nutrients.  So, you know, is that something that's going to be made public?

    MS. GLOVER GLEW:  We're working internally on guidance.  It suffers from the same resource problems that Mr. Lake referred to earlier, but one of the things that, if everything works out in terms of our resources, and how productive we think this would be for industry, we might use the information that we develop today for a molecular biology guidance.

    The compositional guidance we have held off a little bit on because we're waiting to see what the NAS says about the unintended effects.  So, guidance documents are something that we constantly have it in the back of our head in order to give guidance to industry.

    But, as we've just talked about the phytate issue, we weren't--we didn't know that that was something that we probably be asking for perhaps early in the process.  We know now.  So, if we have guidance and it's hard and fast, that leaves us a little less flexibility in order to look at these on a case-by-case basis.  So there's advantages and disadvantages to having written guidance.

    CHAIRMAN BUSTA:  Abigail.

    DR. SALYERS:  I have a question for you, and for Mr. Lake, both.  It has to do with priorities.

    If I were prioritizing issues on your A-, B-, C-lists, I would put bioengineered foods on the E-list, and I'd put bioterrorism on the F-list.  You know, as in forget it, you know.

    And I would put on the A-list things like probiotics and functional foods that have been largely un--not looked at; and also just good old early detection of microbial, unintentional microbial contamination of foods.  And so that we don't have to pull things back after they've

appeared on grocery shelves.

    And so my question is, and I understand why you've had to put bioengineered foods and bioterrorism on the A-list, but so I'm going to

be--this question is kind of pessimistic.  I know you're stuck with that because of political considerations, but are you thinking about ways that you might use whatever money you're pouring into those areas to also address some of these other issues, the real, which in my opinion, the real public health issues, the things that sicken and kill people at still somewhat horrifying level; that there are ways to divert some of this attention and finances into doing something in those areas.

    MS. GLOVER GLEW:  I'm going to let Mr. Lake answer the part about dealing with substances that might kill people.

    DR. SALYERS:  I'm not, I'm not--this is not a hostile question.

    MS. GLOVER GLEW:  I'll answer something that perhaps is underlying your question, and you

may not have intended this to underlie your question, is that we have for bioengineered foods a process that is working, and that we believe is protective of the public health.

    So, there are many ways that we would like to expand our abilities to be responsive to industry in giving them guidance about molecular biology.  That's why we're here.  That's why we're interacting with the National Academy of Science.  There are things that we would like to do to make certain that our regulatory framework and our scientific background is what we need in order to evaluate these things. And I think that we have that, and we'll continue to have that in terms of Center priorities.

    DR. SALYERS:  Well, let me just give you an example.  This is one of these things that happens to me accidentally.  It makes me even more unpopular than I am already.

    But I happen to think probiotics is a good idea, but I found out, sort of accidentally, that most of the strains of bacteria that are used for

probiotics are resistant to vancomycin, which is one of our less antibiotics for treatment of certain types of diseases.

    And so I said to them, to these people, I said, have you--now are you talking about markered antibiotic resistance genes in transgenic plants, which are for, you know, effective against antibiotics that basically are not a problem any more; but here's some vancomycin resistance in these probiotic strains.

    And so I got this storm of anger out of that.  And I said, but you really ought to ask yourself is this just some metabolic thing or some, you know, could possibly pose a public health risk.  And that, as far as I could tell, was not under investigation anywhere.

    And I just wonder how many more examples of that kind are out there in the probiotics, the functional foods area; and then, of course, we have the problem of is there some way that we could try to detect contamination of foods before the food actually gets on the grocery shelves.  So that's

the reason I was asking this question.

    CHAIRMAN BUSTA:  And I'm being very good on chairing this, and letting you ask these questions before we lose Bob.  But that wasn't a terribly expansive question on clarification.  Bob.

    MR. LAKE:  Nonetheless, I think it was a good question, so let me comment to the extent that I can.

    Though we try to do priorities in a way that we think is rational from our perspective, you know, there are a lot of forces out there, including congressional mandates that are, you know, in the case of bioterrorism, very explicit.

    And one of the things that's driving my life now is that Congress, and the law that I mentioned earlier, the new bioterrorism law has a couple of regulations, a couple of requirements, that will go into effect on December 12th of this year--one on registration and one on prior notification on imported foods--that will go into effect whether FDA has regulations on the street or not.  However, we have been mandated to write

regulations, and it is our strong belief, and I think the belief of everybody we're hearing from in other governments and the industry and whatnot, that, if we fail to have regulations on the street, that there will be chaos; that everybody needs those regulations in order to implement this law in an orderly way.

    So, whether we or anyone else, you know, necessarily would have chosen those as being a top priority, it is certainly clear that the events of September 11, 2001 have altered the state of play in a very significant way for FDA and for, frankly, all of the Federal Government.

    But also, I think aside from the very real issues, which I personally believe need to be addressed in the area of bioterrorism, I think we're facing a situation with the registration and prior notice activities, and I will be going

here--from here to a meeting about those because we really need to publish those by October the 10th if we are to have an adequate lead time.  And we've had a huge effort ongoing, and hopefully we'll meet

that date.

    So that's one thing that's kind of out of our control.  But also, it's just one of the realities that, you know, the world sometimes gives us things that we didn't expect.

    With regard to--when you talk about probiotics, I assume you're tying that back to genetic engineering.  And I guess my general comment about that is that we try to keep up with products that are actually entering the marketplace.  And that, of necessity, I think sometimes means maybe we're lagging a bit on things that are under development that are not quite close to being marketed.

    I should, however, note a couple of other things with regard to genetic engineering.  We do have, you know, on the pharmaceutical side of the house, a lot of activity that has been ongoing for a number of years.  And I'm not, you know, qualified to speak about all of that.  But just keep in mind that bioengineered products are not just about foods; they're about other things.  And

the Agency has people heavily involved in many of those areas.

    The other thing is, just to comment on your issue of methodology.  That is something that is receiving attention here and internationally, as well.  But, you know, what we are really focusing on here is our job of evaluating the safety of in particular new plant varieties, and being sure that we're doing that in the right way. And that's why we're seeking the advice that we're seeking here.

    DR. SALYERS:  Well, the reason I asked that question, which our esteemed Chairman obviously thinks is not germane to the issue at hand, and I think you sort of don't either.

    But my point is that, if we're going to talk about technology for evaluating safety, fortunately because of the new types of technology that are available, many of the things that we would talk about here today have broader implications; and maybe we should be aware of those possible broader implications; that there are broader uses.  And that was the only reason I

raised the issue.

    MR. LAKE:  Well, no, I think, you know, I mean you're raising an important point, and the Chair has added to the agenda, if I'm understanding it, the issue of what are topics that this subcommittee perhaps might address in the future; and maybe, at that time, you could, you know, put some of those thoughts on the table.  And we're certainly anxious to hear from all of you on your thoughts, and we'll certainly consider them.

    By the way, in my thing earlier, I did fail to mention the one thing that Jeanette did briefly touch on.  And after I'm gone, if you have any further questions, Dr. Maryanski can address them; and that's the National Academy of Sciences study on unintended or unexpected effects.  And, as Jeanette pointed out, that is being co-sponsored by USDA and EPA, as well.  And we are certainly looking forward to that input.  Thank you.

    CHAIRMAN BUSTA:  Anne?

    DR. KAPUSCINSKI:  Thank you.  Thank you, Jeanette.  That was a really nice, clear overview

presentation.

    My question has to do with when you talk about that you are using the language we look at, for example, when you were showing the slide about intended modifications and unintended modifications, I'd like to just get a better sense of how the look at process really works.  When--if you're going into a consultation with a developer, are you primarily going to look at what that developer on their own has though is necessary to do to look for both the effects of the intended modifications and possible unintended modifications?  Or, to what extent are you--and are you going to basically look at what they provide to you as they think is the information and the issues they should be asking about.  Or, to what extent are you going in with a set of things that you think should be asked about, given their specific case. And then, I guess, as a follow up to that question, how do you envision that might change after the National Academy report on unintended modifications comes out?  And I'm sort of focusing

on the unintended modifications, because that's clearly, I mean, from my perspective, that's sort of the main bug-a-boo in this area.  And, personally, I'm interested in, you know, helping the agency come up a way that those unintended modification issues can be addressed in a way that's not going to completely paralyze the Agency.  I don't think it's realistic for the Agency to be the one that actually carries out the risk studies and all the assessments.  I think the burden of that has to be on the developers.  But I'm interested in helping the Agency figure out what's a good balance so that, you know, there is some kind of independent--if it's not a standard checklist, which may not be always useful, at least some kind of independent process of sort of going through, an eliciting of, you know, have we thought of this.  Have we thought of A, B, C, and D to make sure that the developer has done an adequately thorough job.

    MS. GLOVER GLEW:  Okay.  Excellent.  For a while there, I was going, yes, yes, no, yes, to

your various questions. But since I've lost track of which are yes and nos, I'll try to answer it in a more global sense.

    As I mentioned earlier, there are specific principles and flow charts in our 1992 guidance document that walk the developer through the types of considerations they should be evaluating toxicity, allergenicity, is there a marker gene, is the marker gene expressed for an antibiotic that, you know, is valuable clinically.  So we have principles in general in our 1992 policy.

    Then, when the company comes in for the early part of their consultation, this iterative process, we develop collaboratively what they're going to be doing.  They usually will bring us some early data, and we'll look at it.  And in terms of unintended effects, we may be looking at a Western Blot, and see that there's a protein that, you know, doesn't belong.  It's the wrong shape, size, and it's showing up on--and then we'll be going, what's that?  And why is it there?  And what's your explanation for that?

    And so, they'll go, okay, well, we, you know, sequenced this little piece, and we found out that this happened.  So--it--we have--so what

I'm--I guess I'm trying to say, we have principles that people follow using our 1992 policy, and our 1996 consultation procedures, which are also on the web.  Then we have an iterative case-by-case discussion; it's a chat that we have with these people.  They tell us what they're doing.  We tell them the kinds of regulatory and scientific questions we think arise based upon what they're doing.  And they will go out and develop the data that answer those questions, come back to us with a data package, and we'll say, okay, these are the questions we asked.  Did they address them?  Are more questions raised by the information that they developed?  Do we need to go back again?

    And so it's a collaborative, iterative process based upon established principles, plus a case-by-case interaction.

    And--has that answered at least a piece of your question?

    DR. KAPUSCINSKI:  Yeah, the second piece I guess is I was just wondering how you envision the, you know, the recommendations you get from the NAS?  Do you envision that, at this point, changing this process in some ways and?

    MS. GLOVER GLEW:  I just don't have a good picture in my crystal ball about that.  We're real excited about the potentialities for what we can get, and how we might use that.  We're hoping that they will do something similar to what you're doing today, and say, okay, the technology has changed enough that we can recommend that you ask for this type of information or that they develop this type of data, because this will provide valuable information.  But I'm not sure what's going to happen with that.  But we're looking forward to it.

    CHAIRMAN BUSTA:  Nina?

    DR. FEDOROFF:  My question is partly historical and partly contemporary.  It has always puzzled me that the EPA was approving or not approving StarLink corn based on the potential for allergenicity of the cryonide seed.  That seems to

be your bailiwick, because it's environmental.

    MS. GLOVER GLEW:  Your confusion is understandable.  I didn't spend a lot of time at the very beginning talking about the regulatory framework because I wanted to speed through into FDA's part.  EPA is responsible for evaluating both the environmental and the human food safety for pesticidal proteins, for plant incorporated protectants.  And so this is mostly BT products.  It's the way the framework of the law is divided up.  We will look at the product and see if there are any considerations in terms of compositional changes that might require, like, different labeling.  So we do evaluate the product from FDA's perspective, only we love the fact that on StarLink, we can do this huge burden shift.  It wasn't our responsibility.

