1 
 
                 DEPARTMENT OF HEALTH AND HUMAN SERVICES 
 
                       FOOD AND DRUG ADMINISTRATION 
 
               CENTER FOR FOOD SAFETY AND APPLIED NUTRITION 

 

 
 
                  FOOD BIOTECHNOLOGY SUBCOMMITTEE (FBS) 
 
                                  of the 
 
                         FOOD ADVISORY COMMITTEE 

 

                         Tuesday, August 13, 2002 
 
                                9:00 a.m. 

 

 

 
                     Harvey W. Wiley Federal Building 
                        5100 Paint Branch Parkway 
                       College Park, Maryland 20740 

 
                                                                  2 
 
       PARTICIPANTS 
 
       Acting Chair, Edward N. Brandt, Jr., M.D., Ph.D. 
       Executive Secretary, Dr. Margaret Cole 
 
       MEMBERS 
 
       Fred McDaniel Atkins, M.D. 
       Bob B. Buchanan, Ph.D. 
       Francis Fredrick Busta, Ph.D. 
       Anne R. Kapuscinski, Ph.D. 
 
       TEMPORARY VOTING MEMBERS 
 
       Jonathan Arias, Ph.D. 
       Douglas Gurian-Sherman, Ph.D. 
       Samuel Lehrer, Ph.D. 
 
       INDUSTRY SPECIAL LIAISON 
 
       James Astwood, Ph.D. 
 
       GUEST SPEAKERS 
 
       Paul R. Mayers 
       Dean Metcalfe, M.D. 
       Michael Pariza, Ph.D. 

 
                                                                  3 
 
                             C O N T E N T S 
 
       Welcome and Introductions 
                 Dr. Edward Brandt                                4 
 
       Conflict of Interest Statement 
                 Dr. Margaret Cole                                8 
 
       Overview of CFSAN's Office of Food Additive Safety 
                 Dr. Alan Rulis                                  11 
 
       Charge and Questions 
                 Mr. Robert Lake                                 25 
 
       Basic Food Allergy Background 
                 Dr. Dean Metcalfe                               37 
 
       Questions of Clarification                                68 
 
       Safety Assessment of Enzymes and Protein 
       Ingredients 
       in Foods 
                 Dr. Michael Pariza                             101 
 
       Questions of Clarification                               125 
 
       FDA Food Biotechnology Policy and Current Approach 
       to Allergenicity 
                 Dr. James Maryanski                            127 
 
       Questions of Clarification                               166 
 
       Codex Draft Annex on the Assessment 
       of Possible Allergenicity 
                 Dr. Paul Mayers                                178 
 
       Questions of Clarification                               198 

 
                                                                  4 
 
   1                      P R O C E E D I N G S 
 
   2                    Welcome and Introductions 
 
   3             DR. BRANDT:  Good morning and to those of 
 
   4   you in the auditorium, we are glad you are here. 
 
   5   We have a busy day.  There are several 
 
   6   announcements and then we will go around and let 
 
   7   everybody introduce themselves. 
 
   8             First, tomorrow, we will start at 8:30 
 
   9   instead of 9:00.  The Public Comment period will be 
 
  10   moved to 9:45 a.m. tomorrow. 
 
  11             So we can introduce ourselves so everybody 
 
  12   in the audience will know, I'm Ed Brown.  I am the 
 
  13   temporary chair, called back to active duty after 
 
  14   having been retired.  I am an old professor at the 
 
  15   University of Oklahoma Health Science Center. 
 
  16             DR. ASTWOOD:  I am Jim Astwood.  I manage 
 
  17   the Product Safety Center at Monsanto Company.  I 
 
  18   am the industry representative to this 
 
  19   subcommittee. 
 
  20             DR. LEHRER:  I am Sam Lehrer.  I am at 
 
  21   Tulane University in New Orleans.  I am in the 
 
  22   Section of Allergy, Rheumatology and Clinical 
 
  23   Immunology. 
 
  24             DR. KAPUSCINSKI:  I am Anne Kapuscinski. 
 
  25   I am at the University of Minnesota.  My home 

 
                                                                  5 
 
   1   department is Fisheries, Wildlife and Conservation 
 
   2   Biology.  I also direct Institute for Social, 
 
   3   Economic and Ecological Sustainability.  I have 
 
   4   served on a number of other federal advisory 
 
   5   committees, mostly the USDA, on biotech mostly 
 
   6   focussing on biosafety issues.  I currently also 
 
   7   serve on the Global Environmental Facilities 
 
   8   Scientific and Technical Advisory Panel in the area 
 
   9   of biosafety. 
 
  10             DR. BUSTA:  I am Frank Busta from the 
 
  11   University of Minnesota, Professor Emeritus in the 
 
  12   Department of Food Science and Nutrition.  I am on 
 
  13   the general advisory committee for FDA. 
 
  14             DR. ATKINS:  I am Dan Atkins.  I am an 
 
  15   allergist with an interest in adverse reactions to 
 
  16   foods.  I am at the National Jewish Medical and 
 
  17   Research Center in Denver. 
 
  18             DR. ARIAS:  I am Jonathan Arias.  I am a 
 
  19   plant molecular biologist in the faculty of the 
 
  20   Center for Agricultural Biotechnology at the 
 
  21   University of Maryland Biotech Institute. 
 
  22             DR. GURIAN-SHERMAN:  Doug Gurian-Sherman. 
 
  23   I am the Science Director of the Biotechnology 
 
  24   Project at Center for Science in the Public 
 
  25   Interest. 

 
                                                                  6 
 
   1             DR. BUCHANAN:  Bob Buchanan, University of 
 
   2   California at Berkeley, Department of Plant and 
 
   3   Microbial Biology.  I am a plant biochemist. 
 
   4             DR. COLE:  I am Margaret Cole, Food and 
 
   5   Drug Administration. 
 
   6             DR. BRANDT:  And the one that is going to 
 
   7   run our lives for today and tomorrow, at least.  If 
 
   8   you have any questions about what is going on, ask 
 
   9   her.  Don't ask me, preferably.  Now, back here, 
 
  10   are all these FDA'ers.  Stand up and be recognized. 
 
  11             MS. GLEW:  I am Jeannette Glew.  I'm with 
 
  12   the Office of Food Additive Safety, Center for Food 
 
  13   Safety and Applied Nutrition.  I supervise and 
 
  14   evaluate biotech submissions. 
 
  15             DR. MARYANSKI:  I am Jim Maryanski.  I am 
 
  16   with our Office of Policy and Regulation.  I help 
 
  17   put together our biotechnology policy. 
 
  18             MR. LAKE:  I am Bob Lake.  I am the 
 
  19   Director of Policy and Regulations here at the 
 
  20   Center. 
 
  21             DR. BRANDT:  And now we have a interloper 
 
  22   from the NIH. 
 
  23             DR. METCALFE:  I'm Dean Metcalfe, Chief of 
 
  24   the Laboratory of Allergic Disease, NIH.  I have a 
 
  25   long-term interest in adverse reactions to foods. 

 
                                                                  7 
 
   1             DR. RULIS:  I am Alan Rulis.  I am the 
 
   2   Director of Food Additive Safety in this Center. 
 
   3             MS. AINSWORTH-RAY:  Hello.  I am Karen 
 
   4   Ainsworth Ray.  I am a press officer here.  Is a 
 
   5   member of the periodical press sitting back here? 
 
   6   Someone signed in periodical press.   Okay. 
 
   7             MS. KRETSER:  I am Allison Kretser.  I am 
 
   8   with the Grocery Manufacturers of America.  I am 
 
   9   the Director of Scientific and Nutrition Policy. 
 
  10             DR. PARIZA:  I am Mike Pariza.  I am the 
 
  11   Director of the Food Research Institute at the 
 
  12   University of Wisconsin, Madison. 
 
  13             MR. HINTON:  I am Dennis Hinton.  I am 
 
  14   with the Office of Applied Research and Safety 
 
  15   Assessment.  We have been doing research in 
 
  16   immunotoxicology for over twenty-four years for the 
 
  17   Center for Food Safety.  We are currently working 
 
  18   on food animal models. 
 
  19             MS. FU:  My name is Gigi Fu.  I am with 
 
  20   the FDA Office of Dairy and Food Allergy.  I am a 
 
  21   research scientist working on determining the 
 
  22   severity of allergens and other food proteins. 
 
  23             MR. GENDEL:  I am Steve Gendel.  I am 
 
  24   Chief of the Biotechnology Studies Branch of CFSAN. 
 
  25             MS. MacINTOSH:  I am another interloper.  

 
                                                                  8 
 
   1   I am Sue MacIntosh from Bayer Crop Science.  I am 
 
   2   the Director of Regulatory Affairs and Regulatory 
 
   3   Science in the Americas.  But I am here 
 
   4   particularly to give comments on behalf of HESI 
 
   5   because of the Protein Allergenicity Technology 
 
   6   Subcommittee. 
 
   7             DR. BRANDT:  Dr. Cole? 
 
   8                  Conflict of Interest Statement 
 
   9             DR. COLE:  As I mentioned, I am Margaret 
 
  10   Cole, Executive Secretary for the Food 
 
  11   Biotechnology Subcommittee of the Food Advisory 
 
  12   Committee. 
 
  13             First, I  would like to read into the 
 
  14   record the appointment of our temporary voting 
 
  15   members.  It reads, "By the authority granted under 
 
  16   the Food Advisory Committee charter, I appoint Dr. 
 
  17   Jonathan Arias and Dr. Douglas Gurian-Sherman as 
 
  18   temporary voting members of the Food Biotechnology 
 
  19   Subcommittee of the Food Advisory Committee for the 
 
  20   August 13 through 14, 2002 meeting on food 
 
  21   biotechnology," signed, Joseph A. Levitt, Director, 
 
  22   Center for Food Safety and Applied Nutrition, U.S. 
 
  23   Food and Drug Administration. 
 
  24             Dr. Samuel Lehrer, as Chairman of the 
 
  25   Committee for Allergenic Products in the Center for 

 
                                                                  9 
 
   1   Biologics Evaluation and Research, is appointed to 
 
   2   serve as a temporary voting member for this meeting 
 
   3   by the authority of Linda Skledani, Senior 
 
   4   Associate Commissioner for External Relations, U.S. 
 
   5   Food and Drug Administration. 
 
   6             The following announcement addresses 
 
   7   conflict-of-interest issues associated with this 
 
   8   meeting and is made part of the public record to 
 
   9   preclude even the appearance of a conflict of 
 
  10   interest at this meeting.  All subcommittee members 
 
  11   and temporary voting members have been screened for 
 
  12   financial conflicts of interest. 
 
  13             Based on the agenda made available, it has 
 
  14   been determined that the subcommittee will be 
 
  15   addressing general matters only.  The general 
 
  16   nature of the matters to be discussed by the 
 
  17   subcommittee will not have a unique or distinct 
 
  18   effect on any of the members' personal or imputed 
 
  19   financial interests.  However, the following 
 
  20   interests are being disclosed so the public can 
 
  21   evaluate any comments made by meeting participants. 
 
  22             Dr. Frank Busta has been granted a waiver 
 
  23   because he serves as a consultant to the food 
 
  24   industry on issues not related to the topic of this 
 
  25   meeting.  Dr. Samuel Lehrer has been granted a 

 
                                                                 10 
 
   1   waiver because he owns stock in affected firms and 
 
   2   holds various research grants. 
 
   3             We have asked all our guest speakers to 
 
   4   complete a financial-interest and professional-relationship 
 
   5   certification for guests and guest 
 
   6   speakers to identify any potential conflicts of 
 
   7   interest.  Dr. Michael Pariza has a financial 
 
   8   interest related to food-ingredient companies. 
 
   9             We would like to note for the record that 
 
  10   Dr. James Astwood is participating in this meeting 
 
  11   as a nonvoting industry special liaison acting on 
 
  12   behalf of regulated industry.  As such, he has not 
 
  13   been screened for any conflicts of interest. 
 
  14             In the event the discussions involve 
 
  15   specific products or specific firms for which FDA 
 
  16   participants have a financial interest, the 
 
  17   participants are aware of the need to exclude 
 
  18   themselves from such involvement and their 
 
  19   exclusion will be noted for the record. 
 
  20             This meeting is being transcribed.  When 
 
  21   we reach the discussion portion of the meeting, 
 
  22   please use your microphone and clearly identify 
 
  23   yourself before speaking. 
 
  24             With that, I will turn the meeting back to 
 
  25   Dr. Brandt. 

 
                                                                 11 
 
   1             DR. BRANDT:  I notice he didn't appoint 
 
   2   me.  Anyway, I am here for whatever reason. 
 
   3             DR. LEHRER:  Could I comment on that one 
 
   4   point? 
 
   5             DR. BRANDT:  Yes. 
 
   6             DR. LEHRER:  To my knowledge, I don't own 
 
   7   any stock in any companies that are affected by 
 
   8   this.  All I said was that I had TIAA Kreff and 
 
   9   retirement funds and also mutual funds.  I really 
 
  10   don't have any idea what they own.  I am afraid to 
 
  11   know what they own, actually.  But, in any event, 
 
  12   just in terms of full disclosure, I would imagine 
 
  13   that they own some pharmaceutical companies.  I 
 
  14   have no idea. 
 
  15             But, in terms of my personally owned stock 
 
  16   in any of these companies, I do not. 
 
  17             DR. BRANDT:  Any other statements?  Any 
 
  18   questions? 
 
  19             I want to alert the speakers that we are 
 
  20   sitting up here with a timer.  You have been 
 
  21   allotted certain amounts of time at the end of 
 
  22   which the gavel comes down, whether you are in the 
 
  23   middle of a word.  So, just be prepared. 
 
  24             Dr. Rulis? 
 
  25        Overview of CFSAN' Office of Food Additive Safety 

 
                                                                 12 
 
   1             DR. RULIS:  Good morning. 
 
   2             [Slide.] 
 
   3             I am Alan Rulis.  I am Director of the 
 
   4   Office of Food Additive Safety in the Center for 
 
   5   Food Safety and Applied Nutrition.  My task this 
 
   6   morning, in just a few moments, is to provide a bit 
 
   7   of context for this meeting to point out that the 
 
   8   work that this center does in regard to reviewing 
 
   9   consultations, conducting consultations, with 
 
  10   industry about new plant varieties that have been 
 
  11   altered by recombinant and DNA biotechnology are 
 
  12   actually conducted in the context of the Food 
 
  13   Additive Safety. 
 
  14             So I want to tell you a little bit about 
 
  15   that office so you know something about its makeup 
 
  16   and its history and that will help you, I think, as 
 
  17   we move forward with your discussions. 
 
  18             [Slide.] 
 
  19             Just to remind you that the Federal 
 
  20   Register document that announced this meeting--the 
 
  21   purpose of this meeting is to discuss science-based 
 
  22   approaches to assessing whether new proteins and 
 
  23   bioengineered foods are likely to cause allergic 
 
  24   reactions in some individuals in order to assist 
 
  25   FDA in developing draft guidance for industry. 

 
                                                                 13 
 
   1             [Slide.] 
 
   2             The Office of Food Additive Safety is laid 
 
   3   out like this.  I will take you through it a little 
 
   4   bit so you will understand some of the makeup of 
 
   5   it.  This office is principally comprised of four 
 
   6   divisions.  You can see them across here.  The 
 
   7   historical roots of this office come out of this 
 
   8   division, actually, the Division of Petition 
 
   9   Review.  It turns out that, in 1958, when the 
 
  10   Federal Food Drug and Cosmetic Act was amended to 
 
  11   require premarket approval of new food additives, 
 
  12   FDA had to pull together a cadre of scientists who 
 
  13   could evaluate data submitted to the agency by 
 
  14   industry for the purpose of getting FDA approval 
 
  15   for new food additives. 
 
  16             This division, historically, has had 
 
  17   within it scientists of various backgrounds in 
 
  18   order to do those kinds of reviews. 
 
  19             Actually, the same basic structure occurs 
 
  20   in all divisions of this office, but let me just 
 
  21   explain this one and then I will clone that, so to 
 
  22   speak, into these other divisions.  This division 
 
  23   has within it three types of individuals; chemists 
 
  24   who look at information about the chemical identity 
 
  25   of the substances being added to food, the amounts 

 
                                                                 14 
 
   1   that people are likely to eat, information about 
 
   2   the specifications and purity of those substances. 
 
   3             So we are really looking at the question 
 
   4   of what is the substance and what is the human 
 
   5   exposure to it.  We also have toxicologists who 
 
   6   evaluate, in this case, in this division, mostly 
 
   7   animal feeding studies, traditional short-term of 
 
   8   chronic feeding studies in animals, to look at the 
 
   9   biological effects of food ingredients in living 
 
  10   systems. 
 
  11             We also have a group of people who, in 
 
  12   this case, we have called them regulatory groups, 
 
  13   that are really, in government jargon, consumer-safety 
 
  14   officers.  They are scientists in their own 
 
  15   right.  They almost all have Ph.D.s in various 
 
  16   fields and they are basically project officers. 
 
  17   Their job is to manage the evaluation of petitions 
 
  18   for new food additives, make sure that all the 
 
  19   correct questions have been asked and all the 
 
  20   correct questions have been answered and that there 
 
  21   is an administrative record backing up all of the 
 
  22   work the agency does. 
 
  23             So there is a linear process that anybody 
 
  24   can go to and look at in writing that documents the 
 
  25   agency's work. 

 
                                                                 15 
 
   1             Across the office, the basic makeup of 
 
   2   these divisions in the same as that.  It is a 
 
   3   rather interdisciplinary group of these chemists, 
 
   4   these toxicologists and consumer-safety officers. 
 
   5   Almost everybody has a Ph.D. in one field or 
 
   6   another from chemistry to biology, microbiology, 
 
   7   molecular biology, pharmacology, toxicology. 
 
   8             The division of interest for your purposes 
 
   9   this morning is this one, called the Division of 
 
  10   Biotechnology and GRAS Notice Review.  It turns out 
 
  11   that, under the current statute, there is an 
 
  12   exemption to premarket approval for food additives 
 
  13   if the added substance is generally recognized as 
 
  14   safe.  So there is a class of substances we call 
 
  15   GRAS ingredients--GRAS is an acronym for generally 
 
  16   recognized as safe. 
 
  17             So they are evaluating not only whether a 
 
  18   substance is safe but also whether there is a 
 
  19   general recognition across the scientific community 
 
  20   of that safety.  In addition, they conduct the 
 
  21   consultations with industry for crop products that 
 
  22   are produced using recombinant DNA biotechnology, 
 
  23   and they are looking particularly at the human 
 
  24   health aspects of the injection of those crops, not 
 
  25   the crop characteristics because that is the 

 
                                                                 16 
 
   1   purview of APHIS and USDA and not the pesticidal 
 
   2   traits because that is the purview of the 
 
   3   Environmental Protection Agency. 
 
   4             I will just point out briefly these other 
 
   5   two divisions for your own edifications.  This one 
 
   6   is the Chemistry Research Division where there is 
 
   7   research done on both what we call indirect and 
 
   8   direct food additives--this is chemistry laboratory 
 
   9   research--and an environmental group that looks at 
 
  10   any National Environmental Policy Act 
 
  11   considerations that are associated with any of our 
 
  12   actions. 
 
  13             Down here is a division that is devoted to 
 
  14   food-contact substances.  Here we are looking at 
 
  15   materials that touch food but that are not 
 
  16   intentionally added to food.  But, under the 
 
  17   statute, we have purview over them. 
 
  18             [Slide.] 
 
  19             This, just for your interest, is a rather 
 
  20   busy slide that shows the various areas that come 
 
  21   within our purview.  You can see we have interest 
 
  22   in a whole host of different kinds of things that 
 
  23   end up in food or contacting food.  We look at 
 
  24   direct food additives, sweeteners, preservatives, 
 
  25   nutrients, fat substitutes and so forth. 

 
                                                                 17 
 
   1             Color additives in animal food, drugs and 
 
   2   cosmetics, medical devices.  That includes sutures 
 
   3   and contact lenses, strangely enough. 
 
   4             GRAS ingredients, enzymes, fibers, 
 
   5   proteins, lipids, sugars and so forth, going up to 
 
   6   the upper right.  Processing aids, antimicrobials, 
 
   7   defoamers, ion-exchange resins, radiation 
 
   8   equipment.  It turns out that the statute defines 
 
   9   the sources of irradiation for food as food 
 
  10   additives.  So we review these materials in order 
 
  11   to ascertain that food that has been irradiated for 
 
  12   microbial control is, in fact, safe. 
 
  13             Then we also, as I mentioned, just on that 
 
  14   last division, we look at food packaging and food-contact 
 
  15   substances.  So coatings, paper, metal, 
 
  16   recycled plastics, paper adhesives, and so forth. 
 
  17             And, in the lower left, foods and 
 
  18   ingredients produced using modern biotechnology. 
 
  19             [Slide.] 
 
  20             Within the office, as you recall, I 
 
  21   pointed out that the originating division was one 
 
  22   that conducted premarket safety evaluations for 
 
  23   food additives.  But, in reality, a lot of our work 
 
  24   is done under the rubric of notification these 
 
  25   days.  There are three notification programs 

 
                                                                 18 
 
   1   operating in the office.  There is the one that we 
 
   2   have instituted as a result of the 1997 proposal in 
 
   3   the Federal Register to review industry notices to 
 
   4   us that their product is generally recognized as 
 
   5   safe. 
 
   6             We have a notification process that 
 
   7   relates to food-contact substances and that comes 
 
   8   out of the 1997 Food and Drug Administration 
 
   9   Modernization Act.  Then, we also conduct 
 
  10   consultations on bioengineered foods. 
 
  11             [Slide.] 
 
  12             On the subject of bioengineered foods 
 
  13   consultations, you are probably aware that, in May 
 
  14   of 1992, the FDA published its policy on foods that 
 
  15   are in the marketplace and including those that are 
 
  16   the subject of recombinant DNA biotechnology and 
 
  17   we, as a result of that and after that, began 
 
  18   conducting consultations with industry since '94. 
 
  19   Up until the present moment, we have conducted 
 
  20   about 80, more than 80, of these consultations. 
 
  21   About 50 of them have actually completed the 
 
  22   process. 
 
  23             [Slide.] 
 
  24             If you go to our website and you double-click on 
 
  25   the hypertext link in our website, I will 

 
                                                                 19 
 
   1   try to simulate that here, what you will get is 
 
   2   this HTML screen.  This is a list of completed 
 
   3   consultations on bioengineered foods.  It, in fact, 
 
   4   explains what I just said about the '92 policy and 
 
   5   talks about the consultation process and delineates 
 
   6   the differences between what FDA does with these 
 
   7   types of foods and what the Animal, Plant, Health 
 
   8   and Inspection Service of USDA does and what EPA 
 
   9   does regarding pesticides, and then proceeds to 
 
  10   talk about the consultations that we conduct and 
 
  11   the information that is in this website. 
 
  12             There is a lot of it.  If you go to the 
 
  13   website, you will find that there is a listing that 
 
  14   contains the genetic modification.  The actual gene 
 
  15   or gene product is here.  The source organism, the 
 
  16   intended effect, the industry designation and then 
 
  17   hypertext links to FDA letters to the company and 
 
  18   in response to the consultation.  So you can find 
 
  19   all the information you need for completed 
 
  20   consultations on our website. 
 
  21             [Slide.] 
 
  22             Just to bring you up to date, you probably 
 
  23   are aware that, in 1999, the FDA held public 
 
  24   meetings around the country to discuss its current 
 
  25   consultation process.  It received comments.  In 

 
                                                                 20 
 
   1   January of 2001, we published, in the Federal 
 
   2   Register, a proposal for making these 
 
   3   notifications, these consultations with industry on 
 
   4   crops, mandatory.  We also made available some 
 
   5   draft guidance, a notice of availability of draft 
 
   6   guidance--that is, on the subject of voluntary 
 
   7   labeling. 
 
   8             To this point, we have received over 
 
   9   100,000 comments that are currently being reviewed. 
 
  10             So I think that is pretty much my spiel. 
 
  11   I just wanted to be sure that you saw the work with 
 
  12   this subcommittee within the context of the office. 
 
  13   I hope I have made that clear.  If there are any 
 
  14   questions, I would be happy to take them at this 
 
  15   time. 
 
  16             DR. BRANDT:  Questions. 
 
  17             DR. GURIAN-SHERMAN:  Doug Gurian-Sherman. 
 
  18   I would like some clarification, one, on the 
 
  19   premise of the meeting, itself.  You mentioned, in 
 
  20   the Federal Register Notice, that the purpose is to 
 
  21   determine or avoid--not your words--a protein 
 
  22   likely to cause allergenicity.  I guess I have a 
 
  23   question as to how that relates to the FFTCA's 
 
  24   standard of reasonable uncertainty of no harm.  It 
 
  25   would seem that you are flipping somewhat the 

 
                                                                 21 
 
   1   burden of proof in terms of the level of certainty 
 
   2   that you are looking for when you say that it 
 
   3   should be likely, or identified as likely, to be a 
 
   4   food allergen, that reasonable certainty of no harm 
 
   5   seems to suggest the opposite. 
 
   6             DR. RULIS:  Let me say this.  I purposely 
 
   7   did not launch into a discussion of our legal 
 
   8   framework because I think could take up a 
 
   9   tremendous amount of your time and it would be 
 
  10   probably be derailing the purpose of the meeting to 
 
  11   do so.  I think it is certainly something you may 
 
  12   want to discuss as you go forward, if it does 
 
  13   appear to be needed. 
 
  14             But I think it would probably not serve 
 
  15   purposes of this committee so well to get into the 
 
  16   legal questions.  I think the purview of this 
 
  17   committee is scientific, as I understand it, and I 
 
  18   am going to defer to Bob Lake momentarily to give 
 
  19   the charge and to talk about his view of what you 
 
  20   are here to do and put that in the context of 
 
  21   charge and questions eventually. 
 
  22             But my reading of the current charge and 
 
  23   questions to this subcommittee are really not legal 
 
  24   ones.  They are scientific ones.  We are looking 
 
  25   for your scientific input. 

 
                                                                 22 
 
   1             I would say, just in brief response to 
 
   2   your point, that we have had in place for a long 
 
   3   time premarket safety evaluate scheme for new food 
 
   4   additives that uses the reasonable certainty of no 
 
   5   harm standard.  That is in place and, for some 
 
   6   situations involving biotech foods, it is 
 
   7   conceivable that a protein would be introduced in 
 
   8   such a way that the appropriate modus operandi 
 
   9   would be to go through the premarket approval 
 
  10   scheme and use the reasonably certainty of no harm 
 
  11   standard. 
 
  12             But that has not been the case for the 
 
  13   vast majority of biotech foods that have come 
 
  14   before us.  In that context, we are looking more at 
 
  15   the food in the context of other foods.  The 
 
  16   question before us is as it as safe as its 
 
  17   counterpart food, as safe as is really more the 
 
  18   standard we are using there. 
 
  19             But we have open the possibility of using 
 
  20   the reasonable certainty of no harm standard.  I 
 
  21   think to get into a discussion of the interstices 
 
  22   of that standard probably would not serve us well 
 
  23   this morning. 
 
  24             DR. KAPUSCINSKI:  Anne Kapuscinski.  It 
 
  25   seems somewhat obvious what would constitute the 

 
                                                                 23 
 
   1   end of a consultation for biotech foods but I am 
 
   2   curious because you said that there are 80 since 
 
   3   1994 but 50 have been completed.  So what is the 
 
   4   difference between one that is completed and 
 
   5   uncompleted.  Why is there such a big difference? 
 
   6             DR. RULIS:  It may be that, at some point 
 
   7   in the consultation, we are asking for a package of 
 
   8   information to cover the corrections we might have. 
 
   9   If the company decides, at some point, that they 
 
  10   don't have the information that we are asking for, 
 
  11   they may decide to withdraw. 
 
  12             DR. KAPUSCINSKI:  So is the consultation 
 
  13   completed when either the FDA says, "This looks 
 
  14   fine; you can go forward with it," or the company 
 
  15   decides to withdraw and just doesn't want to do any 
 
  16   more consultation? 
 
  17             DR. RULIS:  We look at the package they 
 
  18   have come in with and ascertain whether we think 
 
  19   all the relevant questions have been answered to 
 
  20   our satisfaction, that they have dealt with all of 
 
  21   the necessary aspects of it.  If they have, in our 
 
  22   mind, then we will write them a letter that 
 
  23   basically says, "It is your responsibility to 
 
  24   market a safe product.  You have brought before us 
 
  25   your--you have laid out before us all the questions 

 
                                                                 24 
 
   1   that you have dealt with and your answers to them. 
 
   2   We have looked at them and have no further 
 
   3   questions at this point." 
 
   4             DR. KAPUSCINSKI:  Okay.  Thank you. 
 
   5             DR. BRANDT:  Any other questions? 
 
   6             DR. BUCHANAN:  I have one question.  This 
 
   7   is Bob Buchanan.  How many products do you see on 
 
   8   the horizon? 
 
   9             DR. RULIS:  I can tell you that, at the 
 
  10   moment, under the rubric of biotechnology, the 
 
  11   number has actually fallen off somewhat.  There was 
 
  12   an initial burst of several dozen and then, in 
 
  13   fact, if I could easily put this HTML screen back 
 
  14   up there, which I can't, I would show you that, in 
 
  15   2001, there were a couple and, in the Year 2000, 
 
  16   there were a couple.  Most of them were 1999 and 
 
  17   before. 
 
  18             So it struck up a bit.  But that is not 
 
  19   necessarily a prediction for the future in that I 
 
  20   know that there is a likelihood that there would be 
 
  21   some new developments on the horizon that would 
 
  22   bring more forward.  But, at the moment, we have 
 
  23   had a slight lull. 
 
  24             DR. BRANDT:  Mr. Lake is now going to tell 
 
  25   us what we have to do. 

 
                                                                 25 
 
   1                       Charge and Questions 
 
   2             MR. LAKE:  My name is, again, Bob Lake.  I 
 
   3   am the Director of Regulations and Policies for the 
 
   4   Center and, as such, represent Center management 
 
   5   for this meeting and, in that capacity, let me 
 
   6   first welcome all of you, to the Food and Drug 
 
   7   Administration, to the Center for Food Safety and 
 
   8   Applied Nutrition and to our new building in 
 
   9   College Park. 
 
  10             Biotechnology is, obviously, a very 
 
  11   important topic for a lot of reasons.  The issue of 
 
  12   allergenicity is also important across the board, 
 
  13   irrespective of biotechnology.  When you get the 
 
  14   two together, you have a particular set of very 
 
  15   interesting issues and it is very important.  It is 
 
  16   not new.  I expect that long after we are done 
 
  17   here, there will continue to be many discussions. 
 
  18             So I would like to, I think, first talk a 
 
  19   little bit about the context of this meeting, sort 
 
  20   of where it fits in and also a little bit about 
 
  21   what may happen in the future. 
 
  22             In the first place, just a little bit of 
 
  23   context, and you will hear a lot more about this, 
 
  24   but we had a Food Advisory Committee meeting back 
 
  25   in '94 dealing with the issue of allergenicity and 

 
                                                                 26 
 
   1   biotechnology.  So that sort of got us started. 
 
   2             We have, through the consultations that 
 
   3   Dr. Rulis was just talking about, gained some 
 
   4   experience that involves  our thinking on this 
 
   5   issue.  In addition to that, as you can well 
 
   6   imagine, this is seen as a very important topic 
 
   7   internationally and we have been actively 
 
   8   participating in an effort about a Codex 
 
   9   Alimentarius Commission to grapple with a number of 
 
  10   issues that relate to evaluating the safety of 
 
  11   bioengineered foods including allergenicity. 
 
  12             You will be hearing more about that as the 
 
  13   day goes on as well.  But we have been active 
 
  14   participants in that process. 
 
  15             We think we are at a place where it is 
 
  16   time for the Food and Drug Administration to put 
 
  17   down on paper, and make public, something we call 
 
  18   guidance.  This is a document that serves several 
 
  19   purposes, or will serve several purposes.  One, it 
 
  20   is, in part, guidance to our own people on how they 
 
  21   evaluate the information that is coming in.  It is 
 
  22   also guidance to the industry.  It tells them what 
 
  23   it is we are going to be looking for so that it is 
 
  24   guidance to them on what kind of work they need to 
 
  25   be doing. 

