AT DEPARTMENT OF HEALTH AND HUMAN SERVICES

 

UNITED STATES FOOD AND DRUG ADMINISTRATION

 

CENTER FOR FOOD SAFETY AND APPLIED NUTRITION

 

 

 

 

 

 

 

 

 

 

 

ADDITIVES AND INGREDIENTS SUBCOMMITTEE

OF THE

FOOD ADVISORY COMMITTEE

 

LATEX ALLERGY

 

 

 

 

 

 

 

Tuesday, August 26, 2003

 

9:10 a.m.

 

 

 

 

 

 

 

 

 

 

 

 

St. Regis Hotel

923 16th Street, Northwest

Crystal Ballroom

Washington, D.C.

PARTICIPANTS

 

Johanna Dwyer, D. Sci., Chair

Richard Bonnette, Executive Secretary

 

MEMBERS

 

    Jeffrey Blumberg, Ph.D.

    Goulda Downer, Ph.D.

    Lawrence Fischer, Ph.D.

    Anthony Gaspari, M.D.

    Robert Hamilton, Ph.D.

    Rachel Johnson, Ph.D.

    Brandon Scholz

    Steve Taylor, Ph.D.

    J. Antonio Torres, Ph.D.

C O N T E N T S

 

Welcome and Introductions

Committee Chair    5

 

Conflict of Interest Statements

Committee Executive Secretary    7

 

Welcome

Alan Rulis, Ph.D.    11

 

Overview of CFSAN's Office of Food Safety

George Pauli, Ph.D.    14

 

Charge and Questions

Laura Tarantino, Ph.D.    29

 

Basic Latex Allergy Background

Jay Slater, M.D.    39

 

Questions of Clarification    70

 

CDRH Proposal

Mel Stratmeyer, Ph.D.    96

 

Questions of Clarification    107

 

Safety Assessment of Food Additives

Anna Shanklin, Ph.D.    128

 

Questions of Clarification    151

 

Specific Background on Food Mediated Latex Reactions

Mark Hepp, Ph.D.    163

 

Questions of Clarification    183

 

Progress in the Management of NRL Allergy

Vesna Tomazac-Jezic, Ph.D.    200

 

Questions of Clarification    212

C O N T E N T S (cont.)

 

Invited Comment

Don Beezhold, Ph.D.    229

 

Questions of Clarification    243

 

Invited Comment from a State with Latex Food Service Glove Prohibition

Michael Heumann    260

 

Questions of Clarification    283

P R O C E E D I N G S

Welcome and Introductions

    DR. DWYER:  Good morning.  Welcome to the latex allergy discussion.  CFSAN's concern with the use of natural rubber latex gloves in retail food establishments and the food service industry is focused on whether such use may result in the production of unsafe food, and that is what we are gathered here this morning to talk about, separating the issues related to worker exposure and occupational safety from those of food safety.

    I am Johanna Dwyer and I am chairing this meeting today.  The task before this Food Advisory Subcommittee is to consider the available information related to food mediated latex allergic reactions and the use of latex food service gloves in establishments that prepare food for public consumption, so specifically, there are several issues that FDA has requested feedback from the committee on.

    The first question that we will return to over the course of the next two and a half days is has a positive relationship been established between the use of natural rubber latex gloves in food service and allergic reactions to food served in food establishments or sold at the market based on the data that are available to the committee.

    If such a relationship exists, what is the strength of that relationship and has it been shown to be causative.  Second, if a positive relationship has been established and shown to be causative, can the Advisory Committee suggest science-based options to mitigate food mediated latex allergy risk?

    Finally, if current evidence isn't sufficient to establish a relationship, what additional questions need to be addressed to adequately understand this issue?

    So, we have got a lot of work to do.  I think our main task is to keep focused on the specific questions the agency has asked us to answer rather than the broader questions that these issues raise.

    Mr. Bonnette.

Conflict of Interest Statements

    MR. BONNETTE:  Good morning.  My name is Richard Bonnette and I am the Acting Executive Secretary for the Additives and Ingredients Subcommittee of the full Food Advisory Committee.

    I will read into the record the temporary voting member appointment and conflicts of interest statement.

    By the authority granted under the Food Advisory Committee charter of July 2002, the following individuals have been appointed as temporary voting members by Joseph A. Levitt, Director, Center for Food Safety and Applied Nutrition.  Anthony Gaspari, Robert Hamilton, and Steve Taylor.

    With regard to the issue of conflict of interest, committee members, permanent and temporary, were screened for interests in latex glove manufacturers.  As a result of this review, in accordance with 18 U.S. Code Section 208(b)(3), Dr. Johanna Dwyer has been granted a particular matter of general applicability waiver that permits her to participate fully in the matters at issue.

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

    We would also like to note that Mr. Brandon Scholz is participating in this meeting as the Industry Representative and is a non-voting participant.

    It should also be noted that Dr. Charles Reed, who will be speaking tomorrow, was invited by the latex glove industry to speak.

    With respect to all other participants, we ask in the interest of fairness that they address any current or previous financial involvement with any firm which makes latex gloves.

    I will just at this time make a few housekeeping notes especially to the committee and to the upcoming speakers.

    When you use the microphone, you have to press a little button to turn it on and then press the button again to turn it off.  That is only an issue because we can only have four mikes open at any one time.

    We will be using, for the speakers we will be using a hand-held wireless mouse, and basically what you need to know to advance your slides is there is a little trigger in the bottom that will move you onto the next slide.

    DR. DWYER:  Could we go around the table and just introduce the various members, Mr. Bonnette.

    MR. BONNETTE:  Sure.

    DR. DWYER:  Mr. Scholz, could you start off.

    MR.  SCHOLZ:  Brandon Scholz with the Wisconsin Grocer's Association.

    DR. DOWNER:  Goulda Downer, President and CEO of Metroplex Health and Nutrition Services.

    DR. JOHNSON:  I am Rachel Johnson.  I am Professor of Nutrition and Dean of the College of Agriculture and Life Sciences at the University of Vermont.

    DR. GASPARI:  I am Tony Gaspari.  I am Professor and Chair in the Department of Dermatology, University of Maryland School of Medicine.

    MR. BONNETTE:  I am Richard Bonnette.  I am the Acting Executive Secretary for this meeting.

    DR. DWYER:  Johanna Dwyer, Tufts University, Schools of Nutrition, Science and Policy, and Medicine.

    DR. BLUMBERG:  I am Jeff Blumberg.  I am a Professor of Nutrition at Tufts University.

    DR. TAYLOR:  Steve Taylor.  I am Professor and head of the Department of Food Science and Technology at the University of Nebraska.

    DR. HAMILTON:  Robert Hamilton.  I am a Professor of Medicine and Pathology at the Johns Hopkins University School of Medicine.

    DR. FISCHER:  I am Larry Fischer from Michigan State University, Director of the Institute for Environmental Toxicology.

    DR. TORRES:  I am Antonio Torres, Professor of Process Engineering, Oregon State University.

    MR. BONNETTE:  Next on the Program we have Dr. Alan Rulis from the Office of Food Additive Safety.

Welcome

    DR. RULIS:  Good morning everybody.  It is my privilege this morning to offer a few words of welcome to this first meeting of the newly created Additives and Ingredients Subcommittee of CFSAN's Food Advisory Committee.

    I am Alan Rulis.  Until recently, I was, for some years, the Director of the Office of Food Additive Safety in the Center for Food Safety and Applied Nutrition.  Now, I am working directly with our Center Director, Joe Levitt, on another area, Applied Nutrition.  But I was granted this opportunity by the Acting Director of the Office of Food Additive Safety, Laura Tarantino, to address you this morning.

    My main message to you assembled Subcommittee members, is thank you for giving generously of your time and letting us benefit of your expert knowledge in dealing with the issue of natural rubber latex in the food setting.

    During my tenure as the Director of OFAS and in other capacities in the Center, I can verify that we have, indeed, benefitted greatly from Food Advisory Committees.  Of those Food Advisory Committees that I have been directly involved with, in particular two that we held on Olestra in November, 1995 and June of 1998 and, last summer, on methylmercury in seafood, I can say that they were extremely helpful to the agency in reaching a solid decision.

    They helped ensure that our decisions of benefit of objective, public, balanced discussion and examination of all issues from all sides.  That has helped assure that we make credible decisions that are founded firmly on scientifically sound principles and evidence.  We expect no less from this meeting in its agenda on the issues of allergy and related issues surrounding the use of natural rubber latex in food service.

    We expect your deliberations will help us greatly.  So, again, welcome and all the best to you in your deliberations today and in the coming day or two.

    Thank you.

    MR. BONNETTE:  Next on the program, I would like to welcome Dr. George Pauli also from the Office of Food Additive Safety.

    DR. DWYER:  Dr. Rulis, while we are waiting for the projection, could you tell us where the methylmercury final decision is posted or published.

    DR. RULIS:  Of course, as with all such public advisory committees, there is a transcript available of that meeting.  There were recommendations that resulted from the meeting.  There was a decision to incorporate in the Center for Food Safety and Applied Nutrition's Priority Program, that is, the so-called Yellow Book that is the publication of the Center's priority activities for any given year, an element that is directly related to that advisory committee to examine the messages that are on labels of fish that will be supplied when fish is offered for sale.

    We are to look at that carefully and decide, based on what we know at the moment and what other organizations are doing, not only federally, but at the state level, to derive an appropriate method for marine seafood that is in interstate commerce relative to the methylmercury issues.

    So, we are in the process of doing that.  We are currently, in this fiscal year, working on that recommendation, and I expect that something public will happen soon, but I can't predict when.

Overview of CFSAN's Office of Food Additive Safety

    DR. PAULI:  Thank you.  Let me also join Alan in thanking you for being here to help us weave through these tricky and sometimes controversial issues.

    I am George Pauli, the Associate Director for Science and Policy in the Office of Food Additive Safety.

    I thought I would take this slide just to acknowledge something that--the name of the subcommittee Additives and Ingredients, most people would probably think isn't that the same thing, but one of the things I want to do today is mention a few of the differences and also, because the Office of Food Additive Safety is responsible for our statutory obligations under the Food, Drug, and Cosmetic Act for both additives and ingredients, I will start by introducing you to the Office of Food Additive Safety, which will give some of you an orientation for future meetings, as well as this one.

    Looking at our mission statement, if I can emphasize a few of those bullets, we evaluate new applications for new ingredients or new additives.  We want to make sure that everything we do meets a high performance standard based on science, and we want to, as we are doing today, monitor safety over time because any decision is made with the information you have, and we are in the business of making decisions, so have to continue to monitor to find if there is any new information that would cause us to rethink some of our decisions.

    We also have a modest research program to try to support this monitoring effort.

    A little introduction to what the office looks like.  I will just emphasize some of the different functions.  The Division of Food Contact, Substance Notification, we have responsibility for anything that becomes a component of food because food is touching it or somehow it is getting in the food even though nobody intends for that to happen.

    We have a Division of Petition Review for essentially new food ingredients and color additives where there is a formal process to get an approval.

    We have a Division of Biotechnology and GRAS Notice Review, which refers to many ingredients don't require approval, but we have to know whether they are ingredients that don't require approval or if they are additives that must be approved through the Division of Petition Review.

    Finally, our research wing on the far right.

    One of the things that is related to this meeting and other meetings we will be having in the future, one of things that has come into context as being very important in recent years is the issue of allergies.  So, we now have for the first time, for about a year now, an allergist in our office, Dr. Luccuoli, who is sitting at the side table over there.

    Food Additive Decision Framework.  I will have to recognize that under the law, different approaches are used for distinction segments or components of food.  Sometimes people are concerned that everything should have the same standard, but there is a higher standard for those substances that are used intentionally in a manner whereby human have a choice to use it or don't use it, or to use it with controls or don't use it with controls.