    DR. FEDOROFF:  Pardon?

    MS. GLOVER GLEW:  It wasn't our responsibility.

    DR. FEDOROFF:  Yeah, I noticed, though--on the other hand.

    MS. GLOVER GLEW:  Because of—

    DR. FEDOROFF:  On the other hand, is there any effort to make the criteria uniform?  Is there any effort to reconcile your criteria and theirs?

    MS. GLOVER GLEW:  Absolutely.  Mr. Lake mentioned the fact that we have collaborative efforts that are ongoing.  We are right in the middle of discussions with EPA and USDA about what our requirements--I say requirements loosely since it's a voluntary program--but what types of information we look at in the data packages that we get.  Mr. Watson, Dr. Watson is working on that right.  He developed this table, and we pay very close attention to the kinds of information that EPA developed in terms of allergenicity detection for the StarLink, because that's something that's real pertinent to us.  Those of you who were on the previous meetings, subcommittee meeting, you know, heard about what we're doing about allergenicity, and the kinds of considerations we're taking.  A lot of that came from our interaction with our counterparts at EPA and their experience with

StarLink.

    CHAIRMAN BUSTA:  Bob?

    DR. BUCHANAN:  A general question: how many new conventional foods and genetically engineered foods do you approve per year approximately?

    MS. GLOVER GLEW:  I'm sorry.  I didn't.

    DR. BUCHANAN:  How many new conventional foods, for example, a new type of nut that existed somewhere, and it's sought to have approval in the U.S., and how many genetically engineered foods do you approve per year?

    MS. GLOVER GLEW:  Per year.  Okay.  We have since 1994, when we first started receiving these biotech notification files, or BNFs, evaluate a little over than 50.  If you're talking about do we have some brand new novel, never-before-seen food on the marketplace, I don't think that you could characterize it that way.  It's mostly people who have taken maize, soybean, cotton, and they have added an herbicide tolerant, or a pest-resistant chain to it.  So it's something that, if

you drove by the field at 55 miles an hour, you'd look out there and say, that's cotton.

So--just--an entirely novel crop isn't something that we see.  We see mostly modifications to existing commodity crops.

    DR. BUCHANAN:  So there's no new macadamia nut or something like that?

    MS. GLOVER GLEW:  No, not at this point in time.

    DR. BUCHANAN:  Thanks.

    MS. GLOVER GLEW:  That could be coming down the research pipeline.  Who knows?

    DR. FEDOROFF:  I think your question was whether your approve, when someone brings in a new whole food from a different part of the world that has not been marketed here before, wasn't that the nature of your question?

    DR. BUCHANAN:  Right.  Yes, right.

    MS. GLOVER GLEW:  Okay, so it's like--

    DR. FEDOROFF:  I misunderstood your question.  Do a kiwi fruit--

    MS. GLOVER GLEW:  --If I showed up from

New Zealand.

    DR. BUCHANAN:  Yeah, kiwi is a great example.

    MS. GLOVER GLEW:  Okay.  If--I mentioned that our post-market adulteration provisions were the primary legal tool for evaluating whole foods.  If something came on the market today, and we didn't have any information indicating that it

was--had toxicant, or wasn't allergic, we probably would have no need to take action; and so we would not utilize our post-market authority to take action against that crop.  However, if something came on the marketplace that was just totally novel for the American food supply, we have our authority under the Act, totally aside from the bioengineered food process.

    DR. BUCHANAN:  Yeah, that was the--

    CHAIRMAN BUSTA:  That's separate from the biotechnology activity.  So I'm not sure that--

    MS. GLOVER GLEW:  Yes.

    CHAIRMAN BUSTA:  I'm trying to keep us obviously focused--

    MS. GLOVER GLEW:  Well, I'm trying to explain is that we still use our authority under the Act for bioengineered foods.  If we needed to see something that was adulterated or, you know, if we saw that something needed to come through the petition process, we would do that for a bioengineered food.  So the Act applies uniformly.  We have the same safety standards for all foods the FDA evaluates.

    CHAIRMAN BUSTA:  First of all, before I call on Doug again, are there others who have not asked a question that want to--clarification questions?

    Or, last call for Bob Lake.

    Doug?

    DR. GURIAN-SHERMAN:  Yeah, I want to make two points of clarification.  They're not actually questions, but they're both points of clarification.  In terms of new foods, I know of at least one that's come on the market in the last few years in the U.S.  It's called Kworn.  It's made with fusarium finatum.  It's a soil fusarium.  It

was never the food supply before; was marked in Europe, and did go through the grasp process at FDA that did have some toxicity studies, animal studies, et cetera that that was subjected to.  That was, again, grasp studies, voluntary.

    To Anne' question, I would just like to venture, and I know the committee isn't really privy to this, but when we did our study looking at FDA, we FOIAed not only the actual data packages that FDA looks at, but also the communications between the developers and FDA.  And I won't say that it's impossible that I missed anything, but only found about six examples where FDA, on record, asked the company, let's say for more data or for clarifications.  And three of those went unanswered or were not, we felt, adequately answered.  So, there certainly is give and take.  Maybe some of it isn't on the record.  It should be.  But there's not, from our perspective of what we saw, a lot of information to indicate that FDA is pushing the companies for more data.

    CHAIRMAN BUSTA:  Doug, to keep us--

    DR. GURIAN-SHERMAN:  So that's—

    CHAIRMAN BUSTA:  On line that's good discussion comment, but not in the presentations.  We have this afternoon to get into discussion.  We're still in the clarification--questions for clarification.  Dennis?

    DR. GONSALVES:  Well, I just was going to add, you know, the question on the whether FDA asked questions that had an impact.  Well, when we were deregulating the transgenic papaya, we actually were moving two lines through the process.  And when we hit the FDA, another line had some other inserts in it, and because of the questioning that we needed more data, basically we withdrew that line, because we did not have enough information.  So the point here is that--the experience that I had was that the questions that FDA did ask had an impact on our actions to withdraw one of the papaya lines.

    MS. GLOVER GLEW:  Just a quick remark.  I'm sorry to interrupt.  I just want to say that FDA, along with all the other regulatory agencies,

occasionally struggles with the do we want to know this or do we need to know this.  And occasionally, we do err on the want to know, but primarily believe that when we ask questions, it's in the need to know area.  And if a company or developer did not provide us with the information that we needed to know to evaluate the safety of that product, we would not give them a letter saying that we had no more questions.

    CHAIRMAN BUSTA:  Any more clarification.  James?

    DR. ASTWOOD:  Thank you.  I have one question, and it kind of relates to Dr. Fedoroff's earlier question.  Would you agree that, although it appears complex that both the EPA and the FDA share jurisdiction over plant incorporate protectants, or BTs in particular, that when you look at the history of the regulation of pesticides and the experience that the EPA has with food-feed environmental safety of chemical pesticides, and then the subsequent history that they have had regulating and evaluating the safety of microbial

pesticides, including BTs, that it makes sense, in fact, for the FDA and the EPA to collaborate and share responsibility for the evaluation of those kinds of products.

    MS. GLOVER GLEW:  Yes, I think the way the roles are laid out right now has been working very successfully.

    CHAIRMAN BUSTA:  I have one last question.  If the use of biotechnology has developed to, let's say, double a specific nutrient--

    MS. GLOVER GLEW:  I'm sorry. I'm not hearing you.

    CHAIRMAN BUSTA:  If one uses a biotechnology to double a nutrient, a given vitamin or whatever, this is arbitrary, would that be in the same consideration?

    MS. GLOVER GLEW:  As I just mentioned briefly is we believe that some of the products that are going to be coming down the research pipeline are going to be products that are targeted to consumers who want to have increased levels of, you know, a fancy nutrient or something.  And

certainly a product that was bioengineered and had an alteration in its nutrients would--we would request that they come to FDA during our--are part of our consultation process.  And if there was a substantial change in nutrients, we would probably have to consider whether or not the product would need different labeling or a different common unusual name.

    CHAIRMAN BUSTA:  We're at break time.  I just would like to--before we come back say that what I'm trying to do is keep us on focus.  Our charge is to consider the current FDA approach to the molecular characterization of bioengineered foods and make suggestions for additional information that will be needed.  We'll try to stay with questions of clarification for the next three presenters.  And then we can get, and after public comment, get into depth of discussion and where we want to--what we want to tear apart and put together.  Let's take 15 minutes.  Let's start promptly at 10:14 on my watch.

    [Whereupon, the meeting went back on the

record at 10:15 a.m.]

    CHAIRMAN BUSTA:  May we reconvene, please.  The next presentation is on the Codex Approach, by Dr. James Maryanski.  I have been negligent in my chairing to remind you all--I've just been calling you by your first name, and it's appropriate that individuals give their name before you make your comments or you ask your questions so that it's in the official record.  I think the stenographer, being that no one has the same first name, we're all right.  But if would be appropriate that everyone give their name as they speak.  And with my voice, I rarely have to do that.  Most people, whenever I talk, people know who I am.  I'm--I guess I've stalled long enough.  We're about ready to--

    DR. FEDOROFF:  Almost everyone's back.

    CHAIRMAN BUSTA:  Almost everybody's back.

    DR. FEDOROFF:  Not quite.  She's still getting coffee.

    CHAIRMAN BUSTA:  Yeah, and we will have Dr. Anne Kapuscinski read her name into the record

when she returns, because she wasn't here on our initial round.  But she is here for the record.

    Dr. Maryanski?

    DR. MARYANSKI:  Okay.  Thank you, Mr. Chairman.  Good morning, ladies and gentlemen.

    I have the pleasure to tell you a real success story in biotechnology this morning.  You know, we hear so much discussion that's often seems either difficult or even contentious; and you often hear of differences between our country and other countries around the world on biotechnology.

    I want to tell you a really different story, a story where everybody actually came to agreement at the end of the day.  So this is really a pleasure to be able to tell you about the new guidelines that have been developed on the--in the international community for assessing the safety of foods developed by biotechnology, and one which we at the Food and Drug Administration have participated in.

    But let me first tell you who Codex is.  Many of you, I'm sure, know, but, in case you don't

know, the Codex Alimentarias Commission is the body that has been established under the U.N. system by the parent organizations--the World Health Organization, the Food and Agriculture Organization.  Codex Alimentarias is Latin.  It means food code.  And, as such, it is a collection of internationally adopted food standards and guidelines, and those are intended to ensure consumers' health, as well as to facilitate free trade.  And, so, this is a body that has been in existence since 1962.  There are about 169 member countries, so this organization has global representation around the world in both developed and developing countries, as well as NGO representatives that include public interest groups, as well as industry.  And so it's a very broad organization.

    Woops.  Wrong way.  Sorry.  In 1999, the Codex decided that it would take on some work in the area of food biotechnology, and it established a temporary committee.  Codex has lots of committees that work on various things.  But it

also occasionally establishes temporary committees for specific purposes; and these are often called ad hoc task forces; and, in this case, with the long title of the Ad Hoc Intergovernmental Task Forces on Foods Derived from Modern Biotechnology was established by the Commission in 1999.  It was given a four-year charter, and Japan was selected as the host country to facilitate this committee. And the Japanese Ministry of Health, Labor, and Welfare was the part of the Japanese government that ran the secretariat, essentially helped organize the meetings for this.

    The task force was chaired by Dr. Ushikora, who is world renowned virologist, and is fluent in both English and French, and Japanese, of course; and did a superb job of negotiating through various complex issues during discussions.  And I think everyone involved recognized that the Government of Japan deserves a great deal of credit for the success of this work.

    Japan did host four meetings of the Task Force that just concluded this past March in

Yokohama.  And the recommendations that came out of that work then were presented to the Commission at its meeting this summer.