 
                                                                 27 
 
   1             It is also an articulation to the public 
 
   2   about what it is we are doing and why.  Under our 
 
   3   current procedures, we have to develop something 
 
   4   called draft guidance, publish it for public 
 
   5   comment and then come back with final guidance. 
 
   6             We think we are at a point where it is 
 
   7   time to begin the drafting of that guidance.  But, 
 
   8   before we do it, we would like to, in effect, 
 
   9   bounce some ideas off of this subcommittee.  So you 
 
  10   will getting a lot of information this afternoon 
 
  11   and tomorrow and then we will be asking you to give 
 
  12   us some feedback. 
 
  13             We will be using that feedback to draft, 
 
  14   do what I will call a preliminary draft, of 
 
  15   guidance.  We will then be getting back to you at a 
 
  16   future meeting to actually have you look at our 
 
  17   preliminary draft before we go public with it.  So, 
 
  18   one of the things I want to leave with you is we 
 
  19   are not going to ask you to solve the whole problem 
 
  20   is this meeting and, indeed, I think as the science 
 
  21   develops, as we get different kinds of submissions 
 
  22   in the figure, the policy will have to evolve. 
 
  23             But, what we are  for primarly now is to 
 
  24   articulate something that is based on the 
 
  25   experience that we have had with the kinds of 

 
                                                                 28 
 
   1   submissions we have been getting and that we expect 
 
   2   to get for the next few years. 
 
   3             We will, if it hasn't already been handed 
 
   4   out, be handing out shortly a copy of the charge 
 
   5   and questions.  You can read that at your leisure 
 
   6   and there will also be an opportunity, before you 
 
   7   begin your deliberations tomorrow, to look at that 
 
   8   in some detail.  So I am not going to spend a lot 
 
   9   of time on that. 
 
  10             I simply wanted to give you the idea that 
 
  11   what we are really asking you to do is to consider 
 
  12   the various pieces of information that you are 
 
  13   going to hear in conjunction with your own 
 
  14   knowledge and to give us some feedback that will 
 
  15   assist us in putting together some draft guidance, 
 
  16   or some preliminary draft that we will then show to 
 
  17   you at a future meeting before we go public. 
 
  18             At least, that is our current intention. 
 
  19   Also, as a part of what we are going to be asking 
 
  20   you, we would like you to spend a little bit of 
 
  21   time, to the extent that you can, identifying areas 
 
  22   where research is needed, either research that we 
 
  23   can do or others could do, that would put is in a 
 
  24   better position and, perhaps, help us to evolve a 
 
  25   better policy, a more definitive policy, for the 

 
                                                                 29 
 
   1   future. 
 
   2             So those are kind of the two big things. 
 
   3   What are kind of your thoughts on what we say now, 
 
   4   what kind of research we ought be doing and then, 
 
   5   to the extent that you can help us, because part of 
 
   6   our document is going to be an explanation to the 
 
   7   public what we are doing and how we do it.  If you 
 
   8   have got any ideas on how we can do that well and 
 
   9   in a way that the public can best understand, we 
 
  10   would appreciate your thoughts on that as well. 
 
  11             Having said that, and I think that is 
 
  12   probably enough to say before you actually have 
 
  13   heard very much of what you are going to hear, it 
 
  14   occurs to me that because this is the first meeting 
 
  15   of this committee, most of you are new to us and we 
 
  16   are certainly new to you.  So I guess I would like 
 
  17   to--I was going to ask the Chairman's permission to 
 
  18   do this, but since he is not here, I will take the 
 
  19   liberty of inviting any questions that you have 
 
  20   about this center, either our structure, our 
 
  21   philosophy, what it is we do, things that help you 
 
  22   understand why we have you here. 
 
  23             But, really, at this point questions not 
 
  24   about biotechnology or allergenicity because others 
 
  25   will talk to you more about that, but questions you 

 
                                                                 30 
 
   1   have about this place, this organization, who we 
 
   2   are. 
 
   3             So let me stop and invite your questions 
 
   4   on that. 
 
   5             DR. BUCHANAN:  Bob Buchanan, again.  How 
 
   6   much research do you do?  I really don't have a 
 
   7   feel for that. 
 
   8             MR. LAKE:  Research is a component of what 
 
   9   we do.  Quite frankly, it is not as large a 
 
  10   component as we would like.  Again, our budgets are 
 
  11   appropriated by Congress.  Our colleagues at NIH is 
 
  12   the place where most of the research as it relates 
 
  13   to the public health ought to be done, so we don't 
 
  14   get a whole lot of it here. 
 
  15             But we do some.  But a lot of the research 
 
  16   we do is focused on helping us to do the other part 
 
  17   of our job which is enforcement.  We make these 
 
  18   kinds of decisions, but we also have the day-to-day 
 
  19   enforcement responsibility.  That requires that we 
 
  20   have methods of analysis so we have a fairly large 
 
  21   effort devoted to that for all of the different 
 
  22   things that we are responsible for. 
 
  23             But, to the extent that we can, we do as 
 
  24   much research as we can do but it is limited.  Now, 
 
  25   you may also know that the University of Maryland 

 
                                                                 31 
 
   1   is within walking distance and we do, even before 
 
   2   we came out here, had created with them something 
 
   3   called GFSAN which is a collaborative research 
 
   4   activity. 
 
   5             We also have some other collaborative 
 
   6   efforts where we, in conjunction with other 
 
   7   academic institutions, try to get some leverage on 
 
   8   some research that is helpful.  But, the general 
 
   9   answer to your question--again, I have to confess, 
 
  10   I have never been in a laboratory except to visit. 
 
  11   That is not my background.  But it is something we 
 
  12   consider important. 
 
  13             DR. GURIAN-SHERMAN:  Doug Gurian-Sherman. 
 
  14   What kind of relationship do you have, let's say, 
 
  15   with NIH in terms of giving them input into what 
 
  16   kind of research would be done, I would imagine NIH 
 
  17   is more focused on basic research and your interest 
 
  18   is, in part, trying to get input that will help you 
 
  19   make regulatory decisions?  Do you have any formal 
 
  20   working relationship in terms of that? 
 
  21             MR. LAKE:  I actually don't know the 
 
  22   answer to that question.  Again, research is not 
 
  23   the area that I am involved in.  It is more policy 
 
  24   development and regulation.  But I know, in 
 
  25   general, our philosophy is to collaborate with 

 
                                                                 32 
 
   1   anybody we can collaborate with to get at the 
 
   2   information that will help us in making our 
 
   3   decisions. 
 
   4             Let me also comment on your previous 
 
   5   question.  I think, at least to some extent, in 
 
   6   some of the further discussion, there will be some 
 
   7   more description of--as we talk about how we go 
 
   8   about our current business that may help answer 
 
   9   your earlier question. 
 
  10             DR. BRANDT:  Other questions?  Yes, ma'am? 
 
  11             DR. KAPUSCINSKI:  I have a question about 
 
  12   how you really make operational coordination under 
 
  13   coordinated framework.  So I guess I am curious, 
 
  14   when an issue such as allergenicity comes up, if 
 
  15   there is a difference of opinion between FDA and, 
 
  16   let's say, EPA that was involving a crop that might 
 
  17   be producing a compound that has questions of 
 
  18   allergenicity but it is a crop that fits under 
 
  19   EPA's purview, how do you resolve the differences 
 
  20   and is there--even though I have studied all the 
 
  21   coordinated framework laws, it is never really 
 
  22   clear to me if there is one law that preempts 
 
  23   another or whether the agencies have some other 
 
  24   process for reaching the actual decision. 
 
  25             MR. LAKE:  A couple of comments around all 

 
                                                                 33 
 
   1   of that.  One of the challenges that all of the 
 
   2   agencies are grappling with is that the statutory 
 
   3   framework that we all are using did not contemplate 
 
   4   biotechnology. 
 
   5             So we are all making do with statutes that 
 
   6   already exist.  It is a challenge.  I mean, it is a 
 
   7   challenge, to be perfectly honest, as somebody who 
 
   8   has done this for a number of years, before, even 
 
   9   internally within a single center such as CFSAN. 
 
  10   When you reach out to other parts of the agency, it 
 
  11   is a bigger challenge and when you go to other 
 
  12   agencies is it still a bigger challenge yet.  But 
 
  13   it is very important.  We take that seriously. 
 
  14             I think we have not had the kind of 
 
  15   conflict that you are describing, those kinds of 
 
  16   differences of opinion.  I think largely the reason 
 
  17   for that is that the responsibilities, even though 
 
  18   it is a coordinated framework, if you look very 
 
  19   carefully, the responsibilities for each of the 
 
  20   agencies is distinctly different. 
 
  21             So, while we want it to mesh, each is 
 
  22   doing a separate piece.  For instance, APHIS has 
 
  23   the responsibility to oversee what is going on in 
 
  24   fetal trials, et cetera.  They do not make 
 
  25   judgments and don't even want to make judgments 

 
                                                                 34 
 
   1   about whether any of these foods, if eaten, would 
 
   2   be safe to the person who eats them.  That is not 
 
   3   their focus. 
 
   4             By the same token, we defer to them in 
 
   5   terms of their oversight of fetal trials and then 
 
   6   whether things are properly contained, et cetera. 
 
   7   There is more likely to be overlap between FDA and 
 
   8   EPA because we actually make similar kinds of 
 
   9   judgments. 
 
  10             But, actually, the division there is that 
 
  11   what they look at are pesticides that are 
 
  12   genetically engineered in food.  With regard to the 
 
  13   pesticide, itself, we defer entirely to EPA.  They 
 
  14   actually have a strong statutory framework for 
 
  15   pesticides.  So if they decide that a protein that 
 
  16   is genetically engineered to be a pesticide in corn 
 
  17   or soy or whatever, if they make a decision that it 
 
  18   is unsafe, we accept that because they do that 
 
  19   process. 
 
  20             What we look at--we look at two different 
 
  21   kinds of things with regard to those crops that are 
 
  22   genetically engineered to contain a pesticide.  As 
 
  23   I said, we defer to EPA on the thing that is the 
 
  24   pesticide in the crop.  What we look at are what 
 
  25   are the other changes that occur in that and is 

 
                                                                 35 
 
   1   there anything about those other changes that would 
 
   2   give us concern. 
 
   3             They, in turn, defer to us on those 
 
   4   questions.  There are, of course, other things that 
 
   5   come to us--again, I think you will hear some more 
 
   6   about them--that don't have anything to do with 
 
   7   pesticides.  So the food-safety question is 
 
   8   entirely one that we grapple with and that the 
 
   9   other agencies both defer to us. 
 
  10             At the same time, we do try to be sure 
 
  11   that are policies are consistent.  The most recent 
 
  12   example is the OSTP document that relates to low-level 
 
  13   presence, unexpected presence, of food things 
 
  14   in other foods.  Again, that was something that we, 
 
  15   in an interagency context, under the leadership of 
 
  16   OSTP, have been working on for quite some number of 
 
  17   months. 
 
  18             Hopefully, that gives you some answer to 
 
  19   that question.  Again, I think some of the later 
 
  20   presentations may touch on that a little bit more. 
 
  21             DR. BRANDT:  Very similar to resolving 
 
  22   differences between two departments in a college or 
 
  23   a university.  About the same thing. 
 
  24             Any other questions? 
 
  25             Thanks very much.  We have this document. 

 
                                                                 36 
 
   1             MR. LAKE:  You should have it. 
 
   2             DR. BRANDT:  Tomorrow afternoon, one of 
 
   3   the things that we will be talking about are the 
 
   4   three questions at the bottom of Page 1 and the top 
 
   5   of Page 2.  So you might start thinking about 
 
   6   those.  They are not particularly in order of 
 
   7   importance, but, certainly, the first two are the 
 
   8   ones that they need a lot of help on.  The last 
 
   9   one, if you have thoughts, why that will be great. 
 
  10             MR. LAKE:  Absolutely.  Again, as I step 
 
  11   down, let me again express my appreciation to all 
 
  12   of you for taking time out of your busy schedules 
 
  13   to be with us during these two days.  Again, this 
 
  14   is the beginning, hopefully of a series of 
 
  15   meetings, at least one of them being on this topic 
 
  16   but then other meetings down the road as well. 
 
  17             I will be here throughout the day.  If any 
 
  18   of you has any, again, organizational kinds of 
 
  19   questions or questions about this place, feel free 
 
  20   to talk to me.  I think it is okay to do that. 
 
  21             DR. BRANDT:  It is up to you. 
 
  22             MR. LAKE:  I will try to answer those 
 
  23   questions.  The other thing I am involved in is 
 
  24   implementation of the new bioterrorism law.  I have 
 
  25   a meeting at the department tomorrow that I must 

 
                                                                 37 
 
   1   attend but I will be back for tomorrow afternoon 
 
   2   for the deliberations. 
 
   3             Thank you very much. 
 
   4             DR. BRANDT:  Thank you. 
 
   5             We will now take a break for approximately 
 
   6   twenty minutes.  Dr. Metcalfe, you will be prepared 
 
   7   to go about ten minutes ahead of time.  That 
 
   8   doesn't give you ten extra minutes, however. 
 
   9             [Recess.] 
 
  10             DR. BRANDT:  We are ready to begin.  Dr. 
 
  11   Metcalfe from the National Institutes of Health is 
 
  12   going to give us his presentation on basic food 
 
  13   allergy background. 
 
  14                  Basic Food Allergy Background 
 
  15             DR. METCALFE:  Thank you. 
 
  16             [Slide.] 
 
  17             As I was just kind of talking to Dan 
 
  18   before I started the lecture, this is a nuts-and-bolts food- 
 
  19   allergy lecture.  A couple of committee 
 
  20   members, maybe more than two, could take over this. 
 
  21   I can show them how to advance the slides.  They 
 
  22   could give this. 
 
  23             I actually have a lecture on how the 
 
  24   decision-tree thing, and everything else--I was 
 
  25   hoping to be able to do that because then I 

 
                                                                 38 
 
   1   wouldn't have to put all these slides on power 
 
   2   point.  But Jim is going to cover that and I am 
 
   3   going to cover the nuts-and-bolts of food allergy. 
 
   4   This power-point presentation is really off of 
 
   5   slides that go back a long time because, in terms 
 
   6   of the basics of food allergy, we haven't seen a 
 
   7   lot of new things to put into this lecture. 
 
   8             I will try to update you on some of the 
 
   9   classification and things of that sort, but it is a 
 
  10   fairly direct lecture and hopefully, it will be 
 
  11   helpful to those of you who don't think about 
 
  12   allergenicity. 
 
  13             I am going to try to make a few comments 
 
  14   about things that you--I am anticipating some 
 
  15   questions as we go through on certain areas of this 
 
  16   and then, hopefully, I will have enough time to 
 
  17   take questions at the end. 
 
  18             [Slide.] 
 
  19             Now, the standard definitions, two 
 
  20   standard definitions, that we work under in this 
 
  21   field are here; food intolerance is really anything 
 
  22   abnormal that you experience with a food that 
 
  23   somebody else does not.  That is everything from a 
 
  24   lactase deficiency, meaning lactose intolerance, to 
 
  25   a true allergic reaction to a food. 

 
                                                                 39 
 
   1             We generally use the word food 
 
   2   hypersensitivity as an abnormal reaction resulting 
 
   3   from a heightened immunologic response to 
 
   4   glycoprotein components within foods.  We could 
 
   5   specify that a little bit more if we talked about 
 
   6   food allergy.  Generally scientifically, we would 
 
   7   be moving toward an IgE mechanism.  To the lay 
 
   8   public, there is not much difference in these 
 
   9   definitions. 
 
  10             [Slide.] 
 
  11             One way to look at the spectrum of 
 
  12   reactions to foods on an immunologic basis that not 
 
  13   everybody experiences is this kind of diagram. 
 
  14   Some of the stuff that I am going to show you is 
 
  15   from an ILSI-sponsored classification approach to 
 
  16   disease, particularly with infants, that can be 
 
  17   extended to adults that was published a couple of 
 
  18   years ago. 
 
  19             So you can kind of go from an IgE to an 
 
  20   non-IgE mechanism in these reactions.  Most of 
 
  21   those that will concern this committee will be IgE 
 
  22   based.  Those are the classic immediate 
 
  23   hypersensitivity reactions, hives, asthma, 
 
  24   gastrointestinal problems and anaphylaxis after 
 
  25   exposure to a food in an immediate sense, within a 

 
                                                                 40 
 
   1   few minutes. 
 
   2             Oral allergy syndrome is an immediate 
 
   3   reaction largely confined to the mouth.  We will 
 
   4   come back to that.  Atopic dermatitis is listed in 
 
   5   the middle because it has an IgE basis but other 
 
   6   things in that person experiencing that reaction 
 
   7   move toward eczema.  But what of what is known 
 
   8   about IgE reaction, particularly published by Hugh 
 
   9   Sampson, has been actually in challenges of 
 
  10   children with atopic dermatitis. 
 
  11             Then there are other diseases such as 
 
  12   allergic eosinophilic esophagitis, gastritis and 
 
  13   gastroenterocolitis that have a strong IgE 
 
  14   component.  Clearly, there is something different 
 
  15   going on that we don't understand from a strict IgE 
 
  16   reaction. 
 
  17             Then there are non-IgE reactions, 
 
  18   virtually exclusively observed in infants and 
 
  19   children, dietary protein enterocolitis, proctitis, 
 
  20   enteropathy and then celiac disease which you will 
 
  21   have to think about, but, since we have a better 
 
  22   idea of the active components, that is an easier 
 
  23   problem to handle, we think, in terms of moving new 
 
  24   proteins into foods.  You would probably not move 
 
  25   the proteins responsible for celiac disease.  That 

 
                                                                 41 
 
   1   is a more obvious question. 
 
   2             [Slide.] 
 
   3             So let's start out with the typical 
 
   4   genesis of an IgE-mediated reaction, the immediate 
 
   5   responses that we are most concerned about.  The 
 
   6   steps are well described.  You have to have some 
 
   7   exposure to the antigen at some point in your life 
 
   8   and then TH2 cells, that is kind of a TH2 
 
   9   phenotype, an allergic phenotype, cells that tend 
 
  10   to make things like IL4 and IL5 rather than gamma 
 
  11   interferon, collaborate with antigen-processing and 
 
  12   these cells to make IgE which then becomes fixed to 
 
  13   high-affinity receptors on the mast cell and, for 
 
  14   that matter, the basophile surface. 
 
  15             Then, on re-exposure of antigen, there is 
 
  16   release of mediators.  That is the allergic 
 
  17   response.  It has been an amazingly difficult 
 
  18   response to fine-tune details about or, for that 
 
  19   matter, to thwart.  There is no, for example, 
 
  20   specific drug known that specifically inhibits 
 
  21   mast-cell degranulation and the regulation of IgE 
 
  22   synthesis has been very difficult although some 
 
  23   approach is now talked about such as anti-IgE 
 
  24   removal from the system so you could have some 
 
  25   promise. 

 
                                                                 42 
 
   1             Now, if you talk about the amount of 
 
   2   antigen required to sensitize, which comes up in 
 
   3   these committees all the time, the answer is 
 
   4   probably it doesn't take very much if somebody is 
 
   5   of the TH2 phenotype.  You could show that in 
 
   6   animal models where you can dose-response 
 
   7   sensitization and, if you use intraperitoneal or 
 
   8   intramuscular, then it is easier to sensitize.  If 
 
   9   you use certain adjuvants like alum, you could get 
 
  10   more IgE. 
 
  11             Then, if you use TH2-responsive animals, 
 
  12   in mice and rats, for instance, it is easier to 
 
  13   sensitize.  So you put all that together and what 
 
  14   that means is that the ability to sensitize to 
 
  15   certain amount of allergen and the threshold is 
 
  16   going to vary on the individual, vary on the 
 
  17   protein, vary on any adjuvant effects. 
 
  18             The end of that is that it has not been 
 
  19   possible, really, to set a level below which you 
 
  20   can assure that someone will be sensitized.  In an 
 
  21   extreme case, somebody with the TH2 phenotype, 
 
  22   highly allergic, genetically predisposed to react 
 
  23   to certain antigens with breaks in the mucosa or 
 
  24   inflammatory valves or wherever you want, would be 
 
  25   sensitized whereas if would never happen in anybody 

 
                                                                 43 
 
   1   else. 
 
   2             In terms of the amount of antigen to 
 
   3   elicit a response, it is a dose response. 
 
   4   Generally, in food allergy, it takes large amounts. 
 
   5   It take milligrams to grams.  But there are 
 
   6   exceptions.  When you look at those exceptions, 
 
   7   like Steve Taylor has done through the Food Allergy 
 
   8   Research Program and some of the industry-sponsored 
 
   9   things he does, you start looking at thresholds in 
 
  10   a feeding, particularly infants or young 
 
  11   individuals, of about a microgram.  But that is 
 
  12   very rare.  You can count those cases. 
 
  13             But if you try to set a threshold and you 
 
  14   get down to that microgram level, in reality, what 
 
  15   is going to protect most things in this system and 
 
  16   most people in this whole system is that a few 
 
  17   things are allergenic and it is awfully hard to 
 
  18   sensitize and it is awfully hard to precipitate a 
 
  19   reaction. 
 
  20             But when you try to set numbers for 
 
  21   thresholds, then you run across huge problems.  So 
 
  22   that is IgE-synthesis mechanism and a few comments 
 
  23   about how difficult it is to set regulatory 
 
  24   guidelines based upon what we know about it. 
 
  25             [Slide.] 

 
                                                                 44 
 
   1             Now, prevalence data.  This is typical 
 
   2   prevalence data.  It is more than existed ten years 
 
   3   ago.  These are a number of studies that have been 
 
   4   published.  I picked them out fairly at random. 
 
   5   Here is one, food Allergy intolerance where they 
 
   6   sampled and challenged of 2.4 percent.  This would 
 
   7   include a lot of things that are nonallergic. 
 
   8   1.3 food-allergy adults, by Woods et al.  This is 
 
   9   very typical of what you see in the literature. 
 
  10             1.1 percent food allergy in children and 
 
  11   adults together to tree nut and peanut.  This is a 
 
  12   random digit-dial survey specifically limited to 
 
  13   these two substances.  So intolerance in infants 
 
  14   and children at 8 percent, if you look within that, 
 
  15   about 2 to 3 percent are IgE-mediate.  Milk 
 
  16   intolerance, the first three years, 2.5 percent. 
 
  17             What does all of this mean?  It means 
 
  18   generally that in children, IgE reactions often 
 
  19   transient, can be seen in 2 to 4 percent of 
 
  20   children, somewhere in that ball park, and, in 
 
  21   adults, it is somewhere around 1 percent.  A lot of 
 
  22   those reactions can be handled. 
 
  23             But, if you look at the total numbers, 
 
  24   now, you are talking about in the United States 
 
  25   somewhere in the neighborhood of 40 or 50 million 

 
                                                                 45 
 
   1   people, potentially, that could be affected through 
 
   2   these IgE-definitive mechanisms.  so it is not a 
 
   3   small number of people.  When you look at the 
 
   4   percent of the total population, it looks small 
 
   5   but, in aggregate numbers, it is large. 
 
   6             [Slide.] 
 
   7             Now most food allergens, as you well know, 
 
   8   are glycoproteins.  They tend to be 20,000 to 
 
   9   40,000 molecular weight.  These are rough 
 
  10   guidelines.  They tend to be protease resistant. 
 
  11   They tend to be acid resistant.  Let me just speak 
 
  12   to that for just a moment. 
 
  13             This is usually, at least over the last 
 
  14   ten years, have often been discussed in the context 
 
  15   of digestibility.  So you eat something and, if it 
 
  16   is resistant, then you are more likely to absorb it 
 
  17   and become sensitized or provoke a reaction. 
 
  18             It is not clear to the structural 
 
  19   biologist who studies allergen structure whether 
 
  20   that is really the issue or whether or not it 
 
  21   reflects something about the tertiary structure of 
 
  22   the antigen which might be more important.  For 
 
  23   instance, it might have more to do with antigen 
 
  24   processing in a macrophage than it really has to do 
 
  25   with digestibility.  My comment here would be think 

 
                                                                 46 
 
   1   about acid and proteases in terms of resistance to 
 
   2   degradation and don't argue about whether or not 
 
   3   something can be digested in the stomach in the 
 
   4   stomach acid of one, fasting, resting and go into 
 
   5   that kind of discussion. 
 
   6             To me, this is really just a 
 
   7   characteristic, a relative characteristic.  It is 
 
   8   not absolute and it just kind of generally can be 
 
   9   used in an assessment program.  It has been 
 
  10   overused and underused.  I know you will probably 
 
  11   discuss this more. 
 
  12             Then there is the whole idea about whether 
 
  13   or not linear or discontinuous or continuous 
 
  14   epitopes and all this are the active component in 
 
  15   food allergy.  Hugh Sampson would argue that many 
 
  16   of the true food allergens are allergens that 
 
  17   provide linear fragments of molecule that can 
 
  18   provoke an allergic reaction.  He will argue with 
 
  19   that. 
 
  20             But there is also evidence that when you 
 
  21   lose the tertiary configuration, that some things 
 
  22   lose their allergenicity.  So probably both are 
 
  23   going on. 
 
  24             [Slide.] 
 
  25             The most common food allergens, and you 

 
                                                                 47 
 
   1   can expand this list, but in children, it is 
 
   2   generally peanut, milk, soy and egg.  In adults, 
 
   3   peanut, crustacea, crayfish, lobster, crab, shrimp, 
 
   4   that sort of thing.  Tree nuts, fish and eggs. 
 
   5   Now, some people would add to this, for example, 
 
   6   sesame and the Europeans like to add celery because 
 
   7   it causes a lot of oral-allergy syndrome. 
 
   8             You can expand this list but this accounts 
 
   9   for about 90 percent of reactions.  A major allergy 
 
  10   within this is an allergy within one of these 
 
  11   proteins that causes more than 50 percent of the 
 
  12   reaction.  So those are two rough definitions. 
 
  13             Again, what I think probably saves most of 
 
  14   us as much as anything else from getting a food 
 
  15   allergy is that is hard to be wrong no matter what 
 
  16   you do because of the ability to find people that 
 
  17   are truly allergen that you can reproduce on 
 
  18   challenge is fairly--is not that common. 
 
  19             So what happens is that you can have a lot 
 
  20   of strategies that appear to work because of the 
 
  21   frequency of these reactions when, in reality, it 
 
  22   really has nothing to do with it and that has a lot 
 
  23   to do with controversial techniques, diagnostic 
 
  24   techniques that I don't think you will get into. 
 
  25   But here are most common food allergens.  And I 

 
                                                                 48 
 
   1   will get into the how you make a diagnosis. 
 
   2             [Slide.] 
 
   3             The diagnosis is both subjective and 
 
   4   objective.  Subjective; history, diet diaries, 
 
   5   elimination diet.  So history is a big thing that 
 
   6   doctors use; were you the only person that got 
 
   7   sick, did everybody get sick.  Look at 
 
   8   epidemiologic factors.  You can send people home 
 
   9   with diet diaries and say, every time you think you 
 
  10   get sick, write it down, what food you are eating. 
 
  11   Then they come back with a long list.  They are so 
 
  12   happy because they found other things they are 
 
  13   allergic to and you are so distressed because you 
 
  14   had enough to worry about before.  So we don't use 
 
  15   them a lot. 
 
  16             Elimination diets really is something that 
 
  17   used to be used more than it is today because you 
 
  18   don't want to send people home and say, "Well, 
 
  19   reintroduce this food," and have them anaphylax at 
 
  20   home.  So they have to be used very cautiously. 
 
  21   So, really, history is the big one here. 
 
  22             Objective is cutaneous testing and then 
 
  23   measurement of allergen-specific IgE by RAST and 
 
  24   ELISA.  Leukocyte histamine release where you take 
 
  25   leukocytes and sensitize them or leukocytes from 

 
                                                                 49 
 
   1   the individual and challenge with antigen is rarely 
 
   2   done just because it is technically more 
 
   3   cumbersome.  Then there is double-blind food 
 
   4   challenge. 
 
   5             I am going to go over just a few points 
 
   6   about some of these very quickly for you. 
 
   7   Cutaneous testing can be used for raw food or 
 
   8   purified allergen from food.  The general method is 
 
   9   to put a drop of this substance on the skin, tint 
 
  10   the skin through it and then look for a local 
 
  11   allergic reaction characterized by itching, redness 
 
  12   and a wheel formation, and then their policy, 
 
  13   generally, but they are more of a control which is 
 
  14   just diluent and you have to have a positive 
 
  15   histamine to skin test to show the person is not 
 
  16   suppressing antihistamines and that sort of thing. 
 
  17             Fairly direct, simple.  Does identify 
 
  18   specific IgE in the skin.  Relatively safe, 
 
  19   although people who are strongly allergic to 
 
  20   something like tree nuts, you probably would not 
 
  21   test them this way, for instance, or peanuts.  So 
 
  22   you occasionally have to worry about severe 
 
  23   reactions. 
 
  24             It is hard to skin test if somebody has 
 
  25   widespread eczema and this sort of thing.  So 

 
                                                                 50 
 
   1   sometimes you have to go to in vitro diagnostics. 
 
   2   Here is the important one.  They are not 
 
   3   diagnostic.  In other words, some of you in the 
 
   4   room probably have skin tests to foods and eat them 
 
   5   without a problem and never realize you have a 
 
   6   positive skin test. 
 
   7             The same thing for pollens.  It is not a 
 
   8   mystery to food.  Some people do have a ragweed-positive 
 
   9   skin tests and won't have a clinical 
 
  10   sensitivity.  But, the other side is very unusual. 
 
  11   It would be very unusual to have somebody who had 
 
  12   an anaphylactic reaction to peanut to have a 
 
  13   negative skin test. 
 
  14             So, they confirm your suspicion but they 
 
  15   cannot work in the absence of an evaluation that 
 
  16   looks at history and other features.  It cannot be 
 
  17   used in isolation. 
 
  18             Now, can it be used for everything?  No. 
 
  19   If you are worried about something that might be a 
 
  20   chemical that might act as a haptene so it has to 
 
  21   bind that body albumin or something before you have 
 
  22   a reaction or be degraded, you wouldn't pick it up 
 
  23   on a skin test, so it doesn't work, for example, as 
 
  24   a general technique for pharmacologic agents. 
 
  25             You have to be very careful when you use 

 
                                                                 51 
 
   1   it because you can easily get a negative skin test 
 
   2   but the person could still be allergic after that 
 
   3   material is degraded or act as a haptene or 
 
   4   something of that sort. 
 
   5             RAST and ELISA have gotten very good. 
 
   6   They are almost as good as skin tests.  You can 
 
   7   kind of quantitate how much IgE there is to an 
 
   8   antigen and, generally, the higher they are, 
 
   9   particularly the Pharmacia cap system which has 
 
  10   been widely studied, the stronger the results are, 
 
  11   generally there is a correlation with more severe 
 
  12   reactions.  But you can have a low cap and 
 
  13   anaphylax to peanut and have a high cap and 
 
  14   anaphylax to peanut.  But there is a general 
 
  15   correlation. 
 
  16             They measure antigen-specific IgE in the 
 
  17   serum.  They are a little bit more costly.  They 
 
  18   are somewhat more remote.  Again, they are not 
 
  19   diagnostic for the same reasons I went over with 
 
  20   IgE testing through skin tests.  The same caveats 
 
  21   apply to positives and negatives. 
 
  22             [Slide.] 
 
  23             Double-blind food challenge is not done 
 
  24   very much.  Doctors don't like to do it in their 
 
  25   office because it is cumbersome and they put the 

 
                                                                 52 
 
   1   patient at risk so only those people really 
 
   2   comfortable with it do it.  If you put it into a 
 
   3   safety assessment, you have to get IRB approval. 
 
   4   Today, at least at my institution, that would be 
 
   5   hard.  It would be hard to do that. 
 
   6             So it is a wonderful test in terms of it 
 
   7   is kind of the gold standard for people who say 
 
   8   they are allergic to food.  It simply involves 
 
   9   putting food somehow or other blinded in capsules 
 
  10   or in a liquid where they can't taste the food. 
 