    So, from that standpoint, food additives, color additives, food contact substances require a pre-market approval of a very high standard of safety.  Ingredients that are generally recognized as safe have essentially already met that safety in the scientific community at large and put in a separate category.

    Dietary ingredients and dietary supplements are under a new framework since 1994, and contaminants, of course, nobody wants, but it is a question of how hard you control it that have to have a different standard, as well.

    Now, one of the things I think that is important is that all authority that we, at the Food and Drug Administration, have to control and enhance the safety of food is derived from the authority that has been given to us by Congress, primarily through the Federal Food, Drug, and Cosmetic Act.

    That is certainly true of the Office of Food Additive Safety where the Federal Food, Drug, and Cosmetic Act is the main authority we have to do anything.  For that reason, we have to look at two standpoints.  Statutory standards, are we doing something we would like to do, or have we actually been given authority to do that, to make that kind of decision.

    The decision we make has to be consistent with the statutory standard that Congress gave us.  One of the good things of the statutory standard is it relies on scientific principles, so we can use our science to get the facts right, but those two parts are so fundamental you can't ignore either one.

    Now, this advisory committee, we bring together scientists to emphasize the scientific principles part, but we just have to recognize that what the ultimate regulatory decision is depends also on the statutory standard.

    Now, the Food, Drug, and Cosmetic Act of 1938, a part of the New Deal legislation, was amended several times, but four times that is particularly important to us.  In 1958, it was amended with the Food Additives Amendment requiring pre-market approval for food additives.

    In 1960, it was amended with the Color Additive Amendments for color additives and foods, drugs, and cosmetics.

    In 1994, it was amended with the Dietary Supplement Health and Education Act that exempted certain ingredients in dietary supplements from the food additive provisions.

    In 1997, with the Food and Drug Administration Modernization Act, the regulation of food contact substances is modified to make it streamlined through a notification program.  However, the safety standard with the notification program for food contact substances is the same as it was before, the data we require are the same as before.  It is just the procedure that we follow to get approvals is a little bit different.

    We look at some of the basic principles of these amendments, defines a food additive with an exemption for those ingredients that are already generally recognized as safe.  I always use my favorite example - no one is ever going to ask us to approve the use of water in soda population.  That is a no-brainer, everyone knows that one.

    Or vitamin C as a nutrient supplement in many foods, however, when you have a new ingredient where there isn't a consensus in the scientific community, where the knowledge of it isn't widely known, then, we have the food additive.

    As I mentioned, there is also an exemption in the food additive definition now for dietary ingredients and dietary supplements.  If something meets the food additive definition, you must have pre-market approval before the product is sold in the U.S.

    The statute establishes the standard of review, establishes the standard of safety, establishes formal rulemaking procedures whereby we can issue requirements or issue approvals.

    Now, the statutory definition is a very broad one, and I do not have all the words of the definition on this slide.  There are several examples given which would run onto about two more slides if I gave them all.

    But we will get very broad.  Any substance which because of how it is being used, intended to be used, not accidentally, but intended to be used results or may reasonably be expected to result, directly or indirectly, in its becoming a component of food or otherwise affecting the characteristics of any food.

    The definition goes on with some examples, such as sources of irradiation equipment which can affect the characteristics of food or food additive, substances used in the packaging, manufacture of food, and that is what we are dealing with this week.

    You have the big exemption for those substances whose use is generally recognized as safe, and let emphasize the word "use."  We do not evaluate the safety of substances, we evaluate the safety of how substances are used.  So, it is very much a safe under intended conditions of use standard.

    Examples of the universe that we are responsible for in our office - direct food ingredients, sweeteners, preservatives, and the like.  That would be generally food additives, but not always.  Color additives are generally recognized as safe ingredients uses, which overlaps with the direct food ingredients certainly, and it also overlaps with food contact substances, such as iron pans for cooking.  Some of that iron is going to get into food, but no one is concerned about that.

    Food ingredients produced using modern biotechnology to ensure that it is still the same food and you haven't come up with something new that we don't understand, in which case it could come in under the food additive provisions.

    Processing aids that may be in contact with food for a short time or that may be used in food, but then are decomposed by heat or something, so that they are no longer in the final product.  As mentioned before, food irradiation equipment and what we are focusing on this week, food packaging and food contact substances.

    Standard for safety, which comes out of the legislative history of the food additive amendment, is reasonable certainty of no harm, and we look at that in the words of Congress there, "The concept involves the question of whether a substance is hazardous to the health of man or animal."

    So the harm we are talking about is harm to health.  It says "man or animal" because the same applications apply to ingredients in packaging used for animal feed for pets or food-producing animals.

    "Safety requires proof of a reasonable certainty that no harm will result from the proposed use of an additive."  You will hear this a few more times before this week is over.

    I have to also note--again, it's the words of Congress--"It does not--and cannot--require proof beyond any possible doubt that no harm will result under any conceivable circumstances."

    I have to say we are in the business of making decisions.  We cannot expect absolute certainty in any decision, but when are you to the reasonable stage, when are you going over the edge, or where don't you have enough information to proceed at all is part of the judgment that comes in here and where we ask for help.

    For a new food additive, petitioner has the burden to demonstrate this reasonable certainty of no harm, and again I have emphasize from the intended use of the additive.  We find that there are some things that we regulate that may cause health problems when used in a totally different manner, and we just can't address other uses outside of the intended use with food.

    From doing that, we look at whether we have adequate data to say reasonable certainty of no harm has been demonstrated.

    Now, part of understanding what reasonable certainty is, is today's food--and I have put in quotation marks, "New" and "Today" because this has been going on for 45 years now--there is an underlying assumption in the food additives amendment that unprocessed food from the farm is safe and that no one should be allowed to use some substance in a manner to make that food less safe.

    So, it gives us a little bit of an idea of what we mean by "safe" and "certainty."  We are looking at food as being the gold standard.  Of course, one thing we know today, that we didn't know in 1958, is that is again not absolute safety.

    The olden days, which I define as from 5 to 30 years ago, we managed to do everything in our office by strong control.  We had food additive petitions, we had color additive petitions, and if something did not require approval because it was generally recognized as safe, we had GRAS affirmation petitions even when approval was not required.

    Now, the petition review process, just to give you an idea of what we were looking at, it is not an academic inquiry or academic research.  Many times one sees data and say this is interesting, I would like to explore that more, but if it doesn't get right at the food safety decision, we don't go there.

    It will have to be focused on safe under conditions of use, not on interesting things that are beyond that.  Therefore, it is not a search for complete knowledge, can't assure safety with absolute certainty, does not weigh risks and benefits.

    People are often surprised at that, but as I mentioned before, there is an underlying assumption that food is safe, if that's the case, why would you take a risk with something, what benefits are there?  You already have a safe food.

    Again, I think we are looking at things maybe a little different in some ways today, but that still is what the law is.  That is still the standard.  We don't weigh risks and benefits, and it is not intended to enforce or limit consumer or producer choices among safe foods.  There is no need base here.

    We sometimes see in some countries of whether there is a need to use something.  That is not one of our standards.  The standard is, is it safe under the conditions of use.  The marketplace will decide whether they need it, the consumer will decide whether to buy it, the producer will decide whether or not it is in their interests to use that substance, that material.

    The food additive decision process does, in fact, ensure safety as we look through what we have done for the last 45 years.  We have a good track record.  Occasionally, uncertainty comes in, but we haven't really seen safety issues with things that have been approved.  The safety issue is more with ingredients that were used prior to that time.

    It is a consensus decision.  No individual is ever responsible for the decision.  We share that responsibility, we argue with each other, and eventually, someone, possibly the Commissioner or possibly the Secretary of Health and Human Services may make the ultimate decision.  The ultimate decision rests with the Secretary of Health and Human Services, but that authority is delegated down for decision.  That doesn't require such a high level of person.

    Today and sort of the shape of the future, we have had consultations on modifications of food through bioengineering actually since 1994.  We now have programs where people who conclude that the way they intend to use an ingredient is generally recognized as safe because the law doesn't require approval.

    We do have a program where they can notify us just to make sure that we don't have people working at cross purposes, one person concluding one thing and FDA concluding something else and saying we will meet you in court, so we have a program where companies do let us know, for those ingredient uses that they think do not require approval, and we have food contact substance notification, which as I mentioned before require all the data of the old petitions, but under a current law, since 1997, a law which took effect a few years later, we get notifications with the data why the use of a food contact substance is safe, and we at FDA have 120 days to disagree with that if we believe that they have not met their burden.

    Now, a final little issue of looking back at everything we look at.  If you look at whole foods, you have to evaluate those differently than you do ingredients.  You don't get 100-fold safety factors from toxicity data for whole foods.

    As we go from the bottom working upward in the slide, we get to human exposure that gets less and less, and where we generally require less data, but we can apply safety factors, we are looking at things that are used at levels faro below where they would cause any harm, and now again, as we are reminding ourselves this week, we are even getting into the allergy area where one question, how low do you have to go when you are considering the safety of something that may be allergenic.

    That is not on this chart, but I would put that up sort of at the top end of the very small amounts of things that we are concerned with.

    I hope this gives you a little understanding of the responsibilities of our office, and, hence, the responsibilities of this subcommittee that we are going to be looking for advice.

    If anyone has any particular questions, I would be happy to try to answer them; otherwise, we will move on to our next speaker.

    DR. DWYER:  Thank you very much.

    Two things, just a quick one.  Does everyone have the handout on the committee?  Okay.  Could you please see to it that everybody has all the handouts.

    Secondly, are there any questions after that illuminating introduction?  Any questions from the committee?

    Thank you for setting this process in context.

    Since there are no questions, I think we can proceed to Dr. Tarantino, who is at the Office of Food Safety and Quality, and she is going to give the committee its charge and review the questions.

    Dr. Tarantino.

Charge and Questions

    DR. TARANTINO:  Thank you, Dr. Dwyer and members of the Additives and Ingredients Subcommittee.  Good morning.

    As she said, I am Laura Tarantino, and as Alan said, I am currently Acting Director of the Office of Food Additive Safety, and my job here is to go from the very general introduction to begin to outline your task that we are going to ask you about for the next couple of days and to amplify a little bit on the charge and questions and what we are after that Dr. Dwyer read to you earlier.

    I am going to join George and Alan in also thanking you for taking time out of what I know are busy schedules to come to D.C. and to help us with what I think you are going to find to be a challenging and a little bit of a vexing issue, at least it has been for us, so we are looking forward to your help.

    That issue obviously has to do with latex allergy and I know we are aware and you are all aware that allergy and response to natural rubber latex is a very real, very significant public health issue, and a very serious and sometimes actually life-altering concern for those that are affected.

    Those that are affected, as you know, are particularly groups that have had prolonged heavy exposure to natural rubber allergens, such as healthcare workers, people in the rubber industry, and patients, particularly young patients who have been subject to a number of surgeries.

    The latex allergy resulting from that occupational exposure or medical exposure has been the subject of a lot of study, a lot of work over the last decade or so, and there has been a variety of government agencies, professional organizations, patient groups, other groups that have been very involved with taking steps to try to reduce the risks associated with that occupational or medical exposure risk.

    You are going to hear about some of those steps at this meeting, but as you heard a few minutes ago, our authority and our focus here is specifically on latex allergy as it relates to food safety and food additive safety.

    As noted in the background materials that you have had, I think, natural rubber is an approved food additive.  It is approved for a variety of uses actually including some food contact applications, and George mentioned those food contact applications being, well, food contact, one of which is latex gloves that are used in food service applications.

    The pertinent regulations that allowed this use were actually promulgated in the 1960s through the process that was outlined by Dr. Pauli, that is, there were petitions.  There were petitions that had data and information which allowed and supported a finding of safety, a finding of reasonable certainty of no harm for those uses.

    Well, why are we here?  What happened since to come before this committee?  Obviously, one of the things that has happened is the use of natural rubber latex particularly for gloves has increased dramatically both in the medical care setting to try to quell the transfer of microorganisms and infectious disease, and in the food setting as we attempted to try to control foodborne illness.