    The Task Force was given, in terms of reference by the Commission, which you see here, very general terms, consideration for the elaboration of standards, guidelines, or other principles for foods from biotechnology.  So a very broad mandate.  The Task Force, at its first meeting, in looking at this mandate, felt that there are many things in the word of food biotechnology, and it would have to somehow identify work that it could accomplish within four years so that it would have something finished at the end of that time; and do that in a way--on a priority basis.  And they felt that since foods derived from crops were already in the marketplace that that should be the top priority; and that they would focus their work on developing guidelines for assessing the safety of those foods for human consumption.

    They also felt that foods developed using

organisms modified using recombinant DNA, using microorganisms modified with recombinant DNA techniques, would also be on the frontier and of a priority.

    Animals, of course, were well understood to be in research, but they felt they were not quite ready to discuss animals yet at this time.

    So that was the order of work that was set out by the Task Force.

    And the work that was accomplished I'm really showing you here the final product, and then I'll tell you what it means.  But the Task Force, within its four years of work, developed three documents.

    One was a--the principles for risk analysis you see here.  That's really an umbrella document that talks about how risk assessment and risk analysis can be carried out within the existing framework of the Codex.  And it's thought to be sort of an umbrella for the guideline documents, but the real crux of the matter, the important work, are the two guideline documents.

The guideline on foods derived from plants, and the guideline on foods derived from microorganisms.  Both of these guidelines have an appendix to them as well that deals with assessing the possibility for allergenicity for new proteins that would be in the foods derived from the plants or microorganisms.  And so those also are important documents that go with and are part of these guidelines documents.

    These documents were presented to the Codex full body at its meeting this summer, and were adopted unchanged.  And they are available, at least in their draft form, on the Codex website.  They will be published simply taking off the draft.  So they are the texts that--I believe we have given you the texts for the guidelines for foods derived from plants, because that's the one we'll be focusing on for the discussion today.

    Now, I want to talk about one of the principles that the Codex felt was important.  The Codex system has a number of defined terms--risk analysis, risk assessment, risk management, and so

forth--that are all well understood withing the food safety system and Codex to deal with things like pesticides and food additives and contaminants in food, essentially single chemical substances.  And often times, certain of those substances will have some hazard associated with them and how to manage that in terms of tolerance setting, for example, for pesticides.  But it was recognized early in the discussion that we're dealing with food crops when we're talking about foods derived from crops, and trying to establish guidelines for safety assessment.  But these are crops we're well familiar with--corn, potatoes, soybeans, and so forth--that are modified in some way, using recombinant DNA techniques; and that often when we go through the process of evaluating these, we don't find a hazard.  In fact, that has been in the case in the 50-some varieties has looked at.

    And so we felt that there really was a new term that was important here.  And so we established the term "safety assessment" as a way of having something to focus on that really takes

the emphasis on making sure that this food is as safe as other foods, but doesn't necessarily find a hazard or a risk.  So, if a hazard is identified, and, of course, there's always the possibility that that could be the case, then that hazard, then, would be treated as it is in the Codex system.  You wold have to decide does this food have to be removed from the marketplace, or are there conditions by which the food can be marketed, recognizing the nature of the hazard; for example, establishing a tolerance for a pesticide as a way to manage a risk.  And so, if there's a hazard identified, then the system would work just the Codex systems normally operates.  But the focus that we're going to talk about is really on safety assessment.

    So safety assessment, then, is something that the Task Force felt was important, recognizing that it does fit within the Codex framework.  But it's--this safety assessment process is really a comparative process.  It is one we recognize that the standard that we have are the crops that are

already out there.  The foods that we have accepted in the marketplace are the gold standard.  That's what we consider to be safe, recognizing that no food is perfectly safe or necessarily safe for all individuals all of the time.  But, in fact, the process, then, is to compare the new food with what has gone before, with its counterpart.  And the purpose of that is to try to identify whether there are any differences in the new food derived from this newly modified plant that would have any effect on health; and where those differences are identified, to make sure that those differences are also safe for the consumer.

    So the idea is to look at what's new; make sure that that's safe for the consumer; make sure that the food is still what it's expected to be, because this is food that we have consumed and have a history of consuming.  And this comparison should take into account both the intended changes that have been made in the plant, as well as, to the best that one can, to look for any unintended changes that may have occurred; and make sure that

if they have occurred and can be identified, that they are also safe.

    This is what we call substantial equivalence, a big, long term that is often confusing, but a very simple concept.  We don't decide at the end of the day that the food is substantially equivalent.  That's not the decision.  This is the tool at the beginning of comparing what's new; what's different about this new product, if anything, and making sure those differences are safe.  That's what we mean by substantial equivalence.

    The Codex has adopted a number of definitions so that they would have terms to use in the documents that would be understood by all the countries.  Modern biotechnology was adopted as the general term, and that was adopted because it had already been defined in the Cartagena Biosafety Protocol, so there was a large agreement on the definition by many countries, and so it was felt that there was no need to create a different definition and that would work for the purpose of

this work of elaborating food safety guidelines.

    The Codex also did something that I think was very useful.  They avoided all the terms that cause everybody a great deal of angst, such as genetic engineering, genetic modification, GMOs, and other kinds of terms that would be difficult to get consensus.  And, so, they simply referred to recombinant DNA plant or recombinant DNA microorganism where they needed to refer to the modified plant.

    And then they did, of course, design--or define conventional counterpart because we have a comparator, they wanted to make clear what we mean by the comparator.  The comparator is a food or a component of food for which there is a safe history of use.  And the Task Force recognized that, in some case, there might have to be more than comparator used in a particular assessment.

    But those are the definitions.  I don't want to spend much time on those, just to make you aware of them.

    And I'll quickly just go through some of

the elements of food safety assessment that are laid out in the Codex guidelines.  These will be no surprise to you, but it is, of course, asking what the plant is.  What's known about the plant in terms of its use for producing food?  How has it been modified?  What are the new techniques that have been used?

    The Codex guidelines use a method of first describing what the developer intends to do, and then going on to characterize what was actually done.  So you will see paragraphs that start description of molecular characterization, for example, or genetic modification rather; and then characterization of the same thing.  That's the reason for the difference.  The idea is, well, they intended to do this.  This is what they started to do.  Now, what did they actually do?  What do you find actually occurred.  So that's how the document is set up.

    In terms of safety assessment, of course, use for substances that would be in the food are really one of the major keys to safety assessment,

and are those substances likely to have any impact on public health, including toxicity or allergenicity.  As I've said, there is a separate guidance that deals with allergenicity.  I think that today that annex represents the best consensus that there is internationally on how to approach the question, is a new protein likely to be an allergen.

    The compositional analyses are part of addressing unintended effects, a part of answering the question, is the food still what we expect it to be?

    Evaluation of metabolites: if there are new substances of food that break down into other metabolites, obviously one wants to be sure that any other substances are also safe.

    Effects on food processing may be taken into account.  In some cases, of course, such as a refined oil, there may be no protein in the food.  Or there may be other cases where the processing may concentrate things in the processing of the food.

    Nutritional modifications.  Obviously, if the food is modified in a nutritional sense, it has to be looked at in terms of the overall diet of what people eat, not necessarily just the modification of this particular food, but how does that affect the diet and what are its implications; and other considerations, such as the use of selectable marker genes and so forth.

    Now, to get more to the topic of today, the guidelines do set out, in a number of paragraphs, first, as I said, describing what the developer has done in terms of a genetic modification, what is the host plant that's being modified, what are all the materials that are contributing to that modification, in terms of the source of the organism; the genetic material that's obtained from those organisms and how that's combined and introduced into the plant; what is introduced; what its size is; what its function is and so forth; and then going to what actually happened in the plant, characterizing the plant in terms of--at the molecular level, what are the

genes that have been inserted; how many sites; how many copies.

    Using sequence data to identify open reading frames, for example, so that one can get a sense of what likely substances are--can be expected, and will those be present in the food.

    The Codex discuss the sequencing of the inserted region and the border sequences, as well.  And they also recognize that there are other ways to get at the question of expressed substances, looking at transcripts and expression products as a way of keying in to what might be new substances that would be present in the food.

    So I think in terms of looking at new substances, the molecular data being used to both establish what is the function of this substance; what's the phenotype of the plant; what is the level of expression.  In other words, one of the common food safety questions is always how much do we eat.  So are these metabolic enzymes or are these substances that are seed-storage proteins.  What will this mean in terms of actual consumption.

    In some cases, we can think back to the old flavor saver tomato.  We may be actually not adding genes, but modifying the genes.

        [Reporter notes that main tape deck stopped here due to a sticky tape.]

inclined to modification.  So that is here in the guidelines, as well.  And there are other things that are taken into account when this genetic material has been inserted.  Have there been rearrangements in the DNA, and is there any consequence of those in terms of safety for health.

    Post-translational modifications of the proteins that may have occurred as a result of changes in protein sequencing and so forth.  And is this material inserted in a way that it will be heritable, stable, over several generations.

    So I think that these are things that are not of any surprise to you.

    So what is the goal of these guidelines?  First of all, that the food should be safe; that it should not, when it's used as it's intended to use, it should be as safe as other foods on the market.

And that's important.  We're not trying to show that this food is absolutely safe or guarantee that the food is safe.  We're comparing it to foods that are already on the market.  We're not accepting foods that would be of a lower standard with respect to safety, so they should be as safe as their conventional counterparts, taking into account any changes in dietary patterns that may occur, if there have been nutritional modifications.  And the idea of these safety standards within the Codex system is then to allow risk managers to have information that if there are hazards identified or other considerations that have to be taken into account, that they have this information that is based on sound science that they can use then to make their decisions about allowing these products to enter the marketplace.

    So this is--these are the new guidelines that have been adopted in the Codex system, and represent an international guideline and, basically, yardstick for countries to look at to see whether a food has been evaluated in a manner

that has been accepted in the international community.  One of the things that these guidelines do note is that while this is all focused on recombinant DNA and was designed to answer questions about recombinant DNA, no one knows any other way to evaluate the safety of a whole food if we were asked to do so.  So if someone came to FDA and said, well, we didn't use recombinant DNA, we used some other method, how should we go about evaluating the safety of this food.

    We would point to similar guidelines.  Our own or these guidelines, because we don't know any different way.  Some of the questions might be different, just as some of the questions might be different for recombinant DNA product that might present different characteristics than have been laid out in this general framework.  But while this focus is on our DNA, you should really think of this as way to evaluate the safety of a whole food using a scientific approach.

    Thank you very much.

    CHAIRMAN BUSTA:  Thank you.  Abigail?

Abigail Salyers.  Say your name, and then we'll have it in the record.

    DR. SALYERS:  Abigail Salyers.  Okay.  So my question is I don't know if any industries are getting ready to do this, but, in theory at least, one could produce foods that are safer.  Take the peanut, for example, if you could produce a peanut that didn't make peanut allergic people sick, and you used recombinant DNA to do that, would proving that that is a--I mean, how would you evaluate something like that?

    DR. MARYANSKI:  I would actually--

    DR. SALYERS:  Casava also has been brought up as a possible case--

    DR. MARYANSKI:  Right.