  11   You start with small amounts and then go up to a 
 
  12   regular feeding. 
 
  13             It is diagnostic if positive. 
 
  14   Occasionally, I think that there are reasons why 
 
  15   you can get a negative and miss it on food 
 
  16   challenge.  Those are not that common.  It is very 
 
  17   difficult work to do with multiple sensitivities. 
 
  18   But, the bottom line is that this is a technique 
 
  19   which, while straightforward, would only be used 
 
  20   when the patient wouldn't be put at great risk, 
 
  21   when you can resuscitate if you have a problem and 
 
  22   the patient agrees. 
 
  23             In the doctor's office, you can elect to 
 
  24   do it.  If you are doing it at a scientific 
 
  25   institution, those people who have done it for many 

 
                                                                 53 
 
   1   years without a problem, like Hugh Sampson, say it 
 
   2   is getting very, very hard to get approvals to do 
 
   3   these kinds of things, at least currently, in the 
 
   4   current IRB--it is just a fact of life. 
 
   5             [Slide.] 
 
   6             Now, the differential diagnosis, I will 
 
   7   not go through.  It is not the purpose of this 
 
   8   slide.  But just to let you know, if you are a 
 
   9   physician and you asked to look at somebody who 
 
  10   flushes after they eat shrimp, there are other 
 
  11   reasons.  It could be a lot of histamine that grew 
 
  12   from bacteria contaminating the shrimp or something 
 
  13   of this sort. 
 
  14             If somebody had bloating or something, it 
 
  15   could be an enzyme deficiency like lactase 
 
  16   deficiency.  If somebody had pain when they are 
 
  17   swallowing, it could be esophageal cancer for all I 
 
  18   know.  So you have to use some common sense here. 
 
  19   You have to look at what else can mimic the 
 
  20   symptoms and make sure that you are dealing with 
 
  21   food allergy and not another disease.  This results 
 
  22   in the common recommendation that people who think 
 
  23   they have food allergy really need to go through a 
 
  24   doctor and vet it because you would be surprised 
 
  25   what kinds of diseases hide under food allergy and 

 
                                                                 54 
 
   1   people don't realize it. 
 
   2             [Slide.] 
 
   3             Food additives.  Food additives have 
 
   4   generally not been associated with allergic 
 
   5   reactions.  There are four here I list.  You would 
 
   6   almost have to talk about every one of them. 
 
   7   Sulfiting agents went through the FDA many years 
 
   8   ago.  If you inhaled the gas sulfiting agent, SO2, 
 
   9   you could provoke asthma. 
 
  10             There were examples that perhaps a few 
 
  11   people recognized sulfite bound to serum albumen as 
 
  12   a haptene.  This is not a major problem any more 
 
  13   since rayon spray-on sulfites were banned, but 
 
  14   there are still a lot of people that think they are 
 
  15   sensitive to sulfites. 
 
  16             With tartrazine, monosodium glutamate and 
 
  17   sodium benzoate, most of the time we are talking 
 
  18   about something associated with chronic hives. 
 
  19   This probably doesn't happen very often.  It may be 
 
  20   real.  You are going to see a lot of confusion as 
 
  21   you go into the literature about chronic hives, 
 
  22   what causes them.  This is because it is so hard to 
 
  23   put somebody on a diet and then challenge them in a 
 
  24   situation where you can be sure that the result is--the hive 
 
  25   that comes up is a result of the 

 
                                                                 55 
 
   1   challenge.  It is very hard to design these 
 
   2   clinically 
 
   3             So you will have people claiming that 50 
 
   4   percent of the people that they see are sensitive 
 
   5   to additives, which is not true, and you have other 
 
   6   people say they could never identify, they are 
 
   7   probably missing few.  Somewhere in here is some 
 
   8   truth, but it is not very common.  Anaphylaxis to 
 
   9   these agents is virtually nonexistent even though 
 
  10   tartrazine causes anaphylaxis.  I don't know who 
 
  11   documented this. 
 
  12             DR. BUSTA:  I have heard a lot comment on 
 
  13   flushing.  Is that equivalent to hives? 
 
  14             DR. METCALFE:  Flushing is simply 
 
  15   cutaneous vasodilatation, vasodilatation of your 
 
  16   surface vessels.  I can happen when you exercise. 
 
  17   It can happen when you get embarrassed.  Some 
 
  18   people have prominent flushes in the face and upper 
 
  19   chest.  It depends on your ethnic background and 
 
  20   your age. 
 
  21             Flushing can result from allergic reaction 
 
  22   when histamine is released.  Many other things can 
 
  23   cause it.  It has been proposed for sulfiting 
 
  24   agents.  You can get a vasovagal reaction that 
 
  25   causes flushing.  Flushing is very nonspecific and 

 
                                                                 56 
 
   1   frequently believed to be important and often is 
 
   2   not. 
 
   3             But, that being said, it is one of the 
 
   4   things that goes along with the systemic allergic 
 
   5   reaction.  But other things that physicians look 
 
   6   for, like conjunctival irritation and things like 
 
   7   that, that we like the signs of systemic 
 
   8   anaphylaxis better than flushing. 
 
   9             [Slide.] 
 
  10             Controversial diagnoses.  These are the 
 
  11   kinds of things you see in the literature that are 
 
  12   due to foods or not.  There is very little evidence 
 
  13   that these are due to foods and I don't think we 
 
  14   will get into these except that, when you see 
 
  15   people come to talk to you about these reactions, 
 
  16   you have to ask them to specify their allergies. 
 
  17             If somebody comes in and says, "I am here 
 
  18   because I have allergy to such-and-such, and they 
 
  19   don't describe what that is, you need to ask them 
 
  20   because, every once in a while, they will say, "I 
 
  21   get tired," or, "I have psychotic episodes."  It 
 
  22   helps define what their definition of allergy is. 
 
  23             All too often, you just assume, oh, 
 
  24   allergy.  They are having hives and anaphylaxis. 
 
  25   But, when you ask them, it is far different.  So 

 
                                                                 57 
 
   1   just a warning about that. 
 
   2             [Slide.] 
 
   3             Now, let's talk about oral-allergy 
 
   4   syndrome.  This is IgE-mediated disease.  It is 
 
   5   believed to be certain people eating fruits that 
 
   6   often have antigens that cross-react with pollens 
 
   7   and latex and other things can eat certain fruits 
 
   8   and vegetables and they get burning and swelling 
 
   9   and itching in their mouth. 
 
  10             The proteins implicated are heat-labile 
 
  11   food and vegetable allergens, often cross-reacting 
 
  12   with some polyallergens and latex cross-reactivity, 
 
  13   believed to be IgE-mediated, generally destroyed by 
 
  14   cooking or by digestion and frequently seen in 
 
  15   people who have allergies. 
 
  16             Rarely do these allergens cause a systemic 
 
  17   reaction but, occasionally, they do.  They are very 
 
  18   labile allergens and most skin-testing materials do 
 
  19   not pick them up because the allergens are degraded 
 
  20   in the bottle of the extract with a lot of 
 
  21   proteases and things like that. 
 
  22             So, again, when you looking at prevalence 
 
  23   of allergen diseases, a lot of European papers, in 
 
  24   particular, will add oral-allergy syndrome and the 
 
  25   numbers go way up.  You have to just be careful of 

 
                                                                 58 
 
   1   that.  This is generally considered to be less of a 
 
   2   problem than the more significant food allergies, 
 
   3   but it does exist.  It is a problem for a lot of 
 
   4   people and you need to know about it. 
 
   5             [Slide.] 
 
   6             Anaphylaxis is the signs and symptoms 
 
   7   resulting for IgE-mediate mast-cell and basophil 
 
   8   activation leading to the release of chemicals 
 
   9   whose target organs are primarily such things as 
 
  10   blood vessels, smooth muscle.  The site of mediator 
 
  11   effects may be local and remote from the site of 
 
  12   allergen ingestion or exposure; for example, you 
 
  13   could have a skin test to peanut right here, but 
 
  14   you would have systemic circulatory flaps. 
 
  15             In other words, it goes from here 
 
  16   everywhere.  Anaphylaxis; some people distinguish 
 
  17   anaphylaxis from anaphylactoid which is the 
 
  18   clinical signs and symptoms of anaphylaxis but we 
 
  19   either don't know the mechanism or it is not IgE 
 
  20   mediated.  Today, most people just say anaphylaxis 
 
  21   and say most of it is IgE-mediated and worry about 
 
  22   the rest later. 
 
  23             But it is life-threatening.  It is the 
 
  24   major problem that we worry about with food 
 
  25   allergies. 

 
                                                                 59 
 
   1             [Slide.] 
 
   2             This is some data from Hugh Sampson's 
 
   3   extrapolation of the number of people who might die 
 
   4   in the United States every year from food 
 
   5   anaphylaxis.  He took the frequency of anaphylaxis 
 
   6   in Denmark.  He looked at the number of patients 
 
   7   seen in the Mayo Clinic experiences foods, did an 
 
   8   extrapolation, came up with 2,500 cases a year in 
 
   9   the United States with 125 deaths. 
 
  10             It is ball-park figure.  It could be off 
 
  11   by 100.  Who knows?  But it just gives you an idea 
 
  12   that it is not that frequent but does exist and it 
 
  13   is what you worry about.  The cases often make the 
 
  14   newspapers.  They are highly visible cases, often 
 
  15   tragic cases, involving healthy children and heart-wrenching 
 
  16   when they occur.  But their numbers are 
 
  17   not great. 
 
  18             [Slide.] 
 
  19             Fatal food-induced anaphylaxis.  This is 
 
  20   an early study.  There are plenty of studies.  I 
 
  21   picked this one up, both males and females, all 
 
  22   ages.  Almost all these people are atopic.  It 
 
  23   usually happens away from home when they don't know 
 
  24   they are eating.  Peanut is a big provocateur. 
 
  25   Often they die because they have had no epinephrine 

 
                                                                 60 
 
   1   early.  The other risk factor is asthma.  Most 
 
   2   people who die from anaphylaxis have asthma.  So it 
 
   3   is a pulmonary death. 
 
   4             These are the features of anaphylaxis that 
 
   5   have to do with foods.  There are a larger series, 
 
   6   but these are the basic determinants of it. 
 
   7             [Slide.] 
 
   8             The diagnosis of an allergy, or an 
 
   9   allergy-causing anaphylaxis is the presence of 
 
  10   allergic signs and symptoms, hives, angioedema, 
 
  11   trouble breathing, et cetera, acute hypotension 
 
  12   and/or upper or lower-airway obstruction.  Often, 
 
  13   people develop laryngeal edema, can't breath.  That 
 
  14   can lead to demise. 
 
  15             Absence of conditions in the differential 
 
  16   diagnosis.  Elevated levels of mast-cell tryptase 
 
  17   release by mast cells where the serum can be used 
 
  18   in post mortem.  Exposure to agents known to be 
 
  19   associated with anaphylaxis or the patient would 
 
  20   have a history of anaphylaxis without knowing the 
 
  21   cause. 
 
  22             So those are basically the nuts and bolts 
 
  23   of anaphylaxis. 
 
  24             [Slide.] 
 
  25             The treatment of IgE-mediated sensitivity 

 
                                                                 61 
 
   1   remains avoidance and prepare to treat inadvertent 
 
   2   exposure.  If you are severely affected, you were a 
 
   3   medic-alert bracelet or a device to notify people 
 
   4   if you are found unconscious.  You give yourself 
 
   5   epinephrine upon exposure to something that you are 
 
   6   anaphylactically sensitive to.  You may take 
 
   7   antihistamines or seek medical help. 
 
   8             Unproven.  We don't have any way to 
 
   9   desensitize to foods.  It is recognized that there 
 
  10   are no prophylactic medications that reliably 
 
  11   prevent.  So, really, the problem, then, for us in 
 
  12   the field and with you is that the prime protection 
 
  13   for people that may have food allergies or may 
 
  14   develop them is simply avoidance.  That goes into 
 
  15   labeling which we are going to talk about.  That 
 
  16   goes into what is going on here. 
 
  17             [Slide.] 
 
  18             Novel approaches to the treatment of food 
 
  19   allergy being discussed; anti-IgE antibodies.  This 
 
  20   takes a lot of IgE out of your system, may make you 
 
  21   less sensitive.  There are some trials going on. 
 
  22   The hope would be that a child extremely sensitive 
 
  23   to peanut taking IgE would have to ingest more 
 
  24   peanut for a reaction.  So it would lower their 
 
  25   risk and that may well be the case. 

 
                                                                 62 
 
   1             There is vaccination with plasma DNAs to 
 
   2   induce responses that are protective.  Antiallergic 
 
   3   immunostimulatory sequences that are supposed to 
 
   4   promote interferon gamma.  We will talk about these 
 
   5   if you want.  The concern there is that if you go 
 
   6   from a TH2 to a TH1 response, instead of allergy 
 
   7   asthma, you end up with Laker's granulomatosis or 
 
   8   something. 
 
   9             But there are all concerns about these 
 
  10   approaches.  Immunotherapy with mutated proteins 
 
  11   and peptides so that you get a new response without 
 
  12   the risk of a reaction.  All of those are being 
 
  13   looked at now and we can talk about them if you 
 
  14   want.  There is nothing I see that is really going 
 
  15   to protect people, at least within the next five to 
 
  16   ten years, I don't think.  So we are stuck with 
 
  17   what we have. 
 
  18             [Slide.] 
 
  19             We have covered this clarification.  Now 
 
  20   we are going to briefly cover some of the others. 
 
  21   I am going to go through these very rapidly. 
 
  22   Allergic eosinophilic esophagitis is carried mostly 
 
  23   in infants and children.  It is such things and 
 
  24   emesis and failure to thrive.  The proteins 
 
  25   implicated include cow's milk.  There is an 

 
                                                                 63 
 
   1   eosinophilic infiltrate.  Poor correlation to skin 
 
   2   tests.  The treatment is protein elimination and, 
 
   3   you can see here, sometimes steroids. 
 
   4             This is a disease which is really of 
 
   5   interest to pediatricians now.  We have learned a 
 
   6   lot more about it.  We don't know a lot about it 
 
   7   right now, but this is what we do know.  It is 
 
   8   largely limited to infants and children.  One of 
 
   9   the themes--I will come back to it in a minute. 
 
  10             [Slide.] 
 
  11             Allergic eosinophilic gastritis is more 
 
  12   likely to be IgE-mediated.  This is associated with 
 
  13   vomiting, abdominal pain, failure to thrive in 
 
  14   children.  Many of the cases are atopic.  Many have 
 
  15   peripheral eosinophilia.  Age of onset, neonate to 
 
  16   adult.  Proteins are the common allergens that we 
 
  17   have talked about. 
 
  18             Eosinophilic infiltration in the gut. 
 
  19   Elevated IgE, although about half you can't find 
 
  20   skin-test specificity to.  The other half have 
 
  21   multiple positive skin tests to foods.  There are 
 
  22   probably two populations in here.  Atopic 
 
  23   predisposition is possible.  Treat with steroids 
 
  24   and try to structure a diet. 
 
  25             We are studying this.  Anti-IL5 will make 

 
                                                                 64 
 
   1   these patients better somewhat, for instance. 
 
   2   These patients tend to be of a strong TH2 
 
   3   phenotype, at least to orally ingested allergens. 
 
   4             [Slide.] 
 
   5             Gastroenterocolitis is basically the same 
 
   6   thing affecting more of the intestinal system.  You 
 
   7   add things like colonic bleeding, protein-losing 
 
   8   enteropathies, but you still have the eosinophilia, 
 
   9   elevated IgE.  Many that have skin-test response. 
 
  10   This is a fairly unusual disease. 
 
  11             [Slide.] 
 
  12             Dietary protein enteropathy.  The rest of 
 
  13   them that we are going to talk about don't have an 
 
  14   IgE basis are seen primarily in infants and 
 
  15   children.  They often outgrow the disease.  If it 
 
  16   occurs in adults, it is hidden within things like 
 
  17   inflammatory-bowel disease and we certainly don't 
 
  18   know about it. 
 
  19             They are caused by proteins.  There are no 
 
  20   known animal models.  There are no known diagnostic 
 
  21   tests.  The reason I am showing you these is 
 
  22   because, no matter what you decide to do about a 
 
  23   food, it may be done for you.  You can't do much 
 
  24   about these because we don't know much about these 
 
  25   and so that is why we have always focused on IgE. 

 
                                                                 65 
 
   1             So, in a child, diarrhea, malabsorption, 
 
   2   failure to thrive, anemia, edema.  They get quite 
 
   3   ill.  No increase in evidence they are of an 
 
   4   allergic phenotype.  Food challenge can result in 
 
   5   vomiting and diarrhea.  Age of onset, up to two 
 
   6   years. 
 
   7             Here are the proteins implicated, common 
 
   8   foods that children often eat.  Pathology is 
 
   9   dramatic, often small-bowel injury, intraepithelial 
 
  10   leukocytes, et cetera.  No food-specific IgE.  You 
 
  11   eliminate the offending allergen and then they 
 
  12   outgrow it. 
 
  13             [Slide.] 
 
  14             Same for dietary proteins; colitis, 
 
  15   diarrhea, vomiting and anemia, failure to thrive, 
 
  16   hypotension, villous injury, colitis, fecal 
 
  17   leukocytes, no food-specific IgE.  With food 
 
  18   challenge, there is believed to be an increased 
 
  19   risk of hypotension and shock and then basically 
 
  20   there is an elemental formula until they start to 
 
  21   outgrown this problem.  Most of these go away. 
 
  22             [Slide.] 
 
  23             Proctitis; basically, the same idea, 
 
  24   limited to the rectal area.  It is not clear what 
 
  25   is going on here.  Probably cells that are 

 
                                                                 66 
 
   1   sensitized are homing to the gut and are causing 
 
   2   disease in this area causing proctitis. 
 
   3             The same kind of idea; fecal leukocytes. 
 
   4   No role for IgE.  Again, a fairly rare disease. 
 
   5             [Slide.] 
 
   6             Celiac disease I mentioned early. 
 
   7   Everybody knows about this disease and pretty much 
 
   8   knows how not to create a new food that would cause 
 
   9   celiacs to have a problem.  Manifestations are 
 
  10   chronic diarrhea, diarrhea and failure to thrive in 
 
  11   infants. Age of onset typically more than six 
 
  12   months.  The protein foods implicated are wheat, 
 
  13   rye and barley, primarily.  Pathology is a villous 
 
  14   atrophy and there are certain characteristics of 
 
  15   certain kinds of lymphocytic infiltrates. 
 
  16             Certain antibodies that can help in 
 
  17   diagnosis.  Treatment is elimination of gluten 
 
  18   associated with certain HLA patterns.  Lifelong 
 
  19   history.  There probably is a lot of gluten 
 
  20   sensitivity that may be one allele instead of two 
 
  21   or something that is really not picked up.  There 
 
  22   may be a lot of subclinical celiac disease. 
 
  23             But, at any rate, this, on the surface, 
 
  24   would appear, at least to most people, to be 
 
  25   something that a company simply would not create by 

 
                                                                 67 
 
   1   moving gluten into some new foods.  So I don't 
 
   2   think this has even been a major issue, but it must 
 
   3   be remembered. 
 
   4             [Slide.] 
 
   5             So, again, this is really what we can 
 
   6   worry about plus atopic dermatitis.  These are 
 
   7   unusual diseases, but they do have an IgE 
 
   8   component.  These are non-IgE-mediated disease, 
 
   9   granted more rare, granted mostly in infants and 
 
  10   children and very difficult to deal with. 
 
  11             DR. PARIZA:  How much atopic dermatitis is 
 
  12   due to food versus other causes? 
 
  13             DR. METCALFE:  In adults, it you look at 
 
  14   the series, it is rarely associated with the 
 
  15   digestion of foods.  So, in adults, atopic 
 
  16   dermatitis is very difficult to associate with 
 
  17   foods.  In children, it is much more common. 
 
  18             DR. ATKINS:  About a third of children 
 
  19   with atopic dermatitis have a food that will 
 
  20   trigger it, is one trigger. 
 
  21             DR. PARIZA:  How do you know that?  Do 
 
  22   they eat a food and then they get it?  Is that the 
 
  23   way you see it? 
 
  24             DR. METCALFE:  Yes. 
 
  25             DR. ATKINS:  Generally within two hours 

 
                                                                 68 
 
   1   ingestion of the food, they develop flushing at the 
 
   2   sites. 
 
   3             DR. PARIZA:  Oh; within two hours? 
 
   4             DR. ATKINS:  Sometimes much quicker than 
 
   5   that, but they develop flushing at the sites of 
 
   6   excema and start to scratch and, the next day, they 
 
   7   will have a rash. 
 
   8             DR. METCALFE:  An awful lot of what is in 
 
   9   the literature that tells us about food allergies 
 
  10   is atopic dermatitis studied by pediatricians.  If 
 
  11   you look at most of the literature that you are 
 
  12   going to base your decisions on, there is very 
 
  13   little evidence from adults.  It is almost all 
 
  14   pediatric data. 
 
  15             Why are we interested in this? 
 
  16             [Slide.] 
 
  17             I am going to show some people from the 
 
  18   lab to jus kind of candid shot of our lab.  You may 
 
  19   have seen this before. 
 
  20             So, I think we have time for questions. 
 
  21                    Questions of Clarification 
 
  22             DR. BRANDT:  We do have.  Questions? 
 
  23   Anybody? 
 
  24             DR. LEHRER:  Sam Lehrer.  You had 
 
  25   mentioned the figure of 40 to 40 million Americans. 

 
                                                                 69 
 
   1   Did you mean have the potential for allergic 
 
   2   responses or that have food allergy? 
 
   3             DR. METCALFE:  Let's talk about that data. 
 
   4   It is only 1 percent to 2 percent that we think 
 
   5   really have it so that is something like 4 to 6 
 
   6   million.  If we look at the people that think they 
 
   7   have it, then you are talking about 40 million. 
 
   8   I'm sorry; I should have made that clear and I am 
 
   9   glad you asked that, because the problem that you 
 
  10   deal with in this area is an awful lot of people 
 
  11   that think they are sensitive but relatively few 
 
  12   that do. 
 
  13             But, still, if you talk about 1 to 2 
 
  14   percent, you are talking about 4 to 6 million 
 
  15   people in the United States.  That is a huge 
 
  16   population.  But if you look at perception, it is 
 
  17   huge. 
 
  18             DR. LEHRER:  I would agree.  Of the 1 to 2 
 
  19   million that have a food allergy, this is all of 
 
  20   the food allergies that we see.  They don't all 
 
  21   react to peanut.  They all don't react to shrimp. 
 
  22   So, if you take one of the major food allergens--I 
 
  23   guess peanut would probably be a likely candidate--how many 
 
  24   people are you talking about, if we are 
 
  25   taking the worst allergen that we know of? 

 
                                                                 70 
 
   1             DR. METCALFE:  That is an interesting 
 
   2   thing to ask.  That is a good question.  Let's say 
 
   3   we have 1 percent of adults who have true food 
 
   4   allergy.  This actually goes back to stuff done 
 
   5   many years ago.  If you look at what most people 
 
   6   react to as adults, it is going to be peanut or 
 
   7   tree nuts or a little bit of crustacean.  Most of 
 
   8   those people react to one allergen, something like 
 
   9   60 percent. 
 
  10             So one could, right away, say, out of that 
 
  11   1 percent, probably half of those individuals, 
 
  12   maybe more, are reacting to one allergen that is 
 
  13   probably going to be peanut or tree nut or 
 
  14   crustacean.  Then you get another 30, 40 percent 
 
  15   that take in the rest of them and start to have 
 
  16   multiple allergies. 
 
  17             Then you have a very small number of 
 
  18   people that seem to be reacting to everything.  We 
 
  19   are not talking about oral-allergy syndrome here 
 
  20   which puts up the numbers.  We are talking about 
 
  21   generally.  Dan, do you want to comment on that? 
 
  22   You have thought as much about this as I have.  Is 
 
  23   that fair? 
 
  24             DR. ATKINS:  That's fair.  You could go to 
 
  25   the telephone surveys that Ann Furlong and her 

 
                                                                 71 
 
   1   group have done.  They have got sensitization on 
 
   2   both adults and kids to peanuts and tree nuts.  I 
 
   3   think, in children, it is supposed to be about 0.5 
 
   4   percent and, in adults, it is supposed to be about 
 
   5   0.7 percent, if I remember right. 
 
   6             DR. BRANDT:  Those are true, or those are 
 
   7   responses? 
 
   8             DR. METCALFE:  That is just a random 
 
   9   digit-dial survey with a high screen.  Those are 
 
  10   undocumented. 
 
  11             DR. LEHRER:  The ones that are reacting, 
 
  12   seem to react to everything.  I know you said it is 
 
  13   a very small group.  Do you have any idea--are you 
 
  14   talking about 0.1 percent? 
 
  15             DR. ATKINS:  I don't think it is that 
 
  16   high.  If you look at the number, probably you pick 
 
  17   up--so, 50, 60 percent, one.  Another two; you 
 
  18   probably pick up another 20 percent so that puts 
 
  19   you up to 80.  Maybe three or more, another 10 or 
 
  20   15 percent.  Beyond that, you have multiple 
 
  21   reactors.  So it is a very small number.  It is 
 
  22   probably--you are right; it is 0.5 or less in the 
 
  23   population. 
 
  24             DR. METCALFE:  But the point is, it can 
 
  25   change over time.  There are children who become 

 
                                                                 72 
 
   1   sensitized to multiple foods; milk, eggs, wheat, 
 
   2   soy and then, by the time they are between five and 
 
   3   seven, they may lose sensitivity to two or three of 
 
   4   those foods, peanut sensitivity or-- 
 
   5             DR. LEHRER:  But just to get some kind of 
 
   6   handle on numbers. 
 
   7             DR. METCALFE:  That's in adults.  If you 
 
   8   look at children, it is more frequent.  The 
 
   9   percentage goes up to 2 to 3 percent and it is 
 
  10   heavily weighted toward milk and soy.  Those 
 
  11   sensitivities are generally lost.  It is very hard 
 
  12   to identify an adult that is allergic to milk or 
 
  13   soy.  It is just hard to find. 
 
  14             DR. LEHRER:  If you eliminate the milk and 
 
  15   soy and you ask for a percentage of children, what 
 
  16   do you think that would drop down to? 
 
  17             DR. METCALFE:  I don't know; about 0.25 
 
  18   percent, maybe?  Dan? 
 
  19             DR. ATKINS:  Again, 90 percent of allergic 
 
  20   reactions to foods in kids are milk, eggs, wheat, 
 
  21   peanut, soy.  By the time kids are five to seven 
 
  22   years of age, they tend to outgrown sensitivity to 
 
  23   milk and wheat and soy and egg and then you are 
 
  24   left with peanut, tree nut, fish, shellfish. 
 
  25             DR. LEHRER:  So I guess the question would 

 
                                                                 73 
 
   1   be of the five-to-seven-year age group, what 
 
   2   percentage? 
 
   3             DR. ATKINS:  We think it drops from about 
 
   4   6 percent in young kids and infants--infants and 
 
   5   young children--to about 1 to 2 percent in adults. 
 
   6   The majority of that occurs over that five to seven 
 
   7   years early on. 
 
   8             DR. METCALFE:  A lot of these reactions 
 
   9   are not life-threatening, either.  Not everything 
 
  10   causes anaphylaxis.  So it is a spectrum, just like 
 
  11   all allergy is, to pollen or anything else. 
 
  12             DR. ATKINS:  The point I want to make, 
 
  13   though, is that it not concerning to the people who 
 
  14   have it.  If you talk about oral-allergy syndrome, 
 
  15   they are still very affected by that.  There are 
 
  16   foods that they can't eat.  Then, if you take a 
 
  17   food and it is not digestible, or we change it so 
 
  18   that it is not digestible, and that patient eats is 
 
  19   and now it gets to the lower gastrointestinal tract 
 
  20   whereas, before, it was digested above, you may 
 
  21   have a group of people that are anaphylaxing who 
 
  22   weren't before exposure to that food. 
 
  23             DR. METCALFE:  The difficulty in this is 
 
  24   that 1 to 2 percent of the population is not a 
 
  25   small number of people.  Then, if you take that up--and I am 

 
                                                                 74 
 
   1   glad you asked that question because we 
 
   2   are really talking about a couple of million people 
 
   3   here.  When you look at the people who think they 
 
   4   are at risk and you have to get through that chaff. 
 
   5             But it is not a small problem.  Of course, 
 
   6   no company wants--I don't want to speak for a 
 
   7   company--but no company wants to create something 
 
   8   that is going to put them into court and put them 
 
   9   out of business.  I mean, things like silicon 
 
  10   breast implants would pale by the consequences of 
 
  11   putting out something as sensitive as peanut into 
 
  12   the general population.  Monsanto or one of these 
 
  13   companies would be out of business, I think. 
 
  14             So, everybody, for various reasons, wants 
 
  15   to protect everyone.  But there is a real risk out 
 
  16   there. 
 
  17             I want to catch a couple of other 
 
  18   questions.  Yes, sir? 
 
  19             MR. HINTON:  Not to change the subject 
 
  20   but, in any case, I was wondering if you would 
 
  21   comment on the potential of animal models in terms 
 
  22   of the mechanisms of allergenicity and so forth 
 
  23   because one of our charges will be in that area in 
 
  24   terms of the mechanisms in animal models being 
 
  25   similar as to what we see in humans. 

 
                                                                 75 
 
   1             DR. METCALFE:  I give you my view on 
 
   2   animal models because--let's talk about 
 
   3   practicality.  First of all, any reasonable animal 
 
   4   model is going to have to use a small animal like 
 
   5   the mouse, I think.  I think dog models and beagle 
 
   6   models and pig models are just not reasonable. 
 
   7             When you go into those animals, then the 
 
   8   purpose of an animal model would be to rank-order 
 
   9   things that are allergenic in the population, from 
 
  10   something non-allergenic to allergenic.  Here, I 
 
  11   don't have any--I would recommend you not recommend 
 
  12   think about trying to mimic human disease, that it 
 
  13   has to be orally fed, that it has to happen on oral 
 
  14   challenge, but simply that you have an animal that 
 
  15   can rank order allergens for a given class of 
 
  16   allergens.  That is my own feeling about it. 
 
  17             If you said the only animal model we can 
 
  18   use has to result from oral sensitization without 
 
  19   and adjuvant and provoke a reaction on oral 
 
  20   administration, I think you are going to have it 
 
  21   extraordinarily difficult to make an animal model. 
 
  22             But if you said, I am going to take a 
 
  23   certain mouse with a certain background that 
 
  24   responds to a certain profile and I am going to see 
 
  25   if, on the basis of skin-test reactivity or IgE 

 
                                                                 76 
 
   1   synthesis or something, rank order those things 
 
   2   roughly to what humans see, then I would say, yes; 
 
   3   that should be possible. 
 
   4             If you are asking for a single validated 
 
   5   model, there is none.  I would even predict, if you 
 
   6   started to see some animal models that worked with 
 
   7   some protein classes, they wouldn't work with all 
 
   8   protein classes.  I, personally, don't think you 
 
   9   are going to ever see one validated model.  I could 
 
  10   be wrong. 
 
  11             And, no matter what happens, it is never 
 
  12   going to be like a toxicology assessment.  I don't 
 
  13   ever see it being perfect.  This is something we 
 
  14   have discussed for ten years and I have just given 
 
  15   you--it needs to be worked on, and I applaud those 
 
  16   people who are trying to do it. 
 
  17             DR. BRANDT:  Why don't we stick here to 
 
  18   the subcommittee members. 
 
  19             DR. METCALFE:  Oh; all right. 
 
  20             DR. KAPUSCINSKI:  This is Anne 
 
  21   Kapuscinski.  When you were talking about the 
 
  22   grains that are known to cause celiac disease, you 
 
  23   made the comment that it would seem that no one 
 
  24   would want to introduce genes from those into other 
 
  25   foods.  But how about if you were to actually 

 
                                                                 77 
 
   1   engineer wheat or barley or oats?  How much do we 
 
   2   know about our ability to predict whether that 
 
   3   would accidently increase the allergenic reaction 
 
   4   or broaden the percentage of people that might get 
 
   5   exposed?  What do we know about that? 
 