    So, during this period, then, there was an increase in exposure to latex by a number of people and during that time, then, there is a population of individuals who are sensitized to natural rubber latex allergens in the population, this population started to appear.

    Then, we at CFSAN started getting reports of people who were sensitized to natural rubber latex allergen, who are allergic to latex, who believed that they were having a reaction to food that had been handled and touched and worked on by food safety workers using latex gloves.

    So, now, then, the question for us becomes what is the evidence that the use of natural rubber latex and contact with food may render the food unsafe.  If you want to put it another way, this use of natural rubber latex, is it possible that that use may no longer reach reasonable certainty of no harm.

    As you are going to hear over the next day or two, this isn't a simple or straightforward question, or maybe I should say the answers to the question aren't simple or straightforward.

    So,  with this background, then, let me return then to the charge and questions that were provided to you this morning and read to you early.

    To repeat what we mentioned, our concern is that this use is focused on whether such use may result in the production of unsafe food and that it is important to separate issues related to worker exposure and occupational safety from those of food safety while not minimizing the issues that are related with that worker safety and occupational use, but that is different from where we want you to focus your attention right now.

    So, the task before you is to consider the available information relating to food mediated latex allergic reactions and the use of latex food service gloves and establishments that prepare food for public consumption.

    That is, we have been collecting relevant information related to reported food mediated latex allergic reactions, and we are asking that you look at this information, tell us whether there is information out there that we are not aware of that is relevant, and evaluate the scientific evidence that is out there and which would serve as the basis for any regulatory action we might take.

    That is, we are asking you what is the strength of the science, what is the strength of the available information, and, in fact, then, considering that available information, this is kind of the threshold question for us - has a positive relationship been established between the use of natural rubber latex gloves in food service and allergic reactions to food served in those establishments based on the available data?  If it exists, what is the strength of the relationship, and has it been shown to be causative?

    So, this is important because any regulatory action we might take is going to have to rely on the scientific evidence, which in a decision we are going to have to document, support by a record, and must withstand scientific challenge.

    So, weighing all the evidence before you here, we are looking for your advice about the strength of the evidence and whether it establishes a link between the use of the gloves and food mediated latex allergic reactions.

    If the answer to that threshold question is yes, the evidence does establish a causative relationship, then, we are asking you where does the scientific evidence lead us to scientifically justifiable options on our part.

    For example, is the evidence out there leading to powder versus non-powder?  Is it leading to protein levels, manufacturing methods?  Are there things that are already happening now that are getting at the question of making these gloves less of a problem?

    So, the meaning of this question is if it's yes, then, what does it tell us and what kind of options should we be looking at that we can justify by the data.

    On the other hand, if the evidence in front of us does not allow us to reach a conclusion, we are looking to you if you have ideas about specific information or data or studies that you think would be particularly helpful for us, so that we can decide whether there is a positive relation or not.

    So, that is pretty much your job.  We are very pleased to begin this discussion with you and look forward to your input and advice, and I look forward to what is going to be I think an enlightening discussion over the next two days, so thank you very much.

    DR. DWYER:  Are there any questions from the committee?  Dr. Taylor.

    DR. TAYLOR:  Dr. Tarantino, your questions to us focus on the use of latex gloves.  Is that the only indirect contact with foods that is to be considered by this committee?

    DR. TARANTINO:  Very good question, because you will hear later this afternoon that there are other uses and food uses both as direct and food contact uses of gloves, so you are quite right.  I think people this afternoon will say most of the association that we have been presented with appears to be with gloves, but I think it is a very, very valid question for you to consider as to whether is it really gloves, is it only gloves.

    This afternoon, people will tell you about the other food contact uses that are out there and approved.  It's a good question.

    DR. DWYER:  But we are to consider only the gloves, is that correct?

    DR. TARANTINO:  If you decide that all the data that you are presented with suggests that there are other sources of latex allergens in food that are relevant, we would like that information.

    DR. DWYER:  Dr. Taylor, do you want to pursue that further?

    DR. TAYLOR:  Well, I am just sitting here thinking that if this committee should decide after hearing all the evidence that this use is hazardous for some consumers, then, that has implications for other uses of latex in contact with food, as well.

    So, it is hard for me to separate the two.

    DR. TARANTINO:  I think in the course of the talks, you will hear what kind of evidence and what is in the literature, and what has appeared to point to gloves as being the primary issue.  It is clear that latex and rubber has been used for millennia, and latex allergy appears to be something that has appeared in recent years.

    I think that is one of the things that you need to be looking at as you are presented with the evidence that is in front of us.

    DR. DWYER:  We will put a placeholder on that and come back to it.  We also need to continually ask the questions of the various speakers, and I think we need to do it right after the speakers speak, because some of them leave.

    Thank you, Dr. Tarantino.

    We are going to take a break now, but we have got a committee that can drink coffee fast, and with your indulgence, we will make the break 15 minutes.

    We will see you back here in 15 minutes sharp, so we can get back on schedule.  We are a little off.

    [Recess.]

    DR. DWYER:  I have been asked, to make it easier, they take complete transcripts of these deliberations and if we could identify ourselves, when you turn on the microphone, if you would just say your name, it makes it much easier for the transcript to reflect who said what.  So, I would appreciate that.

    The next speaker should be particularly informative.  We are fortunate to have Dr. Slater, who is with the Center for Biologics Evaluation and Research at the agency, and he is going to present a useful background for us on the whole issue of latex allergy.

    I also trust that you have all had your box, if you will, or not a box, but a big group of materials that was sent to us late last week, and you may want to refer to that, as well.

    Dr. Slater, are you all set with our audiovisuals?

    DR. SLATER:  I think I am.

    DR. DWYER:  Thank you for coming and we are looking forward to hearing what you have to say.

Basic Latex Allergy Background

    DR. SLATER:  Thank you for inviting me.  When I was asked several weeks ago to present this general overview, I was pleased to accept subject to sort of time constraints in that I just got back from vacation yesterday, but I am especially pleased about two things that surprised me when I came here this morning.

    One is that there are at least two people on your committee that probably could give this talk in my place, so I am glad that they are willing to listen to me.  The other is, as I looked over the program, I see that there are many speakers who are in some ways partially going to be covering the same ground.

    That is, in part, an unavoidable consequence of having several people come up and talk and each give a little bit of background, so I really want to thank the conference organizers, Dr. Hepp in particular, for putting me early in the program, so I have a chance to say the things first and perhaps steal their thunder.

    Latex allergy is a clinical syndrome and it is easy for us to get caught up in words, but I think we have to step back and talk about what it is that we call latex allergy.  Now, there are more precise terms that one could use.  Latex allergy are two words that almost everybody uses.  There is some imprecision there, but I think we can live with that as long as we set the ground rules when we start.

    Latex allergy is a clinical syndrome that is characterized by these kinds of clinical reactions upon exposure to natural rubber latex, and the reactions can be any or all of these types of reactions.  It can be urticaria, which is hives, rhinoconjunctivitis, the sort of standard hay fever symptoms, wheezing, and notice I use wheezing and not asthma, asthma being a chronic disease.  This is acute wheezing associated with latex exposure.

    Finally, the entity that we all fear the most is anaphylaxis, and anaphylaxis is a systemic multisystem allergic reaction that may include any or all of the above plus hypotension and general vascular collapse.

    I didn't bring my favorite anaphylaxis slide, which actually came out of some work that was being done at Johns Hopkins several decades ago with regard to their studies of patients with bee sting allergy, but suffice as to say that anaphylaxis, while we very glibly as allergists sort of hand our patients single doses of epinephrine to treat anaphylaxis, anaphylaxis is, in fact, extremely difficult to treat even under the best of circumstances, and the mortality is significant, and certainly the mortality risk is significant.

    Now, there are other clinical syndromes that are called latex allergy, as well, and I am going to mention those to exclude them at this point.  Contact urticaria, simple hiving at the spot where you are exposed to a substance can be the same kind of reaction as latex allergy, but there are certainly several case reports that suggest that some patients with contact urticaria alone have a different pathophysiologic mechanism going on.

    Certainly, individuals with contact dermatitis, which is a poison ivy-like reaction on exposure to latex product, that is clearly a different pathophysiologic mechanism.  This, by the way, is a fairly common entity among healthcare workers and individuals who wear rubber gloves.  It can also happen as a cause of foot dermatitis from rubber products that leach through the sox to the feet.

    In addition, there is an entity that, for lack of a better term, is called irritant dermatitis, that happens in certain individuals especially when they take gloves and put them on and off, and the way we can distinguish this from latex-associated dermatitis is that this happens regardless of the construct of the glove that they are using.  So, in other words, it would occur with non-latex gloves, as well.

    What we are talking about here today are IgE mediated allergic reactions.  This is sort of the standard garden variety allergy that you are probably all familiar with either from yourselves or from relatives who have hay fever.  In IgE mediated allergy, antigen exposure leads to the generation of a specific antibody called IgE that recognizes that antigen.  The IgE is manufactured, as are all antibodies, by plasma cells.  It is released into the blood, diffuses into the interstitial tissue where it encounters mast cells and binds to the surface of those mast cells.

    The mast cells then are primed and ready for the next exposure to allergen, that, in addition to eliciting further responses among the antigen-presenting cells, T cells and B cells, elicits a very rapid reaction in the tissue mast cells that leads to the release of mediators.

    These mast cells are packed with granules, which you can see here, you can see granules being released.  This release occurs not in minutes to hours, but literally in seconds, and you can talk to any individual who has been subjected to a ragweed inhalation challenge, and they know that they have inhaled ragweed instantaneously, it is very, very quick.

    The mediators that are released immediately are histamine and certain proteins that are released, as well. Subsequently, other mediators that are not preformed are released.  That can elicit just as significant types of reactions.

    Latex allergy has actually been around for a while.  The initial reports were in the German literature in the 1930s.  These involved dental patients who reacted to exposure to latex during procedures.  But then there was a hiatus of something on the order of 40 or 50 years before the next report appeared in 1979 in Europe, and that was followed by a series of reports in the European literature that really didn't receive much attention here on this side of the Atlantic, but retrospectively, really presaged our experience almost entirely.

    The initial reports in North America were in 1989, and those reports were followed by a spate of reports throughout the world.  The reports were all clinical reports in which the device that elicited the allergic reaction was listed, and most of these reports centered on latex gloves, but there certainly are plenty of reports in literature of reactions to other latex devices - condoms, catheters, cofferdams, which are basically large, open sheets of latex that are placed in the mouth or in other cavities to try to block the flow of fluid to a surgical site, surgical drains, what we used to call Penrose drains, have elicited reactions.

    There have been many reports of adhesives causing reactions although very few reports of systemic reactions from adhesives.  Many adhesive materials contain natural rubber latex.  Finally, there have been reactions associated with exposure to latex via latex stoppers.  There are hundreds of other sources of latex that have been listed, but all in relatively small numbers.

    As was indicated before, part of the problem with latex allergy and the reason it seems to have followed the time course that it has, has been associated with the dramatic increase in latex glove sales worldwide, and this is from no less a medical and statistical source than USA Today, in March 1994, which shows nicely and graphically the increase, and this is in billions of gloves that were sold in the United States, going from 1.4 billion in 1988 up to very high numbers within a few years.

    This was associated with universal precautions and has certainly been implicated in a number of sources as certainly an association and possibly causative of the latex allergy that we have witnessed.

    Now, latex allergy can occur in the general population, and we will talk about this in a few slides, but you are also going to hear throughout the day today about specific risk groups that seem to be more likely than the general population to develop latex allergy.

    I really want to preface what I am going to say about this in saying that there is actually considerable controversy about this, and I am going to try to present the balance to you of the controversy.