    DR. SALYERS:  Where they might use recombinant DNA to--

    DR. MARYANSKI:  No, and actually, of course, the Japanese did some early work using antiscents, trying to suppress the allergenic proteins in rice, and, you know, it was partially successful.  The problem with allergenicity is that

there are a number of proteins within any given food that are allergens, and some are more allergenic to some individuals than others.  Dr. Astwood is much more of an expert in this, and Dr. Jones, who works with me, is also much more knowledgeable about this.  But I think the potential is there for--

    DR. SALYERS:  I'm just asking in terms of the Codex, do you think that the basic principles there would apply to cases--

    DR. MARYANSKI:  Well, I think that one of the things that Codex recognized is that these guidelines were set up to assess the safety of food.  They--we--they can't really address that question in the sense that you would have to look at clinically, probably, whether the food still can cause clinical reactions.  In other words, have you eliminated all of the allergenic potential, or at least sufficient allergenic potential that that food is going to be safe for consumers. That's going to be a difficult standard to meet, at least as far as we know technically now.  No reason not

to try, of course.

    CHAIRMAN BUSTA:  Dr. Benedict?

    DR. BENEDICT:  Steve Benedict.  The previous question actually raised another thing.  Isn't it true, though--this isn't my question.  Isn't it true, though, that if someone did attempt to eliminate an allergen, it would still have to go, the product would still have to go through the Codex for changes in safety and unintended effects and other sorts of things?  Exclusive of what you talk about proving no longer allergenicity, you still have to take it through all the recombinant questions; would you not?

    DR. MARYANSKI:  Yes.  I think if you're asking would--for the product to be acceptable in various countries, and it's, you know, modified using these techniques, I think that today at least most countries would expect that it would also

be--you know, these other issues would also be taken into account.

    DR. BENEDICT:  Yes.  So actually my question is fairly trivial; and that is at the

meeting, did anyone discuss the range of sequence, border sequences up and downstream?  How many KB that people thought should be sequenced in order to determine that you're really not near an opening reading frame you could influence?

    DR. MARYANSKI:  I think that certainly one of the questions that was raised was whether there could be any fusion proteins.  In other words, is the insert done in a way that there's not

read-through into the plant DNA; and if there is, then can you identify that.  But there certainly wasn't any boundaries given in terms of how far out one should look.  And, quite honestly, some countries were interested in that more for methods of detection than actual, you know, safety considerations.  So there were various reasons why people are interested in border sequences.  So, but our focus here, of course, is on the safety assessments.  So, but the issue of whether that insert leads to any fusion proteins or read-through into the plant genome that would express different proteins than what the plant normally expresses, I

think is the sort of fundamental question about the region surrounding the insert.

    DR. BENEDICT:  Yeah, one of the things I recall that we sort of discussed in 1994 was insertion into a gene, which you would pick up with just a short distance, inactivation of a host gene.  But the other possibility is that if you're bringing in regulatory sequences, the possibility of some sort of downstream promotion, having not so much to do with fusion, but just is there an opening reading frame nearby that, for some esoteric and maybe unpredicted reason, you can, in fact, activate or inactivate an adjacent gene.  And so that was why I asking how many KB downstream you should go to say, well, there's a low probability we're going to influence a host gene in its expression.

    DR. MARYANSKI:  Well, I think that's a very good question for you to come back with after Dr. Cebula gives his talk.

    CHAIRMAN BUSTA:  Other questions of clarification?

    DR. ARIAS:  Jonathan Arias.  James, I'm--

    CHAIRMAN BUSTA:  Could you?  Why don't you pull the mike in front of you?

    DR. ARIAS:  Is that better?  Okay.  I'm concerned about the issue of substantial equivalence in regard to characterizing the meat food as being no more unsafe perhaps than conventional derivatives.  Does this include

long-term studies, or just acute, sort of toxicology biochemistry?

    DR. MARYANSKI:  No, we have taken

long-term effects into account at FDA, and in the Codex, because long-term effects are, of course, a question and a difficult one.  But we know a lot about the foods that we eat.  There are also a lot of things about foods we don't know.  I don't know what consuming carrots over my life time does for me, other than my mother told me it was good for my eyesight.  But whether it has any other effect on my health over consuming that, or any food does, we know very little about long-term effects of most of the foods that we consume beyond the nutritional

kinds of things that are, you know, we know about saturated fat and so forth.  But we don't really know much about consuming foods to begin with.

    What we do know about foods is that they do contain certain nutrients, certain toxicants, and so forth, and that we have accepted the foods that we have in spite of the toxicants that certain crops have; that at the levels those occur, we've accepted those as safe.  What we believe about the foods that we've seen so far with bioengineering is that the modifications that we see are fairly small modifications of the genome. And most of these, of course, produce metabolic proteins in the case of the proteins that FDA looks at or the BT proteins or viral proteins that EPA has been seeing.  And we know a lot about protein toxicity, and we know that the proteins that we're seeing do not lead to

long-term effects.  So we know at least the introduced proteins do not lead to long-term effects. And we're not aware of any reason why these foods would produce long-term effects any differently than foods developed by other methods

of plant breeding.

    DR. ARIAS:  Thank you.

    CHAIRMAN BUSTA:  Are there other questions.  Dr. Benedict?

    DR. BENEDICT:  Since there's open air--

    CHAIRMAN BUSTA:  It's Steven Benedict.

    DR. BENEDICT:  Steve Benedict, again.  One of the things that, as I read through this, clearly, you're dealing heavily with allergenicity, and the thing that came to mind, and I'm an immunologist, and I'm not sure I have the definition correct, even though I am an immunologist; but, as we all know, there are billions of epitopes going through the system daily, and their toleringenized [ph].  And so we've been tolerant, immunologically speaking, to all of those.  And the lack of tolerance may lead to an allergenic response.  But lack of tolerance might not necessarily be allergenic, but it might, in fact, lead to something that was immunogenic, and I'm not sure that there--this is where I'm not sure that there's a distinction between the two, because

I haven't thought it through for more than five minutes.  But the possibility seems to me that that checking for immunogenicity exclusive of allerogenicity [sic] might be something that someone should think about other than me.  And I'm wondering whether that came up at the Codex discussions.

    DR. MARYANSKI:  Yeah.  I would say yes that it did in the sense that there was certainly a recognition that there is more to allergenicity and immunogenicity than IGE responses.  I think that what was felt to be important is that we do our best to address the issue of the IGE kind of response because we know that certain proteins are allergens through that mechanism, and that the idea of transferring genes from one source to another, and obviously the expression of those proteins, raises the question of whether there could be an IGE-type response.

    I think that your question is one that's much more appropriate when we get to the issue of allergenicity as opposed to the molecular subject

today.  But I just want to recognize that, yes, there is--we don't just simply put blinders on; that we only look at IGE.  But these guidelines are focused on IGE because of the need to address the safety of the new proteins.

    DR. SALYERS:  Just a brief question.  Abigail Salyers.  The--we have people who are today who are living a lot longer than in the past, and we also have people who are alive today, like cystic fibrosis patients, who were not alive in the past, and so did the Codex consider the fact that we've got these new populations of people, especially I'm thinking especially about the geriatric population, where our previous experience may not be as good a guide as we tend to think it is as to effects that foods, even conventionally used foods, might have.

    DR. MARYANSKI:  Yeah.  I'm becoming much more interested in the geriatric population.

    [Laughter.]

    DR. SALYERS:  So am I.

    DR. MARYANSKI:  Actually, the Codex didn't

address the geriatric population specifically, but it did discuss the fact that there are basically subgroups within the population that one needs to take into account, including the elderly, pregnant women, infants and so forth.  And so, yes, while not addressing that in detail, the guidelines do generally recognize that in thinking about the safety of a new product, you do have to think about subgroups in the population as well as the population as a whole.

    CHAIRMAN BUSTA:  Thank you very much.

    DR. MARYANSKI:  Thank you.

    CHAIRMAN BUSTA:  We'll continue on.  Dr. Thomas Cebula on FDA's approach.

    DR. CEBULA:  Thank you.  I'm Tom Cebula.  I'm the director of the Office of Applied Research and Safety Assessment.  I'm also the lead scientist for molecular biology for the Center, and those that know me in the room know that I never give a scripted talk.  I'm taking out a crib sheet because I was taking notes.

    The first thing I'd really like to say

about the process that FDA uses is that it's an evolutionary one.  And, since joining the Center, I've interacted with Jim Maryanski, Bob Lake, others in this room since about 1987, so, like Jim, I'm also worried about the geriatric population.

    In that process, we saw a number of people come to us with a lot of ideas about what they were going to do, and I think Dennis made a very valuable point when, early in a consult, some advice might be given, the company goes back, and we don't hear anything more about it.  So there is a lot of oral history perhaps that should have been captured, and I--the point that you make earlier about how do we see those numbers.  Early in the process, it was an evolutionary one.  I think Jeanette made a very good point about after a series of discussions, clearly, we're trying to make that a very much more transparent process to really capture how many times the sort of advice that's given from this side out has influenced.

    The other point I'd like to make before going into my talk: I think Abigail Salyers made a

very credible point about connecting dots in the scientific community.  All science is interconnected and interwoven.  Jim Maryanski talked about R-DNA and the subject for transgenic plants.  Clearly, we've taken cues from R-DNA in microorganisms.  I serve as one of the experts for WHO for the microorganisms in R-DNA. But Abigail's point about probiotics.  I'd just like to extend probiotics, counter terrorism, and our budgetary process called OMB.  I do believe that what we have heard is that there is a real need to really take some of the counter terrorism dollars and move them into other areas of food safety.

    I believe something that FDA is doing, and our laboratories within CFSAN are actively engaged in.  My office, for example, has the mission to ensure, to do research that ensures food

safety--microbiological food safety--and we also have a team of toxicologists.

    Post 9-11, that mission changed somewhat, and it became food security and food safety.  It's a very valuable point, because the research that

we're doing for food safety could be immediately applied to food security.  And, of course, those dollars that are coming in, we're using as a twofer.  So if we're developing methods for the intentional contamination, those serve for methodologies for accidental.  So, again, we're trying to be very proactive, recognizing that it's a zero-sum game.  There's only a certain number of budgetary dollars out there; and if it's applied to counter terrorism, we have to get the most bang for the buck.

    The point about Vancomycin is a very important one.  And I'm just going to say that probiotics in the genomic era, as people have looked to sequence total genomes, people have looked at probiotic organisms; FDA, in contributing to the genomics project, has often emphasized it is nice to know that a bacillus cereus that is being used a probiotic, we can know the entire genome.  But isn't it more important to know about a bacillus cereus that causes disease.  So, again, FDA is trying to move in the direction of saying if

we're going to use those dollars, let's get some information about food safety from that.

    I just want to make sure that I've covered some of those points.

    The final thing I would say is that since 1987, we have served in a way as internal consultants for some of the process that you've been hearing.  We are primarily the laboratory portion of the Center, and since our hands are the wettest on the techniques, we're often called in to say how would you evaluate this.  So there's a very responsible team, and we interact with that responsible team to offer some advice and also do the consult--also do a review, as well.  So there is, if you might say, there is some partial duplication, but it's a very important duplication, I believe.

    With that said, I'm really going to take some of the slides that Jeanette gave and Jim gave and kind of put our wrinkle on it.

    Jeanette pointed out that really we're asking for companies to come in to provide the

documentation that assures us that there's a reasonable certainty of no harm.  But I think the important caveat is this is the real opportunity to find out what's in the pipeline and what's coming down in the future so that we can be proactive rather than reactive.

    We neither prescribe or proscribe specific tests up front.  We're there to hear what industry has to offer, and somebody said, well, how much input do we have.  Clearly, the input is we are going to offer advice, but we're going to be focused on the characteristics of the food product, as you heard Jim say, as you heard Jeanette say.

    We are there for scientific evaluation.  Our intent is really obviously the food safety question.  But, as scientists in this room, as you heard around the room, often we get off on a tangent.  We talk about the strengths, and that should say limits of a particular technique that might be used, because this helps us in future deliberations.  But our primary focus is food safety, and that's the important thing to remember

for our evaluation here.