   6             DR. METCALFE:  I, personally, don't know 
 
   7   the answer to that.  But it would seem to me that, 
 
   8   because you know what the active ingredient is, 
 
   9   that one of the things you would ask for is a 
 
  10   measurement of the level of gluten.  That can be 
 
  11   determined.  But, certainly, you would want to know 
 
  12   that, that you didn't upregulate its expression. 
 
  13             You could go one step beyond.  You could 
 
  14   actually go into a crop that is not known to 
 
  15   produce gluten and actually ask if it starts to. 
 
  16             DR. KAPUSCINSKI:  Right.  I guess I was 
 
  17   thinking, also, not only the level of the gluten 
 
  18   but do we know enough about the structure of the 
 
  19   gluten?  What about the structure is really causing 
 
  20   an allergenic reaction to know if there could be 
 
  21   subtle changes, again, in its three-dimensional 
 
  22   tertiary structure that could broaden the range of 
 
  23   people that might-- 
 
  24             DR. METCALFE:  There is a fair amount 
 
  25   known.  But it is unclear enough to make me worry 

 
                                                                 78 
 
   1   about trying to get down to the peptide sequence. 
 
   2   There are known peptide sequences that cause the 
 
   3   disease and bind to certain HLA groups.  But there 
 
   4   is enough noise in the background to say that you 
 
   5   don't pick up everything with that that I would 
 
   6   personally recommend a different way to look at it 
 
   7   which would be overall to measure gluten or 
 
   8   glutenagen or something which would have, within 
 
   9   it, the active peptides. 
 
  10             But you should go to somebody that studies 
 
  11   this to ask that question.  If there is somebody 
 
  12   that knows more about that, please comment.  But 
 
  13   that would be my own feeling about that. 
 
  14             I just reviewed this because I just 
 
  15   reviewed a chapter written on celiac disease, just 
 
  16   yesterday.  That is my read on the current state of 
 
  17   the art. 
 
  18             DR. GURIAN-SHERMAN:  I guess the question 
 
  19   I have with the current kind of passive reporting 
 
  20   system, and I am talking about a postmarketing 
 
  21   issue, what do you feel the likelihood is--you 
 
  22   mentioned that companies would certainly be 
 
  23   concerned about liability--but the likelihood that 
 
  24   some of these conditions would be reported if they 
 
  25   are occurring at a fairly low percentage of the 

 
                                                                 79 
 
   1   population and nobody is actively looking for it in 
 
   2   the population. 
 
   3             DR. METCALFE:  I think it is hard for a 
 
   4   passive reporting system to do a good job of 
 
   5   looking for reactions.  I think it works to a 
 
   6   degree if you follow up case report challenge or 
 
   7   something to really find out if you have somebody 
 
   8   sensitive. 
 
   9             The difficulty is that if you had 
 
  10   something that was causing the problem that was in 
 
  11   a common protein source and then got into other 
 
  12   foods, people developing a new reaction would have 
 
  13   a hard time identifying where it was coming from. 
 
  14   So that while it has a value, I think everybody 
 
  15   recognizes the limitations. 
 
  16             Then there is the other side.  Once you 
 
  17   publicize something, then everybody starts saying, 
 
  18   oh, now I know what causes my headaches.  So it has 
 
  19   a value but, in my own judgment, it is seriously 
 
  20   flawed. 
 
  21             I think we try to teach all allergists 
 
  22   that, if they have somebody coming in with 
 
  23   something that they are reacting to that they take 
 
  24   by mouth and it is unclear what that is, then they 
 
  25   should think about what might be novel in that food 

 
                                                                 80 
 
   1   and then they can make extracts of that food and do 
 
   2   skin testing. 
 
   3             There are ways to try to get at the 
 
   4   answer, but I think it is very difficult for the 
 
   5   individual, unless you have engineered a blue 
 
   6   peanut and people say every time they eat a blue 
 
   7   peanut, they react, "And I don't react to regular 
 
   8   peanuts." 
 
   9             But that is not the way it works in 
 
  10   reality.  Then, for a lot of places in the world, 
 
  11   there is no label.  You buy from street vendors and 
 
  12   stuff.  So, really, the way to keep the genie from 
 
  13   getting out of the bottle, I think, is to try to do 
 
  14   a good job on the front end, not the back side.  I 
 
  15   think that is what everybody worries about. 
 
  16             Did you have something, Bob? 
 
  17             DR. BUCHANAN:  Yes; I did.  Bob Buchanan. 
 
  18   I think I need to rise to the defense of the dog. 
 
  19   While not wanting to cover the earth with canines, 
 
  20   I think that the dog has its place in testing, at 
 
  21   least according to current evidence.  It is the 
 
  22   only animal model that I know of that has allergies 
 
  23   similar to humans including clinical symptoms. 
 
  24             We have an article under review now in 
 
  25   JACI, Journal of Allergy and Clinical Immunology, 

 
                                                                 81 
 
   1   that shows that there is a hierarchy, just as there 
 
   2   is in people.  So I think that it may behoove a 
 
   3   company or another interested party to use that as 
 
   4   a test if they are not satisfied with rodent tests. 
 
   5   I think the cost of that would be totally 
 
   6   insignificant compared to what has happened--so I 
 
   7   think it is something that should be considered. 
 
   8             DR. METCALFE:  You have a point, Bob. 
 
   9   They do have a role.  Since I will be leaving this 
 
  10   room shortly, and you will be staying in, I am sure 
 
  11   that the dog-- 
 
  12             DR. BUCHANAN:  I am not as persuasive as 
 
  13   other Virginians have been, but thanks. 
 
  14             DR. ATKINS:  This is Dan Atkins.  In 
 
  15   reviewing source materials, there appear to be two 
 
  16   different approaches.  One is the weight-of-evidence 
 
  17   approach.  The other is the decision-tree 
 
  18   approach.  In reading these articles, you have been 
 
  19   involved in the development of decision trees.  I 
 
  20   was just curious, before you leave the room here, 
 
  21   if you could give us your impression of the two 
 
  22   different approaches and the pros and cons of both. 
 
  23             DR. METCALFE:  This is, of course, a huge 
 
  24   problem.  It is a huge question.  I would say this, 
 
  25   that if you have a decision-tree approach and you 

 
                                                                 82 
 
   1   have defined points where something is rejected 
 
   2   from consideration, then you are going to make 
 
   3   mistakes sometimes in rejecting something you 
 
   4   shouldn't.  That is going to happen. 
 
   5             But what it does from a committee 
 
   6   standpoint is it give you, in essence, some cover. 
 
   7   On the other hand, the weight-of-evidence approach 
 
   8   should work as long as--but it puts more 
 
   9   responsibilities on the committee.  Very few things 
 
  10   are absolute in this decision process. 
 
  11             The only thing I would say is a weight-of-evidence 
 
  12   approach actually puts more of a burden on 
 
  13   a committee and the FDA to look at the weight of 
 
  14   evidence and make a balanced approach.  It may, in 
 
  15   the end, be preferable.  I don't know.  But, from a 
 
  16   committee standpoint, it really makes this 
 
  17   committee extraordinarily important because there 
 
  18   is no automatic rejection at certain contiguous 
 
  19   amino-acid sequences, unless you decide. 
 
  20             There are no automatic rejection points so 
 
  21   you can set that bar as high or as low as you want 
 
  22   it.  Then, from a committee standpoint, you really 
 
  23   have to know what you are doing so you will 
 
  24   understand the difference between a protein made 
 
  25   with E. coli and protein expressed in a plant and 

 
                                                                 83 
 
   1   all these other subtleties. 
 
   2             If you don't know that, then you may miss 
 
   3   critical decision points.  So my general comment is 
 
   4   I have no problem with it but I do think it makes 
 
   5   committees like this extraordinarily important in 
 
   6   the portion in which they look at data. 
 
   7             Does that answer your question? 
 
   8             DR. LEHRER:  Another point that I wanted 
 
   9   to clarify that I think is very relevant to this 
 
  10   committee in our discussions is the amount of food--and I 
 
  11   think we need to consider it in terms of not 
 
  12   the food, itself, so much but a protein, in terms 
 
  13   of sensitizing individuals and also the amount that 
 
  14   can provoke a reaction.  I know this is a tough 
 
  15   question for all the reasons that you mentioned in 
 
  16   your presentation, but could you go over that 
 
  17   again? 
 
  18             I wrote down it was milligrams to grams, 
 
  19   but-- 
 
  20             DR. METCALFE:  If you look at, for adults 
 
  21   and for many children, the amount of food that you 
 
  22   have to eat orally that contains the allergen--I am 
 
  23   not talking about purified allergen--is usually in 
 
  24   milligram-to-gram amounts.  It is a reasonable 
 
  25   amount of food in terms of being able to measure 

 
                                                                 84 
 
   1   it. 
 
   2             But if you look for cases where people 
 
   3   have used purified allergen or the lowest amount of 
 
   4   a compound food that would cause an reaction, you 
 
   5   will find cases at the 1 microgram level.  So, if 
 
   6   you try to set a level below which you can't 
 
   7   provoke a reaction under any circumstances by oral 
 
   8   feeding, it is probably going to be at one 
 
   9   microgram or less. 
 
  10             Some people have argued for 10 nanograms. 
 
  11   But, of course, you are talking about the 
 
  12   absolutely most sensitive child or infant.  I don't 
 
  13   know if other people want to comment on this but I 
 
  14   get very comfortable at the 1 microgram level. 
 
  15             In terms of sensitization, you really have 
 
  16   a huge problem here because cross-reacting 
 
  17   allergens can be, in part, sensitizing.  So I don't 
 
  18   think it is possible to set a level.  I think if 
 
  19   you use a 1-microgram level for provoking, I think 
 
  20   you just accept it for sensitization.  But probably 
 
  21   sensitization is a much more complex procedure. 
 
  22             For instance, we all know the tropomycin 
 
  23   is a major allergen in shrimp.  It is also in 
 
  24   cockroach.  Shrimp and cockroach are more closely 
 
  25   related, as you well know, Sam, because Sam has 

 
                                                                 85 
 
   1   done a lot of a work on this.  So sensitization may 
 
   2   be much more complex than just things that you 
 
   3   thought you had eaten. 
 
   4             So sensitization, I think, is an 
 
   5   enormously difficult thing to try to address.  I 
 
   6   would only be relevant if you said, if this stuff 
 
   7   is in less than X number of nanograms that it won't 
 
   8   sensitize somebody.  If you had to reach for a 
 
   9   figure there, I would probably think in the 
 
  10   microgram, nanogram, range but I would have a hard 
 
  11   time defending that. 
 
  12             DR. LEHRER:  Can we glean any information 
 
  13   out of the foods that we know are major allergens 
 
  14   and the eating habits of the population; for 
 
  15   example, something like peanuts, which are exposed 
 
  16   at a relatively young age in large amounts in the 
 
  17   American population as opposed to maybe other 
 
  18   populations and which seem to be such an important 
 
  19   food allergen. 
 
  20             DR. METCALFE:  There are general things 
 
  21   you can say.  As a population, in general, is 
 
  22   exposed to more allergens, peanut or whatever, the 
 
  23   reactions to that go up.  So there is an 
 
  24   association with exposure. 
 
  25             But if you go down to the specific, you 

 
                                                                 86 
 
   1   will find cases of children who had their first 
 
   2   peanut and anaphylaxed and you don't know where 
 
   3   they got sensitized.  Those are the two polar ends 
 
   4   of it. 
 
   5             DR. ATKINS:  The point is about 70 percent 
 
   6   of kids who are allergic to peanut have their 
 
   7   reaction on first known injection of peanut.  So 
 
   8   the point is that they are probably sensitized 
 
   9   through breast milk, mom ingesting peanut butter 
 
  10   while she is breast feeding, sensitizing her.  At 
 
  11   least a large percentage are sensitized that way. 
 
  12   That is what we think, unless there is some cross-reacting 
 
  13   allergen out there that we haven't picked 
 
  14   up yet. 
 
  15             So, again, if you are talking about 
 
  16   sensitization, the amount is small. 
 
  17             DR. METCALFE:  This is really the issue in 
 
  18   children particularly.  If you look at adults who, 
 
  19   let's say--but there are a lot of cases of adults 
 
  20   who, in their twenties or teens, first get allergic 
 
  21   to shrimp and they have been eating them regularly. 
 
  22   So they have probably had a whole lot of exposure 
 
  23   before finally something happened and they lost the 
 
  24   ability to regulate IgE to it. 
 
  25             In children, though, it is very clear.  I 

 
                                                                 87 
 
   1   would take that data and say that it is very clear 
 
   2   that nanograms to microgram levels are sensitizing 
 
   3   those children. 
 
   4             DR. ATKINS:  Right.  Again, you have got a 
 
   5   special case here.  Their GI tract may not be 
 
   6   mature.  Their immune system is not quite mature. 
 
   7             DR. LEHRER:  In those children that are 
 
   8   sensitized, possibly sensitized, to peanut via 
 
   9   mom's breast milk, have those moms been shown to be 
 
  10   eating high doses of peanuts or is there any 
 
  11   correlation with that at all? 
 
  12             DR. ATKINS:  I am not aware with a 
 
  13   correlation with dose. 
 
  14             DR. LEHRER:  Nothing is known about it? 
 
  15             DR. ATKINS:  In regard to tolerance, we 
 
  16   don't know if it is a small amount fed frequently 
 
  17   or larger amounts at intervals. 
 
  18             DR. METCALFE:  Then there is the argument 
 
  19   because this is genetically predisposed, do we do 
 
  20   children a disservice, on an epidemiologic basis, 
 
  21   if we don't expose them to small amounts when they 
 
  22   are children to tolerize.  So you have a 
 
  23   counterargument that, if you go overboard on this, 
 
  24   that you will get more children sensitized and 
 
  25   there is evidence for that. 

 
                                                                 88 
 
   1             There is evidence that more children get 
 
   2   sensitized to peanut when their mothers stay away 
 
   3   from peanuts breast feeding, at least one study I 
 
   4   know of.  So it is a moving target, really.  It is 
 
   5   very difficult to make absolutes in allergic 
 
   6   diseases. 
 
   7             There are generalities that we know.  I 
 
   8   think the more we know, the more difficult it will 
 
   9   become.  It is not that we are going to find 
 
  10   something out that is going to solve this problem. 
 
  11   The more we find out, the more difficult the 
 
  12   problem has become over the last decade.  So that 
 
  13   is why I think, going back to Dan's question, that 
 
  14   people have gone after the weight-of-evidence 
 
  15   approach, because, with time, absolutes seem less 
 
  16   absolute.  But it does mean that the committee does 
 
  17   has to very informed. 
 
  18             Can I take one question back here? 
 
  19             DR. BRANDT:  Yes. 
 
  20             DR. METCALFE:  You had a question? 
 
  21             DR. PARIZA:  I was just wondering.  I 
 
  22   heard several of you say something about outgrowing 
 
  23   these allergies.  What is the cellular or 
 
  24   molelcular basis for this.  Does anybody know?  Do 
 
  25   the plasma cells die off?  What happens? 

 
                                                                 89 
 
   1             DR. METCALFE:  No.  It is tolerance.  What 
 
   2   happens is you tolerize yourself through regulatory 
 
   3   t-cells and other things.  There are a lot of ways 
 
   4   to tolerize and specific mechanisms in the specific 
 
   5   instance you could give.  But your global question 
 
   6   is difficult. 
 
   7             Let me just make this point.  You have a 
 
   8   child sensitive to milk and they have an IgE 
 
   9   response.  Then, when they grow up, they are no 
 
  10   longer sensitive to milk and they probably will not 
 
  11   have IgE to the milk most of the time and they will 
 
  12   not have a TH1 response.  They don't see the 
 
  13   antigen. 
 
  14             So if you look at--take something we know 
 
  15   more about, say, ragweed.  If you look at people 
 
  16   that are not sensitive to ragweed, they do not have 
 
  17   a TH1 response to ragweed with gamma interferon 
 
  18   production.  They have no response.  They are TH0. 
 
  19             The problem with most of these strategies 
 
  20   is to try to counteract the TH2 with a TH1.  What 
 
  21   you really want is to take a TH2 and make it TH0. 
 
  22   That is a very important concept because when you 
 
  23   start overproducing gamma interferon in response to 
 
  24   an allergen, then you start to get other kinds of 
 
  25   diseases. 

 
                                                                 90 
 
   1             DR. KAPUSCINSKI:  I appreciate your 
 
   2   concerns about labeling.  Do you think, though, 
 
   3   that there is any other kind of approach for 
 
   4   postmarket monitoring like some kind of planned 
 
   5   epidemiological tracking that could be done that 
 
   6   would still allow us to gather some information 
 
   7   after the fact?  I guess I am interested in sort of 
 
   8   pressing on that because, given your last comments 
 
   9   about the fact that the more we know, the more 
 
  10   complex it is and the fact that there is not a very 
 
  11   good chance we are going to complete a magic-bullet 
 
  12   answer, every time I think about that, in risk 
 
  13   assessment, I find myself thinking, well, clearly, 
 
  14   then the most useful package for risk assessment or 
 
  15   risk management would be to make the best up-front 
 
  16   decision but then follow up to see if what we 
 
  17   thought was our best decision really was so, and 
 
  18   sort of prepare ourselves for--be better prepared 
 
  19   for surprises or problems, detect things before it 
 
  20   really gets out of hand. 
 
  21             DR. METCALFE:  This is the best question 
 
  22   you could ask and the most difficult question to 
 
  23   answer because you could start out with a 
 
  24   dramatically different approach than is used for 
 
  25   foods.  You could take a new product and you could 

 
                                                                 91 
 
   1   say it has to go through clinical trials, you have 
 
   2   to feed people that might potentially be sensitive. 
 
   3   How many would you have to feed?  Thousands and 
 
   4   thousands. 
 
   5             And then you would have to say that, we 
 
   6   don't see a response, or, nobody got allergic. 
 
   7   Then you would release it.  So that is one side of 
 
   8   the coin. 
 
   9             Then, if you don't want to do that, which 
 
  10   is extraordinarily difficult and no one wants to 
 
  11   get into, really, at this point in the world, then 
 
  12   you have to say, we are going to release it into 
 
  13   the population but we want to monitor for 
 
  14   reactions.  The only way you can do that is to know 
 
  15   who it is released into, tell everybody to look for 
 
  16   the reactions, particularly physicians, and raise 
 
  17   the awareness of this. 
 
  18             Of course, you get a lot of noise.  There 
 
  19   are a myriad problems with that approach.  But you 
 
  20   could do it.  Labeling, I think has a role.  It has 
 
  21   a role in protecting against allergens in general 
 
  22   and it is always debatable, in terms of genetically 
 
  23   engineered foods because foods lose their identity. 
 
  24             But there are people and places and groups 
 
  25   that have decided that labeling, they are going to 

 
                                                                 92 
 
   1   try for good, bad or indifferent.  I think it has a 
 
   2   role.  People would have to decide what that is.  I 
 
   3   wouldn't be so bold as to say that.  But that is 
 
   4   the way you would have to do it. 
 
   5             Then kind of the third tier down is to 
 
   6   say, well, let's just have people self-report if 
 
   7   they have a reaction.  Most of the time, they don't 
 
   8   know what they are eating.  They don't know if 
 
   9   something new is introduced.  That makes it as a 
 
  10   kind of safety assessment, very, very weak. 
 
  11             So those are, really, the three broad 
 
  12   things I think you are asking. 
 
  13             DR. BRANDT:  There is another problem that 
 
  14   most all epidemiologists have, having been one at 
 
  15   one time, and that is that, once you let it be 
 
  16   known that you are out looking for something like 
 
  17   this, you will get flooded with people.  The 
 
  18   classic case of increasing the incidence of 
 
  19   tularemia in Arkansas by a hundred-fold simply by 
 
  20   announcing that they were going to go out and look 
 
  21   for it. 
 
  22             Almost everybody that had seen a rabbit 
 
  23   had tularemia.  It is very difficult to do that 
 
  24   postmarketing if you announce in advance that that 
 
  25   is what you are going to do. 

 
                                                                 93 
 
   1             DR. LEHRER:  Just a quick question about 
 
   2   physician follow up on reactions or reported 
 
   3   reactions.  A patient comes into his office and it 
 
   4   is difficult to identify.  One of the real 
 
   5   problems, as I think you alluded to, is reagents 
 
   6   and availability and knowing how to trace things. 
 
   7             Do you think that, perhaps, if a panel of 
 
   8   these reagents was made available so this could be 
 
   9   used for testing such patients, this would be a 
 
  10   useful way of following it in a controlled 
 
  11   environment as opposed to-- 
 
  12             DR. METCALFE:  By reagents, do you mean 
 
  13   the genetically engineered form, raw extract, or do 
 
  14   you mean the genetically engineered protein 
 
  15   purified? 
 
  16             DR. LEHRER:  No; the raw extract.  The 
 
  17   extract in terms of whatever is being used as a 
 
  18   component in the food. 
 
  19             DR. METCALFE:  There is a certain value. 
 
  20   I don't know how practical it is.  If somebody came 
 
  21   into your office and said, "For the first time, I 
 
  22   am reacting to corn."  And you said, okay; you 
 
  23   found out that that was engineered.  So you say, 
 
  24   all right, I can call away to a certain place and I 
 
  25   can get an extract of that corn.  I can get an 

 
                                                                 94 
 
   1   unengineered in that corn, too.  I can skin test. 
 
   2   Yes; I think that has value. 
 
   3             Whether or not it is practical, because 
 
   4   there are so many things engineered, I don't know. 
 
   5   And I don't know how you vet it and purify it.  I 
 
   6   don't know about liability and I don't know how you 
 
   7   would set up the system.  But there would be a 
 
   8   certain value. 
 
   9             If you think about the way people make 
 
  10   skin-test extracts, I don't think that they are 
 
  11   paying any attention, engineered or not, right now. 
 
  12   You go get a corn extract from Hollister Steer, 
 
  13   they are going to the supermarket.  They are buying 
 
  14   what is on the market. 
 
  15             They are not saying, wow, this is 
 
  16   genetically engineered corn.  So, the stuff in the 
 
  17   bottle, most of the stuff, if it is engineered from 
 
  18   corn, it has already got the stuff in it. 
 
  19             DR. GURIAN-SHERMAN:  It would have to be 
 
  20   updated over time as they are introducing new 
 
  21   proteins. 
 
  22             DR. METCALFE:  The way that extracts are 
 
  23   made, if you talk to people at Hollister Steer, 
 
  24   they used to send the technician down to the 
 
  25   supermarket.  That is the way they do it. 

 
                                                                 95 
 
   1             DR. ATKINS:  The other thing, though, is 
 
   2   that these extracts are unreliable for fruits and 
 
   3   vegetables.  So if you are talking about corn, you 
 
   4   would have to have them bring in the corn and make 
 
   5   up a fresh extract. 
 
   6             The point I wanted to ask you about is you 
 
   7   made it sound like challenging humans with the food 
 
   8   was going to be impossible because you would have 
 
   9   to challenge so many people.  But, to me, we are 
 
  10   going to make the jump from animal models and serum 
 
  11   testing to releasing it out into the public and 
 
  12   basically exposing everybody with that. 
 
  13             So, just like we are contemplating here 
 
  14   looking at serum reactions, why wouldn't we take 
 
  15   the population of patients that we would think 
 
  16   would be at highest risk and feed them the food and 
 
  17   see what happens in that group. 
 
  18             DR. METCALFE:  Let me be clear.  First of 
 
  19   all, Dan, I didn't say not to do it or it was 
 
  20   unreasonable.  I just said it is an option that 
 
  21   people have looked at and decided that they don't 
 
  22   want to do for various reasons.  For a lot of 
 
  23   regulatory reason, statutory reasons, practical 
 
  24   reasons, everything else, this has been an approach 
 
  25   that has not been institutionalized. 

 
                                                                 96 
 
   1             My guess is that is not the purview of 
 
   2   this committee.  But you could have a real think 
 
   3   tank about this and look at the pros and cons of 
 
   4   it.  There are ethical issues.  If you don't have 
 
   5   to eat an engineered food, a lot of the Helsinki 
 
   6   rules become a problem, as you know, because you 
 
   7   then have to put people to a risk that they might, 
 
   8   arguably, never have in the real environment. 
 
   9             I don't say that that is not a hurdle you 
 
  10   can't get over but when you start to look at this 
 
  11   issue, there are a lot of things that you have to 
 
  12   discuss before you would  institutionalize such a 
 
  13   procedure. 
 
  14             I am not saying I am against it.  I am not 
 
  15   so sure some day, in the future, people might not 
 
  16   do this if there is a huge error made in screening 
 
  17   these crops. 
 
  18             DR. ATKINS:  To me, the logical problem is 
 
  19   we are going to take people that agree to do it and 
 
  20   have read the pros and cons, and we are going to 
 
  21   take that stuff out and feed it to the public 
 
  22   without informed consent.  I don't understand that. 
 
  23             DR. BRANDT:  Let me ask a question.  For 
 
  24   seventy years, we have been genetically engineering 
 
  25   foods by hybridization and cross-breeding, 

 
                                                                 97 
 
   1   selective-breeding, all the other techniques and we 
 
   2   haven't seen much as a result.  There have been new 
 
   3   corns put out all the time, for example, new beans, 
 
   4   new strawberries, that are not being done in the 
 
   5   lab but are being done by people out--grafting and 
 
   6   doing other kinds of things that people like that 
 
   7   do.  Being a gardener, I have bought them many 
 
   8   times. 
 
   9             Yet, the allergic responses to those, and 
 
  10   the allergens--and there you are doing very gross 
 
  11   transfers and it would be easy to transfer almost 
 
  12   anything--we haven't seen all of this that I know 
 
  13   of.  What is the evidence that, over the years, we--I doubt 
 
  14   if you can buy a food on the market today 
 
  15   that was there seventy-five years ago, that isn't 
 
  16   genetically engineered. 
 
  17             DR. METCALFE:  I wouldn't argue with your 
 
  18   premise.  I would say that it shows you that most 
 
  19   of the time that you do traditional plant breeding 
 
  20   and most of the time, fortunately so far, it looks 
 
  21   like all the time, when you approve something that 
 
  22   is genetically engineered, you have not had a true 
 
  23   allergy created that caused a problem. 
 
  24             It doesn't mean that it won't happen 
 
  25   tomorrow.  That is the problem. 

 
                                                                 98 
 
   1             DR. BRANDT:  Yes; I understand that. 
 
   2             DR. METCALFE:  Obviously, the number of 
 
   3   things that cause true allergies are fairly 
 
   4   circumscribed.  For all the reasons I have said, 
 
   5   there are a lot of alternative practices of 
 
   6   medicine.  You can say, "I have a food allergy," 
 
   7   and they will put you on a light box and they will 
 
   8   give you acupuncture and you can get better.   A 
 
   9   lot of things just aren't real. 
 
  10             So what you really are looking is the fact 
 
  11   that it is fairly uncommon and it protects you and 
 
  12   gives you layers of a kind of security that has 
 
  13   nothing to do with your intellectual prowess or the 
 
  14   scientific prowess or just the odds of creating 
 
  15   something that is going to be allergenic is going 
 
  16   to be unusual. 
 
  17             DR. BRANDT:  One more question. 
 
  18             DR. ASTWOOD:  Jim Astwood.  Dr. Metcalfe, 
 
  19   how do you feel about, given some of the slides 
 
  20   that you showed that a lot of the anaphylactic 
 
  21   reactions that result in death, particularly, are 
 
  22   due to unexpected exposures?  That is basically 
 
  23   when someone stumbles across peanuts, they are 
 
  24   peanut-allergic, and they didn't expect it to be 
 
  25   there. 

 
                                                                 99 
 
   1             Given what you just said, and given the 
 
   2   public-health dimension, how do you feel about 
 
   3   current methods in terms of their adequacy to 
 
   4   identify important current allergens? 
 
   5             DR. METCALFE:  Jim, are you talking about--see, a 
 
   6   lot of these cases are where a child ate 
 
   7   something that wasn't supposed to have peanut that 
 
   8   did.  So it becomes an issue of how clean are the 
 
   9   food lines, what are the thresholds.  It seems to 
 
  10   me that the big problem here is that the existing 
 
  11   guidance is not followed in most of these cases. 
 
  12             DR. ASTWOOD:  Right.  So, for us, for the 
 
  13   biotech folks, how do you feel about our ability--when we 
 
  14   are thinking about moving a specific gene 
 
  15   from one food to another, how do you feel about the 
 
  16   methodologies that are available to actually 
 
  17   identify and prevent, or identify, "Ah; that is a 
 
  18   peanut allergen or that is a kiwi allergen?" What 
 
  19   do you think of those categories of methodologies? 
 
  20             DR. METCALFE:  The one thing you can do is 
 
  21   not transfer a known allergen.  You know you can 
 
  22   prevent that. 
 
  23             DR. ASTWOOD:  Would you say that we have 
 
  24   adequate methods to do that? 
 
  25             DR. METCALFE:  Yes; you have the methods 

 
                                                                100 
 
   1   to do that.  What you don't have is when you get 
 
   2   into the gray areas of bringing in, expressing more 
 
   3   protein from some source like some soil bacteria or 
 
   4   you bring in an allergen from something that people 
 
   5   commonly don't eat, or you are worried about 
 
   6   changing something in its endogenous expression, or 
 
   7   you are worried about some other unintended 
 
   8   consequence in some other protein. 
 
   9             That is where the real difficulty is.  And 
 
  10   we know that.  I think this committee--I don't 
 
  11   think you are going to see that.  Nobody is going 
 
  12   to say, well, we have engineered this tomato to 
 
  13   express peanut storage proteins that are 
 
  14   allergenic.  Why would you want to do that? 
 
  15             DR. BRANDT:  You wouldn't sell it, 
 
  16   probably. 
 
  17             DR. METCALFE:  I don't think you are ever 
 
  18   going to see that. 
 
  19             DR. LEHRER:  If you do, you will never 
 
  20   sell another tomato. 
 
  21             DR. BRANDT:  Let's go to lunch.  Then we 
 
  22   will reassemble here at 1 o'clock. 
 
  23             [Whereupon, at 11:30 a.m., the proceedings 
 
  24   were recessed to be resumed at 1:00 p.m., this same 
 
  25   day.] 

 
                                                                101 
 
   1                A F T E R N O O N   S E S S I O N 
 
   2                                                    [1:00 p.m.] 
 
   3             DR. BRANDT:  We are ready, Dr. Pariza. 
 
   4             Safety Assessment of Enzymes and Protein 
 
   5                       Ingredients in Foods 
 
   6             DR. PARIZA:  Thank you very much.  I am 
 
   7   very glad to be here today. 
 
   8             [Slide.] 
 
   9             I am going to talk now about determining 
 
  10   the safety of microbial enzymes used in food 
 
  11   processing. 
 
  12             [Slide.] 
 
  13             There is a little bit of history that I 
 
  14   would like to begin with in describing this to you. 
 
  15   I got involved in this area since the early 1980s 
 
  16   and we published, really, three successive 
 
  17   improvements, I would say, on the original concept 
 
  18   as things evolved since then. 
 
  19             But, back in the early 1980s, there was a 
 
  20   considerable problem, both within industry and 
 
  21   within FDA, of how to determine the safety of 
 
  22   enzymes.  The problem is that an enzyme that is 
 
  23   used in food processing is not a single entity.  It 
 
  24   is really a gemish.  It is a ground-up organism of 
 
  25   some sort that happens to contain the enzyme 

 
                                                                102 
 
   1   activity that you are after. 
 
   2             There might be some modest amount of 
 
   3   purification that goes on but, in no sense, would 
 
   4   it be the kind of instrument we would take in the 
 
   5   laboratory to study enzyme kinetics or something 
 
   6   like that. 
 
   7             So the question was there were general 
 
   8   rules, or general regulations, that said that 
 
   9   enzymes could be derived from microorganisms as 
 
  10   long as they were nonpathogenic and nontoxogenic. 
 
  11   But then they listed various organisms that could 
 
  12   be used, one of them Bacillus cereus, for example, 
 
  13   which we know is a pathogen that produces toxins. 
 
  14             So the issue was how do you go about 
 
  15   determining that, in fact, these enzymes are safe. 
 