    But it was clear from initial reports, from all of the initial reports, that there seemed to be a greater likelihood of this happening in certain groups, and the group that I studied back in the early 1990s was the group that had meningomyelocele or spina bifida, and children with urogenital abnormalities, all of whom underwent multiple courses of surgery and again from many medical centers, mainly pediatric medical centers seem to be at fairly high risk of Type 1 latex allergy.

    Other groups that unlike myself, were not pediatricians, but took care of adults, seemed to focus mostly on healthcare workers who appeared with latex allergy, and, in addition, there were some reports of rubber industry workers being at increased risk, as well.

    So, the first question is why latex and what is it about latex that seems to elicit these kinds of reactions.  Well, the answer is that latex is a natural product.  It actually been discovered by the native populations of South and Central America a long time ago, was used largely for recreational purposes and sometimes to provide wound dressings, but the widespread use of natural rubber latex really didn't develop until the 19th century when Dr. Goodyear discovered that by a process of vulcanization, which is heating latex in the presence of sulfur, you could make a product that really was thermally stable.

    The British, when they first got to the New World instantly saw a use for the latex that they saw the natives getting out of the trees, and the dipped cloth into this latex material and sent it home and voila, raincoats.  The problem was that when the latex got to the temperatures in northern Europe, the latex actually flaked and was highly brittle and wasn't particularly useful.

    So, what Dr. Goodyear discovered was a way of turning this natural product into something that was stable and had properties that were of great use.

    The Europeans, mainly the British, invested considerable effort to getting the latex plants out of the New World and into the Old World, as they did with many of the plants that they found in the New World, and Kensington Gardens in London basically originated as a place to take New World plants and try and grow them in the Old World.

    This met with no success when they tried to export these plants to Europe, but they did have success in setting up plantations in North Africa, and these plantations have names like Goodyear and Firestone, and latex is now grown in these essentially huge biofactories that consist of the latex trees, which are called Hevea brasiliensis.

    The latex is harvested by scoring the tree with a sharp implement, placing a spout at the bottom of that score, and then placing a cup under the spout.  The workers go out in the pre-dawn hours, they will score the tree, put the cup in place, take a break, and come back and collect the ounces of latex from each tree.  It is actually incredibly labor-intensive work.

    The plantations actually have their own latex manufacturing plants usually on location.

    Here is just a diagram of the bark of the latex tree.  This is the outer bark.  It shows these transverse vessels in which the latex is transported to the surface. Latex is actually not a sap, it's a common misnomer.  Sap, as we know from maple trees, is an extracellular product that contains sugars and relatively little else.

    Latex is an intracellular product that is very rich in nucleic acids, fats, as well as proteins, and it actually has an organelle structure to it of which the essential function unit is the rubber particle, which is about the size of a human red cell.

    This rubber particle contains, in its interior, pure cis-1-4-polyisoprene.  That is the hydrocarbon polymer that we all want and that we all use, but in addition, the rubber particle is coated with multiple proteins, and there are other multiple proteins that are present in latex as it comes out of the tree.

    Another important thing to realize is that latex gloves are dipped products.  It was realized fairly early on that not all things made out of natural rubber latex had the ability to elicit allergic reactions with equal likelihood.

    For instance, we all know why Goodyear and Firestone have latex plantations.  They are making tires.  It's relatively uncommon to find somebody who works in an auto shop who has latex allergy or who works in a tire place who has latex allergy.

    It has happened, but when it has happened to me, I have always been able to associate it with a medical exposure to latex gloves.  Latex gloves belong to a class of latex products that are dipped products.  The tires are molded products.  In general, what has been found just by association is that the dipped products seem to elicit reactions much more likely.  That includes condoms, balloons, and lots of other devices.

    Presumably, the reason for this is that the temperatures that the latex is exposed to are considerably lower in the dipping process.  It also may have something to do with the surface area of the product itself and simply the exposure of proteins to the surface.

    There are specific allergens that have been identified, many specific allergens.  This is up to date as of last month when I updated a review article.  For those of you that aren't familiar with the allergy nomenclature, the standard allergen nomenclature is to take the first three letters of the genus name of the source material, the first letter of the species name, and then you have a serial number 1, 2, 3, that is an arabic numeral, which is assigned by the committee that accepts the names for these.

    So, latex trees are Hevea brasiliensis, hence, the first latex allergen described is called Hev b 1, which was known as rubber elongation factor.  There probably are even more latex allergens that have not yet been described.

    One of the things that really was learned fairly early on, and key in the science involved in this, is Dr. Tomazac here from CDRH, who will be talking to you later in the program today, is a glove powder seems to be an important vehicle for the dissemination of latex proteins.

    Gloves needed to be powdered in order to lubricate them.  If you take a latex glove that hasn't been specially treated in some way, or powdered, and you try and pull it on your hand, you just can't do it.  Just sort of imagine, you know, kids trying to pull on a bathing suit that is slightly wet, it just won't slide on the skin.

    Powdering latex gloves with powder is a form of lubricant.  In the bad old days, that lubricant was talc.  When the surgeons discovered that it was bad to get talc into a surgical site, it was switched to cornstarch, which is highly absorbable.  But glove powder clear absorbs latex antigens and disseminates the antigen proteins on the surface of the powder.

    This is a picture of a glove with powder in the palm.  This is a nice touch, taking all the powder that is on the glove and putting it in one spot, so you can see it graphically.  This is not really what happens in real life.

    This does happen in real life.  This is a catheter that has been handled with a powder-free latex glove, and this is a catheter that has been handled with an powdered latex glove, and you can see the powder sitting on the surface.

    So, as an allergist, how do we diagnose latex allergy?  The fact is as an allergist, the diagnosis of latex allergy is usually not all that hard to make because, as a physician sitting across the table from an individual patient, we have a lot of tools that really help us to make that diagnosis.

    Of course, the first tool is a good, careful clinical history of what happened, a description by the patient of what the events were that led up to the reaction and/or reactions, and identification, if possible, of what the risk factors in the specific individual might have been.

    After we do a clinical history and review all these data, then, we start looking for evidence of latex-specific IgE, and we have two theoretical tools available to us.  One is to do skin tests, standard allergy skin tests, injecting a small amount of the allergen into the surface of the skin and attempting to elicit a localized allergic reaction, or we can look for latex-specific IgE in the serum.

    This is a blood test.  One form is the RAST test you may have heard of, but there are several that are available.  We will talk about this a little bit more.  There is no licensed skin test reagent in the United States, but there are several products outside the United States that are available for those outside of the U.S.

    There are several studies that have been done with extemporaneously prepared latex skin test reagents that really suggest that they are highly sensitive and specific.  There have been studies with commercially prepared latex skin test reagents that indicate that they are highly sensitive and specific, as well, but because there is not yet an approved product in the United States for this purpose, there has been a tremendous effort in the serologic diagnosis of latex allergy.

    There are at least three different broad commercially available products - Pharmacia product, Hycor product, and the AlaSTAT product from DPC.  These products are of varying sensitivity and specificity.  Dr. Hamilton has studied this in great detail, and the sensitivities range from 80 to 85 percent and up, the specificities range from 80 to 85 percent and up.

    So, for an individual physician taking care of a patient, this is actually a very useful tool because the predictive value of the test in a patient in whom you have sort of narrowed down the risk is really quite substantial.

    In addition, an individual physician with a patient has the advantage of attempting certain interventions.  We can try challenges if the data here are ambiguous.  We can certainly try avoidance measures to see if we can make the patient better.

    These tools that the individual physician has are not really readily available to the scientist of epidemiologist who is trying to determine the prevalence of latex allergy in a population.  It is a much more difficult process to do that, because the tools that the epidemiologist has are the questionnaire, the same latex-specific IgE tests, but remember if you are attempting a prevalence study in a population in which the prevalence may be relatively low, a lack of specificity in your testing can be devastating in terms of estimating the prevalence of the problem, and the predictive value therefore is highly questionable.

    Again, for skin testing, none is licensed in the U.S.  Outside the U.S. there are at least four products that are currently available.  These products are standardized after a fashion and have been used in studies and are certainly used clinically, extensively outside the U.S.

    The serum-specific IgE tests, again as reviewed by Dr. Hamilton, the Pharmacia CAP, the Hycor HyTECH, the DPC AlaSTAT, these are the sensitivities and specificities.  Again, as I said before, for the individual physician taking care of a patient, these are very potent products, they are very useful, but in terms of determining population prevalence, they can be hard to use.

    Specific allergens appear to be important, and this is sort of obvious if you think about it, but it needs to be reemphasized.  For the value of any test that uses an allergen mixture, it is important that the allergens in that mixture be relevant.

    For instance, no one here would think that if I skin-tested patients for latex allergy using a cockroach allergen extract, that that extract would be of any value whatever.  It is not, and if it were of any value, it would be purely by accident.

    What you have to have in the allergen mixture that you are testing the patient with, either with the skin tests or with the in vitro tests, you have to have an allergen mixture that is relevant.

    For instance, Lundberg demonstrated that by adding Hev b 5 to the Pharmacia CAP test, you could increase the sensitivity by 1 to 2 percent, suggesting that the Pharmacia CAP test for some reason has a relatively deficient amount of Hev b 5 in the solid phase.

    Likewise, Dr. Kurup showed that using a mixture of Hev b 2, 3, and 7 was 100 percent sensitive for spina bifida patients, and the other allergens therefore don't appear to be necessary.

    Don't take home the message that the other allergens aren't important, these are relatively small studies in defined populations, but it is important to realize that when we look at these tests, we need to actually think about what allergens they have in them and what the stability of those allergens might be.

    So, based on all these caveats of the difficulty of prevalence studies, let's just look very quickly at some of these prevalence studies.  In the general population, seroprevalence studies are fairly wide ranging.

    In one study, the prevalence was 8 percent, Reinheimer, which as a series of sequential blood donor sera, the prevalence was 12 percent, and in Garabrant study, the prevalence was somewhere between 8 and 37 percent depending on the subgroup of subjects that were examined.

    Skin test studies again show between 5 and 10 percent prevalence in the general population.  None of these studies went back and actually looked at these individuals to see whether they were clinically allergic.

    Those studies that have been done have typically shown that clinical allergy appears in fewer than half of the individuals that are either skin tests or seropositive to latex.  This shouldn't disturb anyone in the room.  This is actually typical of specific IgE testing and is something that we are all well familiar with.

    Now, what about the healthcare worker data?  This is the discussion that probably has generated the most heat and possibly the least light of anything in the discussions about latex allergy.

    For years, the estimates that you could glean from articles is that the prevalence of latex allergy among healthcare providers is something on the order of 5 to 10 percent, and there are lots of studies, especially from the 1990s, that demonstrated that the prevalence in an individual hospital was significantly greater if you looked at the operating room personnel or the ICU personnel, and if you went to the social workers and the psychiatrists, there was a substantially lower prevalence in that group.

    The NHANES II data showed a modest increased risk, an odds ratio of up to 2.5, but in some subgroups of healthcare workers, the odds ratios were considerably lower.  Now, the problem with the NHANES II data is that the data includes 1988, 1989, and 1990, which is clearly before latex allergy really started to take off, and so one of the problems with this particular study is that it probably underestimates the prevalence of latex allergy in healthcare workers on two bases.

    One is that people who are exquisitely latex allergic in the healthcare field usually leave the healthcare field, and therefore they don't count the healthcare workers in the study.

    The second is that this was really started before the big upswing occurred.  Horowitz and colleagues did a series of studies looking at Workmen's Comp data from several states and really concluded in state after state that latex allergy was not a significant cause of work-associated disability.

    Now, remember if seroprevalence data is setting sort of a low standard, Workmen's Comp data probably sets the very highest standard, and that is, you have to have enough latex allergy for it to interfere with your work and for you to go through the process of filing a Workmen's Comp claim.  So, as usual, the truth lies somewhere in between.