    Again, borrowed from Jeanette, we do take a multidisciplinary approach, but I want to point out that the duplication is very important, because we're going to be really focused on the molecular analysis and really talking about the genetics of a particular manipulation or a particular plant.

    We often get clues from the chemical and nutritional analysis about stability and genetic stability, so we're looking at pretty much the same thing that a chemist might be looking at, a nutritionist, but perhaps from a different slant.

    Clearly, as you've heard, we want to know about the identity and source of introduced genetic materials because that will tell us a lot about what are the potential food safety concerns.  For example, in a sidebar during the break, we were talking about transferring genetic material from one microorganism to another.  I point out that the nomenclature has changed over the years, and something that is streptococcus a few years ago and may have been considered commensal is now

enterococcus and is a pathogen.  So we definitely ask people to identify the organism, but to trace the nomenclature of that organism to ensure that we have taken into consideration that nomenclature changes haven't affected our assessment.

    And, again, the intended changes of the composition of the food--clearly, we're always concerned about the intended effect, but, as you heard from all of the discussions, clearly, in evaluating food safety, it is often the unintended effects--allergenicity, toxins, and I should add the toxicants that Jeanette mentioned--because in a manipulation, as you heard, if you happen to insert and get downstream expression, you might get the expression of a toxicant.  We want to know that.

    The allergenicity, as you've heard, will be a separate discussion, but I would point out in our evaluation, since we are seeing sequenced data, the bioinformatics tools are there to say what sites could be potentially glycosylated; and these days, with the glycosylation kits, we're often seeing the data for whether those sites are,

indeed, glycosylated.

    The nutrient levels.  Again, you've heard why we look at that, but I would just like to take a digression, and say when we talk about natural foods, and we're looking at a nutritional status of anything be it a nutrient and this is also true for a toxicant, you would expect a normal distribution from the natural varieties over time.  When you're looking at a R-DNA plant, since the manipulations are among one variety, we would expect that distribution to be much tighter, and the sort of data that we see says that.  And so, if we're looking for toxicant values, which might also be this value, where this is low to high, clearly the data that we have been seeing up until now is that can fall on the low side of the toxicant.  So, when we're considering an R-DNA plant versus a natural variety, we find that all of the data, thus far, seems to follow the strength; that you're getting nutrients that you expect, with a narrow distribution, and lower toxicant values.  And I would say that's a fairly general way of stating

the sort of data that we have been looking at.

    And finally, something I neglected to say that our laboratories are very interested in DNA repair and effects on the emergence of antibiotic resistance, and the penetrants of virulent straits.  We are very interested in evaluating antibiotic resistance.  And, again, from an evolutionary perspective of the process, as you are all aware, the primary marker that was used early was antibiotic resistance, and we now see a drift away from antibiotic resistance.

    Now stealing some of Jim Maryanski's slides and the Codex slides, I would really like to emphasize some points, but I'm not going to reiterate all the points.  When we're describing the genetic modification, the sort of data that we have been seeing is people are showing you the nucleotide sequence of the material that they're starting with.

    They're telling you about the promoter set they're using.  They're telling you about the terminator set they're using.  That's a very

important piece of data, because that's direct information, and now you can use indirect methods; and there's a host of indirect methods that could be used to evaluate the construct once it's inside the plant.  And that's a very important point as we consider do we need sequence data and how much sequence data do we need.

    What I'm establishing here--if you know the sequence, you then can do a restriction map and ask does--is the restriction map consistent with the sequence that was delivered to the plant.  You can look at restriction maps.  You can look at expression.  Northerns.  We actually--or expressions of the protein, Westerns.  Now, clearly, there's a distinguishing factor here.  If you look at expression, Western analysis of the protein, you're usually looking at the intended effect.  The Northerns, however, give you a lot of information, because, if there are other transcripts made, that's something that we would be looking for as an unintended effect.  So unless it is stated that the intended effect is, any Northern

expression that would be aberrant, we would be questioning what is the significance of this RNA, this extra RNA.

    Again, I've already made the point about marker genes and the nutritional modification, so I'm just going to skip this slide and talk about the transformation process that Jim alluded to.

    Again, when you are talking about a ballistic method of random insertion, we might have a number of things that we're looking at.  You know, how many sites does this randomly insert.  If we're talking about site-specific recombination, if it is a site-specific recombination, it's a more tailored type of mechanism.  So, again, in making the point that it is a case-by-case analysis, it's important that if you prescribe the tests too soon, scientifically some of those tests would not make sense or some of the questions would not make sense.  So we're very interested in the DNA to be introduced--the genes, the markers, the regulatory sequences.  But Steve Benedict mentioned a point about regulatory sequences and sequencing, and I

really would like to make the following points right here.

    We are consistent, I think, with Codex, we're talking about size, identity, and location.  If we're saying we know that there is material inserted into a genome, say, the tomato genome.  We are also consistent in saying we would like to know orientation of that insert.  However, the location down to the nucleotide is something that we personally don't ask for.  And the reason is, and I should state it up front: all of the effects that we're looking at are SIS proximal because you can sequence 10 KB, 20 KB versus a trans effect from another chromosome, you're going to miss it anyway.  So I would really view them as a--up until now, we have said that we are looking at SIS proximal effects and the integrity of the genome in the intended and unintended effects the researcher has inserted into a gene.

    As far as the data that we've been seeing, basically, there have been times over the years, I can remember where people have provided inside-out

PCRs as to tell us some conference.  Okay so I will leave it at that to say that the location to us is that it is inserted and that it is stably inserted.

    The number of sites and organization.  Clearly, we all know that when the material goes in, that you have duplication.  Okay, so at the same site, you can have many inserts lined up or you can have many inserts lined up at different sites in the chromosome.  One is more important in our evaluation than another.  If you have multiple copies at different locations, the chance for recombination, reassortment, rearrangement, and ultimately effects on genetic stability are much more of a concern than if you have a single insert.  So that's why talk about wanting to know how many inserts and how are they located.  And, of course, as Jim emphasized, we are definitely interested in any open reading frame and insertions the possibility of fusion proteins.

    The important thing here I wanted to emphasize un-translated RNA.  Jim mentioned one possibility.  If the intent is to make antiscents

RNA, it's not going be translated.  We want to know about that.  But there's another--it seems every journal you pick up at least there are two articles in each of the journals talking about un-translated small RNAs.  That is not our intent.  We're not asking for people to tell us about every small RNA that's produced in the plant, because I don't know what those data would tell us.  But I leave that to you.  That is a very burgeoning field right now, the un-translated small RNAs that act as regulatory molecules.

    And, again, the intended effect and heritable stability.  I've mentioned a couple of ways we measure genetic stability or we assess genetic stability.  One of them is the Mendelian inheritance.  Clearly, if the insert is unstable and is hopping, the mosaicism rather than the Mendelian inheritance pattern would be seen.  So that's a very important thing.  But some of the other data that we've been talking about, the expression data et cetera, are also measures of stability also.

    And, again, these should read strengths and limits rather than limitations, because from the perspective of an R-DNA, it's important to realize that one or only a few genes are being incorporated into the plant.  There's a limited number of manipulations.  One can talk about unintended effects, and we'll get to that in a moment.

    But it's also important to remember that, as genes have been introduced by R-DNA techniques, those genes will become the docking points for traditional breeding, and those sites, then, will be now the conventional traditional breeding that we're all used to.  So, again, as people talk about propagation of R-DNA, the R-DNA will be propagated by traditional breeding also.

    So the questions that I took from this were what tests are necessary and are there tests that should be required.  I think those are all the questions in your minds, and you will be discussing this afternoon.

    I'd really like to point out that Mendel

did a nice experiment many, many years ago, talking about round and wrinkled peas.  And that experiment was reproduced in the molecular era about a decade ago or so.  And basically, if you do traditional breeding, and you get round or wrinkled peas, and then subject it to some proteomics, you find that 62 of the 636 protein spots are qualitatively different.  The R-locus, of course, now we know affects sugar content, lipid content, storage protein composition.  But the round pea is safe to eat, and so is the wrinkled pea.  Okay.

    The way I would like to look at this is as we were musing about this in Paris at a meeting, I went off to the Monet exhibit at the Musee Marmite, and there's some wonderful water lilies, canvases that just dominate.  For those that have seen, this is definitely Monet.  Everybody knows the blues, the greens, the purples.  This one happens to be the blues and the greens and the whites, but this is also Monet.  It looks more like a Jackson Pollard.  And this is about 1917.  The other one was 1880.  Okay.  But they're Monet, and I submit

to you that they're safe to consume.

    [Laughter.]

    It's also important that Gottlieb and de Vienne in '88 did an experiment also that found that if you take the AF mutants, you'll see that tendrils can replace the leaflets.  So it's something that you wouldn't want to see in a plant. Weeding this is not a good characteristic, but, basically, the protein profiles were absolutely identical.  So, again, the tests would not reveal a difference, whether it was a food safety issue or not. I'd leave that for discussion.

    I said I'd return to unintended effects, because, again, I think we have to recognize that, as the techniques get better and better, pleiotropy will be a universal trait of any mutation.  We know how much cross-talk is going on in the cell, and within an organ, and within an organism so that there will be always cross-talk anytime a mutation is introduced; and now I'm talking about a point mutation, be it an insert of a couple of genes or a point mutation, a base substitution.

    So, again, not to argue that pattern recognition can't work, okay.  We are believers and users of technologies like genomics, like DNA arrays, like proteomics.  But, again, I'll borrow from the impressionists and say that pattern recognition works Seurat proved that points of paint on a canvas can be recognized.  It can look like a lighthouse, or it can look like an afternoon on the island of the Grand Jatte.

    However, in a regulatory setting, I want you to concentrate on the dog, because that dog is very docile, at least captured at this moment.  So when we are doing expression profiles, if that dog changes to green, red, polka dot but remains docile, it is not a food safety question.  If that dog happens to bit that individual in front, it becomes a food safety question.

    I submit to you that we're at a stage to recognize that expression arrays do, indeed, work, but it's not at a point where we can find and isolate the genes that define safety.  And so, as people are talking, I would suggest that we talk

about the new technologies as they relate to food safety.  And with that, I'll stop.

    CHAIRMAN BUSTA:  I just want to make a comment.  You didn't need your entire 55 minutes.

    DR. CEBULA:  That was intentional.  I really wanted this to be a conversation, and, as I had pointed out, I would--

    CHAIRMAN BUSTA:  Dr. Salyers.

    DR. SALYERS:  I have a question.

    CHAIRMAN BUSTA:  Please identify yourself.

    DR. SALYERS:  Oh, Abigail--Abigail Salyers.  I have a question about the extent to which or how you see your group's position vis a vis advising industry about what it should do.  I'm struck, as I talk to various, especially the small biotech companies, but even the bigger--people at the bigger companies like Monsanto is the extent to which they have a very narrow range of expertise.  And even in the big companies, where they might have a broader range of expertise, the components don't necessarily communicate freely with each other.

    You're a world renowned scientist with a lot of contacts, and I'm sure that you've--so you're the sort of person I wish we had more of in industry, but we don't.  And I'm sure you've assembled a group that is--has outstanding representation of the various sciences; and that you are probably more like to the many people in industry to become aware of changes in the basic science technology.  So my question is one would hope that the FDA somehow could serve in an advisory capacity to industry; and yet, of course, you see the other side of it, which is the conflict of interest side I guess.  But how do you see your role as an advisor of people in industry?

    DR. CEBULA:  I believe the--when I said that we were serving a consulting role, I meant within the context of FDA.

    DR. SALYERS:  No, I understand that.

    DR. CEBULA:  Oh, okay.

    DR. SALYERS:  So I'm just asking you to expand on the outreach part of it.