  16   So we began, in 1983, Mike Foster and I--it took us 
 
  17   about three years actually to come up with the 
 
  18   paper that was ultimately published.  I want to say 
 
  19   that Pete Reed, who is now deceased but who then 
 
  20   was the chief microbiologist of FDA, was quite 
 
  21   helpful in developing this as were the industry 
 
  22   people, in developing the initial concepts. 
 
  23             In 1990, the concept was expanded to 
 
  24   include microorganisms that were genetically 
 
  25   modified and then, most recently, in 2001, we 

 
                                                                103 
 
   1   published the latest version of this which now 
 
   2   takes into account the potential for protein 
 
   3   engineering. 
 
   4             So I would like to discuss, then, each of 
 
   5   these and lead you to where we are today on our 
 
   6   thinking. 
 
   7             [Slide.] 
 
   8             The first paper that was published in 
 
   9   1983, the focus was for enzymes produced by 
 
  10   traditional methods from microorganisms, plants and 
 
  11   animals.  Plants and animals didn't present much of 
 
  12   a issue because these were enzymes being derived 
 
  13   from plants and animals that were already 
 
  14   considered food. 
 
  15             So the focus quickly became, really, 
 
  16   primarily in microorganisms.  We considered a 
 
  17   number of issues by way of discussion points.  The 
 
  18   first and foremost is the safety of the production 
 
  19   strain which we refer to as the source organism 
 
  20   with particular regard to toxigenic and pathogenic 
 
  21   potential of those strains.i 
 
  22             We came to the conclusion that the enzyme, 
 
  23   itself, should not be focus of toxicological 
 
  24   evaluation because the enzymes that one is using in 
 
  25   food processing are carbohydrases or proteases or 

 
                                                                104 
 
   1   enzymes that already have--so the focus, we 
 
   2   determined, should not be on the enzyme, itself, 
 
   3   because the enzymes that one typically uses in food 
 
   4   processing are not associated in any sense with 
 
   5   toxic responses in animals. 
 
   6             What you really ought to be focusing on 
 
   7   are the other things that can be in the microbial 
 
   8   preparation, the other metabolites of the 
 
   9   microorganism and the potential for toxins to be 
 
  10   associated with the other metabolites within the 
 
  11   organism. 
 
  12             So the conclusion that we reached was that 
 
  13   the enzyme, itself, is not the issue but really the 
 
  14   other things that could accompany the 
 
  15   microorganism.  So it became a matter of how do you 
 
  16   determine the safety of the microorganism so that 
 
  17   it can be used as a source of enzymes. 
 
  18             [Slide.] 
 
  19             We considered a number of possible issues 
 
  20   including allergies and primary irritations.  That, 
 
  21   back in 1983, quickly reduced to the idea that 
 
  22   there are allergic and irritating reactions that 
 
  23   are associated, of course, with enzymes, 
 
  24   particularly proteases, but they are limited, 
 
  25   certainly in those days, to uses where you would 

 
                                                                105 
 
   1   get into inhalation.  So it would be either worker 
 
   2   exposure or the potential for their use in 
 
   3   detergents and that kind of thing. 
 
   4             We were unable to find any instance where 
 
   5   an allergy had been associated with an enzyme that 
 
   6   had been used in food processing that had been 
 
   7   ingested.  To my knowledge, that is still true 
 
   8   today.  There are, certainly, allergies and 
 
   9   irritations that one can have from enzymes but, 
 
  10   like I say, those are primarily through worker 
 
  11   exposure in manufacturing or they are due to their 
 
  12   use within certain specific applications like a 
 
  13   detergent.  That area has been largely cleaned up 
 
  14   due to the reduction of dust generation. 
 
  15             But I would like you all to think about 
 
  16   that.  If I am wrong, I would sure like to hear 
 
  17   about it, but I am unaware of any instance where an 
 
  18   enzyme used in food processing has ever caused an 
 
  19   allergy. 
 
  20             DR. ATKINS:  What about papain? 
 
  21             DR. PARIZA:  A papain allergy? 
 
  22             DR. ATKINS:  Yes. 
 
  23             DR. PARIZA:  To a person ingesting where 
 
  24   papain was used? 
 
  25             DR. ATKINS:  Or injected into, papain 

 
                                                                106 
 
   1   injected or papain in foods.  I thought that was an 
 
   2   allergen. 
 
   3             DR. PARIZA:  I am not aware of it.  I 
 
   4   would like to hear more about that. 
 
   5             DR. ATKINS:  I just remember reading about 
 
   6   sensitivity to papain in the past.  It is an enzyme 
 
   7   and it is used in food processing as a meat 
 
   8   tenderizer. 
 
   9             DR. PARIZA:  The question here is whether 
 
  10   there is any residual papain to result in an 
 
  11   exposure. 
 
  12             DR. ATKINS:  That is part of a meat 
 
  13   tenderizer.  You would sprinkle it on the meat and 
 
  14   the meat would be tenderized and it can be 
 
  15   sensitized. 
 
  16             DR. PARIZA:  I have to admit that I am not 
 
  17   familiar with that particular one.  But, as far as 
 
  18   I know, if that is an enzyme sprinkled on it, that 
 
  19   would be one thing.  I guess I am thinking 
 
  20   particularly of a commercial application where the 
 
  21   enzyme has been put in food. 
 
  22             DR. LEHRER:  You were saying bacteria, 
 
  23   weren't you? 
 
  24             [Multiple conversations.] 
 
  25             DR. BRANDT:  I have to remind you, speak 

 
                                                                107 
 
   1   into the microphone.  I have already been chewed 
 
   2   out once. 
 
   3             DR. METCALFE:  The point is the bacterial 
 
   4   enzymes that are part of this, that was the primary 
 
   5   focus.  I should say that, for example, we were 
 
   6   aware of people that--there are fungal 
 
   7   carbohydrases, for example, there are well-known 
 
   8   allergies to that in workers, but we were unable to 
 
   9   document that that occurred as a result of people 
 
  10   ingesting food that had been treated with those 
 
  11   enzymes. 
 
  12             There are reasons for this.  The enzymes 
 
  13   that are used in food processing are used at low 
 
  14   levels and it is generally well less than 1 
 
  15   percent.  That would be of the mixture, so the 
 
  16   actual enzyme would be much lower than that.  The 
 
  17   second part of that would be that there is heat 
 
  18   processing involved and you guys would know more 
 
  19   about that than I would, but, certainly, that would 
 
  20   be a factor in all this. 
 
  21             So I think those are considerations but, 
 
  22   in terms of the microbial enzymes, I still think 
 
  23   that what I said holds.  So we did consider that as 
 
  24   a factor. 
 
  25             We also looked at the issue of carcinogens 

 
                                                                108 
 
   1   and mutagens, teratogens and reproductive effects. 
 
   2   These are certainly effects that are produced by 
 
   3   small organic molecules but, so far as we know, 
 
   4   proteins are not involved in these effects and 
 
   5   there is no product toxicity that you wouldn't pick 
 
   6   up as an acute effect due to a protein or an 
 
   7   enzyme, particularly an enzyme exposure. 
 
   8             We looked at the issue of antibiotics. 
 
   9   Certainly some microorganisms can produce 
 
  10   antibiotics.  This needs to be part of any 
 
  11   screening assay that you are doing.  We considered 
 
  12   the question of products of enzymatic reactions. 
 
  13   Again, I will refer to the original paper but the 
 
  14   issue here refers to fairly standard reactions that 
 
  15   are occurring as a result of enzymes that would be 
 
  16   fairly well known.  It is not exotic enzymes doing 
 
  17   exotic things to foods. 
 
  18             Interactions between enzymes and other 
 
  19   food components was another factor that we looked 
 
  20   at as well as the issue of direct effects of 
 
  21   enzymes on consumers.  Again we are talking about 
 
  22   the enzymes that would actually be used in a food-processing 
 
  23   setting. 
 
  24             [Slide.] 
 
  25             We developed a decision tree for 

 
                                                                109 
 
   1   determining the safety of enzymes in this original 
 
   2   paper.  It was aimed at  focusing on toxigenic 
 
   3   potential, primarily of the source organism.  It is 
 
   4   important here to consider that you have got 
 
   5   bacteria, yeasts and fungi and they all are 
 
   6   different and you need to consider them differently 
 
   7   when you are thinking about toxigenic potential. 
 
   8             For example, the toxins that bacteria 
 
   9   typically produce, the toxins that will produce 
 
  10   some type of an adverse reaction upon ingestion, 
 
  11   are protein toxins.  They are enterotoxins.  There 
 
  12   are a number that have been described.  They will 
 
  13   produce a very rapid response as a result of 
 
  14   ingestion. 
 
  15             Yeast present, as far as I know, no known 
 
  16   problem because they are not known to produce 
 
  17   toxins.  If you read the microbiology textbooks, 
 
  18   they all tell you that yeasts--there are certainly 
 
  19   pathogenic yeasts but not toxins associated with 
 
  20   yeasts unless, of course, you consider alcohol a 
 
  21   toxin. 
 
  22             There is another issue with these that you 
 
  23   can get into and that concerns urethane which 
 
  24   potentially is carcinogenic, but that is a separate 
 
  25   issue.  It depends on how the organism is grown.  

 
                                                                110 
 
   1   So that needs to be taken into account when you are 
 
   2   dealing with yeast fermentations. 
 
   3             Finally, we get into the filamentous fungi 
 
   4   and molds.  Here, of course, there is a whole slug 
 
   5   of toxins that one could be concerned with, small-molecular- 
 
   6   weight toxins, that are potentially 
 
   7   carcinogens and mutagens and teratogens and so on. 
 
   8   In fact, if you want a life career as a young 
 
   9   microbiologist, just go into the mycotoxin area 
 
  10   because I don't think you would ever run out of 
 
  11   things to do.  There is no end to the problems that 
 
  12   molds can cause. 
 
  13             Fortunately, there are ways of screening 
 
  14   for these.  So a lot of the known toxins can be 
 
  15   readily screened for in the laboratory so you can 
 
  16   get around those problems fairly easily.  The other 
 
  17   thing is that, by doing the relatively short-term, 
 
  18   say a three-month, study, one could easily 
 
  19   determine whether there was something in a mold 
 
  20   preparation which was, in fact, producing a toxic 
 
  21   response in an animal.  So subchronic feeding test 
 
  22   is very useful for determining the toxigenic 
 
  23   potential of a filamentous fungi, of mold. 
 
  24             So the emphasis that we developed was to 
 
  25   do specific screening for chemical and biochemical 

 
                                                                111 
 
   1   tests.  Of course, in 1983, the ability to do this 
 
   2   was nowhere as near as sophisticated as it is today 
 
   3   but the idea is to do screening tests with 
 
   4   biochemical tests for toxins and to rely on animal 
 
   5   tests at the end of the game once you have 
 
   6   convinced yourself that there is nothing that ought 
 
   7   to stop you earlier.  So you are relying primarily 
 
   8   on the chemical tests early on to screen out 
 
   9   potential bad actors before you get to the animal 
 
  10   tests. 
 
  11             [Slide.] 
 
  12             At the end of the day, we reached the 
 
  13   conclusion that the enzymes, per se, that are now 
 
  14   used or are likely to be used in the future in food 
 
  15   processing are inherently nontoxic and that safety 
 
  16   evaluation should focus on possible contaminants 
 
  17   which could be present. 
 
  18             Assuming good manufacturing practices are 
 
  19   followed, toxic contaminants could only come from 
 
  20   the enzyme source, itself.  In other words, we are 
 
  21   assuming that the ingredients one uses ought to be 
 
  22   food grade.  I think it is very important that the 
 
  23   manufacturers use ingredients in enzyme 
 
  24   fermentations that are, in fact, safe to begin with 
 
  25   and approved by FDA. 

 
                                                                112 
 
   1             So, therefore, you are really talking 
 
   2   about toxic contaminants that are coming from the 
 
   3   source, from the organism, in this particular case, 
 
   4   the microorganisms that are producing the enzymes. 
 
   5   So the safety of the source organism should be the 
 
   6   primary consideration in determining the safety of 
 
   7   the enzyme preparation. 
 
   8             [Slide.] 
 
   9             So that paper was quite well received and 
 
  10   particularly the microbiologists liked it.  I have 
 
  11   had long talks with toxicologists about the ability 
 
  12   to be able to do things or think about things in 
 
  13   this kind of a manner with regard to determining 
 
  14   the safety. 
 
  15             So things went along pretty well until we 
 
  16   reached the early 1990s when, by then, it was clear 
 
  17   that genetic modification was coming into the fore 
 
  18   and so this presented, then, new challenges that 
 
  19   needed to be addressed. 
 
  20             If you look at the paper, Biotechnologies 
 
  21   in Food: Assuring the Safety of Foods Produced by 
 
  22   Genetic Modification, which was published in 1990 
 
  23   produced by the International Food Biotechnology 
 
  24   Council, one of the chapters deals with food and 
 
  25   food ingredients including enzymes which are 

 
                                                                113 
 
   1   derived from genetically modified organisms.  The 
 
   2   enzymes was the particular part that I dealt with. 
 
   3             Incidently, that still represents a very, 
 
   4   very, very comprehensive list of all the known 
 
   5   toxins that are associated with plants, 
 
   6   particularly plants, but there are also microbial 
 
   7   toxins listed as well, although, in that case, 
 
   8   because of the mycotoxins, that part of the list 
 
   9   could be updated. 
 
  10             But if you want to see a really 
 
  11   comprehensive list of toxins associated with 
 
  12   plants, this is an excellent source.  There are 
 
  13   something like 225 toxins that are associated, that 
 
  14   were identified and discussed, at least to some 
 
  15   extent in this report and so I would refer you to 
 
  16   that as a very nice compilation of things. 
 
  17             [Slide.] 
 
  18             So the new discussion points that we 
 
  19   considered in 1990 were information on antibiotic 
 
  20   resistance genes, vectors, DNA inserts, DNA from 
 
  21   intermediate posts.  These were all the things that 
 
  22   came into consideration in our 1990 presentation. 
 
  23             [Slide.] 
 
  24             We, basically, at the end of the day 
 
  25   reaffirmed the basic concept of the original 

 
                                                                114 
 
   1   decision tree but we added on top of that six new 
 
   2   decision-tree questions regarding genetic 
 
   3   modification. 
 
   4             [Slide.] 
 
   5             Those are as follows: does the microbe end 
 
   6   up in the food?  Is the organism free of 
 
   7   transferable antibiotic resistance genes?  Does a 
 
   8   resistance gene code for resistance to a substance 
 
   9   used in the control of disease agents in human or 
 
  10   veterinary medicine?  Are the vectors characterized 
 
  11   and free of attributes that would render them 
 
  12   unsafe for constructing microorganisms to be used 
 
  13   in food-grade products?  Does the DNA insert code 
 
  14   for a substance that one could consider safe for 
 
  15   use in food.  Finally, is the microbe free of DNA 
 
  16   from some intermediate host which could code for a 
 
  17   toxic product. 
 
  18             So these are the new questions that we 
 
  19   felt were relevant to the whole issue of using an 
 
  20   organism, a microorganism, specifically, as a host 
 
  21   for a gene that could then produce a new enzyme 
 
  22   that that organism would not have otherwise have 
 
  23   produced, would not naturally produce. 
 
  24             So these are the questions, then, that we 
 
  25   felt needed to be put on top of the original 

 
                                                                115 
 
   1   decision tree to come to grips with this. 
 
   2             [Slide.] 
 
   3             This is just a rendition of what I just 
 
   4   said. 
 
   5             [Slide.] 
 
   6             So the focus of the decision tree is on 
 
   7   the safety of the organism and the products it 
 
   8   produces.  It is assumed, again, that if the 
 
   9   organism is nontoxigenic and nonpathogenic, then 
 
  10   foods and food ingredients produced from the 
 
  11   organism under good manufacturing practices will be 
 
  12   safe to consume.  That was a conclusion that was 
 
  13   reached in 1990. 
 
  14             Now, we have reached 2000.  We have 
 
  15   reached the new millennium and we have discovered 
 
  16   there are yet--or we have put into practice, I 
 
  17   should say, yet other ways of modifying enzymes. 
 
  18   So now one needs to consider the possibility of 
 
  19   engineered enzymes that may vary slightly from 
 
  20   their naturally occurring progenitors. 
 
  21             One thing to consider in this case is that 
 
  22   the kinds of engineering that one is doing--I will 
 
  23   talk about this in a little more detail in a few 
 
  24   minutes, but the kind of engineering that one talks 
 
  25   about doing is within the variation that one might 

 
                                                                116 
 
   1   normally find.  We are not talking about wholesale 
 
   2   reconstruction of an enzyme, but usually a change 
 
   3   of an amino-acid sequence here or there which would 
 
   4   make the enzyme, either increase its activity under 
 
   5   some particular condition to increase its 
 
   6   resistance to heat and that kind of thing. 
 
   7             So they are relatively small changes. 
 
   8   Fortunately, there are very large databases that 
 
   9   one can use.  I will refer you to the paper.  In 
 
  10   fact, I think we are going to have copies of it for 
 
  11   all of you which will give you, really, a very 
 
  12   large compilation of all the databases that are 
 
  13   available for being able to consider what kinds of 
 
  14   changes are out there naturally, what kinds of 
 
  15   things one could potentially do with an enzyme. 
 
  16             The other thing about this new paper that 
 
  17   you will find; Table 1 has an enormous listing of 
 
  18   enzymes.  It goes on for four pages.  I thought we 
 
  19   had them all but, even with four pages, we missed a 
 
  20   couple.  But at least you will find most of the 
 
  21   enzymes, virtually all the enzymes, anyway that are 
 
  22   currently in use or at least were in use as of 
 
  23   2001. 
 
  24             So you can get some feel for the kinds of 
 
  25   enzyme products that are used in this case 

 
                                                                117 
 
   1   worldwide. 
 
   2             [Slide.] 
 
   3             Another part of this is that we have also 
 
   4   now come to recognize something that wasn't so 
 
   5   clear in 1983 and that is that all microorganisms 
 
   6   are, to some degree, genetically unstable.  So it 
 
   7   is important to consider these factors in 
 
   8   determining the safety of the producing strain and 
 
   9   the products that it produces.  This is something 
 
  10   that is very important to keep in mind. 
 
  11             [Slide.] 
 
  12             We revamped and expanded the decision tree 
 
  13   to fully encompass current industry practice and we 
 
  14   worked with the industry, the enzyme-manufacturing 
 
  15   industry, to find out what it is that is actually 
 
  16   being done because, when I went into this project, 
 
  17   I said, we don't want to be talking about things 
 
  18   that could be done or might be done or maybe were 
 
  19   done last year.  We want to know what is being done 
 
  20   so that we can evaluate things based on current 
 
  21   industry practice, and so that is really where an 
 
  22   important focus is here. 
 
  23             As I say, we included an almost complete 
 
  24   list of microbial enzymes.  In fact, I think it is 
 
  25   a complete list of microbial enzymes used in foods. 

 
                                                                118 
 
   1   One enzyme I know we missed was a nonmicrobial 
 
   2   enzyme.  So, again, we were primarily focused on 
 
   3   microbial enzymes. 
 
   4             [Slide.] 
 
   5             Now, this is a very important concept, 
 
   6   particularly with what we know about microorganisms 
 
   7   today, and that is the safe strain lineage.  There 
 
   8   are strains that industry, that various enzyme 
 
   9   manufacturers, have been using for a long time, 
 
  10   producing different products, different enzymes in 
 
  11   particular, using a specific strain which is kept 
 
  12   in house, which is controlled, which is kept away 
 
  13   from contamination. 
 
  14             Those are the strains that one feels most 
 
  15   comfortable with.  If you go out in the back yard 
 
  16   and you dig something up, you might think it looks 
 
  17   exactly like the one you have got in the lab but it 
 
  18   may not be.  And that gets back to this whole 
 
  19   issue, again, of genetic stability. 
 
  20             If you want to go through the trouble of 
 
  21   sequencing it and showing that it is exactly the 
 
  22   same thing that you have in your lab, that's fine, 
 
  23   or in the plant, that's fine.  But an important 
 
  24   consideration in terms of safety evaluation is safe 
 
  25   strain lineage. 

 
                                                                119 
 
   1             If you are able to determine that an 
 
   2   organism, in fact, doesn't produce toxins, doesn't 
 
   3   produce adverse problems that one would be 
 
   4   concerned with, then you should be able to use that 
 
   5   organism as a starting point, logically, for 
 
   6   further modifications.  It would make more sense to 
 
   7   begin with that than it would be to begin with 
 
   8   something that is less characterized and less well-known. 
 
   9             [Slide.] 
 
  10             So this is the decision tree.  I won't 
 
  11   begin to ask you to go through all this stuff from 
 
  12   this, but this just shows you how complicated it 
 
  13   gets.  But I will go through just a few of the 
 
  14   issues. 
 
  15             [Slide.] 
 
  16             Number 12 tells you that is where you will 
 
  17   end up if things don't get booted out of this at 
 
  18   any point.  Number 12 says that and undesirable 
 
  19   trait or substance may be present and the test 
 
  20   article is not acceptable for food use.  If the 
 
  21   genetic potential for producing the undesirable 
 
  22   trait or substance can be permanently inactivated 
 
  23   or deleted, the test article may then be passed 
 
  24   through the decision tree again.  The test article 

 
                                                                120 
 
   1   in this case would be the enzyme preparation, what 
 
   2   you are actually selling, not purified enzyme, per 
 
   3   se, unless you are selling a purified enzyme. 
 
   4             DR. ASTWOOD:  A quick point of 
 
   5   clarification.  On Number 11 there, the no-adverse-effect 
 
   6   level, is that a subchronic study or an 
 
   7   acute study? 
 
   8             DR. PARIZA:  It could be either one.  A 
 
   9   lot of this is based on comparative toxicology.  It 
 
  10   depends on the organism.  It depends on the 
 
  11   background of what you are talking about.  But I 
 
  12   will come to that in a moment. 
 
  13             [Slide.] 
 
  14             This is such a long thing, I thought I 
 
  15   would split it up so it is a little more readable 
 
  16   for you, but it begins with the question, is the 
 
  17   production strain genetically modified.  If the 
 
  18   answer is yes, you go on.  If it is no, you go to 
 
  19   6, and we will come to 6 in a minute. 
 
  20             If it is genetically modified, then you 
 
  21   ask question like, is the production stream 
 
  22   modified using our rDNA techniques  It would be 
 
  23   possible to modify an organism without that; for 
 
  24   example, through traditional mutagenesis. 
 
  25             Then if you are using recombinant DNA 

 
                                                                121 
 
   1   techniques, then you go on to specific questions 
 
   2   relating to recombinant DNA.  That is what 3a, b, 
 
   3   c, d and e refer to.  One of these, you will see, 
 
   4   again, refers to a NOAEL, no observable adverse-effect 
 
   5   level.  Short-term oral studies, we are 
 
   6   talking about studies that are designed for the 
 
   7   questions being asked. 
 
   8             If you are working with a bacterium and 
 
   9   you are worried about the potential for an 
 
  10   enterotoxin, then you design your tests in certain 
 
  11   ways.  If you have organisms that have the 
 
  12   potential to produce small molecular-weight toxins--for 
 
  13   example, molds--you would design your tests in 
 
  14   other ways. 
 
  15             Of course, you first do your chemical or 
 
  16   biochemical screening before you even get to this 
 
  17   question.  But these animal studies are tailored 
 
  18   and designed to go after the kinds of issues that 
 
  19   could be associated with the particular strain that 
 
  20   one is concerned with. 
 
  21             Questions about antibiotic resistance 
 
  22   gene, whether those genes are coding for drugs that 
 
  23   are related to the treatment of disease in humans 
 
  24   or in animals and other introduced DNA and whether 
 
  25   or not it is safe for constructing food-grade 

 
                                                                122 
 
   1   organisms. 
 
   2             [Slide.] 
 
   3             Then we go on to the next part of it which 
 
   4   just says concerns, if the DNA is randomly 
 
   5   integrated into chromosomes, another issue that one 
 
   6   needs to consider.  Is the production strain 
 
   7   sufficiently well-characterized so that one may 
 
   8   reasonably conclude that unintended pleiotropic 
 
   9   effects--that is another issue that you need to be 
 
  10   concerned with.  This was first described in plants 
 
  11   where one gene can affect a whole bunch of other 
 
  12   genes. 
 
  13             That is a very important consideration, 
 
  14   particularly with eukaryotes, again in the molds 
 
  15   and things.  So, again, if you have got a lot of 
 
  16   information from safe-strain lineage, it makes it a 
 
  17   whole lot easier to do these characterizations.  If 
 
  18   you are working with brand-new strains, you have to 
 
  19   do a lot of work to get to the point where you can 
 
  20   be sure that you, in fact, have something that is 
 
  21   safe to use. 
 
  22             That is where 6 comes in, safe strain 
 
  23   lineage, as previously demonstrated by repeated 
 
  24   assessment via a  evaluation procedure like this or 
 
  25   one that is very similar.  If that is the case, 

 
                                                                123 
 
   1   then, at that point, you couldn't separate it. 
 
   2             If there are still questions, then you 
 
   3   need to go on and ask, for example, is the organism 
 
   4   nonpathogenic.  Is the test article free of 
 
   5   antibiotics.  I know a lot of screens that one 
 
   6   could potentially do.  Is the test article free or 
 
   7   oral toxins known to be produced by other members 
 
   8   of the same species?  Are the amounts of such 
 
   9   toxins in the test article below levels of concern? 
 
  10             Then, the one that you asked me for which 
 
  11   is about the no-observable adverse-effect level. 
 
  12   There are a number of different tests, animal 
 
  13   tests, that we describe in here that are aimed at 
 
  14   going after the kinds of issues that might be 
 
  15   associated with the organism, source of organism, 
 
  16   that one is concerned with. 
 
  17             Again, I will refer you to the paper.  I 
 
  18   think you all be getting copies so you can look at 
 
  19   this in depth regarding that. 
 
  20             [Slide.] 
 
  21             These are the issues that I think address 
 
  22   the toxicology, what I would call or what Dr. 
 
  23   Metcalfe referred to before, as the traditional 
 
  24   toxicology questions.  Of course, we don't have 
 
  25   worked into this some kind of a test for 

 
                                                                124 
 
   1   allergenicity, per se. 
 
   2             It is really up to you to come to grips 
 
   3   with the whole issue--that is what you are doing 
 
   4   here today--the whole issue of allergenicity.  I am 
 
   5   not going to pretend to have any answers for you, 
 
   6   per se, but there are some considerations that I 
 
   7   think you need to keep in mind when you are dealing 
 
   8   with enzymes used in food processing. 
 
   9             One is the low level, the control level, 
 
  10   that one can use in this particular case and that 
 
  11   compared certainly to other proteins that are 
 
  12   present the levels are quite low.  The second issue 
 
  13   is, of course, that the food almost always go 
 
  14   through some heat processing step which would 
 
  15   likely certainly inactivate the enzyme, would 
 
  16   likely denature other proteins that are in there, 
 
  17   too, to some extent. 
 
  18             The other important question is the whole 
 
  19   idea of safe strain lineage because, generally, at 
 
  20   least the kinds of enzymes that traditional 
 
  21   manufacturers are going to produce today to build a 
 
  22   food, are going to be enzymes that are coming from 
 
  23   organisms that they have used over the years and 
 
  24   they have made modifications here and there to 
 
  25   improve enzyme yield, or they might not be 

 
                                                                125 
 
   1   engineering those enzymes to--making very small 
 
   2   modifications to increase the ability of the enzyme 
 
   3   to tolerate heat, and that sort of thing, maybe 
 
   4   change some of the substrate specificity. 
 
   5             Again, the changes that are being made are 
 
   6   very conservative and within the range of what one 
 
   7   would find in nature.  That is an important 
 
   8   consideration.  It is certainly an important set of 
 
   9   questions to ask and that is what this is all 
 
  10   about. 
 
  11             So, I don't think the allergenic potential 
 
  12   for food-processing enzymes should be a real top 
 
  13   priority for you compared to some of the other 
 
  14   things you have heard about today. 
 
  15             So, at that point, I will stop and ask for 
 
  16   questions. 
 
  17             DR. BRANDT:  Questions? 
 
  18                    Questions of Clarification 
 
  19             DR. BUCHANAN:  Yes; I have a question. 
 
  20   Bob Buchanan.  Approximately how many enzymes have 
 
  21   been added to food and none of which has yet been 
 
  22   shown to cause an allergy? 
 
  23             DR. PARIZA:  The only exception I can 
 
  24   think of is the papain story.  I guess the issue is 
 
  25   whether it is really the papain or something else 

 
                                                                126 
 
   1   that might be in there.  With that exception, and I 
 
   2   have to admit I am embarrassed and I should know 
 
   3   more about it. 
 
   4             In terms of microbial enzymes, you are 
 
   5   talking--well, you can look at the list.  I didn't 
 
   6   count them, but I am going to say there are 
 
   7   certainly well more than 100 here.  You will have 
 
   8   this paper very soon.  There are many, many, and 
 
   9   there have been more added in the last ten years. 
 
  10   But they are generally from the same organisms. 
 
  11   These are new enzymes that are being used but there 
 
  12   is not a big change in the strains. 
 
  13             DR. BUCHANAN:  Even so, they are different 
 
  14   proteins. 
 
  15             DR. PARIZA:  Yes.  That is another 
 
  16   important consideration.  People think that, 
 
  17   because they call an enzyme by a certain name, that 
 
  18   if the enzyme comes from another organism it is the 
 
  19   same enzyme.  That is not true.  We know that.  The 
 
  20   protein structure can certainly change. 
 
  21             DR. BRANDT:  Other questions?  Thank you 
 
  22   very much. 
 
  23             We need Dr. Maryanski. 
 
  24             DR. LANE:  If I am guessing right, he is 
 
  25   scrambling from the auditorium to here.  He wanted 

 
                                                                127 
 
   1   to see how the presentation was coming in. 
 
   2             DR. MARYANSKI:  I just spent a little time 
 
   3   in the hinterlands, meaning the auditorium.  I 
 
   4   would suggest that we do try to speak into the 
 
   5   microphones and one person at a time.  It is 
 
   6   difficult for the people in the auditorium to hear 
 
   7   otherwise. 
 
   8             So I will try to use a louder voice and 
 
   9   hope it holds up. 
 
  10             DR. BRANDT:  I just want to remind 
 
  11   everybody that I have now been sensitized.  So, the 
 
  12   next time you don't use the microphone, I am going 
 
  13   to have an anaphylactic--please use the microphone. 
 
  14            FDA Food Biotechnology Policy and Current 
 
  15                   Approaches to Allergenicity 
 
  16             DR. MARYANSKI:  Thank you very much, Mr. 
 
  17   Chairman.  Good afternoon, ladies and gentlemen. 
 
  18   Again, on behalf of all of us who have worked and 
 
  19   put this meeting together, we really appreciate all 
 
  20   of you taking the time from everything else that is 
 
  21   very important to you to come and help us out with 
 
  22   this.  We look forward to working with you over the 
 
  23   next couple of years, actually, hopefully. 
 
  24             This is a first meeting.  We want to 
 
  25   provide you with enough background so that you have 

 
                                                                128 
 
   1   a good sense of how we have got to where we are 
 
   2   today.  So part of my presentation is going to be 
 
   3   quite old information for a number of you, but we 
 
   4   thought it was important to give you a sense of 
 
   5   what our policy is, the point we have reached today 
 
   6   and why we are where we are. 
 
   7             Then I will also give you some information 
 
   8   about what our current policy is.  So this is all, 
 
   9   again, by way of giving you some background 
 
  10   information so that you will have that as you being 
 
  11   your discussions. 
 
  12             [Slide.] 
 
  13             The Food, Drug and Cosmetic Act, as I 
 
  14   think you have probably understood by now, is the 
 
  15   statutory authority, the legal basis under which we 
 
  16   work and that really guides everything that we do 
 
  17   in the sense of what we can do and what we cannot 
 
  18   do. 
 
  19             The Act is very broad.  I won't go into 
 
  20   all of its provisions but it has basically been in 
 
  21   place in essentially its current form since 1938. 
 