    One of the more interesting studies came from Garabrant in 2001, and that was the only study that I am aware of that actually looked at the incidence as opposed to the prevalence of latex allergy in apprentices, apprentices being people that haven't started yet in their new chosen field, and you get them before they start in their chosen field, and then you watch them as they are learning the ropes of their chosen field.

    In this particular study, 769 apprentices were recruited all prior to entry into their training programs.  This included dental students, animal care technicians, and pastry makers, all of whom were chosen because they all have exposure to latex gloves.

    The assessments were done on the basis of skin testing both for latex allergen and for program-specific allergens.  So, program-specific allergen in dental students is just latex, but for animal care, it would be latex in addition to dog, cat, rodent allergies, and in pastrymaking, it was wheat allergy.

    They followed these apprentices for between two and four years.  Really, the maximum was 44 months follow-up, and I am only showing the latex allergy data here because it is all that is really relevant to us, but among the dental students, the incidence was 2.5 percent a year.

    Now, that is very consistent with what we have learned in terms of the prevalence data, so that certainly was interesting.

    The animal care workers, oddly enough, had a lower prevalence of 0.4 percent a year, and the pastry workers were somewhere in between.  What was very interesting, though, is that the likelihood of developing program-specific allergy for both the animal and the pastry workers was considerably higher than this.

    So, if you were in an animal care technician program, you were much more likely to develop allergy to rodents than you were to latex during your apprenticeship. Likewise, the pastry workers had much more of a problem with developing antibodies to wheat than to latex.  But, again the prevalence here is really pretty consistent with what we have seen before.

    Now, among the children with urogenital abnormalities, and I am sort of lumping spina bifida in, the prevalence appears to be quite high, up to 37 percent in some of our earlier studies.

    Children with bladder exstrophy, cerebral palsy, spinal cord injury are all at risk, and there seem to be several independent risk factors at work here.  Among the spina bifida patients, the spina bifida is an independent risk factor, atopy is an independent risk factor, and the number of surgical interventions are independent risk factors.  So, all of these things seemed to be associated with increased risk of latex allergy.

    Now, the next three slides are virtually unreadable in your handouts, and they are only slightly more readable here.  This was my attempt to summarize the data for individual latex allergens that have been described both in terms of what are the data that were actually exposed to these individual allergens and what are the data that people are actually allergic to these latex allergens.

    I will just skip quickly ahead, so that you can see that in terms of the seroprevalence and skin test prevalence data, there are studies that really will demonstrate that there are reactions to these specific allergens among all groups of patients although the prevalence is certainly higher in some groups of patients, you will notice, though that this is a selective list.

    I mean, for instance, there is no Hev b 9 listed here, there is no Hev b 12 listed here.  That is because I wasn't able to find any data that anyone had measured these antibodies to specific allergens in individuals.

    But if you want to look at what the data are that were exposed to specific allergens, it is actually quite easy.  There are only two allergens that I was able to find any evidence that these allergens existed in commercial products.

    The first was Hev b 1, in which there is really a wealth of data from mattresses, certainly from gloves, but also a breathing zone analyses of individuals as they go through their work day.

    So there is really very solid evidence that people are exposed to Hev b 1 probably in relatively large amounts.  There is also evidence that people are exposed to Hev b 5 through latex gloves, but I was unable to find any evidence of any other of these other allergens.  This doesn't mean that people are not exposed.  It just means that it hasn't really been sorted out yet.

    Latex avoidance is hard for several reasons.  It is hard because latex ubiquitous in the healthcare environment.  Labeling in the past had been erratic.  That has definitely improved dramatically through the efforts of CDRH.

    But the other problem that we are facing is that threshold doses are really unknown both for sensitization and for reactivity.  The final reason that latex allergen avoidance is hard is that there is this problem of cross-reactivity with foods, which I felt would be of special interest to this committee, so I thought I would spend a couple of slides just talking about this.

    Really going fairly far back into the clinical reports of latex allergy were reports of individuals who were reactive both to latex and to certain fruits.  The first reports were to banana, avocado, chestnut, and if you look, it is a laundry list of basically all fruit products.

    These reports were always a little bit hard to interpret because it was always a little hard to sort out whether this was true cross-reactivity or just co-sensitization, but co-sensitization is an odd thing, as well, because we don't often see co-sensitization of banana and other product.

    There is clearly a well-documented pattern of cross-reactivity between fruits and certain pollens that is highly specific, but this was a little hard to sort out clinically, but since then, there were a number of immunochemical studies that clearly showed that there was, in fact, true cross-reactivity through inhibition.

    Even sequencing studies have gone along with the idea that there is cross-reactivity between latex allergens and other allergens that one might encounter in a variety of food products.  Hev b 3 has strong heat sequence homology with a protein from red kidney beans, Hev b 5 with kiwi, Hev b 6 with wheat germ agglutinin, Hev b 7 is a form of potaten, which is a storage protein in potato, Hev b 8 is a profilin.  This is a ubiquitous class of proteins in the plant kingdom.  Hev b 9 is an enolase and has strong cross-reactivity with fungal enolases, Hev b 10 is a superoxide dismutase likewise, and the lysozymes that have been identified in latex are also ubiquitous proteins.

    There are other approaches that have been attempted.  I actually should step back.  The other thing to remember about avoidance is that it works, it really actually works.  Avoidance measures, when they have been put into place for individual patients, really can help dramatically, and avoidance measures put into a workplace.  There have been studies that have clearly demonstrated that by reducing latex allergen exposure in a clinical laboratory in a specific unit, you can substantially reduce the reactivity of the workers in that setting.

    So, other approaches might be better methods of prevention.  I will talk briefly about premedication regimens just because you will hear mention of it and you should sort of know what the limitations are of that.

    In addition, there have now been at least two small studies using immunotherapy, classical immunotherapy that appear to show some promise.  Peptide-based immunotherapy and naked DNA immunotherapy is of interest, but has not reached any stage of being studied in humans yet.

    Allergists sometimes use premedication regimens when we know that somebody is going to be exposed to an allergen, and these actually have been best described in the context of contrast media reactions when individuals are exposed to radiocontrast media.  A good percentage of individuals have mild allergic reactions which are not much of a problem, but a small percentage of individuals have significant allergic reactions.

    It was shown long ago that by using a premedication regimen consisting either of an H1 antagonist, an antihistamine, and a glucocorticoid, or sometimes these two drugs in the context of H2 antagonist and sympathomimetics could really substantially reduce the likelihood of reaction to contrast media.

    The problem with premedication regimens is it is plausible that it might work, but there is really no evidence that it works.  There is substantial evidence with contrast media that it works, but there is almost no evidence that it really works with protein allergens.

    There has certainly been anecdotal reports of failure and my problem with premedication regimens is it tends to make people sloppy.  If I am going into surgery and I am allergic to latex, I really want everybody in that room to take my latex allergy very seriously from the chief surgeon to the head nurse, to the anesthesiologist, to the medical student that is sort of dragging in just to look at what is going on.

    I don't want anybody to say, oh, the allergist gave him a premed regimen, I think you are okay.  I really want everyone to take it seriously.  So, since I continue to think that avoidance is the mainstay of treatment, I am reluctant to talk about premedication regimens just because I think it's likely to make people sloppy.

    So, let's just make some final points and then I will be happy to take questions.  At this time, prevention is the only effective treatment for latex allergy.  Latex allergens are ubiquitous, but gloves are the most important source of latex allergen in the healthcare environment.

    It is easy to look at a list of everything that has latex and begin to lose heart and begin to think that this is an impossible task.  If you set as your goal to expunge the environment of any latex proteins, you have established an impossible task for yourself.

    If you establish as your goal to substantially reduce the risk and reduce exposure, we know how to do that, and the way to do that is to deal with the gloves first. Since so many individuals in hospitals are directly exposed to catheters, catheters are also important, but on a national basis, on an epidemiologic basis, gloves are the most important source of latex allergen.

    All latex allergy tests, whether they are RAST, ELISA, skin tests, or challenges, are only as good as the allergens that are used.  The allergens must be intact and all significant specific allergens must be represented in the mix used.

    Testing is readily available now.  It is not perfect, but it is certainly good enough for us to use.  The predictive value of testing as a diagnostic tool is excellent, however, the value of such testing as a screening tool is uncertain.

    Premedication does not work.  You should always consider food allergy.  There is probably no way to construct a latex-free environment in the healthcare setting, but it is certainly possible to construct a latex-safe environment, and this is a concept that was introduced many years ago, and I think is really as valid today as it was before.

    I think the more we think about latex-safe as opposed to latex-free, the more practical we are going to be able to be to actually help people, and I think that is probably relevant for your discussion for the rest of this session, as well.

    All latex avoidance measures come with a price - money, resources, risk of contamination, diminished barrier protection, therefore, latex avoidance measures should be consonant with the risk.  Again, I think this is something that you need to consider in your deliberations here, as well.  Even those of us that have seen the damage caused by latex allergy as up close as anyone, have to acknowledge that latex provides a very useful service, and we should make sure that we are not throwing out the baby with the bath water.

    History alone is a poor predictor of latex allergy, but the predictive value of not obtaining a history is zero.  Again, I am directing this more towards doctors, asking your patients if they have symptoms consistent with latex allergy is cheap, it costs nothing, it is quick, and it should be part of routine screening for all medical and dental practitioners.

    Thank you very much.  I am happy to take any questions.

Questions of Clarification

    DR. DWYER:  Does the committee have questions?  Dr. Hamilton.

    DR. HAMILTON:  That was really a great, great overview.  Thanks.

    In reading the papers that we are going to be considering for evidence that latex allergy when transferred onto foods causes symptoms, could you describe for us the classical food allergy symptoms?  They were not in your second slide of classical latex allergy symptoms.

    DR. SLATER:  Sure.  You mean the classical food allergy symptoms from foods or from--

    DR. HAMILTON:  Yes, from foods.

    DR. SLATER:  Typically, most individuals with food allergies in the United States are children.  Food allergy is typically a disease of young children.  In that population, there are really two broad syndromes that occur. One is latex-induced atopic dermatitis, not latex, food-associated atopic dermatitis or eczema.  These tend to be relatively young infants.

    The onset of the eczema used to be thought to be chronic, but actually, Hugh Sampson's studies clearly showed that it was just about as immediate as any other allergic reactions that we see in patients.

    Again, removal of the food from this infant's diet typically leads to a substantial improvement in the eczema if, in fact, it is associated with that food.

    The other syndromes can be urticaria, hives, and then finally, can be respiratory including rhinoconjunctivitis, wheezing, and, of course, the one that we are the most concerned about is anaphylaxis.

    So, there can be a full range of reactions. Because food is ingested rather than inhaled, the time course of the reaction can be somewhat more prolonged than what we see with inhaled or even injected allergens.  It can be as long as an hour or even two hours after exposure that it occurs although typically, a severely allergic patient will have a very, very rapid reaction.

    Did that answer your question?

    DR. HAMILTON:  Excellent.

    DR. DWYER:  Thank you.

    Dr. Johnson and then Dr. Downer.

    DR. JOHNSON:  Thank you.  You talked about the number one treatment as avoidance, so my question is how do you counsel people with this allergy to avoid foods that have been in contact with latex?  You addressed it from a healthcare perspective, but didn't year you--

    DR. SLATER:  To be candid, I don't usually address that specifically.  When I have a patient who is documented to be latex allergic, obviously, the things that we focus on are what has caused them to react.

    Usually, that's an exposure in the healthcare setting, either my patients with spina bifida or a healthcare worker if I am taking care of an adult.  We then will focus on the cross-reactivity between latex and foods to alert them to the possibility that they should be aware that if they start itching when they are exposed to bananas, they should take it seriously, and not just ignore it.

    But typically, I don't talk to them about the generic problem of indirect latex exposure.  It has not been my general experience that it is that much of a problem with my patients.  I have had patients who have come to me asserting that they were having multiple reactions from occult sources, and that is very difficult to sort out, and it is certainly possible that for those patients, the occult source was an indirect exposure.