    DR. CEBULA:  In the outreach, I believe,

as I said since '87 or thereabouts, everybody time somebody has decided to talk to Jim or Bob Lake, Jim Maryanski has graciously said, well, why don't we get Tom involved.  He may have some ideas.  When we're out at meetings, we are scientists; and, clearly, if there's a technique out there, you know, we're doing that right with pyrosequencing.  Pyrosequencing is a very valuable technique.  Some people haven't heard about it.  We're using it.  We're saying how about this.  So it is scientist to scientist.  We're trying to exchange information and the technologies as we see it, and we're welcoming the input the opposite way.  We're getting fantastic input from academia and from industry; and we're working collegially I think--is the important thing.  And if I might say something about the whole process, again, over time, let's start when we first consulted, if we said, do you have data.  The first response was why.  I believe now it is, you know, developed to a point where people are saying, well, these are the sort of data, and this is--there's scientific reasons for

the data.  So, I believe there is a trust in its finest sense of the word, a mutual trust, that questions aren't being asked for it would be nice to know, but as was stressed in the two talks here, there is a need to know because it may impact a safety decision.

    And so I think there's been a good rapport built up over time.

    DR. FEDOROFF:  Nina Fedoroff.  I was very struck by your cogently pointing out that you can have many differences, and the foods are still safe.  I think if people had suggested that we would knock out starch genes and get sweet corn, somebody would haven't objected to the religious grounds or ideologically grounds.

    In any event, the other point that you made that I'm struck by, and that leads to my question, is that, so far, your assessments have indicated that the distributions are narrower and that none of these unintended effects have surfaced.  My question is: how many instances do you have to assess before you can evolve your

guidelines to say, okay, this is not a major problem, we don't have to collect all of these data.

    DR. CEBULA:  Well, I think one thing you've heard from the two speakers before me, we are clearly waiting to hear what the National Academy has to say.  We're awaiting what the input of your group will say.  But, clearly, I wanted to point out there will be unintended effects. The question is, will those unintended effects affect the quality or food safety of--

    DR. FEDOROFF:  Sure.

    DR. CEBULA:  Okay.

    DR. FEDOROFF:  But the other thing is that there are--in--in-those of us who work on little experimental plants have been making insertions left, right, sideways, hundreds of thousands of them.  And the information that comes back is that plenty few of them make a huge difference.  In fact, people struggle to identify insertions that change how the plant grows, flowers, reproduces.  It's a very small fraction of them.  And the

ability of insertion--even when people set out to activate genes by pointing a promoter out, that doesn't even work much of the time.  It does work occasionally, but not--certainly not as frequently as you'd expect.  And it seems to me that there's a large volume of information, not just new techniques, but accumulating information from actually insertions done for mutagenic purposes that one could bring to bear to increase the amount of information that you have available to you in making judgments about how frequently there are unintended consequences.

    DR. CEBULA:  Those data, indeed, would be very helpful.  I think when we were talking about CalGene, I think that you were on the committee then, and I was giving a talk.  And I--you said the problem is that the negative experiments are seldom, or can't be published, and we're saying that we need that database, whether that database is in the published literature or available, we would like to see the number of cases so that that can really help us.

    DR. FEDOROFF:  That's a real challenge because people frequently don't--you know, they put a lot of effort into identifying mutants.  They don't put a lot of effort into quantifying the frequency of those mutants.

    CHAIRMAN BUSTA:  Doug.

    DR. GURIAN-SHERMAN:  Doug Gurian-Sherman.  I think that whole issue brings up a discussion that we should, you know, probably take up at some point.  But, with time limited, I wanted to focus on a whole other issue.

    You mentioned several instances of types of data that you look for, so you--you know, you talked about stability, and, you know, differences in nutrient levels, and all that kind of stuff.  One concern that I have that maybe you could address is, what the level or type of analysis that you consider to be acceptable, because, again, and I have to put this in context of the studies that I looked at that you folks looked at, and often found there was limited methodology described, limited statistical analysis.  You know, stability is one

thing brought up.  Half the cases we looked at--a lot of them did look at Mendelian analysis.  Probably half of them didn't do any statistical, like the chi square analysis to tell you--I mean, you're not going to get a perfect four to one ratio in most cases, so you have to have some kind of analysis that tells you how much of a deviation you get, and then try to figure out what that means.

    So, I mean, I think a whole other issue the quality of the data, and the expected level of analysis, and how--I mean, you know, one standard could be comparable to what goes into a peer review journal.  To be frank, I don't think that, on average, that was the case.  So how do you decide what the quality is that's acceptable?

    DR. CEBULA:  I think it's very important to recognize that I said several times that one way of measuring genetic stability is Mendelian inheritance.  As I said, if it weren't Mendelian inheritance, there would be a large deviation.  However, if those were the sole data that we were looking at, I would say yes, you would have to do a

very sophisticated statistical treatment to unequivocally say it's Mendelian inheritance.  But there's a body of other evidence that says, the material is still where it is because on the second generation, we've done, you know, a map that has provided us other data that supports it's sitting in the same site that it started out with.  It's also being inherited at almost, or, I mean, I'm taking your word.  You know, I don't know which data you are speaking to.  But if it's almost Mendelian, and it's sitting at the same place, it's likely to be Mendelian rather than some runaway jumping gene.  And that's so--you use the different techniques.  I would rather see the company offer three different techniques to verify it rather than working on the statistics to come up unequivocally to come up with a Mendelian inheritance.

    DR. GURIAN-SHERMAN:  I think that's a good point, but, again, you know, addressing that issue: you know, when we looked at this, some companies did do things like expression analysis for a bunch of plants that, you know, the F-3 generation or F-4

generation, but many of them didn't.  And similarly, you know, some companies did bioassays, but at levels of expression that might be, you know, 20 times over the lethal dose, so variations that could be fairly substantial wouldn't even necessarily show up.

    So, I think, you know, what it comes down to often is a lot of times the devil is in the details, as we'd all expect, you know, in empirical science.  And I'll just raise it and leave it as a concern that there need to be sufficient analytic standards, redundancy if you want in tests, but then they need to be there.  And I didn't find that that kind of redundancy was there in many cases.

    CHAIRMAN BUSTA:  Jim.

    DR. ASTWOOD:  This is Jim Astwood.  Dr. Cebula, thank you for the thoughtful presentation and interesting art.  In thinking about it, I was wondering if you could comment on, what seems to be in this presentation, an analysis at the genotype level, you know, fundamentally, if you think about it as a geneticist.  What importance should be

placed on the phenotype, the agronomic evaluations, the compositional analyses, which can be thought of as biochemical sampling--these other factors.  How do you, as a molecular biologist, how do you sort of think about the weight of those different aspects?

    DR. CEBULA:  Well, the agronomic issue I believe is away from my bailiwick.  I'm expecting a company to make a decision if there's, I hate to say it, but there's a different bottom line.  If it's going to be developed and marketed, there has to be one bottom line.

    The molecular analysis, by the time somebody has made the decision that they're going to bring something forward, I believe they've already done some of the routine analysis that impinges upon molecular biology; and that is the genetic stability, the ease of manipulation, and when I say stability, I mean it on two different levels: the internal rearrangements that could occur, the possibility of methylation and silencing--all of those have been done by the time

they came in.  So, in that sense, by the agronomic consideration that a company might do, I feel that a lot of experiments have been done that we haven't seen the data for.  But, again, the data that we're analyzing supports the notion that you have a stable insert; and it supports the notion that it is constantly being expressed.

    I presume, again as Nina Fedoroff said, those data are to come by, but within the notebooks, they are probably a lot of failures to come forth simply because a methylation pattern decided to silence a gene or something.  But those are the data that we don't see, so we can't give statistics on those.  But, by the time we're seeing the data--

    DR. KAPUSCINSKI:  Thank you, Dr. Cebula.

    CHAIRMAN BUSTA:  Identify yourself.

    DR. KAPUSCINSKI:  Anne Kapuscinski.  I also appreciate your presentation, and, by the way, I'm a lover of that art, and I was born in Paris, so it kind of got under my skin a little bit.

    But I have a question.  It seems to me

 that the question about these genomic and proteomic methods for the committee should really be, and I assume, therefore, for the FDA, should really be how could using those help to improve sort of strategic searching for the few cases where something unanticipated might cause a real food safety problem, rather than asking about those techniques alone.

    So, I would like to get your feedback on that.  What I'm really getting at is I think I want to ask sort of what Dr. Astwood asked but a little bit differently.  Isn't it better for us to think about how can we direct the use of these techniques in combination with information at the level of biochemistry, and then at the level of the whole plant, phenotype, et cetera, rather than ask to only look at those techniques alone.  I think if we just look at those techniques alone, we're kind of barking up the wrong tree.  And I fully appreciate, you know, your concern that the status of the technology right now is you could generate tons of data about transcripts and expressed proteins and

not really know what it means.  But I think it seems to me what we need to do is figure out how can we, knowing that there's that limit, how can we direct the Agency, and maybe even direct recommendations for research, to improve the use of that technology in a very strategic, focused way so that it could add to the toolbox that you have right now.  Because it seems like the bottom line challenge in this area is that, yes, the large majority of the time, there isn't going to be a problem.  We just want to make sure that that doesn't make us complacent so that it becomes hard to proactively detect the few cases where there will be problem. And we all know that coming down in the future, this technology is becoming more and more powerful, and there's going to be chances to make much larger scale changes as we get into gene stacking and genes that we know will have major effects on composition because you actually want them to have major effects.  So, that definitely raises the question that they might also have some major unanticipated effects.  So, we have to be

looking at the future.  So, what's your reaction to what I'm saying?

    DR. CEBULA:  I think these technologies are wonderful technologies to do just what you said, search and discovery.  If I could read into your question and say, what could you do to help, the first message that I would do--ask you to send is to ensure that any of the technologies being used have been validated, because there are a number of these expression chips out there, and you read the same literature that I do.  Recently, one of the major manufacturers of a particular chip, there was an article in Nature, called "When the Chips are Down."  The company in their quality control missed the fact that they put the wrong strand, and, even then, 30 percent of their sequences were aberrant sequences.  And this was sent out, and people are using them, and flooding the literature with array papers.

    DR. KAPUSCINSKI:  Trash.

    DR. CEBULA:  The rush to public a new technique has often showed us that there are lot of

holes in the technique.  So, I would say that what you could do is make sure that we don't damn a technology because we got started with the technology prematurely.

    So, for expression, there are some very good examples.  David Bottstein teamed up with Stanford to come up with a lymphoma chip, very predictive.  But to get to using a lymphoma chip, they had to go back and show that the repository for the sequences were cluttered with about 24 percent of the sequences that had the wrong sequence.

    So, everybody's using these chips, and it takes a couple of scientists to say, well, let's not rush to publish.  We'll just go ahead and find out what's going on first.

    So, my first message would be could you carry back and say, let's go slowly but very together on making sure that the chips we're going to use to evaluate biotechnology, natural foods, or any other is the best chip to make sure that it's right.  We don't repeat mistakes.  I mean, we saw

the same thing with the emerging PCR technology.  Everything gets exponential the first few years, and that's where the mistakes are buried.  I'm sorry.

    CHAIRMAN BUSTA:  Dr. Fedoroff.

    DR. FEDOROFF:  But I think that's missing the point.  In order to make a lymphoma, and you've made the point earlier, in order to make a lymphomas chip, it's not only important to have accurate sequences, but it's important to have the lymphomas.

    DR. CEBULA:  That's right.

    DR. FEDOROFF:  Okay.  And that's really the whole point--is that we're--we need to avoid focusing on the technology when we don't know what we're measuring.  There is a huge range of permissible compositions that are perfectly good foods, okay?  We seem to slip off that over and over and over again.  And I think it's extremely important because some of the notorious incidents that have hit the press worldwide have been based on the lack of recognition that the very processes

of transformation, the culturing of cells, which has been used to generate variation, does generate variation.  And, so, people attribute variation to somehow this terrible recombinant DNA when it has to do with tissue culture.