  22   So it has been around a long time.  It has been 
 
  23   amended many times, as you heard earlier, in 1958, 
 
  24   to give us authority to approve the food additives. 
 
  25   But the Act is very broad.  It gives us both 

 
                                                                129 
 
   1   authority over the safety of foods and sets the 
 
   2   standards for those foods.  It also gives us 
 
   3   enforcement action, to take action if anyone or any 
 
   4   product violates the Act. 
 
   5             We base our policies and our regulations 
 
   6   on the best science that we have at the time.  That 
 
   7   is one of the reasons that we are all here today, 
 
   8   to examine what the science is in a particular 
 
   9   area. 
 
  10             Our authority is about products that are 
 
  11   in interstate commerce and products, that means 
 
  12   products that are imported into the United States, 
 
  13   products that are moving within the United States. 
 
  14             We do not regulate research.  I think that 
 
  15   is an important point but it is also important to 
 
  16   understand that developers tend to come in and see 
 
  17   us early in the process and we encourage them to do 
 
  18   that.  So we have a number of interactions at the 
 
  19   research level, but we do not have authority to 
 
  20   regulate research in the development of food, food 
 
  21   ingredients. 
 
  22             Of course, our mission is to ensure a safe 
 
  23   and wholesome food supply.  I think I will 
 
  24   emphasize the fact that, while we talk about 
 
  25   biotechnology a lot and I, in particular, talk 

 
                                                                130 
 
   1   about it a lot, we are not proponents of the 
 
   2   technology or the products.  Our role is protecting 
 
   3   public health.  So that is our mission. 
 
   4             [Slide.] 
 
   5             You have already heard about this.  I am 
 
   6   going to go through this very quickly now, but just 
 
   7   to give you a sense of what our authority covers. 
 
   8   There are three agencies, federal agencies, that 
 
   9   are primarily responsible for the safety of food 
 
  10   produced by biotechnology, FDA, EPA and USDA. 
 
  11             We, of course, are responsible for most 
 
  12   foods.  Meat, poultry and certain egg products are 
 
  13   regulated by the Department of Agriculture and 
 
  14   USDA.  FDA regulates everything else in the grocery 
 
  15   store, so all the other packaged foods, all the 
 
  16   fruits and vegetables, all fall under FDA's 
 
  17   authority.  So, in terms of crops, the foods 
 
  18   derived from crops all fall under FDA's authority. 
 
  19             USDA, in terms of products produced by 
 
  20   modern biotechnology, is primarily responsible for 
 
  21   ensuring that those crops are not plant pests and 
 
  22   that those products can move into the country as 
 
  23   plant products.  So their oversight takes into 
 
  24   account most of the environmental issues that might 
 
  25   be thought about for these products. 

 
                                                                131 
 
   1             So, as you heard earlier, we defer to USDA 
 
   2   on most environmental issues.  The growing of 
 
   3   crops, you might think of as primarily being under 
 
   4   USDA and the safety of those foods, feeds, derived 
 
   5   from those crops is FDA. 
 
   6             [Slide.] 
 
   7             EPA has authority to regulate pesticides 
 
   8   under both FIFRA, which is the Federal Insecticide 
 
   9   Fungicide Rodenticide Act but, also, under the Food 
 
  10   Drug and Cosmetic Act.  EPA sets tolerances for 
 
  11   safe levels of pesticides or exemptions from 
 
  12   tolerances including tolerances and exemptions 
 
  13   under the Food Drug and Cosmetic Act for pesticides 
 
  14   and foods. 
 
  15             So, if you think of biotechnology corn, 
 
  16   for example, where it is a BT corn, you have the BT 
 
  17   as a pesticide trait.  It is a characteristic that 
 
  18   has pesticide properties.  So that trait, the BT, 
 
  19   falls under EPA.  They do the safety assessment of 
 
  20   BT. 
 
  21             USDA has authority over the growing of 
 
  22   that crop during the field testing and the 
 
  23   exception from their regulations for commercial 
 
  24   growing.  FDA has authority over the corn products 
 
  25   that would be used, say, as high-fructose corn 

 
                                                                132 
 
   1   syrup or animal feed that are derived from those 
 
   2   corn plants.  So, in the case of a BT corn plant, 
 
   3   all three agencies have some authority over that 
 
   4   product. 
 
   5             [Slide.] 
 
   6             In 1992, we published what we call a 
 
   7   policy statement.  This was our attempt to answer 
 
   8   questions that were coming to us early in the 
 
   9   development of crops produced by modern 
 
  10   biotechnology.  Companies were at the point where 
 
  11   it was obvious they were going to eventually want 
 
  12   to market foods derived from these crops.  They 
 
  13   knew this was a new technology and so they were 
 
  14   asking us questions about what would be the legal 
 
  15   basis for how these foods would be regulated and 
 
  16   what would be the safety testing that would be 
 
  17   needed to ensure that these products were safe for 
 
  18   the public. 
 
  19             The '92 policy, which is available on our 
 
  20   website, was our effort to answer those questions. 
 
  21   We set out the legal basis for how we regulate 
 
  22   foods.  We explained the various provisions of the 
 
  23   Act that apply to regulating foods and food 
 
  24   ingredients but, more importantly, we set out the 
 
  25   issues that we thought should be taken into account 

 
                                                                133 
 
   1   for safety of these products. 
 
   2             We did that through both text and a series 
 
   3   of decision trees that explain what the issues are. 
 
   4   We do not describe specific tests.  We simply 
 
   5   indicated what kinds of questions should be asked. 
 
   6   That was done so that developers would have the 
 
   7   advantage of our guidance early in the process 
 
   8   before the products came to market. 
 
   9             This policy statement covered fruits, 
 
  10   vegetables and grains, basically foods that are 
 
  11   derived from crops, and it applied to all methods 
 
  12   of plant breeding.  We did this for the purpose of 
 
  13   answering questions about modern biotechnology--that is, the 
 
  14   use of recombinant DNA techniques, but 
 
  15   we thought that these products should meet the same 
 
  16   standards that apply to all other foods. 
 
  17             If a food is derived by conventional 
 
  18   hybridization, or embryo rescue, or some clonal 
 
  19   selection or recombinant DNA, those foods should 
 
  20   all meet the same standards under the Act.  So the 
 
  21   '92 policy really is about all foods derived from 
 
  22   crops but intended to answer the questions about 
 
  23   the use of rDNA. 
 
  24             When I speak of foods, unless I 
 
  25   specifically mention feeds, I am also speaking of 

 
                                                                134 
 
   1   feeds.  Feeds are included in our definition, our 
 
   2   legal definition, of food.  So the policy does 
 
   3   apply to both foods and feeds. 
 
   4             [Slide.] 
 
   5             I am going to give you a little bit of a 
 
   6   sense of just what are the very broad-brush legal 
 
   7   tools that we have to ensure the safety of foods. 
 
   8   There really are two provisions.  Foods, under the 
 
   9   Act, are not subject to a requirement for review or 
 
  10   notification or an approval by FDA before they are 
 
  11   placed on the market. 
 
  12             The first time kiwi, for example, was 
 
  13   introduced into U.S. grocery stores, no one was 
 
  14   legally required to tell FDA about that.  On the 
 
  15   other hand, the Act does set out the safety 
 
  16   standards for foods so the developer, or the 
 
  17   sponsor who is putting that product on the market, 
 
  18   has a legal duty, under the law, to ensure that 
 
  19   that food is safe. 
 
  20             FDA has enforcement authority to take 
 
  21   action if that product is not safe.  If that 
 
  22   product violates the law in some way, then we have 
 
  23   the authority to take action to prevent that 
 
  24   product from continuing in the marketplace.  We 
 
  25   even have authority, under some circumstances, to 

 
                                                                135 
 
   1   initiate criminal prosecution if someone breaks the 
 
   2   law. 
 
   3             So the system works for foods in the sense 
 
   4   that a developer does not want to put a product on 
 
   5   the market that would be called into question in 
 
   6   terms of its legal status or that FDA would raise 
 
   7   questions about.  A company who is buying a product 
 
   8   wants to make sure that any product they buy from a 
 
   9   developer meets all the provisions of the Act so 
 
  10   they will ask, is this okay with FDA.  So that is 
 
  11   built into the system and it is why this system 
 
  12   works effectively. 
 
  13             We do have premarket authority for food 
 
  14   additives, as you heard Dr. Rulis mention earlier. 
 
  15   In 1958, we were given authority and the 
 
  16   requirement to assure that any substances that were 
 
  17   added to food or were intended to become components 
 
  18   of food did undergo premarket review and approval 
 
  19   and the issuance of a regulation by FDA before they 
 
  20   were used in food, but there is, as you heard, an 
 
  21   exemption for those substances that are generally 
 
  22   recognized as safe. 
 
  23             Of course, there are many substances that 
 
  24   are in the marketplace under that exemption. 
 
  25   Things like salt and vinegar and pepper and other 

 
                                                                136 
 
   1   common things added to food were generally thought 
 
   2   to be generally recognized as safe.  Congress 
 
   3   provided a mechanism for newer substances to be 
 
   4   considered safe if there was this wide recognition 
 
   5   among experts that the substance was safe for use 
 
   6   in food. 
 
   7             Just to show you how we have applied this 
 
   8   to bioengineered foods, we have said that, if a 
 
   9   gene is introduced into a crop plant and that gene 
 
  10   then results in a protein, for example, or some 
 
  11   other substance that is new to the food, that 
 
  12   substance will be treated as a food additive  if 
 
  13   there is not a basis to consider it generally 
 
  14   recognized as safe. 
 
  15             So this is our legal tool to be sure that, 
 
  16   if there is any modification of the food that 
 
  17   introduces a substance that, in fact, should be 
 
  18   reviewed as a food additive, we have that authority 
 
  19   to do so. 
 
  20             What we have seen to date have been 
 
  21   mostly, almost entirely, metabolic enzymes that are 
 
  22   very similar to enzymes that are components of food 
 
  23   already.  So we have only used the food-additive 
 
  24   authority one time, at this point, and that was at 
 
  25   the request of Calgene when they were developing 

 
                                                                137 
 
   1   the Flavr Savr tomato, which was the first product 
 
   2   we were asked to review.  They wanted to be sure 
 
   3   that that product was shown to meet the highest 
 
   4   standard it could meet under the Food Drug and 
 
   5   Cosmetic Act. 
 
   6             So they actually asked us to regulate that 
 
   7   kanamycin-resistant enzyme in the tomato as a food 
 
   8   additive.  So we did not regulate the tomato as a 
 
   9   food additive, but that one substance which was the 
 
  10   only new substance in that tomato.  So there is a 
 
  11   food-additive regulation for the enzyme that is 
 
  12   produced by the kanamycin-resistance marker gene. 
 
  13             But, to date, we have seen a very narrow 
 
  14   class.  That is one of the things you will probably 
 
  15   hear from us several times over the next couple of 
 
  16   days is that, at this point, we are looking at a 
 
  17   very narrow range of the possible proteins that we 
 
  18   might be dealing with.  I think that is an 
 
  19   important consideration. 
 
  20             We did issue, as I said, guidance to the 
 
  21   industry.  That basically gave them a yardstick to 
 
  22   know if they were meeting the expectations that we 
 
  23   would have for safety testing.  We recommended that 
 
  24   companies come in and consult with us.  We said 
 
  25   this is new technology.  It is important that we 

 
                                                                138 
 
   1   know about these products before they go to market 
 
   2   even though there is not a legal requirement for 
 
   3   companies to come in. 
 
   4             Our experience has been that, as far as we 
 
   5   know, and as far as anyone has been able to report 
 
   6   to us, all the products that have gone to the 
 
   7   market in the U.S. have been through FDA's 
 
   8   consultation process before they have gone to 
 
   9   market.  We also, in the '92 policy, laid out our 
 
  10   preliminary thinking on the labeling of products. 
 
  11   I won't say much about that except to say that any 
 
  12   characteristics that are new to the product, that 
 
  13   make that product substantially different, would be 
 
  14   required to be labeled to disclose that difference. 
 
  15             So, if there is a new allergen in the 
 
  16   food, that would have to be disclosed in the 
 
  17   labeling.  If there is a nutritional difference 
 
  18   that is different from what the consumers expect, 
 
  19   then that would have to be labeled.  The consumer 
 
  20   has to know how to cook the food or prepare the 
 
  21   food in some different way.  That information would 
 
  22   have to be labeled. 
 
  23             [Slide.] 
 
  24             We did establish, as I have said, a basis 
 
  25   for companies to come in and talk to us.  We really 

 
                                                                139 
 
   1   started out wanting to make sure that we were 
 
   2   operating, treating everyone internally, by some 
 
   3   standards.  So we developed some internal operating 
 
   4   procedures which really became our consultation 
 
   5   procedures.  We made those public so that everyone 
 
   6   would know how we were operating. 
 
   7             Those were put out in 1996.  They were 
 
   8   based on the experience that we had had up to that 
 
   9   point in developing our 1992 policy, the evaluation 
 
  10   that we did on the Flavr Savr tomato and other of 
 
  11   the first products that came to market shortly 
 
  12   after our first decision in 1994. 
 
  13             We had some meetings of our Food Advisory 
 
  14   Committee in 1994 where we discussed our policy and 
 
  15   our scientific approach with the committee and we 
 
  16   used the Flavr Savr tomato and other products as 
 
  17   examples of products that were evaluated under the 
 
  18   approach we had put out.  At that time, the 
 
  19   committee felt that, for the types of products we 
 
  20   were seeing at the time, that that was a reasonable 
 
  21   scientific approach for assuring that these 
 
  22   products would be as safe as other foods on the 
 
  23   market. 
 
  24             One thing that we have always encouraged 
 
  25   developers is to come to see us early and often.  

 
                                                                140 
 
   1   That is very important when products are new.  We 
 
   2   don't expect them to come in on products that we 
 
   3   know, that we are very familiar with, and they are 
 
   4   familiar with what needs to be done to assure that 
 
   5   they meet all the provisions of the Act.  But when 
 
   6   something is a new product, has new traits, new 
 
   7   characteristics, then it is important that they 
 
   8   come in very early in the process so that our 
 
   9   scientists can have a dialogue with their 
 
  10   scientists about the issues that need to be 
 
  11   examined and the appropriate tests that would be 
 
  12   carried out. 
 
  13             [Slide.] 
 
  14             I want to give you just some general ideas 
 
  15   about some of the issues we have thought about in 
 
  16   developing our guidance to industry on safety 
 
  17   testing.  If you think about it was about 1989 when 
 
  18   Calgene started to ask questions about the Flavr 
 
  19   Savr tomato and other companies were also coming in 
 
  20   at that time. 
 
  21             We realized that they were asking us a 
 
  22   question we really hadn't been asked before.  We 
 
  23   are very used to dealing with food additives and 
 
  24   other ingredients that are added to food.  But we 
 
  25   were being asked about a whole food.  As I told 

 
                                                                141 
 
   1   you, there is no requirement for new varieties of 
 
   2   corn and soybeans and potatoes to come to FDA 
 
   3   before they go to market. 
 
   4             But now companies were saying to us, we 
 
   5   have a new tomato, for example.  We want to know 
 
   6   what kind of testing will show that it is safe for 
 
   7   people to eat.  That was really a new question for 
 
   8   us in the late '80s.  So we had to decide how to go 
 
   9   about that. 
 
  10             We weren't the only ones.  This was being 
 
  11   discussed in the international community as well. 
 
  12   But one of the things that we decided, after 
 
  13   looking at the kinds of products, was that these 
 
  14   were basic food crops, fundamentally.  They had 
 
  15   been modified using recombinant DNA techniques to 
 
  16   introduce new traits into those crops, but, 
 
  17   basically, it was still corn, potatoes, soybeans, 
 
  18   and so forth. 
 
  19             So we weren't really dealing with an 
 
  20   entire new entity.  We were dealing with new crops 
 
  21   with new traits.  So we thought that the best way 
 
  22   to approach that would be to compare the new 
 
  23   variety with its traditional counterpart.  This was 
 
  24   for the purpose of identifying, first of all, what 
 
  25   is different about the new product compared to what 

 
                                                                142 
 
   1   has gone on before it, so that we can make sure 
 
   2   that any differences that have been introduced are 
 
   3   safe, and then, secondly, to make sure that the 
 
   4   food still is what you would expect it to be for 
 
   5   that particular crop. 
 
   6             This required a different approach.  For 
 
   7   food additives, we were very used to characterizing 
 
   8   the additive and using a series of toxicological 
 
   9   tests to establish its safety.  But it was obvious 
 
  10   from other things we had learned, from protein 
 
  11   supplements and other complex mixtures, that a 
 
  12   substance such as a tomato or a potato or corn that 
 
  13   is, in fact, a complex mixture of chemicals, would 
 
  14   not work as well in the traditional kinds of 
 
  15   toxicological battery of testing. 
 
  16             So we worked out a different approach that 
 
  17   takes into account several different kinds of 
 
  18   information.  The first is really the screen that 
 
  19   plant breeders do all time with new varieties. 
 
  20   Plant breeders look at the agronomic 
 
  21   characteristics, the growth of the plant, the 
 
  22   setting of seeds, flowering of the plant, the yield 
 
  23   from the plant, how it grows in different regions. 
 
  24   That is the first screen and that still occurs with 
 
  25   products produced by modern biotechnology just as 

 
                                                                143 
 
   1   it does with conventional varieties. 
 
   2             That is one of the mechanisms that 
 
   3   developers have to screen out the so-called 
 
   4   unintended effects.  They occur by all methods of 
 
   5   plant breeding. 
 
   6             But we also have new tools in terms of 
 
   7   molecular analysis now.  We know much more about 
 
   8   the traits that are being introduced into the 
 
   9   plant.  We know what the gene is.  We know the 
 
  10   function of that gene.  So we can focus safety 
 
  11   assessment on the new characteristics of the plant 
 
  12   based on what that substance is. 
 
  13             We also, then, look at other aspects of 
 
  14   the food.  Has it been changed in any ways with 
 
  15   respect to nutrition.  Does it still have the same 
 
  16   vitamins, the same minerals, the same components of 
 
  17   the plant in terms of toxins, antinutrients or 
 
  18   nutrients that are expected for that crop.  Each 
 
  19   crop, of course, is different. 
 
  20             It is taking all of this information into 
 
  21   account that gives us a picture of is this product 
 
  22   safe in terms of the changes that have been made in 
 
  23   the product as well as is this food still basically 
 
  24   the same food in addition to those changes. 
 
  25             We do not run, normally, toxicological 

 
                                                                144 
 
   1   tests because of the difficulties of testing whole 
 
   2   foods.  But, nevertheless, if this information does 
 
   3   not resolve all of the questions, then one could 
 
   4   design an animal test, for example, to answer a 
 
   5   specific question. 
 
   6             That is sort of, in a nutshell, the basis 
 
   7   of safety assessment. 
 
   8             [Slide.] 
 
   9             But, just to give you a sense, while I say 
 
  10   we don't generally do toxicological testing, that 
 
  11   is not to say that we would never do it.  In fact, 
 
  12   there would be circumstances where we would.  If 
 
  13   there is a really new substance in the food that we 
 
  14   don't have any knowledge about its ability to be 
 
  15   consumed safely, then that substance would need to 
 
  16   be subjected to the more traditional kinds of 
 
  17   toxicological tests.  We haven't run into any of 
 
  18   those, so far. 
 
  19             [Slide.] 
 
  20             This is just to give you a sense of some 
 
  21   of the major elements of the safety assessment and, 
 
  22   again, to emphasize that what we are looking at is 
 
  23   both the intended change in the plant--that is, are 
 
  24   there new substances that will be in the food and, 
 
  25   if so, what are they, what is their structure and 

 
                                                                145 
 
   1   function, and do they come from a source that would 
 
   2   create questions about allergenicity. 
 
   3             This is really where we are focusing much 
 
   4   of our discussion these two days; can we digest 
 
   5   this substance.  Is it consumed normally and how 
 
   6   much do we eat.  These are standard food-safety 
 
   7   questions.  There is nothing exotic about these 
 
   8   questions for bioengineered plants.  They are the 
 
   9   same questions we would ask for a non-bioengineered 
 
  10   plant. 
 
  11             But we also take into account unintended 
 
  12   modifications because we know that unintended 
 
  13   changes occur by all methods of plant breeding.  As 
 
  14   I have said, it is something breeders have to deal 
 
  15   with normally. 
 
  16             So, in addition to the screen that 
 
  17   breeders usually do, we also have the ability now 
 
  18   to make sure that the genetic material is stably 
 
  19   incorporated.  This is one way of making sure that 
 
  20   changes don't continue to occur in successive 
 
  21   generations. 
 
  22             We also expect companies to look at the 
 
  23   composition for these nutrients and toxicants to 
 
  24   make sure that, basically, the food is what we 
 
  25   expect it to be.  This is another way of monitoring 

 
                                                                146 
 
   1   for changes that would have occurred in the food in 
 
   2   addition to all of those things that the developer 
 
   3   looks at in terms of how the plant grows in the 
 
   4   field. 
 
   5             So it is taking into account all of this 
 
   6   information, then, that gives us a sense of whether 
 
   7   this food is as safe as other foods that are on the 
 
   8   market.  That is just to emphasize the fact that 
 
   9   the developers have the first stage.  That is just 
 
  10   an example of just a few of the characteristics 
 
  11   that are examined for soybeans, in terms of their 
 
  12   agronomic characteristics. 
 
  13             [Slide.] 
 
  14             This is a slide to really emphasize--we 
 
  15   talk about consultations and we have often said 
 
  16   that companies submit a summary of data to us as 
 
  17   part of these consultations.  I just have two quick 
 
  18   slides here to show you that this is not a postcard 
 
  19   to FDA.  When we say that companies are providing 
 
  20   us information about their safety review, we do not 
 
  21   ask them for all the raw data.  But we do ask them 
 
  22   for enough data to show what kind of issues they 
 
  23   have addressed, what kinds of tests they have done 
 
  24   and what the results are that they have found. 
 
  25             [Slide.] 

 
                                                                147 
 
   1             These are just examples.  So a submission 
 
   2   on a consultation will be, say, 100 to 200 pages, 
 
   3   just in round numbers.  So we are not talking about 
 
   4   a letter to FDA saying, "I am going to market with 
 
   5   this product."  This is the culmination of 
 
   6   discussions with our scientists about the testing 
 
   7   on these products. 
 
   8             [Slide.] 
 
   9             This is just to give you a sense of the 
 
  10   fact that there are a number of major crops that 
 
  11   have been developed by recombinant DNA.  We have 
 
  12   beet, canola, corn, cotton, potato, soybeans, flax, 
 
  13   radicchio, squash and tomato.  So there are about 
 
  14   ten crops there, but some of them are very major 
 
  15   crops.  So the techniques are being used to a 
 
  16   limited basis in terms of the breadth of the food 
 
  17   supply but some of these are very major components 
 
  18   of foods. 
 
  19             And the number of traits is also 
 
  20   relatively limited at this point.  There are many 
 
  21   products that are resistant to various pests and 
 
  22   disease as well as tolerant to chemical herbicides. 
 
  23   We have several products that are modified--vegetable oils-- 
 
  24   but most of them are, at this 
 
  25   point, for agronomic traits. 

 
                                                                148 
 
   1             So, in terms of how we look at these, and 
 
   2   there was a question raised this morning about 
 
   3   reasonable certainty of no harm, we are looking at 
 
   4   the safety of a food here.  The standard that we 
 
   5   expect developers to meet is to show that the new 
 
   6   food is, in fact, as safe as other foods on the 
 
   7   market. 
 
   8             So it is a little bit different standard 
 
   9   than for the specific food additive.  This is not a 
 
  10   comprehensive review where we look at all of the 
 
  11   data and we establish an administrative record for 
 
  12   that data and a regulation which is the process for 
 
  13   food additives. 
 
  14             This is a process that is one where we 
 
  15   satisfy ourselves and our scientists that the 
 
  16   company has addressed all the scientific questions. 
 
  17   We reach a point where we are satisfied that there 
 
  18   is no scientific issue related to the safety of the 
 
  19   food for human consumption that has been left 
 
  20   unresolved. 
 
  21             [Slide.] 
 
  22             In 1999, we conducted some public 
 
  23   meetings.  This is a picture of an exciting meeting 
 
  24   we held in Oakland, California.  We held three 
 
  25   meetings and the purpose of these meetings was to 

 
                                                                149 
 
   1   listen to the public.  At that time, we were 
 
   2   getting an increase in the number of questions 
 
   3   about these products from the public and we also 
 
   4   wanted to have an opportunity to explain to the 
 
   5   public what we were doing, what our policy had been 
 
   6   up to that point. 
 
   7             But we really needed to hear what the 
 
   8   basis was for the concerns that were being 
 
   9   expressed.  At these public meetings, we had panels 
 
  10   in the morning and afternoon, one on scientific 
 
  11   issues, one on public-information issues, including 
 
  12   labeling. 
 
  13             There were a number of panelists and 
 
  14   speakers.  We had the panelists and, of course, we 
 
  15   had public speakers at each of these meetings.  We 
 
  16   had written comments submitted.  This was a very 
 
  17   important process. 
 
  18             One of the things that we learned from the 
 
  19   public meetings is that there was no information 
 
  20   presented to us that would question the safety of 
 
  21   products that had been through FDA's consultation 
 
  22   process.  There was a lot of concern about the fact 
 
  23   that that process was a voluntary one in the sense 
 
  24   that companies were not required to come to FDA for 
 
  25   these consultations.  That was something that the 

 
                                                                150 
 
   1   public was really not comfortable with. 
 
   2             Now, the Food Drug and Cosmetic Act is not 
 
   3   voluntary.  I think it is important to understand 
 
   4   that.  But it is voluntary for companies to 
 
   5   actually come in and consult with us.  Calgene 
 
   6   could have put the Flavr Savr tomato on the market 
 
   7   at any point they had decided to do that, except 
 
   8   for the fact that they had asked for a food-additive 
 
   9   regulation for the enzyme.  But, 
 
  10   basically, the point is that they were not legally 
 
  11   compelled to come to us.  But that is something the 
 
  12   public was not comfortable with. 
 
  13             So, as probably most of you know, we have 
 
  14   proposed to make the current consultation process 
 
  15   mandatory, to require companies to notify us 120 
 
  16   days prior to marketing.  We would still continue 
 
  17   our normal consultation process but the final step 
 
  18   of actually submitting the information about their 
 
  19   safety assessment to us would become mandatory. 
 
  20             We heard some other things, too, from the 
 
  21   public meetings.  One of the things we heard was 
 
  22   that there may be products in the future that will 
 
  23   be more complex than we have had up to now.  We, of 
 
  24   course, are aware that the science is advancing. 
 
  25             One of the messages that we got from our 

 
                                                                151 
 
   1   earlier 1994 food advisory committees where we 
 
   2   looked at Flavr Savr tomato and other products was 
 
   3   that the committee members, after hearing about all 
 
   4   the data that had been developed on the Flavr Savr 
 
   5   tomato said to us, this is very interesting, it was 
 
   6   very good exercise for the first product. 
 
   7             They thought that FDA and the industry did 
 
   8   a very good job in terms of all the scientific 
 
   9   tests and the evaluation of those tests.  But they 
 
  10   also recognized that, in fact, that product did not 
 
  11   raise any substantial public-health issues and they 
 
  12   actually suggested to FDA that, for products that 
 
  13   were similar in nature, that we might want to have 
 
  14   a more abbreviated process. 
 
  15             That was the genesis of our consultation 
 
  16   process because we agreed, based on the types of 
 
  17   products we were seeing, that this consultation 
 
  18   would be an appropriate level of oversight given 
 
  19   the kinds of products we were seeing, always with 
 
  20   the recognition that, if a product had different 
 
  21   characteristics that raised particular scientific 
 
  22   issues, that it should undergo an appropriate level 
 
  23   of review. 
 
  24             But, from the information we heard at the 
 
  25   public meetings, we realized that it is important 

 
                                                                152 
 
   1   that we take steps to keep up with the science. 
 
   2   The forming of this subcommittee is one of those 
 
   3   steps.  We have this committee established so that 
 
   4   we can bring to this subcommittee questions about 
 
   5   the science that we are dealing with at the time. 
 
   6             By having the committee established, that 
 
   7   gives us an easier mechanism to do that on a more 
 
   8   routine basis. 
 
   9             A question? 
 
  10             DR. ATKINS:  Dan Atkins.  I have a 
 
  11   question.  Is 120 days adequate?  Maybe in this 
 
  12   environment, where there are fewer applications, 
 
  13   but what if there are more?  Can you keep up with 
 
  14   the load if that increases, et cetera? 
 
  15             DR. MARYANSKI:  Yes.  And that is 
 
  16   something that we have thought about.  Based on our 
 
  17   best projections in terms of what we expect 
 
  18   development to be, we do think that 120 days is 
 
  19   probably going to be an appropriate time frame. 
 
  20             This is a proposal.  It is open for 
 
  21   comments.  I should say that we have received 
 
  22   something over 100,000 comments.  We have now 
 
  23   distilled those comments down, so we are actually 
 
  24   beginning to review the comments.  But that is one 
 
  25   of the issues that we will be looking at in terms 

 
                                                                153 
 
   1   of moving toward a final rule on this. 
 
   2             DR. BUSTA:  Frank Busta.  Earlier you 
 
   3   indicated that any kind of new variety is assessed 
 
   4   in the same fashion.  If there is a new variety of 
 
   5   barley or wheat, that you would run--that any 
 
   6   variety, generated in any way, would be evaluated 
 
   7   by FDA. 
 
   8             DR. MARYANSKI:  No.  Our '92 policy does 
 
   9   cover all new varieties of plants in the sense that 
 
  10   we set out what the legal standard is and what we 
 
  11   would think the questions we be about safety.  What 
 
  12   we have said is we want companies to consult with 
 
  13   us on the specific use of the new technologies.  So 
 
  14   we do not have companies coming in to talk to us 
 
  15   about varieties that are developed with 
 
  16   conventional techniques. 
 
  17             What we are saying is they have to meet 
 
  18   the same legal standards under the Act in terms of 
 
  19   the foods that are placed on the market.  But we 
 
  20   are only asking companies to come to us who are 
 
  21   using the newer techniques.  We have had, in fact, 
 
  22   once or twice, companies come to us and say, "I 
 
  23   haven't used recombinant-DNA techniques but I have 
 
  24   a question about a new variety," and we can do the 
 
  25   same kind of consultation. 

 
                                                                154 
 
   1             DR. BUSTA:  This is only for bioengineered 
 
   2   foods and not the other? 
 
   3             DR. MARYANSKI:  The actual consultation 
 
   4   process is set up for bioengineered foods.  The 
 
   5   reason for that is because they all raise a similar 
 
   6   set of questions.  We wanted to establish this 
 
   7   process so that the companies--we would treat 
 
   8   everybody the same. 
 
   9             Yes? 
 
  10             DR. LEHRER:  Sam Lehrer.  I have a 
 
  11   question about the notification in terms of the 
 
  12   process, itself.  The notification occurs and then 
 
  13   what happens after that? 
 
  14             DR. MARYANSKI:  There are two steps to the 
 
  15   process in a broad sense.  The first step is the 
 
  16   early consultations where we have a scientific 
 
  17   dialogue between our scientists and the company 
 
  18   scientists in terms of design of tests and so 
 
  19   forth.  At the point where the company believes 
 
  20   that they have done all of the testing that needs 
 
  21   to be done to market a safe product, we ask them to 
 
  22   submit that information to us, information that 
 
  23   explains what they have done, not all of the data 
 
  24   but information that is sufficient to give our 
 
  25   scientists a sense of what they have actually 

 
                                                                155 
 
   1   found. 
 
   2             Once we have reviewed that and we are 
 
   3   satisfied that we have no further questions, we 
 
   4   send them a letter that says essentially that, 
 
   5   that, based on what you have told us about this 
 
   6   product, the testing that you have done, we have no 
 
   7   further questions. 
 
   8             As you may have had Dr. Rulis say this 
 
   9   morning, our letter also says--we remind them that 
 
  10   it is their continuing responsibility to ensure 
 
  11   that that product meets the provisions of the law. 
 
  12   So, on other words, the burden is always on the 
 
  13   developer for a food to ensure that that product is 
 
  14   safe and wholesome. 
 