    You should understand that even though I am hedging a little bit about indirect exposure in food, there clearly are clinical reports of indirect exposure occurring and clearly can occur.  I mean the most dramatic one that everyone has sort of read the old literature on this, is the nurse who retired from nursing because of her latex allergy, who would have a severe allergic reaction whenever her physician husband came home if he didn't change and shower before he came into the house because he had latex powder all over him that was eliciting reactions in her.

    So, indirect exposure clearly can occur.  It is just that when you have a specific patient in front of you, you sort of work with what they are telling you.  If they tell you they are anaphylaxing at work, you don't start wondering whether they are also anaphylaxing at McDonald's because it is likely they would have told you that.

    You have to also understand that whenever you evaluate a patient with any allergy, you always have to rule out alternative hypotheses.  So, I always spend a lot of time with a patient who says they are latex allergic, making sure that they are not allergic to lots of other things in their environment, so we really do cover that ground.

    DR. DWYER:  Thank you.

    Any additional?  Dr. Downer.

    DR. DOWNER:  Dr. Slater, thanks for a very informative presentation.

    At the beginning, you mentioned Type 1 latex allergy.  It leads me to believe that there are more than one type.  Can you tell me what they are and discuss them briefly?

    DR. SLATER:  As I said Type 1, I realized I was introducing a term that I wasn't defining, so after telling you how careful we had to be define terms, I violated what I was going to day.  Type 1 is a terminology that I would rather I not have used.  It is an old classification of immunologic reactions designed by Gel and Coombs.  Type 1 reactions were what they called IgE mediated reactions.

    The distinction among the reactions was very clear to them, but there are certainly overlap syndromes, and I think it is better to really describe the mechanism itself. So, in the Gel and Coombs terminology, though, contact dermatitis, the poison ivy-type reaction would have been called a Type 4 reaction.  You will still hear people say Type 1 versus Type 4, but there is no Type 2 and Type 3 for latex.

    DR. DWYER:  Thank you.

    Now, we have got some questions on this side from Dr. Fischer and then Dr. Torres.

    DR. FISCHER:  I am wondering if a person has latex allergies, what do you think was the sensitizing agent, do you think it was their food initially, or is the latex proteins, are they sensitizing initially?  Do you get the question?

    DR. SLATER:  I can give you my instinct, but I think the approach that you would take to answer that question would be to look at food allergic patients and to try to decide whether they have an increased risk of latex allergy.

    Well, we know that they do because we know that atopy is associated with latex allergy, and people that are food allergic are atopic, but does a person with banana allergy or kiwi allergy, are they more likely to have latex allergy than someone who has seafood allergy or peanut allergy, and the answer is no, they are really not, at least that has not been my experience.

    Bob, correct me if I am wrong, I think I saw one study and there was really no evidence of an increased prevalence among food allergic patients in particular.

    The converse, of course, is not true.  There is an increased prevalence of food allergy among latex allergic individuals.  It is not dramatically increased, but there is an increased prevalence among latex allergic individuals.

    So, I would think that from those data, there is not much to support the idea that the initial sensitizing antigen exposure is foods.  In terms of human data, I think that is just about all we have.

    DR. DWYER:  Dr. Torres and then Dr. Gaspari.

    DR. TORRES:  Page 5 of the material that was provided to us said the FDA had proposed to require an expiration date for latex gloves.  Is there any allergic reaction based on the decision behind this?

    DR. SLATER:  I am sorry?

    DR. TORRES:  It said that it proposed to require expiration dating.  Is there a reason from an allergy reaction that you would like to have an expiration date?

    DR. SLATER:  I am not the right person to answer that question.

    DR. TORRES:  Only from an allergy reason.

    DR. SLATER:  I have nothing useful that I could say about that.  Believe me, if I had something I would tell you.  I just have no answer to that.

    DR. DWYER:  Mr. Bonnette, would you try to help us to identify, over the next couple of hours, a person who can answer that question and get back to us?  Good.  The question is why did the regulations specify expiration date, was there something about the old latex gloves having different properties, and we will get a definitive answer from a technical expert on that point.

    Dr. Gaspari.

    DR. GASPARI:  Dr. Slater, can you address the spectrum of the severity of the problem in latex hypersensitivity, and other than presenting symptomatology like the patient with mild localized urticaria after exposure to rubber latex gloves versus the patient that anaphylaxes if there is latex powder in the room, so how good are the tools we have at differentiating the spectrum of the exquisitely sensitive patient that is at risk for anaphylaxis versus the patient with the mild tolerable response?

    I am interested in this question because intuitively, I might think the patient that has a reaction in a restaurant from latex carryover may be in the more severe category, and what kind of tools do we have using RAST beyond clinical symptomatology to assess that spectrum.

    DR. SLATER:  I think that is a very good question, and I think what I would focus on in the answer is whether the amount of latex-specific IgE that has been detected correlates with the severity of the response or can predict the severity of responsiveness.

    Again, I think the answer is probably yes.  If you recall, one of my earlier slides, I kind of put contact urticaria as one of the syndromes that I wasn't really sure were always IgE related.  The reason for that is probably that it is IgE related, but they have very small amounts of serum-specific IgE, and at least at the time that the study was done, they may simply not have been detecting the specific IgE that was causative of the reaction.

    Certainly, with other allergies, with peanut allergy, for instance, there is a correlation between the amount of peanut-specific IgE and the severity of reactivity.  It is not necessarily highly predictive in an individual patient, but certainly in a population basis, you can divide up a population into those that are more likely to have those kinds of reactions than not.

    I think the problem with moving from that kind of discussion into saying this person is likely to have a restaurant reaction, this person is less likely to have a restaurant reaction is that that assumes that we understand that the dose that one receives in a restaurant is always going to be exquisitely low and that therefore those individuals are always going to exquisitely sensitive.

    I don't know those data, I don't really know that.  I do know that when one makes that conclusion about, for instance, the amount of contaminating peanut protein that might be present in a product that was made in a factory in which there were peanuts being made, that is highly variable, and in some cases, the amount of peanut protein is trace, and in other cases, it is substantial because we don't really know what goes on behind those closed doors and how much the exposure is.

    So, I would worry a little bit about, even though I intuitively agree with you, the patient that reacts to restaurant food by indirect exposure has got to be very sensitive, I would worry a little bit without having the quantitative data as to what the exposure really is and what the range of exposure is

    DR. DWYER:  Thank you.

    Are there other questions?  Dr. Hamilton has another question.

    DR. HAMILTON:  Because you won't be here when we discuss this paper, I wanted to get your feedback on it.  Back in 1998, McGadey and the group at Philadelphia showed that you could--he took initially three in his abstract and then he published a paper later, a couple of years later in the Canadian Journal of Allergy where he actually administered oral latex to latex-allergic individuals.

    I would like you to just overview for us this whole philosophy of oral tolerance induced by high-dose oral desensitization, and within the context of low versus high in threshold levels, and just sort of put that in context for us.

    DR. SLATER:  Sure.  The underlying question that you are probably getting to is, is a small dose of latex by mouth not so bad.  This is sort of the underlying issue that is behind that kind of question.

    The idea of tolerizing somebody to an allergen by the oral route is very attractive conceptually.  Remember, we have oral exposure to not grams, but hundreds of kilograms of foreign proteins every year.  Our GI tract is intended to prevent us from reacting to these proteins, and we are, in fact, highly tolerant to proteins that we take in by mouth in general.

    Food allergies are a spectacular exception to that.  The question has been raised as to whether the oral route would be the best way to try to tolerize people to proteins to which they are currently allergic.

    There have been studies that have suggested that this actually works.  The question then is what doses would actually work, and the answer clinically, certainly if you look at oral immunotherapy and sublingual immunotherapy regimens that are being studied more and more in Europe at this point, is that it seems that in the end, you have to reach a fairly high dose in order to really tolerize somebody to a protein.

    Starting out at a low dose is good, but working up to a relatively higher dose is what you really need to achieve tolerance.

    Contrast that to studies of chronic allergen exposure in terms of the prevention of allergies, and in those situations, it seems that chronic low dose allergen exposure may well actually prevent allergies.  These don't reach very high doses, but that is actually a different issue.

    The study to which Dr. Hamilton was referring was one in which a small number of study subjects were given latex solutions by mouth, and they seemed to be tolerized to latex.  It is a very small number, and it is very hard to interpret, and certainly something we don't recommend.

    DR. HAMILTON:  Could I just follow up with a question?  The fact that these individuals didn't have any apparent systemic reactions, they started with very low concentrations of oral latex and then increased--this was ammoniated latex--is that significant to our discussion with regard to food contamination and exposure for a latex-allergic individual?

    DR. SLATER:  My memory of this study was that there was no challenge arm at all, in other words, these were people that came in with a strong history of latex allergy, but they weren't challenged on entry into the study to see that they really did react even to any exposure.  Am I correct?  They were challenged after the study.

    DR. HAMILTON:  They had positive skin tests.

    DR. SLATER:  They had positive skin tests, but they didn't have clinical challenge.  So, in other words, I don't know what I am comparing their failure to have an adverse reaction to the oral latex solution to.

    In other words, if these were people that were entered into a study, had a positive challenge of some sort, ocular challenge, nasal challenge, or skin challenge, and then had no reaction to the oral desensitization, then, had a negative challenge afterwards, that would be more convincing.

    If I remember this study, it is one in which they had a very compelling history, had a positive skin test, and were able to go back to work afterwards.  That is not tight enough for me to draw conclusions.

    DR. HAMILTON:  And that was exactly the reason they couldn't get it into the JCI was that absence of a control group.

    DR. DWYER:  Dr. Taylor, did you have a comment?

    DR. TAYLOR:  I am not familiar with that study, and I am not sure we shouldn't have that one in our packets if it might at all be relevant to this consideration.

    Jay, does that mean that if you took an unselected group of people with latex positivity by skin tests, that this study could be used to document that the majority of them would not be sensitive to oral intake?

    DR. SLATER:  You could do that study.  We could also predict that that would be true.  That is the nature of skin testing to allergens.  It is the nature of the predictive value of a challenge test.

    Many of us, especially those with the FDA, think that a challenge test is really the gold standard, and it is because it is the best we have, but it's not 100 percent sensitive.

    DR. TAYLOR:  But the FDA's standard of safety, as we heard it from Dr. Pauli, is to protect the vast majority, so are the vast majority of the sensitive population even susceptible to oral intake of latex is my question.

    Would this study help to answer that question?

    DR. SLATER:  This would be the way to address that study, but I think you would also have to have individuals who had a history of latex allergy plus had a positive skin test, and then you would have to challenge them.

    But then the discussion that you and I would have is what dose would you challenge them with.

    DR. TAYLOR:  Oh, I understand how difficult that study is.  I just wanted to know if this study has enough information in it for us to begin to get at the broader population of latex-allergic individuals.

    I might agree with you after I read it that a subset of that population still needs to be studied to answer the questions posed to this panel.

    DR. DWYER:  Any other questions?  I have about three.

    The first is which allergens are the most likely to be a problem.  I was surprised to see there are probably over a dozen of these substances.  Which are the ones--you mentioned two--but was that just because those two were the ones in the kits?

    DR. SLATER:  The allergens that are most likely to elicit reactions may be different in different populations.  Hev b 5 appears to be a significant allergen in both children with spina bifida and in healthcare workers.

    Other allergens can be very important in certain populations and less important in others, and actually, the numbers in that table show the prevalence data in individual subpopulations, so you can look in that and get a sense that certain allergens are more important among healthcare workers and others among the children with spina bifida.

    In general, the most important allergens are the ones that are sort of early in the list, you know, I would say Hev b 1 through Hev b 8 are the ones that have been the most important.

    DR. DWYER:  Just to follow up on that, because you are probably one of the national experts on spina bifida and these allergies in those patients, it would seem to me that many of those patients might be given stool softeners like Metamucil or some other one.