    But it's not an unexplored territory.  And so the question is one of connecting the limits of variation with permissible--and I think that we're going about it the wrong way.  Instead of saying what is--characterizing the entire range of variation for every component of foods, we need to collect the information on what has proven to be problematic health wise--glycoalkaloids in potatoes, sugar binding proteins, which are lectins, which are under characterized as yet in both plants and animals.

    But it's not an infinite variety.  One doesn't have to look at everything.

    DR. KAPUSCINSKI:  That was why I was asking about, to kind to get your input, on how your thinking about potentially directing the use of these new technologies for strategic searching

for the things that might go wrong, sort of playing off of what Nina is saying.  So, I just wanted to get a sense of whether you, as a molecular biologist, are thinking in those terms and whether you realize that or to what extent you're thinking on drawing on information from the biochemistry and other levels of the phenotype to guide, then, how you would use, for example, a DNA chip.

    CHAIRMAN BUSTA:  That the first comment there was Dr. Fedoroff.  The second one was Dr. Kapuscinski.

    DR. KAPUSCINSKI:  Sorry.

    CHAIRMAN BUSTA:  We'll let you respond, and then we've got two more over here.

    DR. CEBULA:  I apologize.  Nina, thank you for bringing me back.  You're absolutely right.  That is the major point.

    The one thing that I think would be very helpful, and this is something that we've discussed internally, is that narrow distribution versus the broad distribution is, in a way, comparing apples and oranges, because that is the gamut of varieties

versus one variety.

    DR. FEDOROFF:  But only for one component.

    DR. CEBULA:  No, I know.  And no, no.  And what I meant to imply is if we are going to use the new technologies, it might be important to really do counterpart, the natural counterpart to, the variety from whence it came compared to the transgenic and then ask, because I've looked at some data where clearly there are differences in expression, but I don't know what it means; because I don't know what the variety used, how that compared to the manipulated variety.

    So I think first of all we have to do some fundamental genetics.  If you're going to approach it, approach the new technology, take the new technology and combine it with some good genetics.  That's all I'm saying.  And, there, I would say that we would like to see, you know, again,

data--if you're doing it strategically, as you're suggestion, I would say that any gene that you see from an array would be verified by another technique, a more sensitive technique.

    To say, if you have a knockout, do you get the expression that you expect or the

non-expression.  It's what's going on in the field right now in array technology everywhere else.  So, if it's going to be applied, and I'm not saying I'm recommending it, I'm saying if it's going to be applied, it should be applied in a very structured way to follow the sound scientific principles.

    CHAIRMAN BUSTA:  First Jonathan, then Calvin.

    DR. ARIAS:  Jonathan Arias.  Thank you for the very interesting and informative presentation.  I had two points, or questions, actually, to address.  One is in regards to the overall view of risk assessment and safety.

    And it seems to me that one of the difficulties intrinsic in these more computational biological approaches of genomics and such is ultimately how to interpret all of this data.  Genes will go up.  Genes will go down.  And are those changes in ways--or confer changes in the plant that would be significant in terms of health.

And I think that's a real challenge, that maybe the answer isn't quite known at present.

    The second point is related to more global issues, and that is, the input of safety analysis.  You mentioned that, and I commend, that the FDA has a consultative process with developers, and, as part of that, wants to get heads up about new products in the pipeline.  Likewise, does the FDA also communicate what they would perceive as recommendations to minimize risk intrinsic in the state-of-the-art technologies, for example, the use of strong viral promoters that can activate genes at distances might be, for instance, less preferred than using more tissue of targeted promoter systems.  Obviously, if a product is expressed in non-food components, it may be less of a concern than if it's generically expressed in the plant, including in the food component.  So, is that dialogue also two ways?

    DR. CEBULA:  I'll answer the second first.  I believe it is.  I think over the years, there have been a number of times when, in a very

interactive discussion, FDA scientists have made some suggestions, and that has led to a shift in the thinking of what was going to be used.  There have been cases where we suggested an experiment, and I keep on saying it was an evolutionary process; so these are earlier times, where the very technique, there was a concern that there may be read-through through a border sequence, and we suggested some experiments that ultimately turned out to be a very nice publication for the company.  I noticed that in the acknowledgment that FDA scientists weren't acknowledged.

    [Laughter.]

    You know those things happen, but it was a good experiment.  It was a nice experiment.  So, I mean, I think it happens, but again it's part of that consultative nature: that somebody comes forward and shows you the data.  I think I said in the sidebar, I almost treated it as an academic, you know, show me what you've done in the lab lately.  And over the first few consultations, it was why do you want to know this.  And, over time,

people said, I did this experiment but.  And, you know, that's how you find how people are thinking.  You know, we really--it was more collegial, and people were opening up to say we were trying this.  It didn't work.  We were trying this.  It did work.  That's the process that I'm trying to define, and I'm probably not doing a good job of it.  But it is a learning process on both parts.

    DR. ARIAS:  I think we recognize that in very few cases are we going to find clearly demonstrable risks associated with a particular transgenic plant.  I mean, those would be probably be quite evident in the range of studies that are done to date.  And it's the more subtle ones that we would obviously be--considered as problematic.  Thus, using new to change the overall level of risk or probability of risk would seem to be also intrinsic in this process.  And I gather that's what I'm hearing, as well.

    DR. CEBULA:  I would just like to return to your first question of combinatorial.  I actually should have put a slide in here, because I

usually keep the yeast genetics--the yeast array up there.  Brown, out at Stanford, now has looked at 20 different strains of yeast, using a chip that has about 2,000 pieces of DNA down there, so 2,000 reporting groups for each experiment.  And he's done it under seven different environmental conditions.  So, you have 2,000 to the 20 times 7, 2,000 to the 140th power, bits of information coming in.  And so that's why I'm saying, let's be careful what we ask for because that information cannot be sorted through.  And we will always see genes go up and genes go down, but the question, again, remains is it a food safety concern.

    CHAIRMAN BUSTA:  Dr. Qualset.  You've been very patient.  I appreciate that.

    DR. QUALSET:  This is Cal Qualset.  I've sort of forgotten what I was going to talk about--

    [Laughter.]

    Because I'm intrigued with this discussion.  I'm a old-fashioned plant breeder.  And I see us drifting quite a ways from the 1992 policy; that is, product versus process issue.

    What I understand is that FDA will receive a product--is that not on?

    DR. FEDOROFF:  I think it's not close enough to you.

    DR. QUALSET:  Okay.  Anyway, I think that we are drifting away from the discussion of approval of a product versus discussion of all the academic issues of process.  So, I think we need to, as a committee or a group, needs to slow down on this and decide what is important to know about a product.  And it's a--the developer is already obligated to product a product that is stable; that demonstrates the functionality of a gene or segments being introduced; and to show how they established the stability, the genetic stability as well as the performance stability, over environments in which a plant will be grown.

    So I think it will be nice to know about these various kinds of molecular things that can happen with genes jumping around and all that.  But the issue is, is the product produced and is it stable.  We cannot understand every genetic thing

that could happen.  But if the product is as advertised, and it does not have any risks with human food safety as a whole food or as a processed food, I think that we are thinking steps further than are necessary for the evaluation process.  So that's just my comment.  I'm throwing that out as a point for detailed discussion I think by the people who understand both product marketing, development; and they understand whether they're on the right track.

    So, I like the idea that there's consultative process with FDA, so they can kind of get a clue of where the product--what the targets are for a new product.  But the developers really have to provide the information to support the claims.  So, I hope we can discuss that further.

    CHAIRMAN BUSTA:  Bob.  Identify yourself.

    DR. BUCHANAN:  Bob Buchanan.  I was intrigued by your discussion of Mendel and the proteomic analysis.  Of the 62 proteins that differ, did any, would any raise eyebrows as to whether the product might be a problem?  We know

the peas are safe. Do any of the protein changes look suspicious?

    DR. CEBULA:  Well, I gave you some classes.  Some affected sugar content.  Some affected sugar storage.  But none of those changes said, you know, there's an unknown toxicant, cryptic toxicant peas that came up.  That answer is--yeah.

    DR. BUCHANAN:  That's good to know.

    DR. CEBULA:  Right.

    DR. GURIAN-SHERMAN:  Just--did they actually look for--

    CHAIRMAN BUSTA:  Ah, yeah—

    DR. GURIAN-SHERMAN:  Doug Gurian Sherman.  I'm sorry. Just for clarification in that study, did they look for those kinds of changes?  I mean, we assume they're safe, and they're probably safe, you know.  But in terms of specific new anti-nutrients, you know, toxicants, were those looked at in that study or they looked at just general classes, like protein, starches, et cetera?

    DR. CEBULA:  What they did was they

resolved over 600 proteins on a two-D gel, found approximately 10 percent changed, and then went about to characterize all 10 percent qualitative changes, and showed that, you know, it was sugar storage.  It was lipid storage.  So, they would have--if there were a toxicant, they would have had an unknown protein, but it didn't show up in their analysis.  Sixty-two of them were fully characterized.  So.

    DR. GURIAN-SHERMAN:  Well that's--just again to follow up.  Doug Gurian-Sherman.  I mean, most--many products, especially legumes do have toxicants and anti-nutrients, and they're often removed through the process, and through cooking, they're not--for instance, they're not heat stable.  So, you know, if there's a change in levels, some of them could theoretically have been, you know, toxicants and anti-nutrients.  I guess what I was getting at was were they trying to identify whether those proteins were, you know, trypsin-inhibitors, or amylase-inhibitors, or, you know, whatever things that--maybe it wouldn't be problematic

anyway, because they may be removed through processing; but others that if the level was increased--I mean, some allergens are also, you know, some of these types of proteins that might have an effect, and that's what I was getting at.

    DR. CEBULA:  I really don't know if the wrinkled peas in that experiment were consumed by the investigators.  I am sure they went a lot of blood, sweat, and tears to get it published in Genetics, but that was the standard.

    DR. FEDOROFF:  What does conventional alleles work?  That wasn't recombinant DNA anything.

    DR. CEBULA:  It wasn't.  No, no.

    DR. FEDOROFF:  It was just round peas and wrinkled peas.

    DR. CEBULA:  It was a natural.  Right.

    CHAIRMAN BUSTA:  You know the conversation is rolling toward lunch.  Any other questions for clarification?  The speakers will be around this afternoon, correct, as we go to discussion for additional expansion if we need it?

    DR. CEBULA:  I will be on a conference call, but I said I would be available.

    CHAIRMAN BUSTA:  Okay.

    DR. CEBULA:  I will be on a conference--

    CHAIRMAN BUSTA:  But, if we have to, we can drag you in; right?

    DR. CEBULA:  Okay.

    CHAIRMAN BUSTA:  Any--immediately after lunch, we will have the public comment.  Is that one?  Is that correct?  And we will have that public comment--it's generally set for 10 minutes, and then we will go directly into the summary and discussion.  Anne?

    DR. KAPUSCINSKI:  I was reminded that you need to read my name.

    CHAIRMAN BUSTA:  I was going to do that right after lunch, but do it right now.  We have the time.

    DR. KAPUSCINSKI:  Okay.  So, my name is Anne Kapuscinski, and I'm from the University of Minnesota; and I'm on the subcommittee, and I'm really here.

    CHAIRMAN BUSTA:  And she showed up immediately after we went through that activity this morning.

    DR. KAPUSCINSKI:  Twice.

    CHAIRMAN BUSTA:  Twice.

    DR. KAPUSCINSKI:  That's because I have to get some good coffee.  It's my one weakness.  One of my weaknesses.