  15             Our review gives us the comfort that they 
 
  16   have done all the things that we think should be 
 
  17   done before that product goes to market.  So this 
 
  18   is a different kind of process than a food-additive 
 
  19   review process. 
 
  20             DR. LEHRER:  You also have the option of 
 
  21   not agreeing? 
 
  22             DR. MARYANSKI:  Yes; we do not issue that 
 
  23   letter until we are satisfied that all the 
 
  24   questions have been addressed. 
 
  25             Now, this morning you heard about eighty 

 
                                                                156 
 
   1   consultations and fifty that have been final.  Just 
 
   2   to give you a little clarification, some of those 
 
   3   are recent submissions that we are just beginning 
 
   4   to review.  Some of them are very old, products 
 
   5   that companies have probably given up on and will 
 
   6   never complete for various reasons. 
 
   7             DR. BRANDT:  Are you through?  Or do you 
 
   8   have other-- 
 
   9             DR. MARYANSKI:  I have just a couple of 
 
  10   slides on our allergenicity approach. 
 
  11             DR. BRANDT:  Fire away. 
 
  12             DR. MARYANSKI:  Okay. 
 
  13             [Slide.] 
 
  14             Now I want to just give you an overview of 
 
  15   the approach that we have been using to assess the 
 
  16   likelihood that a new protein would be an allergen; 
 
  17   in other words, to make sure that we are not 
 
  18   introducing any new allergens into foods.  I think 
 
  19   you have heard that virtually all allergens are 
 
  20   proteins.  On the other hand, there are thousands 
 
  21   of proteins that make up the food supply and, at 
 
  22   least as far as we know, only a small percentage of 
 
  23   proteins are found to be allergens. 
 
  24             In terms of the use of recombinant-DNA 
 
  25   techniques, that means transferring genetic 

 
                                                                157 
 
   1   material from one source--it can be any source, 
 
   2   plant, animal, microorganism--to a food crop.  That 
 
   3   genetic material often results in the production of 
 
   4   a new protein that may even be present in the 
 
   5   finished food--not in all cases, but in a number of 
 
   6   cases. 
 
   7             So the question is will these proteins be 
 
   8   allergens.  That is really what we are here to talk 
 
   9   about over the next couple of days. 
 
  10             [Slide.] 
 
  11             We have been talking about this for a long 
 
  12   time, as you can see from this slide, and we expect 
 
  13   to be talking about it for a good bit longer. 
 
  14             Just to remind you again, in terms of 
 
  15   developing our draft guidance, we see this as the 
 
  16   beginning of that process.  And so we are looking 
 
  17   for your initial thoughts on this and we will be 
 
  18   back to talk to you more about this. 
 
  19             But, in our 1992 policy statement, we 
 
  20   recognized that this was a very important component 
 
  21   issue for safety assessment.  What we said at that 
 
  22   time was we thought about the fact, as Dr. Metcalfe 
 
  23   said earlier, there are certain foods that are 
 
  24   commonly allergenic such as fish and milk and 
 
  25   soybeans and so forth. 

 
                                                                158 
 
   1             We thought that, well, if someone removes 
 
   2   genetic material from that source, they could 
 
   3   remove material that would encode for an allergen. 
 
   4   Now, obviously, there are many genes in that plant 
 
   5   and there are many genes that will not be an 
 
   6   allergen, even in a plant that is known to produce 
 
   7   allergic reactions, but we thought that our first 
 
   8   approach should be to assume that, in fact, an 
 
   9   allergen has been transferred for something that is 
 
  10   commonly allergenic unless the scientific 
 
  11   information can demonstrate otherwise. 
 
  12             This is to make sure that there is not 
 
  13   really going to be an allergen that we know would 
 
  14   create a serious reaction from something like 
 
  15   peanut, for example, transferred into another food 
 
  16   crop.  Our sense is that no one is going to 
 
  17   transfer any genetic material from a crop such as 
 
  18   peanut because we know about the seriousness of 
 
  19   those reactions. 
 
  20             But we knew about genetic material based 
 
  21   on the source of the gene in terms of if that 
 
  22   source was a material that produces allergic 
 
  23   reactions.  We knew that was a concern in 1992. 
 
  24   The harder question at that time was, well, what 
 
  25   about most of the genes we are seeing in 

 
                                                                159 
 
   1   bioengineered foods which really don't come from 
 
   2   these sources.  We didn't have any that come from 
 
   3   those sources.  They come from bacterial sources or 
 
   4   plants that are not food sources. 
 
   5             So, at that time, we simply asked for 
 
   6   comments.  We didn't get very many.  But we did do 
 
   7   some other steps to make sure that we were 
 
   8   addressing this based on the best science that we 
 
   9   had at the time.  The three agencies convened a 
 
  10   scientific conference that was held in Annapolis 
 
  11   when we convened a group of food allergists from 
 
  12   around the world, actually.  We looked at this 
 
  13   issue and they gave us some suggestions about how 
 
  14   to deal with it. 
 
  15             We also discussed this approach with our 
 
  16   Food Advisory Committee back in 1994 in terms of 
 
  17   establishing our policy and our evaluation of the 
 
  18   first products that had gone through the system. 
 
  19             [Slide.] 
 
  20             So the approach that we are using today 
 
  21   was established back in about 1994.  That approach 
 
  22   involves comparing a new protein with proteins that 
 
  23   are known to be food allergens to make sure that a 
 
  24   protein that is now introduced into a food crop 
 
  25   does not have any of the characteristics that are 

 
                                                                160 
 
   1   known for food allergens.  That involves, of 
 
   2   course, looking at the source of protein to be sure 
 
   3   that it doesn't come from a source that is known to 
 
   4   produce food-allergy reactions and also looking at 
 
   5   its sequence to be sure that it is not similar in 
 
   6   its sequence, both in terms of its overall sequence 
 
   7   and in terms of what they call epitopes which are 
 
   8   the regions that may be binding to IgE and protein, 
 
   9   to make sure that there are no known matches to the 
 
  10   protein and to look to see if that protein is 
 
  11   readily degraded by acid, by digestive conditions 
 
  12   and so forth. 
 
  13             That, as you have heard, is not a 
 
  14   definitive test.  But proteins that are readily 
 
  15   digestible, for the most part, usually are not food 
 
  16   allergens.  In the area of allergenicity, as you 
 
  17   may have already gotten a sense, there is an 
 
  18   exception to everything that one might put forward 
 
  19   as a general principle.  So you always have to keep 
 
  20   that in mind. 
 
  21             But the idea here was that, in taking into 
 
  22   account a number of different kinds of information, 
 
  23   altogether, that that would basically give us more 
 
  24   confidence that this protein is not likely to be an 
 
  25   allergen. 

 
                                                                161 
 
   1             What the experts said to us is that, in 
 
   2   terms of these proteins derived from bacteria, we 
 
   3   can't say that a protein will never be an allergen. 
 
   4   But they didn't expect that most proteins would be 
 
   5   and so they felt that this was the best scientific 
 
   6   approach that we had at this time. 
 
   7             Obviously, if the protein is derived from 
 
   8   a source that we know to be allergenic, then there 
 
   9   is a different approach and there is a sound 
 
  10   scientific approach that can be used using sera 
 
  11   from patients that are sensitive to that particular 
 
  12   source. 
 
  13             [Slide.] 
 
  14             In fact, I will start at the bottom with 
 
  15   the example.  We had a product that was developed 
 
  16   and it was a soybean in which a gene from Brazil 
 
  17   nut was introduced.  It was a gene for the 2SL 
 
  18   human protein which is a gene that confers a 
 
  19   storage-protein characteristic to make a storage 
 
  20   protein in Brazil nut. 
 
  21             We know that certain individuals are 
 
  22   allergic to Brazil nut.  Steve Taylor's group at 
 
  23   the University of Nebraska looked at this product 
 
  24   that was developed by Pioneer Hybrid and they found 
 
  25   that, in fact, the protein in soybean, this Brazil-nut 

 
                                                                162 
 
   1   protein in soybean did cross-react and, in 
 
   2   fact, listed its skin reactions in individuals who 
 
   3   were allergic to Brazil nut.  That product was 
 
   4   discontinued.  It never went to market, never made 
 
   5   anyone sick. 
 
   6             To date, we have had about 50 products, 
 
   7   different varieties of crops, that companies have 
 
   8   completed food-safety consultations with us since 
 
   9   this approach was put into place.  There are about 
 
  10   eighteen new proteins in those crops that we have 
 
  11   looked at so far. 
 
  12             All of these proteins lack any similarity 
 
  13   to known allergens.  They are also all readily 
 
  14   degraded.  Remember that FDA deals with the 
 
  15   nonpesticidal substances, that we are not looking 
 
  16   at the BT proteins.  We have always thought we have 
 
  17   all the easy things because at least we know of any 
 
  18   toxicity to the substances that we are dealing with 
 
  19   up front. 
 
  20             But, actually, seriously, to date, the 
 
  21   proteins that have been engineered in the plants 
 
  22   are almost all metabolic enzymes, so they are 
 
  23   enzymes involved in the ethylene pathway, for 
 
  24   example, or they affect the amino-acid synthesis 
 
  25   pathway and, therefore, are used for herbicide 

 
                                                                163 
 
   1   tolerance.  But they are basically common enzymes 
 
   2   in the food, is the point. 
 
   3             We have seen a very narrow class of 
 
   4   proteins.  What we are going to be asking you to 
 
   5   think about is that the draft guidance that we 
 
   6   prepare will be based on the kinds of proteins that 
 
   7   we have seen.  There will be other proteins in the 
 
   8   future that will raise different issues, but, right 
 
   9   now, we want to focus on what we are experiencing 
 
  10   and we will deal with the things in the future that 
 
  11   raise different issues because we don't know what 
 
  12   those are so we don't know how we would deal with 
 
  13   those. 
 
  14             So this is, I think, a very important 
 
  15   point to keep in mind for you to think about. 
 
  16             [Slide.] 
 
  17             This has been discussed not just here at 
 
  18   FDA, by any means.  We have been working with 
 
  19   international groups.  Others have looked at this 
 
  20   as well.  The industry, through the International 
 
  21   Life Sciences Institute and the International Food 
 
  22   Biotechnology Council, published a very 
 
  23   comprehensive paper on assessment of allergenicity 
 
  24   in bioengineered foods in 1996.  So there have been 
 
  25   a number of activities. 

 
                                                                164 
 
   1             More recently, the international community 
 
   2   has looked at this issue, and you are going to hear 
 
   3   more about this very briefly now, but what has 
 
   4   happened in that the experience that has been 
 
   5   gained and all of the discussions have really 
 
   6   crystallized to a point of at least, now, we 
 
   7   believe there is a general consensus on an approach 
 
   8   for the kinds of products we are seeing today. 
 
   9   That is reflected in what are now the international 
 
  10   guidelines in the Codex and, since probably some of 
 
  11   you might say, what it the world is Codex, I have a 
 
  12   slide to answer that question. 
 
  13             [Slide.] 
 
  14             The Codex Alimentarius Committee is a body 
 
  15   that was established under the U.S. system by the 
 
  16   World Health Organism, WHO, and the Food and 
 
  17   Agriculture Organism, FAO, in 1962.  It was 
 
  18   established to guide and promote the elaboration 
 
  19   and establishment of definitions and requirements 
 
  20   for food and to assist in their harmonization and, 
 
  21   in doing so, to facilitate trade. 
 
  22             What is important about this is that now, 
 
  23   under the GATT agreement and the World Trade 
 
  24   Organization being established, the Codex is 
 
  25   recognized as the international body for setting 

 
                                                                165 
 
   1   standards and guidelines for food safety.  So the 
 
   2   guidelines that are established under Codex are 
 
   3   particularly important. 
 
   4             The Codex is made up of about 165 member 
 
   5   countries from all around the world.  The voting 
 
   6   members of Codex are all government 
 
   7   representatives.  There are also non-government 
 
   8   organizations, both industry and public-interest 
 
   9   groups, who are observers of the Codex process and 
 
  10   participate in the process, but the voting is all 
 
  11   done by the member countries. 
 
  12             One of the things that I am going to tell 
 
  13   is our bottom line, at the moment, for you think 
 
  14   about and you may disagree, of course--that is why 
 
  15   we have asked you to think about it--but it is our 
 
  16   feeling from the experience we have had and the 
 
  17   discussions we have had in the international 
 
  18   community that what you are going to hear about, as 
 
  19   the current guidelines that have been developed 
 
  20   internationally are something that we want to 
 
  21   consider very seriously in developing our draft 
 
  22   guidance. 
 
  23             We think that it is very consistent with 
 
  24   the approach that we have used to date for the 
 
  25   kinds of products that we are seeing.  So we think 

 
                                                                166 
 
   1   that it deserves serious consideration and we are 
 
   2   very happy to have an expert to tell you about that 
 
   3   process. 
 
   4             DR. BRANDT:  Questions? 
 
   5                    Questions of Clarification 
 
   6             DR. GURIAN-SHERMAN:  Doug Gurian-Sherman. 
 
   7   I have a couple of questions.  Why don't I start 
 
   8   with two of them.  I don't want to keep beating a 
 
   9   dead horse, and I don't think it is quite dead yet, 
 
  10   on a reasonable-certainty-of-no-harm issue, the 
 
  11   reason I bring it up is because I think the level 
 
  12   of oversight that you intend or will give these 
 
  13   products has some influence on the level of 
 
  14   scientific rigor that goes behind it.  So I think 
 
  15   it is a relevant issue. 
 
  16             I think it was Bob Lake mentioned earlier 
 
  17   that you want harmonization as much as possible 
 
  18   between agencies which I think makes sense.  My 
 
  19   understanding--maybe I am wrong and you can correct 
 
  20   me if I am, EPA, when they are looking at 
 
  21   allergenicity, which is a similar issue when you 
 
  22   are looking at allergenicity for a given protein, 
 
  23   say, cryoprotein, I think the standard is 
 
  24   reasonable certainty of no harm. 
 
  25             I understand what you are saying in terms 

 
                                                                167 
 
   1   of the whole food being "as safe as," but when you 
 
   2   are talking about the protein, itself, it you want 
 
   3   harmonization, it seems like the standard would be 
 
   4   reasonable certainty of no harm for allergenicity 
 
   5   or toxicity or whatever of the protein, itself. 
 
   6             That is one issue.  The other question I 
 
   7   have is, on enforcement, and, again,  think this is 
 
   8   relevant because I think it would have implications 
 
   9   for what we would recommend should be done up front 
 
  10   in assessing the proteins as opposed to afterwards. 
 
  11   My understanding is that the burden of proof would 
 
  12   be on FDA. 
 
  13             If there was some alleged adverse effect 
 
  14   of the genetically engineered food that went on the 
 
  15   marketplace, FDA would have to show that there was 
 
  16   an adverse effect under the notification process if 
 
  17   it was shown to be GRAS as opposed to, just in 
 
  18   contrast, if it went through the food-additive 
 
  19   process.  Then it was be automatically considered 
 
  20   adulterated if there was a problem. 
 
  21             Maybe you could just address those issues. 
 
  22             DR. MARYANSKI:  Mr. Lake, you need to come 
 
  23   up here.  First of all, before I turn the mike over 
 
  24   to my boss, I don't believe there will be any 
 
  25   difference.  We don't anticipate any difference in 

 
                                                                168 
 
   1   the safety review of the proteins in terms of 
 
   2   allergenicity and we are working very closely with 
 
   3   EPA because, basically, they are looking at protein 
 
   4   safety for the pesticide products including 
 
   5   allergenicity and we are doing the same thing for 
 
   6   the nonpesticide proteins. 
 
   7             So, in terms of the science that would 
 
   8   underpin the decision, we don't see that there will 
 
   9   be any difference. 
 
  10             MR. LAKE:  Let me address your other 
 
  11   question because it is important.  Again, though, 
 
  12   before I do that, let me emphasize the point that 
 
  13   Jim just made which is, from the standpoint of 
 
  14   science, we are absolutely trying to look at this 
 
  15   the same way. 
 
  16             The issue you are raising is really a 
 
  17   legal issue.  I don't represent our chief counsel's 
 
  18   office, but let me give a crack at this because I 
 
  19   am not only familiar with what we do but have had a 
 
  20   lot of interaction with EPA over the years. 
 
  21             Going back to the discussion we had 
 
  22   earlier, the law has a very rigorous system in 
 
  23   place for those things that are defined as food 
 
  24   additives.  But it also has a major exemption for 
 
  25   things that are generally recognized as safe.  The 

 
                                                                169 
 
   1   prevailing view is that those things that are 
 
   2   relatively minor modifications of existing foods 
 
   3   are in the GRAS category rather than the food-additive 
 
   4   category.  We have had lots of discussions 
 
   5   with our lawyers about that and I don't want to 
 
   6   rehash all of that. 
 
   7             But, the things we are talking about, that 
 
   8   we have been looking at, all fit within the GRAS 
 
   9   box.  There is certainly the potential in the 
 
  10   future for seeing many things that are in the food-additive 
 
  11   box.  It is in the food-additive box that 
 
  12   the reasonable-certainty-of-no-harm standard 
 
  13   applies. 
 
  14             So, for things that got into that box, 
 
  15   they would be evaluated the same way we would 
 
  16   evaluate any other food additive including using 
 
  17   the reasonable-certainty-of-no-harm standard. 
 
  18             The difference with EPA is sort of as 
 
  19   follows.  Again, I am oversimplifying something 
 
  20   that is actually a lot more complex, but when the 
 
  21   pesticide law that EPA administers was amended in 
 
  22   1996 by the Food Quality Protection Act, prior to 
 
  23   that time, they also had a GRAS exemption for 
 
  24   pesticides. 
 
  25             Congress chose, in 1996, when amending the 

 
                                                                170 
 
   1   pesticide law, to do away with the GRAS exemptions 
 
   2   for pesticides.  So all of the pesticides that EPA 
 
   3   would look at, whether they are chemical or 
 
   4   bioengineered, whatever, have to go through the 
 
   5   standard that is set forth for pesticides. 
 
   6             It actually happens to be in our Act, or 
 
   7   the Act that we think of as ours, the Food, Drug 
 
   8   and Cosmetic Act, but it is Section 408 of that Act 
 
   9   whereas food additives are in 409.  So there is a 
 
  10   difference in the Food, Drug and Cosmetic Act 
 
  11   whereas GRAS standard exists still, as it always 
 
  12   has, under 409 for food additives or things that 
 
  13   are exempt from that. 
 
  14             But, with regard to pesticides, that 
 
  15   exemption was done away with and also the Congress 
 
  16   chose, at that time, to take the reasonable-certainty-of-no- 
 
  17   harm standard which had been in 
 
  18   place for food additives for a long, long time and 
 
  19   to explicitly apply it to pesticides really for the 
 
  20   first time beginning in 1996. 
 
  21             So now when EPA evaluates a pesticide, 
 
  22   they are using all of the criteria that were added 
 
  23   by the Food Quality Protection Act of 1996.  In 
 
  24   contrast, when we are looking at these things, we 
 
  25   are looking at the state of the law as it was in 

 
                                                                171 
 
   1   1958. 
 
   2             Now, I understand that people can make a 
 
   3   policy argument that maybe the food-additive law or 
 
   4   some special law ought to be passed by Congress to 
 
   5   deal with bioengineered foods as better looked at 
 
   6   by FDA.  But that is not our issue for this meeting 
 
   7   and not a question that we can resolve in any 
 
   8   event. 
 
   9             So what I would come again to Dr. 
 
  10   Maryanski's point.  I think the focus that we would 
 
  11   like this group to take is on the scientific aspect 
 
  12   of this, not on the legal or legislative component 
 
  13   of it, and give us the best advice that you can 
 
  14   give us in terms of the science. 
 
  15             We very much, of course, want to be 
 
  16   consistent with our colleagues at EPA on that and, 
 
  17   indeed, have a very strong desire to have as much 
 
  18   consistency as possible internationally.  We will 
 
  19   be hearing some more about that, too.  Let me just 
 
  20   say, around that, too, before we have Dr. Mayers 
 
  21   come up, that we very heavily participated in that 
 
  22   international effort. 
 
  23             Do you have a follow-up question? 
 
  24             DR. GURIAN-SHERMAN:  Yes.  I guess that 
 
  25   issue is around kind of harmonization conceptually, 

 
                                                                172 
 
   1   but the other question, in terms of enforcement, I 
 
   2   think is relevant, again, because it goes to how 
 
   3   much emphasis you might be able to put in premarket 
 
   4   scrutiny versus postmarket.  If it is more 
 
   5   difficult to address a potential problem once it is 
 
   6   on the market, from a legal standpoint, it has 
 
   7   indications, I think, for the scientific issues 
 
   8   because you may want to put a higher emphasis on 
 
   9   your premarket considerations knowing that you have 
 
  10   less of a handle on the postmarket.  So that is why 
 
  11   I was getting at that. 
 
  12             MR. LAKE:  I'm sorry.  I forgot-- 
 
  13             DR. GURIAN-SHERMAN:  There were two 
 
  14   questions. 
 
  15             MR. LAKE:  I forgot to answer your second 
 
  16   question so let me respond to that a little bit. 
 
  17   It is certainly true that the burden, basically, if 
 
  18   we find something in the marketplace, whether it is 
 
  19   bioengineered things or anything else, that is out 
 
  20   there that we believe is in violation of the law, 
 
  21   the burden is on the Food and Drug Administration 
 
  22   to go into court and make that case. 
 
  23             By the same token, though, if, again, 
 
  24   under the regime as it stands right now, there is 
 
  25   nothing that requires a company to come to us and 

 
                                                                173 
 
   1   say boo, although we strongly encourage them to do 
 
   2   so and, so far, they have always done so and, after 
 
   3   a lot of discussion with our  lawyers, they agreed 
 
   4   we could propose to require in the future. 
 
   5             But we would have the same situation if 
 
   6   somebody simply went to market without consulting 
 
   7   with us, we would have the burden of demonstrating 
 
   8   that what they were doing was inappropriate.  By 
 
   9   the same token, I think it is also true that, if we 
 
  10   were to apply a standard that is not clearly 
 
  11   recognized by the law and we were challenged, we 
 
  12   would have the burden in court to explain to the 
 
  13   court why it is, under the law as it stands, that 
 
  14   we are requiring this standard. 
 
  15             I think the concerns you are raising are 
 
  16   important concerns.  Again, I would just come back 
 
  17   to I think they are really outside the purview of 
 
  18   this discussion and are actually probably a lot 
 
  19   more complicated than I have indicated.  But I 
 
  20   think, for purposes of this discussion, we really 
 
  21   like your best advice on the science and, 
 
  22   particularly, with regard, in this meeting, to the 
 
  23   issue of allergenicity.  Presumably, we will have 
 
  24   other issues in the future. 
 
  25             DR. BRANDT:  Other questions? 

 
                                                                174 
 
   1             DR. KAPUSCINSKI:  Anne Kapuscinski.  I 
 
   2   would just like some clarification from Dr. 
 
   3   Maryanski, or if you want to answer.  It doesn't 
 
   4   matter.  I think it was towards the end of your 
 
   5   presentation, you said something to the effect that 
 
   6   you are looking to this committee to advise you on 
 
   7   science issues that are in the guidance document 
 
   8   for the current kinds of proteins you have been 
 
   9   looking at? 
 
  10             I had maybe misinterpreted, in the 
 
  11   briefing documents, that you actually looking 
 
  12   forward more to the new things that you are know 
 
  13   are coming, the dietary supplements, even the fact 
 
  14   that some crops that might engineered might produce 
 
  15   some kind of pharmaceutical or some kind of health 
 
  16   product, they might desire to put parts of it into 
 
  17   the food supply. 
 
  18             So I would appreciate clarification.  Is 
 
  19   it just that narrow group of metabolic enzymes you 
 
  20   have seen up to now or do you want our input on 
 
  21   this other stuff that is waiting in the wings? 
 
  22             DR. MARYANSKI:  That is a good question. 
 
  23   Let me try to clarify that.  In terms of actually 
 
  24   developing draft  guidance for the proteins in 
 
  25   bioengineered foods, it is our sense that the 

 
                                                                175 
 
   1   guidance that you are going to hear about in terms 
 
   2   of the international guidance has been developed 
 
   3   mainly with an eye to the kinds of products that we 
 
   4   have seen to date. 
 
   5             So, in terms of drafting our guidance, we 
 
   6   are going to primarily be thinking about that. 
 
   7   That is what we want to do first because we expect 
 
   8   to see a number of products down the road that will 
 
   9   be very similar.  So that is the highest priority. 
 
  10             Now, we obviously realize that other 
 
  11   products are going to be coming in the future, too. 
 
  12   So we do have an eye to the future an we, 
 
  13   obviously, are interested in your thoughts about 
 
  14   that to the extent that you might have some.  But I 
 
  15   think, in terms of the priority and the focus for 
 
  16   helping us get to the next step of producing a 
 
  17   draft document that then you can look at again, we 
 
  18   would like the emphasis on those substances that 
 
  19   were seen at this time that we have seen in the 
 
  20   past. 
 
  21             Is that helpful? 
 
  22             DR. BRANDT:  Yes; but that doesn't keep 
 
  23   you from looking to the future, is what he is 
 
  24   trying to say. 
 
  25             DR. MARYANSKI:  Right.  That is what I am 

 
                                                                176 
 
   1   trying to convey to you is that, if you have 
 
   2   thoughts about things that you think we need to 
 
   3   know about in the future or look at in the future, 
 
   4   we welcome those thoughts as well. 
 
   5             DR. BRANDT:  Other questions? 
 
   6             DR. BUCHANAN:  Bob Buchanan.  The current 
 
   7   President of the Deutsche Forschung Gemeinshaft, 
 
   8   the DFG, and I were post-docs together in Berkeley 
 
   9   not that many years ago and we have kept in touch. 
 
  10   He tells me that the German government often 
 
  11   consults the FDA with respect to new 
 
  12   pharmaceuticals that are emerging and to be 
 
  13   marketed. 
 
  14             I see now that this cooperation at an 
 
  15   international level regarding bioengineered foods 
 
  16   but I wondered, is that a new thing or have 
 
  17   governments, in the past, consulted the FDA for 
 
  18   common problems? 
 
  19             DR. MARYANSKI:  Yes.  I think we don't 
 
  20   consult with all governments on a routine basis but 
 
  21   we do consult with other governments on specific 
 
  22   issues.  We do, for example, have dialogue with the 
 
  23   European Union at the agency level on food issues 
 
  24   generally. 
 
  25             DR. BRANDT:  But the Codex was put into 

 
                                                                177 
 
   1   effect thirty-four, thirty-five years ago.   So 
 
   2   that has been going on for a long time. 
 
   3             DR. MARYANSKI:  Yes.  Most of our work is 
 
   4   done through the Codex in terms of our 
 
   5   international work with other governments.  That 
 
   6   provides the mechanism for us to talk to other 
 
   7   governments. 
 
   8             DR. BRANDT:  I can tell you when I sat on 
 
   9   the board of the World Health Organization, the 
 
  10   Codex was regularly brought to us, the Codex 
 
  11   discussions regularly come to us just for 
 
  12   information and sometimes action we had to take to 
 
  13   implement them or otherwise.  So it has been around 
 
  14   for a long time and intermittently effective. 
 
  15             DR. GURIAN-SHERMAN:  I would like a little 
 
  16   further clarification on what you want from us. 
 
  17             DR. BRANDT:  We are really going to talk 
 
  18   about that a lot tomorrow. 
 
  19             DR. GURIAN-SHERMAN:  I can wait until 
 
  20   then, if that is better. 
 
  21             DR. MARYANSKI:  It is summarized in that 
 
  22   paper that you have on charge and questions. 
 
  23             DR. BRANDT:  The draft that you have in 
 
  24   front of you. 
 
  25             DR. MARYANSKI:  When you get a chance to 

 
                                                                178 
 
   1   look at it, which we haven't given you just yet. 
 
   2             DR. BRANDT:  You just got it today, so you 
 
   3   can read it tonight and then we can talk about it. 
 
   4   That is one of the reasons why we don't want to 
 
   5   talk about. 
 
   6             Other questions?  Hearing none, we are 
 
   7   going to break.  According to the official time 
 
   8   clock, it is 2:45 p.m. and we reassemble at five 
 
   9   after 3:00. 
 
  10             [Recess.] 
 
  11             DR. BRANDT:  We have on the next agenda 
 
  12   item where we are going to be talking about the 
 
  13   draft Codex and the assessment on possible 
 
  14   allergenicity.  The document is Tab 9, in front of 
 
  15   Tab 9, in your book.  The actual section begins on 
 
  16   Page 12 of that. 
 
  17             Dr. Mayers, we are ready for you. 
 
  18               Codex Draft Annex on the Assessment 
 
  19                    of Possible Allergenicity 
 
  20             DR. MAYERS:  Thank you, Mr. Chairman. 
 
  21             [Slide.] 
 
  22             I am Paul Mayers.  I work in the Food 
 
  23   Directorate in Health Canada.  My colleague, Jim 
 
  24   Maryanski, commented that I was an expert in the 
 
  25   Codex work.  I don't know that I would take it that 

 
                                                                179 
 
   1   far.  I have been involved a lot with the Codex 
 
   2   work and so when the kind invitation was made to 
 
   3   come down and talk about it, I was more than happy 
 
   4   to do that because, obviously, we are going to be 
 
   5   very interested in Canada in the output of what you 
 
   6   do here because we have done a lot of work 
 
   7   together, all through this Codex process.  Where 
 
   8   you go from here in terms a national strategy is 
 
   9   obviously going to be very interesting and relevant 
 
  10   to us. 
 
  11             [Slide.] 
 
  12             Since you have already had the 
 
  13   introduction of Codex in general, let me start with 
 
  14   the Codex ad hoc Intergovernmental Task Force on 
 
  15   Food Derived from Biotechnology because this is the 
 
  16   body in Codex which has been charged with the 
 
  17   development of guidance pieces around food 
 
  18   biotechnology. 
 
  19             It was established in 1999 and with a 
 
  20   specified time limit to develop standards, 
 
  21   guidelines or recommendation for foods derived from 
 
  22   biotechnology and was very ably hosted by the 
 
  23   government of Japan.  As I mentioned, being time 
 
  24   limited, they are intended to complete their 
 
  25   mandate by next year. 

 
                                                                180 
 
   1             [Slide.] 
 
   2             As part of facilitating the process which, 
 
   3   within that short time period, if you have had any 
 
   4   involvement with Codex, one of the things that you 
 
   5   will probably have taken note is that Codex tends 
 
   6   to work in glacial time.  Standard setting in that 
 
   7   Codex process within the time-limited period of 
 
   8   this task force was going to be a challenge. 
 
   9             In order to accommodate that challenge, 
 
  10   FAO and WHO, committed to supporting the work of 
 
  11   the task force.  The mechanism that they used in 
 
  12   terms of that support was a series of expert 
 
  13   consultations. 
 
  14             At the very first session of the task 
 
  15   force, the issue of allergenicity was already very 
 
  16   much right at the center of the challenge faced by 
 
  17   the task force.  They put forward a question for 
 
  18   consideration by a joint FAO/WHO consultation and 
 
  19   that was what scientific approach can be used to 
 
  20   assess allergenicity, a fairly broad question and a 
 
  21   fairly challenging one. 
 
  22             Of course, the expectation was that the 
 
  23   outcome of the consultations would contribute to 
 
  24   the consideration in the work of the task force. 
 
  25             [Slide.] 

 
                                                                181 
 
   1             FAO and WHO have certainly been active in 
 
   2   this area with expert consultations both before the 
 
   3   genesis of this task force and Codex as well as 
 
   4   since that time.  I have noted here three in 
 
   5   particular because, in each of these three 
 
   6   consultations in 1996 and 2000 and in 2001, 
 
   7   allergenicity formed a part of the discussion. 
 
   8             Of course, in the 2001 consultation, it 
 
   9   formed the very basis of the consultation and each 
 
  10   of these pieces continued to contribute important 
 
  11   considerations to the debate that was going on 
 
  12   internationally around addressing this particular 
 
  13   subject. 
 