    Isn't there a cross-reactivity between those?

    DR. SLATER:  Between psyllium?

    DR. DWYER:  Am I right about that or wrong?

    DR. SLATER:  I am not aware of it.

    DR. DWYER:  No?  Okay.

    DR. SLATER:  I mean if you told me it was true, I would believe you.

    DR. DWYER:  No, I am not telling you, I am asking.  I am asking an expert.  I am certainly not an expert.

    Do the specific IgE tests have all of the allergens or only Hev b5, 1 through 8?

    DR. SLATER:  That is exactly the question.  We don't really know the answer.  The fact that by adding Hev b 5 to the solid phase of the Pharmacia CAP, you could increase the sensitivity, suggests that there is too little Hev b 5 in it.

    I would assume, and my assumption is that they are not full representative of all the allergens because they are made with crude latex mixtures, and the amount of a specific allergen in that mixture may or may not be adequate.

    One of the aims of identifying all the important allergens and sequencing them and cloning them is to be able to construct a diagnostic tool that has all the relevant allergens in it.  Once you have done that, then, you may learn that of those 13 allergens that I have put up on the screen, only four of them are important, but that is what you need to learn.

    Certainly, Kurup's study suggested that for spina bifida patients, you only needed three to get 100 percent sensitivity.  That doesn't mean that the others, that they are not reacting to the other proteins, it just means you can achieve 100 percent diagnostic sensitivity by looking at those three indices.

    DR. DWYER:  I am still puzzled, though, I must ask you another question, and that is, the amount of the various allergens in these diagnostic kits is not known?  Is that what you are saying?

    DR. SLATER:  That is correct, because the diagnostic kits are made with crude latex preparations.

    DR. DWYER:  Thank you.  What a surprise.

    One other question that came up at the coffee break is I understand that years ago, latex was used in chewing gum.  My source for that is Dr. Taylor, who knows all about food additives.  Apparently, if what you people were talking about with respect to oral challenges was true, what is the history of what happened in those old days when thousands of children were chewing gum with latex in it?

    DR. SLATER:  I haven't a clue.

    DR. DWYER:  Dr. Taylor, do you know?

    DR. TAYLOR:  I actually don't know very much about the history of use of latex in chewing gum.  I am always provoking FDA on this point, because it is actually in the Code of Federal Regulations as an approved food additive only for chewing gum purposes, and I pray and hope that no food company is actually using it today, but it is actually permitted.

    But I don't know what the quality of that material was.  I am guessing that we are talking decades back that it was approved for that use and that, if anything, the latex was probably a cruder preparation in those days than it was in the late 1980s when this other kind of exposure began to reveal people who had reactions.

    But I am not aware that medical literature contains from the 1920s and 1930s any great spike of concern about reactions in habitual users of chewing gum.

    DR. SLATER:  Now was there was any spike about the use of peanuts when peanuts--

    DR. TAYLOR:  I know.  You would think that anyone who is already sensitized might encounter difficulties if they used a chewing gum with natural rubber latex in it, but I don't know much about the actual history.  I have looked for it, but I just haven't ever even found a case, which is kind of curious because I assume it was actually used in the early days because the synthetic materials that are used today were not available then.

    DR. DWYER:  Interesting.

    Dr. Downer.

    DR. DOWNER:  One of the questions that the committee is charged with is to look to see whether there is a positive relationship which has been established between the use of the natural rubber latex gloves, and if it exists, what is the strength of the relationship.

    You mentioned in your presentation that there is a lack of specificity to estimate prevalence in the U.S., and I guess in the absence of adequate quantitative data, my question is what are the evaluation parameters would you suggest this committee to use in deliberations?

    DR. SLATER:  In terms of determining the positive relationship between indirect latex exposure in foods and the likelihood of developing latex allergy?

    DR. DOWNER:  Sensitivity.  You mentioned that there is a lack of specificity to estimate the prevalence in the U.S., and we can't tell if we don't have enough quantitative data, and that is part of the charge of this committee.

    DR. SLATER:  I don't think the prevalence data are going to help you there at all, because I think, you know, unless we can show that there are certain populations that are much more likely to have restaurant-associated latex exposure than others, I don't see how you can use prevalence data to achieve that even if you had perfect tools.

    I suppose you might try to develop a prospective experiment of looking at incidence, and if you are doing that and you are using the same tools as you go along, you can circumvent the problem of the lack of specificity.  I mean these are not completely unspecific tests, specificity of 70s, 80s, low 90s.

    So, if you are following a population especially if you have serial serum samples from individuals in a population, you can do the tests concurrently and actually come to valid conclusions, but I don't really see how you can use prevalence data, you can use prevalence data and try to answer that question.

    DR. DOWNER:  One of the things I was looking to do is look at not just the incidence, but the prevalence, as well, and do some cross-checking, so that is what I was looking for.

    DR. SLATER:  But I think one of the ways to circumvent the problem is to collect all your sera and evaluate them concurrently, and if you are looking at incidence data, then, you can circumvent the problem somewhat.

    DR. DWYER:  Thank you.

    Let's just go around the table and make sure we have got all the questions out because you may run off after this over.

    Dr. Torres?  Dr. Fischer?

    DR. FISCHER:  I do have one.  The Garabrant study, which showed the prevalence of latex reaction in various groups, dental versus others, you mentioned that the incidence of latex allergies were less--this is what Garabrant showed, I think you said--less than program-specific allergens that they were exposed to.

    What is your interpretation of those results?

    DR. SLATER:  My interpretation is when you are an animal care technician, you have more exposure to mouse urine proteins than you do to latex allergens, and therefore, if you are in a program where you are exposed to mouse urine proteins, which people in these room just inhale in huge amounts, and latex allergens, which--you know, when  you go into a mouse room, you have 50 mice in that room.  They are generating protein.  You may have one box of latex gloves, which one glove is pulled out at a time.

    I think it is just a matter of exposure.

    DR. FISCHER:  So, you are saying it is just a matter of the incidence of exposure.

    DR. SLATER:  I think it's exposure.

    DR. FISCHER:  To the different allergens.

    DR. SLATER:  That's right.

    DR. DWYER:  Thank you, Dr. Fischer, and Dr. Slater.

    Dr. Hamilton?  Dr. Taylor?

    DR. TAYLOR:  I suppose I should ask you--we have had in our packet provided by FDA the case reports about adverse reactions associated with residues from use of gloves in the preparation of foods.

    Are you familiar with any case reports in all of your reading of the literature of other indirect contact between latex and foods that led to an adverse reaction that was not glove related?

    DR. SLATER:  No.

    DR. DWYER:  Thank you.

    Dr. Blumberg?  Dr. Gaspari?

    DR. GASPARI:  A question about the changing prevalence.  Do you really believe that the--maybe I should say incidence of latex sensitization is decreasing based on better gloves, higher quality gloves with lower protein content and the loss of the use of powder, cornstarch powder, and whether this would have any impact on carryover in the foodstuffs?  Can you comment on that?

    DR. SLATER:  Again, I don't know about the carryover because I don't know about the quantification of latex allergen acquisition by foods.  I do think that the incidence is dropping.  I do think it has to do with steps that have been taken regarding glove exposure.

    Certainly, in the population of patients that I used to take care of most intensely among the spina bifida patients, the incidence dropped dramatically when the surgical specialists who took care of them understood the importance of latex allergen avoidance from birth.

    It made a huge difference in that population very rapidly.  I think the data on the decreased incidence among healthcare workers is still early, but it's impressive.

    DR. DWYER:  Do you want a follow-up question, Dr. Gaspari?  Dr. Johnson?  Dr. Downer?  Okay.  Any other questions?

    Thank you.  We put you through the wringer, but  you have been very informative.  Thank you very much.

    We will go now after that interesting presentation to the CDRH Proposal, and Dr. Stratmeyer from the Center for Devices and Radiologic Health will present this talk.

    Dr. Stratmeyer.

CDRH Proposal

    DR. STRATMEYER:  I have got a branch that is a research and risk assessment.  That is what they do.  The research is in the area of toxicology and infection control, and basically, we are trying to understand how the tissue interacts with medical device materials.

    So, how did I get into latex?  Well, first of all, I have got to say I am latex allergic, not the type allergy that you guys are thinking of, but I developed an allergy because I thought back in 1990 that this was something that I would be through with in about two or three months, and, let's see, this is 2003, so I have developed a real allergy to it, let me tell you.

    First of all, I would like to just point out that the Center for Devices and Radiological Health's mission is to ensure the safety and effectiveness of medical devices, and this means that we look at both risk and benefit, and if I understand right, you were asked to look only at risk.

    So, you have got to remember that there are differences in the laws under which these various centers operate.  So, as I go through this, bear that in mind.

    First of all, I would like to sort of describe the process that we use to ensure the safety and effectiveness of natural rubber-containing medical devices.

    First of all, problem identification, and then I will go into how once we identify the problem, we used our advisory role to get the message out to industry, to the medical community, to the public.  I will mention the fact that we do do research since that is the job of my group, and then I will finally try to tell you how this led to the regulatory initiatives that we have undertaken.

    First of all, adverse event reporting system.  This is the first sense that we had that there was a problem.  We found in that adverse event reporting system, 15 deaths were reported due to anaphylactic reactions to a barium enema catheter that were reported in 1989 and 1990.

    Originally, our quick look at it says, well, gee, maybe there is something with the barium solution.  However, after researching the issue, we began to believe the problem was caused by natural rubber latex.  Anaphylactic reactions had been reported with other natural rubber devices also.

    Research on high-risk populations also pointed toward the involvement of natural latex allergy.  I won't spend any time here.  You have had an expert present all this to you, but one of the populations was the spina bifida population.  That is where we got a lot of our information and our clues to begin with, healthcare workers and rubber industry workers.

    Because once we identified what we thought was the source of the problem is natural rubber latex, the first thing we did was we put out a Medical Alert, and it was distributed throughout the medical community in March of 1991.

    We also, at the same time, prepared and distributed a list of pertinent publications and published a review article to inform healthcare workers and consumers. At this point, we also sat down with industry and tried to convince them that there was a problem, initial research in our lab had demonstrated antibodies from latex-sensitive individuals, reacted to a number of natural latex proteins from natural rubber latex-containing devices.

    With this data and published data from the literature, we sat down with industry and convinced them that this was a serious problem that existed.  We urged them to promote cooperative efforts to develop standards and reduce natural latex protein levels.

    I must say, and like I say, this is very early in the game, and I must compliment industry for working with us.  Once we convinced them, we have had very good cooperation.

    Then, in 1992, we organized an International Conference on Sensitivity to Natural Latex and Medical Devices, and this was put together to address scientific, clinical, manufacturing, and regulatory issues, and we got a lot of information from this, because a lot of the Europeans had already been involved in this and done a lot of work.

    One of the other things that I mentioned a little earlier that we talked to industry about, and we got very involved in through the ASTM, was development of standards.

    Since our early research efforts uncovered an unanticipated problem, that was unreliable measurements of protein that were extracted from natural rubber latex-containing devices, in cooperation with industry and ASTM, a standard for measuring total extractable water-soluble protein was developed using a chemically-based analytical method, and efforts to improve the methods for detecting protein antigens, allergens, still continues today to develop more sensitive methods with ASTM and, like I say, industry.

    I don't want to get into the research in any detail.  I would just like to point out that active research in our lab, in collaboration with other research in other clinical labs, has served as a basis for risk assessment, methods development, and regulatory actions.

    Again, I will point out that as for methods developments, we have had active participation in the development and credentialing of standard methods through the ASTM.  This includes protein antigen and residual powder, and we are also working on and looking at an allergen test now.

    Now, active research is still ongoing to develop new and improved methods for risk assessment of NRL medical device products.