    CHAIRMAN BUSTA:  Thank you all.  I'd like to thank all the speakers this morning--and for your tenacity and the group.  I look forward to an exciting discussion after the public comment this afternoon.

    [Whereupon, the meeting went back on the record at 1:05 p.m.]

    CHAIRMAN BUSTA:  We have one public comment, and Mike Watson will introduce it.

    UNIDENTIFIED SPEAKER: We have one public comment from Dr. Michael Hanson, from Consumers' Union, and he asked for 10 minutes to present to the committee.

    CHAIRMAN BUSTA:  Yes, please.  Use the

microphone, so it's recorded.

    DR. HANSON:  Thank you.  My name is Dr. Michael Hanson.  I work for Consumers' Union.  They're the people that publish Consumer Reports magazine.  And we've been very interested in genetic engineering issues; have actually been commenting on all the--ever since 1992, on the FDA's various bio tech proposals.  And I should also point out that Consumers' Union is part of the international network called Consumers International, which is composed of 270 consumer organizations in 117 countries.  And we have observer status at the U.N., and we've also been very actively involved in the whole Codex process.  We went to all the meetings of the Task Force on Biotechnology.  And we would actually agree with Dr. Maryanski that that was a very positive process.

    What I'd like to do here today is very quickly just make a few comments about molecular characterization.  And these are the few points that I want to make.

    First, we think that it's a very good idea that the FDA is now talking about requiring a lot of molecular characterization data, as is laid in these Codex documents.  But we have a basic question, and that is, whether this will be mandatory and not voluntary, and also to what extent data is going to be required post transformation.  Because, in what you were told earlier today, it made it seem like the FDA has sort of been requiring this data all along.  But that's not really true.  That was a new requirement that came in with this 2001 policy.  And I'll tell you about three years ago, I was on a State Department Committee, this Trans Atlantic Policy Project, and it was focusing on biotechnology; and the idea was to try to get the U.S. and Canada and the European Union to work toward harmonization.  There was a lot of debate within the subcommittee, because, first, they wanted to look at full biotechnology, like a--and they argued about should we require, should we look at a human data package or environmental issues.  And they couldn't decide

on anything, so the one thing that they decided on in this working group was to focus just on molecular characterization. And what happened, this was I think in 2000, late '99, early 2000; when we finally met, data had come in from both the U.S. and Canada saying here is the molecular characterization data that's required.  And the European Union, because I guess the data is different in different countries, they actually never submitted anything.  So, this subcommittee has only met twice.  We still haven't gotten any data from the European Union.  But it should be pointed out that the data that was submitted by the U.S. and Canada, the molecular characterization that they said they were requiring, was functionally complete maps of the vectors and plasmids and what you were going to insert.  But post insertion, it was just information to show that the transformation had been complete; that is, that the gene was in there and was active.  But there was no requirement in terms of the data that they were showing us to do this--these nice maps of

how many insertion sites, what the structure is at each insertion site.  So, that's what caused us some concern, and we really think that all that information needs to be in there.  I would also point out that, in the 2001 pre-market biotech notification proposed rule, it says in this paper that was handed out today that it's just an extension of the 1992 policy.  But it really isn't because there's, in the Federal Register Notice, they said for the first time they will be requiring data, and the data that they--part of the reason that they said that they were going to be requiring data is they said that the unintended effects that come from the random insertion, they called it insertional mutagenesis, because that can differ between different transformation events, the Agency said that they would require data on each separate transformation event, even if the vectors and plasmids used were the same, and the genetic background used was the same; that they would require separate data.

    We think this is a very positive thing,

but we wonder whether the FDA is actually going to move forward with those rules, because I should point out that the molecular characterization data, for example, for the BT crops that EPA used in their safety assessment, they actually bridged, they allowed companies to use data from separate transformation events and have it go collectively.

    And--so, we think that the data that should be required is that there should be complete molecular characterization of each line with respect to identity, stability, and unintended positional and pleiotropic effects.  And the agency--the components of a complete molecular characterization should, for molecular identity, would include for each transgenic or transformed line the total number of inserts; the location of each insert, whether organelle, chloroplast, mitochondria, et cetera, or chromosomal; the exact chromosomal position of each insert; the structure of each insert, whether duplicated, deleted, rearranged, et cetera; the complete genetic map of each insert, including all the elements--the coding

region, non-coding regions, marker gene, promoters, enhancers, enterons, leader sequences, terminators, T-DNA borders, plasmid sequences, linkers, et cetera, including any truncated incomplete sequences; also the complete nucleotide base sequence of each insert.  And we also suggested that the base sequence of at least 10 kilobase pairs of flanking post-genomic DNA on either side o the insert, including changes in methylation patterns.  The reason for this is because the prominent use of hyper-promoters, such as the CAMV-35S promoter.

    And the other main point I wanted to make is for determining molecular stability, we think there needs to be data on both functional and structural stability.  And the functional stability should be the level of expression remains constant over time and over successive generations.  And I would point out that just requiring Mendelian data is not good enough.  For example, with the BT crops, there's a high dose strategy, and the high dose is defined as 25 times the LD-99.  And so, if all you're doing, in some of the data that was submitted to the EPA, they would just say to show that something's stable, you just had to show that the trait still worked; that is, that it still had activity against these insects.  Well, if you're talking about a high does being 25 times the LD-99, you could have variability, and one trait could be 20 times lower and only have 5 times the LD-99 of the cryoprotein in there.  But if you did a simple bioassay with caterpillars, you would find that 99 percent of them still die.  That is, you couldn't see the variability there.

    So, that's why we think that for structural stability that the FDA would need data on the physical location of the insert in the genome, as well as on the structure of the insert throughout the lifetime of the plant and over successive generations, say, three to five generations.  And, particularly, to look at that structural stability, we think there needs to be data on the flanking sequences, so you can see whether it's moving around inside the plant or not,

because we noticed that those kind of data were not submitted for the majority of crops that have gone through this process.  Of the 54 crops that--54 things that have gone through the FDA's process, I believe only two of them have gone through since 2001.

    And finally, for the other form of stability, we think that the FDA--I'm sorry--to look at the tests for unintended positional effects, we believe the FDA could carefully look at methylation patterns of genes in the flanking host genome DNA.  And that's, again, 10,000 or 10 kilobase pairs upstream and downstream of the insertion site.

    So, in sum, we think this is a very positive movement that the FDA is proposing, but we do have the question of whether these data, which they say are going to be required through the PBN, since we hear that that's going to fall off the radar screen, not be on category list A or B, whether the FDA will be requiring all these data that they said they will in the future.  Thank you.

    CHAIRMAN BUSTA:  Thank you.  Any burning questions?  Just one.

    DR. SALYERS:  I just want to make a comment about this.  Monsanto must love you, because if that grocery list is actually enacted as obligatory, it's going to make it even harder for small companies to get into the biotech; and for developing countries who follow our lead, even though they're not bound by our requirements to develop their own products.

    So, I just think that we need to be careful about--it's always appealing to add on another item to the long list of existing ones.  But the question is, is there a reason to do it?  And are we doing anything but further increasing the power of the big companies in this area?

    DR. HANSON:  Well, my response to that is I think that all we're asking for is the kind of data that has now been agreed upon internationally; that are actually--it's in paragraphs 30 to 33 of this Codex document that was agreed upon.  And the reason that this is important is, written into the

GAT agreement, which set up the World Trade Organizations, if there is disputes between countries, they'll look, written into the GAT agreement is, indeed, Codex Alimentarias is considered the neutral, scientific standard.  So the concern we have is that some other countries could pass laws saying that they require all the data that is mentioned in here, and then they could turn around, and since this data is not required in the U.S., they could exclude products coming from the U.S., saying that they don't meet this standard.

    So, we're not suggesting that further data should be added.  We're asking that the FDA require the level of data that has now been agreed upon internationally so that there is not a problem with trade, potential trade impacts with products that come from the U.S.  Because you should know, most of the world did agree that these safety assessments should be required.  The U.S. does not require that at this point.  So, that's why--we're not asking for extra data that will overly burden

developing countries.  It's just the data that has been agreed upon globally.

    CHAIRMAN BUSTA:  Now, it's Dr. Salyers.

    DR. SALYERS:  Abigail Salyers.  Sorry, I didn't hear--

    CHAIRMAN BUSTA:  Dr. Qualset.  Go ahead.

    DR. QUALSET:  Okay, it's Cal Qualset speaking.  It seems that if the developers are developing a product for U.S. markets, then why would they be required to get data that isn't essential to the evaluation of the efficacy of the product in terms of food safety?  If the developers want to go to international markets, they can follow the international standards.  But why make everybody fall into this, whether it's a small university, a small company, or large company?  I think it should be clear that we have to evaluate for the product safety, and not necessarily all the ins and outs of its development.

    DR. HANSON:  Well, but I think a response to that is the main crops are engineered right now, corn and soybeans and cotton, are actually used a

lot in international commerce and are submitted--if this is only something used within the U.S., then that could be a different story.

    DR. QUALSET:  What I'm thinking is that there are people considering doing modifications to minor crops that may not ever get into the export stream, and they can't afford to go through all of this for a crop that will be sold to small farmers, for example.

    CHAIRMAN BUSTA:  Dr. Fedoroff.

    DR. FEDOROFF:  Nina Fedoroff.  I guess my question is, could you say there's data from the literature that would suggest that this information that you think should be made mandatory is predictive of--is useful in predicting unintended consequences that affect food quality?

    DR. HANSON:  I can get back to you on that.  There is--all I can say is that there was a lot of data that was talked about at these Codex meetings, and part of the problem is you have to know what you're dealing with before you can start to figure out what the safety implications are,

right?  And so, with the unintended effects, since that's actually a new field, and there was a huge discussion at Codex.  There's quite a number of paragraphs on that.  They're talking about these metabolomics and the use of genome arrays.  And I think that's useful, but I agree with the other scientists here.  The basic problem is how do you take, once you've identified all those differences, how do you then figure out what the safety implications of them are.  But before you can figure them out, you have to know what they are.

    CHAIRMAN BUSTA:  Dr.

    DR. FEDOROFF:  Yeah, but my question to you was how does accumulating all of these sequences and methylation patterns help you identify what the safety--that the food quality implications are?

    DR. HANSON:  Well, I can point to studies in the scientific literature with yeast and actually with tobacco where there have been unexpected effects that have led to toxins that were not previously present in the plants or to

things that have an--would have an adverse effect on DNA or other things, I mean.

    DR. FEDOROFF:  That's what I'm asking for.  Could you cite those references?

    DR. HANSON:  Yeah, I can get those.  One of them is Enos and Eurata.  I mean, we can talk afterwards.  I mean, I do have a list of those various studies that I can get to you--

    DR. FEDOROFF:  Please do.

    DR. HANSON:  And I will submit them.

    CHAIRMAN BUSTA:  Dr. Gurian?

    DR. GURIAN-SHERMAN:  Yeah, I guess one issue in terms of--

    CHAIRMAN BUSTA:  Introduce yourself.  No, introduce yourself.

    DR. GURIAN-SHERMAN:  Oh, I'm sorry.  Doug Gurian-Sherman.  I think the economic issues kind of go beyond, you know, what we're supposed to be talking about here, and I don't think we're qualified to really even talk about them, because there's--you know, we could get into all kinds of sidetracking to discuss those.  For instance, you

know, for pesticides, where there's a minor crop issue to getting pesticides for minor crops comparable to this with biotech, there's a set-up system that is not as effective as it could be but could be stronger called IO4 that probably a lot of your are familiar with to help small companies and minor crops get through the system.  So I think we're just getting into areas that are way beyond what we need to be talking about here, which is the safety issue.