  14             In 1996, and again considered in the 2000 
 
  15   consultation, there was a decision-tree approach 
 
  16   that was available for consideration and had been 
 
  17   considered by the expert consultation.  Within the 
 
  18   context of that decision-tree approach, not unlike 
 
  19   what you heard in Dr. Maryanski's presentation, 
 
  20   considerations related to the source of the 
 
  21   introduced protein, impact of the actions on that 
 
  22   protein such as digestion and processing, and 
 
  23   sequence similarity to known allergens were key 
 
  24   considerations. 
 
  25             [Slide.] 

 
                                                                182 
 
   1             Here you see what that decision tree looks 
 
   2   like and you will note that there are two sides to 
 
   3   the tree determined by the outset by the nature of 
 
   4   the source of that introduced material.  So where 
 
   5   it is not a known allergenic source, then the 
 
   6   physical, chemical characteristics of the protein 
 
   7   and its stability to digestion and processing being 
 
   8   used to contribute to an identification of the 
 
   9   potential for allergenicity and, down the other 
 
  10   side, where the source is known to be allergenic, a 
 
  11   more direct application of the available tools 
 
  12   using solid-phase immunoassay as the mechanism. 
 
  13             There was a certain level of confidence 
 
  14   with one side of this.  The other side continued to 
 
  15   generate questions.  So, in 2001, the expert 
 
  16   consultation which focused very specifically on 
 
  17   allergenicity introduced new elements to the 
 
  18   approach, elements that responded to the questions 
 
  19   but also elements that were taking into account 
 
  20   interests, challenges, new developments. 
 
  21             So a couple of issues to highlight from 
 
  22   their report was that, in addition to the sequence-homology 
 
  23   analysis from allergenic and nonallergenic 
 
  24   sources being considered, that the issue of 
 
  25   targeted serum screening would be added to the 

 
                                                                183 
 
   1   specific serum screening as a strategy, the 
 
   2   targeted serum screening being added with the 
 
   3   intent to  identify allergens that might not be 
 
   4   caught with the other strategies. 
 
   5             The narrowed the physical characteristic 
 
   6   focus to resistance to pepsin, quite specifically, 
 
   7   and introduced, as an additional consideration, the 
 
   8   use of animal models in the strategy. 
 
   9             [Slide.] 
 
  10             So, we now see, then, a revised decision-tree 
 
  11   strategy having been proposed as the result of 
 
  12   the 2001 expert consultation.  You will note that, 
 
  13   while there continues to be the question regarding 
 
  14   the source of the gene and its known allergenicity 
 
  15   that the two sites interact much more than they did 
 
  16   previously through the consideration after sequence 
 
  17   homology in both cases of targeted and specific 
 
  18   serum screening dependent on where the first 
 
  19   question led. 
 
  20             [Slide.] 
 
  21             This all, then, became fodder for the 
 
  22   discussion in Codex.  The output of these expert 
 
  23   consultations were taken very much into account 
 
  24   during the discussion in drafting general 
 
  25   principles and a specific guideline document in 

 
                                                                184 
 
   1   Codex.  The work of the expert consultation on 
 
   2   allergenicity specifically was considered very 
 
   3   useful, but it was recognized that it also proposed 
 
   4   a very significantly different approach. 
 
   5             In addition, in the discussion, many 
 
   6   delegations expressed a real interest in what was 
 
   7   presented by the FAO/WHO expert consultation but 
 
   8   questions remained regarding the practicality of 
 
   9   certain parts of the strategy proposed in terms of 
 
  10   the ability to apply them currently with the level 
 
  11   of development of tools such as, for example, 
 
  12   animal models. 
 
  13             So, to allow for a more detailed 
 
  14   consideration of the allergenicity assessment 
 
  15   procedure than would be permitted in an open-forum 
 
  16   Codex discussion with 65 country delegations and, 
 
  17   in addition to that, another 40 or so nongovernment 
 
  18   delegations, the task force made the decision to 
 
  19   create and an hoc open-ended working group to 
 
  20   develop guidance for consideration by the broader 
 
  21   task force. 
 
  22             [Slide.] 
 
  23             So, in consideration of this ad hoc open-ended 
 
  24   working group, it was requested to take into 
 
  25   account the information that was available 

 
                                                                185 
 
   1   including the output of the 2001 expert 
 
   2   consultation.  The government of Canada was asked 
 
   3   to take the lead for the working group.  Canada 
 
   4   agreed to do that and convened the working group 
 
   5   September 10 to 12, 2001 in Vancouver. 
 
   6             It was my privilege to chair that working 
 
   7   group.  You will probably have taken note in the 
 
   8   dates of some of the challenges that that group 
 
   9   faced, and I must pause and commend those members 
 
  10   of the working group because I know that it was a 
 
  11   tremendous challenge, one to continue the work in 
 
  12   that period, which all delegations agreed to 
 
  13   continue, and, two, many of my colleagues ended up 
 
  14   with some tourist time in Vancouver that was 
 
  15   unplanned, as you might imagine.  I know some took 
 
  16   some interesting routes to get back to their homes 
 
  17   and, for some, it was a lot later than they 
 
  18   planned. 
 
  19             So the government of Canada very much 
 
  20   appreciated the commitment that delegations made to 
 
  21   completing the working in such trying times. 
 
  22             [Slide.] 
 
  23             So, in terms of the work of the working 
 
  24   group, we started the proceedings with 
 
  25   consideration of a discussion paper that had been 

 
                                                                186 
 
   1   prepared by a drafting group.  We felt that it was 
 
   2   very important to put before the group, in order to 
 
   3   progress the work, a paper developed by a smaller 
 
   4   group that would raise questions, propose 
 
   5   strategies and take into account the range of 
 
   6   information that was available at the time. 
 
   7             We also benefitted from the presence of 
 
   8   the secretary of the FAO/WHO 2001 expert 
 
   9   consultation who made a presentation on the work of 
 
  10   that expert group because we thought that it was 
 
  11   very important, as a starting point, to start from 
 
  12   where that group concluded in terms of their 
 
  13   recommendations. 
 
  14             In organizing the guidance, within the 
 
  15   working group, the decision was taken to organize 
 
  16   it rather than a single schematic into two parts, 
 
  17   an initial assessment that would be the practical 
 
  18   solution to consideration of the steps that would 
 
  19   likely be taken anyway and then the subsequent 
 
  20   detailed considerations based on the output of that 
 
  21   initial assessment. 
 
  22             There was a very clear recognition that 
 
  23   the initial assessment was not intended to be 
 
  24   conclusive but that these were the considerations 
 
  25   that would be relevant to all expressed proteins. 

 
                                                                187 
 
   1             So you see, as I go forward, the group 
 
   2   tried not to focus on guidance that might be 
 
   3   construed as yes/no questions.  There was a 
 
   4   concerted decision to move from that style of 
 
   5   guidance to a broader style which has its 
 
   6   detractors, I can guarantee you, because, as 
 
   7   always, if the questions aren't definitive as 
 
   8   yes/no, it introduces a level of interpretation 
 
   9   that can be challenging, and I think appropriately 
 
  10   challenging, because of the nature of the issue 
 
  11   being considered. 
 
  12             But I can also note that it does raise 
 
  13   questions for some. 
 
  14             [Slide.] 
 
  15             So, as we worked forward, what we wanted 
 
  16   to do was introduce, consistent with the rest of 
 
  17   the guidelines--and if you have taken the time to 
 
  18   look at the totality of the Code guidance, not just 
 
  19   the part on allergenicity, you will take note very 
 
  20   quickly that none of the guidance provides a simple 
 
  21   yes/no answer. 
 
  22             In fact, throughout the guidance that the 
 
  23   task force was already very advance in elaborating, 
 
  24   there was a very strong influence of weight of 
 
  25   evidence as the consideration being undertaken.  

 
                                                                188 
 
   1   So, in the working group, that contribution, in 
 
   2   terms of weight of evidence, influenced the way 
 
   3   that the working group concluded and put forward 
 
   4   recommendations back to the full task force. 
 
   5             In having reported back to the task force, 
 
   6   in plenary, the task force was able to undertake a 
 
   7   I wouldn't say detailed but an extensive discussion 
 
   8   of the proposals of the working group and while 
 
   9   certainly made modifications, many, I think 
 
  10   significant improvements, the general strategy 
 
  11   proposed by the working group was accepted. 
 
  12             [Slide.] 
 
  13             So, in terms of that strategy, by way of 
 
  14   introduction, it focused specifically in IgE-mediated 
 
  15   allergenicity.  There had been an interest 
 
  16   expressed to also consider celiac disease, for 
 
  17   example.  The working group didn't believe that it 
 
  18   had the competence to address that particular 
 
  19   challenge in the same way that it would the IgE-mediated and 
 
  20   so limited its focus to IgE-mediated 
 
  21   allergenicity. 
 
  22             The approach, therefore, rather than a 
 
  23   decision tree was an integrated stepwise but still 
 
  24   case-by-case approach.  Case-by-case here doesn't 
 
  25   mean that you reinvent the strategy for each 

 
                                                                189 
 
   1   product.  What it means is that the strategy needs 
 
   2   to take into account the nature of the product and 
 
   3   be appropriately tailored to address the issues 
 
   4   raised by the nature of the product, itself. 
 
   5             Of course, in terms of the goal, the 
 
   6   endpoint of the assessment is a conclusion as to 
 
   7   the likelihood of the protein under consideration 
 
   8   being a food allergen. 
 
   9             [Slide.] 
 
  10             The strategy, as I mentioned, starts with 
 
  11   an initial assessment consideration.  These are 
 
  12   things that you certainly heard in the presentation 
 
  13   earlier, the source, the amino-acid sequence 
 
  14   homology.  I must note here that the working group 
 
  15   had significant discussion around the actual 
 
  16   process of sequence-homology assessment because 
 
  17   there had been significant interest in fixing a 
 
  18   number of contiguous amino acids that would be used 
 
  19   for the search. 
 
  20             The discussion went back and forth between 
 
  21   six amino acids and eight.  There was a recognition 
 
  22   that, at eight amino acids, there were concerns 
 
  23   regarding misses that would yield false negatives 
 
  24   and, equally at six, there were concerns related to 
 
  25   hits that would yield false positives. 

 
                                                                190 
 
   1             In typical Codex fashion, after much 
 
   2   discussion, the working group decided that, rather 
 
   3   than fix a specific number, instead it would 
 
   4   recognize that, for a valid search, consideration 
 
   5   needed to be given about the appropriate number for 
 
   6   the nature of the product under consideration and 
 
   7   that the number selected should be based on an 
 
   8   appropriate scientific rationale. 
 
   9             So, rather than fixing a number in the 
 
  10   guidance, it recognized the issues in terms of both 
 
  11   false negatives and positives but created 
 
  12   flexibility in defending the selection that is made 
 
  13   in order to carry out the test. 
 
  14             DR. LEHRER:  Could I ask a question? 
 
  15             DR. MAYERS:  Of course. 
 
  16             DR. LEHRER:  Sam Lehrer.  I have a 
 
  17   question about appropriate scientific rationale. 
 
  18   Could you be a little more specific about that? 
 
  19             DR. MAYERS:  In terms of the rationale, 
 
  20   the expectation would be, and this is where 
 
  21   national governments as opposed to Codex will have 
 
  22   to make decisions because Codex doesn't make 
 
  23   decisions about products.  It has provided 
 
  24   guidance. 
 
  25             National governments have to interpret 

 
                                                                191 
 
   1   that guidance.  National government will have to 
 
   2   apply that reasoning, so let me speak to it from 
 
   3   the Canadian perspective, if you will allow.  In 
 
   4   this case, for us, an appropriate scientific 
 
   5   rationale would be a detailed discussion on the 
 
   6   selection based on the information available 
 
   7   regarding amino-acid-sequence tests where six or 
 
   8   eight or twelve, if someone selected to do that, 
 
   9   were conducted in terms of rates of false positives 
 
  10   and false negatives and the arguments that might be 
 
  11   available if we are dealing with a particular 
 
  12   category of allergens in terms of issues like 
 
  13   epitopes. 
 
  14             It is not something that I am going to 
 
  15   suggest is cut or dried.  I believe that each 
 
  16   argument is going to have to be carefully 
 
  17   considered.  I would hope that we will get to a 
 
  18   point where we will have seen sufficient arguments 
 
  19   to begin to characterize that particular guidance 
 
  20   more specifically but I can tell you right now, we 
 
  21   are certainly not ready to do that in Canada in 
 
  22   terms of fixing a number. 
 
  23             So what we are doing for each product, 
 
  24   what we are looking for is not just the results of 
 
  25   the homology comparison, but we want some 

 
                                                                192 
 
   1   discussion around the validity of that comparison 
 
   2   in terms of addressing the issues of false 
 
   3   negatives and positives. 
 
   4             I know that is not as specific as I would 
 
   5   like it I were asking the question but, 
 
   6   unfortunately, that is the reality. 
 
   7             DR. BRANDT:  Go ahead and finish up your 
 
   8   presentation.  We will come to questions 
 
   9             DR. MAYERS:  Continuing, then, with that 
 
  10   initial assessment portion, the structural 
 
  11   properties including issues like susceptibility to 
 
  12   enzymatic degradation, heat stability and acid 
 
  13   processing. 
 
  14             [Slide.] 
 
  15             Once we get beyond that initial assessment 
 
  16   consideration, then we get into the more specific 
 
  17   considerations.  For proteins originating from a 
 
  18   source known to be allergenic or with sequence 
 
  19   homology, then specific serum screening recognized 
 
  20   as being a very useful tool. 
 
  21             Where those proteins are not coming from 
 
  22   an allergenicity source or not exhibiting the 
 
  23   homology, then consideration of target serum 
 
  24   screening--and you will note the "may" here; that 
 
  25   "may" was very important given concerns expressed 

 
                                                                193 
 
   1   regarding the validation of targeted serum 
 
   2   screening strategies. 
 
   3             There was a very clear recognition of the 
 
   4   utility of the tool recommended by the 2001 expert 
 
   5   consultation, but there was an equal recognition 
 
   6   that work needed to take place in order to 
 
   7   facilitate the use of this tool by developing more 
 
   8   clear strategies and validating them. 
 
   9             Recognition in terms of this part of the 
 
  10   consideration, that the results from in vitro amino 
 
  11   assays may not, in fact, be sufficient.  So a 
 
  12   negative result where this was warranted, again 
 
  13   taking into account the totality of the evidence as 
 
  14   opposed to simply one aspect of that evidence may, 
 
  15   therefore, prompt additional testing, a positive 
 
  16   result being considered an indication of a 
 
  17   potential allergen. 
 
  18             [Slide.] 
 
  19             There were, of course, other 
 
  20   considerations that were highlighted in the draft 
 
  21   annex; the nature of the product, itself--i.e., the 
 
  22   form to be consumed being taken into consideration 
 
  23   in determining for the strategy what types of 
 
  24   processing would actually be taken into account, 
 
  25   so, rather than automatically defaulting to a 

 
                                                                194 
 
   1   particular set of processing tests for the protein, 
 
   2   taking into account the food product, itself. 
 
   3             So, again, when we say case-by-case, we 
 
   4   are not talking about making it up as you go. 
 
   5   Instead, what we are talking about is structuring 
 
   6   the strategy to most effectively deal with the 
 
   7   particular product under consideration and the 
 
   8   recognition that both the targeted serum screening 
 
   9   and the use of animal models have tremendous 
 
  10   potential to add value to the assessment but 
 
  11   require validation in order to allow regulatory 
 
  12   agencies the level of comfort in their application 
 
  13   that would be appropriate for regulatory decisions. 
 
  14             [Slide.] 
 
  15             Also, recognizing that while calling for 
 
  16   serum screening is very useful, the availability of 
 
  17   sera represents a very real challenge.  So the 
 
  18   need, in order to facilitate that work, the 
 
  19   organization of an international serum bank, for 
 
  20   example.  Further, even more detailed assessment 
 
  21   may be possible once methods related, for example, 
 
  22   to examination for T-cell epitopes and structural 
 
  23   motifs, which are associated with allergens, are 
 
  24   appropriately evolved to applied in regulatory 
 
  25   decision making. 

 
                                                                195 
 
   1             [Slide.] 
 
   2             The task force, having taken into account 
 
   3   the report of the working group and, having had its 
 
   4   discussion, made some decisions and I have 
 
   5   indicated here some of the next steps.  It referred 
 
   6   the issue of the gluten insensitivities to the 
 
   7   Codex Committee on Nutrition and Foods for Special 
 
   8   Dietary Uses for their information. 
 
   9             It wasn't possible for the task force to 
 
  10   go beyond information.  That Codex committee will 
 
  11   have to make decisions as to whether they are at a 
 
  12   stage where they could consider more detailed work 
 
  13   in terms of gluten insensitivities, for example. 
 
  14             The Annex was advanced to Step 5.  In the 
 
  15   Codex process--I know we didn't give you Codex 101, 
 
  16   but, within Codex, for a standard to be adopted, 
 
  17   there is an eight-step process.  The Annex was 
 
  18   advanced to Step 5 of that Codex procedure and 
 
  19   forwarded to the commission with the recommendation 
 
  20   that it be adopted at Step 8, which is the final 
 
  21   step, with the omission of Steps 6 and 7. 
 
  22             So that means, once considered by the 
 
  23   commission, in June of next year, then if accepted 
 
  24   by the commission, including acceptance of the 
 
  25   recommendation to omit Steps 6 and 7, that Annex 

 
                                                                196 
 
   1   will then be adopted as part of a Codex standard. 
 
   2             The full Codex guideline and the 
 
   3   principles have been forwarded, as well, to the 
 
   4   commission for consideration at Step 8 of the 
 
   5   procedure. 
 
   6             [Slide.] 
 
   7             Finally, since, having come from Canada, I 
 
   8   believe I would be remiss if I didn't give you at 
 
   9   least some insight into some of our thinking in 
 
  10   regard to some of these pieces because, we, too, 
 
  11   have been thinking very hard around the issue of 
 
  12   allergenicity and continuing to enhance the 
 
  13   addressing of allergenicity in our guidance. 
 
  14             We have undertaken a couple of initiatives 
 
  15   that I would note.  One, in November of last year, 
 
  16   we held an international workshop on animal models 
 
  17   for the detection of allergenicity and, from that 
 
  18   work, we have continued to integrate into the 
 
  19   research program in the Food Directorate in Food 
 
  20   Canada where I work some research initiatives 
 
  21   regarding the issue of models. 
 
  22             We are, as well, pursuing some research 
 
  23   partnerships with regard to new tools for the 
 
  24   assessment of longer-term health effects including 
 
  25   toxicology where, in particular, we are focusing on 

 
                                                                197 
 
   1   the issue of whole foods and biological markers of 
 
   2   relevance in toxicological assessment so as to 
 
   3   enhance the toxicological testing element of our 
 
   4   assessment strategy. 
 
   5             You may have taken note that the Royal 
 
   6   Society of Canada, at the request of our 
 
   7   department, along with others, had formed an expert 
 
   8   panel which provided us with recommendations so we 
 
   9   are now in the process of updating our guidelines 
 
  10   for the safety of assessment of novel foods.  We 
 
  11   expect to have a draft in consultation in the fall 
 
  12   which will take account of those recommendations as 
 
  13   well as the guidance by Codex. 
 
  14             We are a bit ahead of the game in that 
 
  15   Codex has not formally adopted them but we have 
 
  16   been appropriately impressed with the work 
 
  17   accomplished in Codex and so we believe that, even 
 
  18   without their adoption, there are interesting 
 
  19   elements presented in the Codex guidance that we 
 
  20   would like to see brought into our strategy earlier 
 
  21   rather than later. 
 
  22             We are also doing some work on guidance 
 
  23   for transgenic animals which, hopefully, we will 
 
  24   have open consultation later this year, but that is 
 
  25   not particularly relevant to this discussion so I 

 
                                                                198 
 
   1   won't take that any further. 
 
   2             So, Mr. Chairman, I will be more than 
 
   3   happy to try to take questions. 
 
   4             DR. BRANDT:  Thank you. 
 
   5             Let me remind all of you that tomorrow, on 
 
   6   Question No. 1, that they are seeking advice has to 
 
   7   do with the Codex because, specifically, every 
 
   8   national government now has to address it totally 
 
   9   independently, as it were, because it is not 
 
  10   imposing rule. 
 
  11             So Question No. 1 that we will be talking 
 
  12   about tomorrow, as listed in your two-page 
 
  13   document, will be addressing that specific thing. 
 
  14             So let's go to questions. 
 
  15                    Questions of Clarification 
 
  16             DR. GURIAN-SHERMAN:  Doug Gurian-Sherman. 
 
  17   Two questions.  One is, could you clarify a little 
 
  18   bit what the steps that the current process is at 
 
  19   and are there provisions in Codex to modify a final 
 
  20   decision.  Do I understand correctly, the task 
 
  21   force has recommended to Codex to accept the Annex; 
 
  22   is that right?  And then what is the procedure for 
 
  23   the full Code committee?  Can they modify  it?  Can 
 
  24   they just accept or reject?  That is the first 
 
  25   question. 

 
                                                                199 
 
   1             The second question is, going back to the 
 
   2   5 and 6 contiguous amino acids, did the FAO--did 
 
   3   the task force decide--I want to be clear about 
 
   4   this--that, if you set eight amino acids as the 
 
   5   limit, that you could miss active epitopes.  So 
 
   6   then the question becomes how do you justify the 
 
   7   false positives?  Either the greater false 
 
   8   positives for six or the greater false negatives 
 
   9   for eight?  Is that an accurate assessment of what 
 
  10   FAO decided? 
 
  11             DR. MAYERS:  Let me take the first one and 
 
  12   then, if I don't remember well enough, remind me. 
 
  13   In terms of the procedure, the commission will have 
 
  14   the flexibility to adopt based on the 
 
  15   recommendations or to not adopt.  That is why they 
 
  16   are the commission. 
 
  17             They also will have the flexibility to 
 
  18   make decisions in between, if you would, in that 
 
  19   they might ask for further consideration of 
 
  20   specific issues.  That will be challenging, given 
 
  21   that the commission will be meeting after the 
 
  22   mandate of the task force itself is complete.  That 
 
  23   means that there won't be a body to refer that work 
 
  24   to, but that doesn't mean that the commission has 
 
  25   to adopt the guidance whether it be principles, the 

 
                                                                200 
 
   1   guidelines, or, specifically, the Annex. 
 
   2             In terms of the step procedures in Codex, 
 
   3   the procedures are there to ensure that there is 
 
   4   appropriate input from delegations.  So, along that 
 
   5   path, certain steps of the procedure involve 
 
   6   consultative mechanisms.  One consultation 
 
   7   mechanism has been engaged and the proposal to 
 
   8   eliminate two steps would remove one of those 
 
   9   consultative mechanisms.  It hasn't removed all of 
 
  10   them, but it would remove one. 
 
  11             In terms of the other issue, in terms of 
 
  12   the working-group discussion around the contiguous 
 
  13   amino acids, there was sufficient recognition that, 
 
  14   within the working group, we didn't have enough 
 
  15   information around the impacts to fix a specific 
 
  16   number, nor did we have sufficient time to analyze 
 
  17   the issue sufficiently deeply to propose a specific 
 
  18   number, that the issues of false positives and 
 
  19   false negatives were both relevant. 
 
  20             So there wasn't a simple balancing of, 
 
  21   well, we might hit it or we might not.  It was 
 
  22   simply a recognition that fixing a specific number 
 
  23   with the current knowledge would be inappropriate 
 
  24   at this time and so, therefore, the proposal that, 
 
  25   instead, the approach taken for an individual 

 
                                                                201 
 
   1   comparison would need to be defended, based on the 
 
   2   nature of the comparison, itself, and the product 
 
   3   under consideration. 
 
   4             DR. BRANDT:  Other questions? 
 
   5             DR. KAPUSCINSKI:  Anne Kapuscinski.  You 
 
   6   seem to indicate that there is a clear distinction 
 
   7   between the weight-of-evidence strategy and the 
 
   8   decision-tree strategy.  When I reviewed the 
 
   9   documents we have about this Codex endeavor, it 
 
  10   seemed to me like the two go hand-in-hand.  It 
 
  11   looks like the decision tree is just a way of kind 
 
  12   of visually showing the order in which you deal 
 
  13   with the different lines of evidence so that then 
 
  14   you do actually consider the whole weight of 
 
  15   evidence. 
 
  16             So am I missing something? 
 
  17             DR. MAYERS:  I don't think so.  I would 
 
  18   share your interpretation.  The only challenge with 
 
  19   the decision tree wasn't the questions that are 
 
  20   posed.  It was the fact that it identified yes/no 
 
  21   answers.  Some of the answer are going to be made-- 
 
  22             DR. KAPUSCINSKI:  Are not flexible; right. 
 
  23             DR. MAYERS:  So that is really the issue. 
 
  24             DR. KAPUSCINSKI:  I have one more 
 
  25   question.  In at least one of the Codex documents, 

 
                                                                202 
 
   1   I think it was the joint FAO/WHO expert 
 
   2   consultation, there is a lot of talk in there about 
 
   3   suggesting further study for postmarket 
 
   4   surveillance and monitoring. 
 
   5             Since it seems to be couched mostly in the 
 
   6   general language of suggestions and rating some 
 
   7   issues to be considered, what do you think will 
 
   8   happen after the CAC meets in 2003 regarding that 
 
   9   particular issue? 
 
  10             DR. MAYERS:  The issue of postmarket 
 
  11   surveillance is dealt with quite specifically in 
 
  12   the principles document, in the FAO/WHO expert 
 
  13   consultation, being an expert consultation, it 
 
  14   provides recommendation while the Codex has the 
 
  15   responsibility for the standard setting. 
 
  16             So the language in the Codex principles is 
 
  17   more specific.  It recognizes that postmarket 
 
  18   surveillance may be a very valid tool where a 
 
  19   specific question is identified and the strategy 
 
  20   for postmarket surveillance is designed to respond 
 
  21   to that question. 
 
  22             What it doesn't do is it doesn't simply 
 
  23   propose that postmarket surveillance always be 
 
  24   applied for every product. 
 
  25             DR. GURIAN-SHERMAN:  I have one more 

 
                                                                203 
 
   1   question.  This is Doug Gurian-Sherman.  Back to 
 
   2   Anne's question of the decision tree versus weight 
 
   3   of evidence.  I have heard some definitions of the 
 
   4   decision tree that suggest that, of course, I think 
 
   5   there is pretty wide recognition that, let's say, 
 
   6   with the digestibility assay, if you get stability, 
 
   7   it doesn't mean that something is going to be an 
 
   8   allergen or vice versa. 
 
   9             So that is a maybe answer.  But I think, 
 
  10   in terms of decision making, some definitions of 
 
  11   the decision tree suggest that, if you got a 
 
  12   certain answer, that we be a no-go on the product 
 
  13   whereas, in weight of evidence, you are considering 
 
  14   everything and putting them altogether and saying, 
 
  15   well, we got this answer for this and this answer 
 
  16   for this.  Based on our understanding of all of 
 
  17   these together, we make this decision.  Is that 
 
  18   correct, because that is certainly a difference 
 
  19   that I have heard debated and that there is a 
 
  20   certain amount of concern about, I think, in the 
 
  21   consumer community. 
 
  22             DR. MAYERS:  I think there are a range of 
 
  23   interpretations.  That is part of the challenge 
 
  24   with trying to simplify a complex assessment 
 
  25   strategy in a pictogram.  But, a pictogram is very 

 
                                                                204 
 
   1   powerful because it gives you insight.  Personally, 
 
   2   I am a bit torn.  I like the simplicity of 
 
   3   understanding the totality of what you are trying 
 
   4   to do that a pictogram represents. 
 
   5             I do get concerned if the interpretation 
 
   6   then becomes so rigid that we forget that we are 
 
   7   dealing in a scientific endeavor with questions 
 
   8   that don't always lend themselves to a simple 
 
   9   cause-effect response especially if we are dealing 
 
  10   with something like the results of a digestibility 
 
  11   assay. 
 
  12             DR. BUCHANAN:  This is Bob Buchanan again. 
 
  13   Assuming an ample international serum bank, is 
 
  14   there some way that targeted serum screening can 
 
  15   give information as to whether or not a protein to 
 
  16   which human populations have not been exposed in 
 
  17   their diet, dietarily, can be assessed to be an 
 
  18   allergen? 
 
  19             DR. MAYERS:  That is a great question.  I 
 
  20   think there are people in the room who are probably 
 
  21   way better than I to answer that because that, in 
 
  22   itself, is, I think, a very interesting and 
 
  23   significant debate.  But I certainly hold some hope 
 
  24   that targeted serum screening will give some 
 
  25   insight.  I don't know if it will answer that 

 
                                                                205 
 
   1   question but I think it certainly can contribute 
 
   2   effectively if there is a good bank of sera against 
 
   3   which to challenge a particular protein. 
 
   4             But I certainly don't have the expertise 
 
   5   to take that particular debate to its fulfillment, 
 
   6   I don't believe. 
 
   7             DR. ATKINS:  Dan Atkins.  You mentioned 
 
   8   that the stepwise approach was a bit more 
 
   9   cumbersome.  We talked about six versus eight amino 
 
  10   acids.  But we are not challenging people anywhere 
 
  11   here.  Part of the thing that concerns me about 
 
  12   that is that, if you take, for example, fruits and 
 
  13   vegetables, if your RAST assay or ELISA doesn't 
 
  14   incorporate all the allergens, or they are 
 
  15   different in fresh products, now you are going to 
 
  16   have a negative test, you are going to open this up 
 
  17   to everybody, and there is a population that is 
 
  18   going to react to that and you are going to miss 
 
  19   them in your whole process. 
 
  20             So, are food challenges going to be 
 
  21   incorporated in here at some point before we 
 
  22   release this into the general population or not? 
 
  23             DR. MAYERS:  When you say "food 
 
  24   challenges," I had to respond with a question, but 
 
  25   who are we going to challenge? 

 
                                                                206 
 
   1             DR. ATKINS:  You have a population that 
 
   2   you are going to say they are important enough you 
 
   3   are going to look at their serum to see if they are 
 
   4   allergic to the product, so why wouldn't you 
 
   5   challenge them, for example? 
 
   6             DR. BRANDT:  Remember that that is a point 
 
   7   you can really raise with the FDA because each 
 
   8   country is going to have to make that decision.  It 
 
   9   is not going to be an issue that that task force or 
 
  10   the Codex or the WHO or the FAO is going to decide. 
 
  11             DR. ATKINS:  What they did was they 
 
  12   dropped out the challenges of individuals in the 
 
  13   first study and then they went away from the step-wise 
 
  14   approach to the weight-of-evidence approach 
 
  15   which means you can say, well, we, as a group, want 
 
  16   to discount this data because we don't think it is 
 
  17   that important.  Would you get the same if you had 
 
  18   several groups?  Would you get different opinions? 
 
  19   How do you defend that to the public.  How do you 
 
  20   explain that to the public?  It is okay this time? 
 
  21   It is not okay that time?  It is going to make it 
 
  22   harder. 
 
  23             DR. BRANDT:  It is advice, though, that we 
 
  24   can give the FDA about further steps. 
 
  25             One more question and then we are going to 

 
                                                                207 
 
   1   quit. 
 
   2             DR. ASTWOOD:  Jim Astwood here.  I was 
 
   3   going to follow up on Dan's question.  Just for 
 
   4   clarification, in the original '96 and in Year 2000 
 
   5   FAO/WHO expert recommendations, the food challenge 
 
   6   appeared and was recommended in cases where the 
 
   7   source of the gene was from something known to 
 
   8   cause allergies. 
 
   9             So the debate is around whether that 
 
  10   should be in or out.  As a practical matter, I am 
 
  11   not aware of any product, and Dr. Maryanski could 
 
  12   confirm, that the FDA has considered where such a 
 
  13   gene has actually be put into a crop and a petition 
 
  14   has been made on it.  So there is a certainly 
 
  15   element of hypothetical consideration there, but it 
 
  16   is an important point. 
 
  17             DR. BRANDT:  Okay.  We are going to meet 
 
  18   again at 8:30 tomorrow. 
 
  19             [Whereupon, at 3:50 p.m., the proceedings 
 
  20   were recessed, to resume on Wednesday, August 14, 
 
  21   2002 at 8:30 a.m.]