    Let's finally get to the regulatory initiatives.  In 1995, we came out with a protein content guidance.  We put this guidance out to allow manufacturers, if they wished, to label total extractable protein content using the ASTM standard.

    Then, in 1997, we came out with a labeling regulation, it was finalized in 1997.  This labeling regulation required statements on medical devices containing natural rubber--and this includes natural rubber latex and dry natural rubber products--that contacts living human tissue.

    We also required that the claim of hyperallergenicity be removed, and I am going to go back and use a couple of old terms, that is just horrible, the main reason because the hyperallergenicity claim on some of these products, particularly in gloves, was that it was really tested for what I would call a Type 4 or a delayed type of hypersensitive reaction rather than what we were really concerned about was the Type 1 immediate type hypersensitive reaction.

    Then, in 1999, we published a proposed rule, because this is the way you have to go, first, you have to have a proposed rule and then everybody comments on it, you respond to the comments and try to address it and everything, and then eventually, you make any changes that are necessary and come out with a final rule.  We are in the proposed rule stage.

    Basically, this proposed rule was only on gloves.  The other rule that I talked about, the labeling rule, affected all medical device products if the natural rubber contacted human tissue.  This was only on gloves.

    This would reclassify them from Class I to Class II.  One of the reasons to do that was because with Class II devices, we rely, not just on what they call general controls, but also special controls, and I hope you don't ask me too many questions about a lot of these terms, because one of the other reasons I am allergic to latex is I got stuck--I am a researcher--I got stuck with being in charge of developing these regulations, so I had to learn a little bit of this legal terms, but I don't consider myself an expert there at all, let me tell you.

    Anyway, by using special controls, a number of things could be used.  We could require certain labeling that we could not with just general controls.  I am trying to find out whether or not there is any difference in the reporting requirements for adverse events, I am not sure there is, but there are some differences in the way that the Office of Compliance can react to a problem with a Class II device as opposed to a Class I device.

    Anyway, the special controls were, first of all, label caution statements that would include recommended limits, and these would be on all natural rubber latex gloves.  The caution statement was different for synthetic gloves, and that was only on gloves that contained powder, because the statement included both latex and powder.

    We also would require that the protein levels that the glove contained be labeled.  In other words, they could be over the recommended limit we had, but the consumer had to know that they were over, because they would also have to label exactly what the glove content was.

    The same thing with powder labels, the powder level would have to be labeled on all gloves.  Again, somebody asked about expiration dating.  Expiration labeling would be required.  The reason expiration labeling would be required is because one of the things that we wanted to see happen was, number one, we wanted to see the protein content or the allergens to go down; number two, we wanted to see the powder to go down, because, as you were told, the protein adheres or the allergen adheres to the powder and can become airborne, and is probably a very good way of dispersing the allergen.

    But one of the ways of getting rid of powder and making a powder-free glove is by chlorinating it.  If the chlorination process is not done correctly, it can affect the life term or the life span of the glove.  Again, remember we are interested, not just in safety, but also effectiveness.  So, the expiration dating was based more on effectiveness issues than on safety issues.

    I don't want to waste a lot of time.  I could go through and give you the caution statements and everything, and I can do that if anybody is interested, but I won't waste your time doing it right now.

    I would like to say that since we came out with a proposed rule, we have worked with the ASTM, and the ASTM has also come out with recommended maximum limits for rubber exam gloves, rubber surgical gloves, and synthetic exam gloves.  These are powder and protein or these maximum limits are very similar to the limits that were in the proposed rule.  But again, I think it is an example of how the industrial community has worked with us, through ASTM, in order to try to address this problem.

    I will just make a real quick mention of some of the other government agencies that have also been involved with this whole issue, with the glove issue.  For example, OSHA has a Technical Information Bulletin that states, "When selecting NRL gloves, choose those that have lower protein content.  Selecting powder-free gloves offers the additional benefit of reducing systemic allergic reactions."

    NIOSH put out a Safety Alert that stated, "If you choose latex gloves, use powder-free gloves with reduced protein content."

    Again, I already talked about the FDA medical glove proposed rule.  I should point out that one of the options that we considered and is published in the medical glove powder report that we put out in 1997, was to ban powdered gloves at a predetermined time in the future.  This is something that we decided was not the way to go because of concerns about the changes in manufacturing that take place in order to produce powder-free gloves, what changes they might have on barrier properties, durability, and the availability and adequate supply of high-quality medical gloves.

    Anyway, let me end this up here and again state that our goals are to prevent sensitization and to prevent adverse reactions, and we are trying to achieve these goals by providing adequate information to the consumer, and that means all the way from not just John Public, but the medical profession, to permit the medical institutions and users to make informed decisions when choosing medical gloves.

    Thank you.

    DR. DWYER:  Thank you, Dr. Stratmeyer.

    Does the committee have questions?  Dr. Torres and then Dr. Blumberg, Dr. Gaspari.

Questions of Clarification

    DR. TORRES:  My question is whether you know whether the industry is using all this labeling about protein content, non-powder, et cetera, et cetera, also on gloves that have been sold to the food industry applications.  You spoke of medical applications.

    DR. STRATMEYER:  Unfortunately, I am not an expert in what is used in the food handling industry, so I can't tell you.

    DR. BLUMBERG:  I have the same question about the medical gloves versus food handlers' gloves, but you also mentioned earlier on about the adverse event reporting system, and our document has a comment that the CFSAN Adverse Event Reporting System, on page 10 of our report, it says, "To date, FDA has received one report through the CAERS Reporting System of an allergic reaction to food that was believed to be due to NRL."

    I was wondering, over what time period was this Adverse Event Reporting System in effect.

    DR. STRATMEYER:  I will let somebody here talk about that, because again, our Adverse Event Reporting System, we look only at medical device adverse reports. Somebody from the Center for Foods will address that.

    Again, as you are seeing, there is some real differences between how various products are handled based on what part of the law they are regulated by.  In fact, you will be able to probably get some answers.  I believe that the manufacturers have a speaker this afternoon or tomorrow, and you can probably ask the manufacturers your question about food-handling gloves.

    DR. DWYER:  Thank you, Dr. Stratmeyer.

    We have two questions, Mr. Bonnette, that we need answered with someone from the agency today.  One is medical gloves versus food handlers' gloves.  Could you please get someone who can talk about that.

    The second is the issue of the CAERS and how long this Adverse Event Reporting System was in place to produce one.

    Dr. Torres, you will be at the end after the others.  Dr. Gaspari, I think is the next speaker.

    DR. GASPARI:  My question is related to the prevention issue.  The goal is to prevent sensitization, and there is it looks like three different agencies are recommending the same thing - NIOSH, OSHA, and your agency also, are all recommending decreased protein content and avoiding the use of cornstarch.

    This recommendation seems to be somewhat intuitive in that if patients become allergic to polypeptides in natural rubber latex, if you decrease the antigen content, you are decreasing their potential exposures below the threshold of sensitization.

    But my question is, this recommendation, is this based on intuition or is there a prospective study comparing low protein latex gloves to the older form of high protein versus the cornstarch-free versus the cornstarch-containing gloves over the 48-month period as was described earlier, and is it based on science or is it based on intuition in terms of that recommendation?

    DR. STRATMEYER:  Bob may be able to speak to this,  too, but my reaction is that it is based on intuition more than--it is very difficult to get these data in a controlled fashion.  That is one of the problems that you see, the argument about the prevalence or the incidence of the allergy.

    DR. DWYER:  Our next question is from Mr. Scholz.

    MR. SCHOLZ:  Maybe this is more of a follow-up to Dr. Torres' question, but on the proposed rule, did it deal at all with retail, the retail food side, or was it healthcare field only?

    DR. STRATMEYER:  We don't deal with the--if it were sold on the retail, you mean in a drugstore?

    MR. SCHOLZ:  Drugstore, restaurant, grocery store.

    DR. STRATMEYER:  If it were sold as a medical glove, it would--Wava, would you agree, if it's sold as a medical glove, even though it is sold in a drugstore, it would be considered a medical device?

    MR. SCHOLZ:  So, the rule did not deal at all with use of the glove in those establishments?

    DR. STRATMEYER:  Well, the use of the glove--all right, no, I see what you are saying.

    MR. SCHOLZ:  What I am trying to find out is if there are any comments on the rule proposed in '99 from the retail food sector.

    DR. STRATMEYER:  No.

    DR. DWYER:  The answer is that there were no comments in '99 from the retail food sector.

    DR. STRATMEYER:  No.

    DR. DWYER:  Dr. Torres.

    DR. TORRES:  In your list of research ongoing, you mentioned that there were more work on methodology.  So, my question is whether all this labeling in terms of levels that are recommended for protein content, are those based on science or in the sense of this is the detection limit of our method, or they are based on what is the protein level that would require for an allergic reaction.

    DR. STRATMEYER:  In other words, what the recommended levels were based on.

    DR. TORRES:  Right.

    DR. STRATMEYER:  They were based on as low as reasonably achievable.  In other words, I think it is very difficult to put the threshold level which would cause sensitization.  In fact, for some individual, it might be down to molecules for all I know, it would be very low.

    So, as a result, this was something that rather than raising the price of an exam glove up to $5.00 a glove, which we could put in requirements, that the cost of manufacturing would go so high, that would be a disaster also.  So, it was just as low as was reasonably achievable, and then again, that is sitting down with industry and trying to battle it out.

    DR. DWYER:  Thank you.  What protein is it, please?

    DR. STRATMEYER:  Pardon?

    DR. DWYER:  What protein is it, is it a mix of proteins?

    DR. STRATMEYER:  In the proposed rule, it's a mix of proteins, it is just a general protein test.  Now, ASTM has come out with tests and some levels for also antigens and I believe also allergens, or looking at allergens.

    DR. DWYER:  Thank you.

    Dr. Johnson has a question.

    DR. JOHNSON:  You stated at the end that your goal is to provide adequate information to the consumer, so they can make informed decisions to avoid sensitization and adverse reactions.

    I am just wondering if you have a view on whether that adequate information includes information to the consumer if their food has come in contact with latex during its processing, preparation, or service.

    DR. STRATMEYER:  I don't feel confident enough of my immunology to know.  I haven't looked at the oral side of it, so I wouldn't feel very comfortable trying to say whether or not--I don't know whether there is a problem, in other words.

    We came to the conclusion with respect particularly to healthcare workers, that there was a problem and that we wanted to make that information available to them.  That is sort of what you are trying to do, is decide whether or not there is enough information to say that there is a risk.

    DR. DWYER:  Dr. Torres has another question, and then Dr. Hamilton.

    DR. TORRES:  So, the target for the information that you are generating, it is the healthcare worker.  So, a patient going to a dentist or any other medical service, as a patient, there is no information disputed to you?

    DR. STRATMEYER:  We have web sites and everything, and I think that if you go to an awful lot of the medical facilities now, you will see that this is a non-latex, you know, a latex-free area, or if you take a look at the glove box, you can tell exactly what it is.

    Like I say, one of the things with patients is we saw a lot less problems in the Adverse Event Reporting System simply because of the fact they aren't exposed that much unless they have multiple surgeries, whereas, the healthcare worker can be exposed on a daily basis.

    DR. DWYER:  Thank you, Dr. Stratmeyer.

    Dr. Hamilton had a question.

    DR. HAMILTON:  I would like to step back and ask the question, is there in the United States a distinction between medical gloves and all other gloves, are they called consumer gloves?  I mean I hear of food handlers' gloves, I hear--do we have a terminology that defines it, because in Australia, they call them consumer gloves and medical gloves.

    DR. STRATMEYER:  When I talk about a medical glove, I am talking about something that is defined in the bylaw as a medical glove.  You could sell that latex glove and not call it a medical glove, and you could sell it for home cleaning, you could sell it for I guess food handling or whatever.  It doesn't have to be labeled as a medical glove, but if it is labeled by a medical glove, it is affected by Center for Devices and Radiological Health's regulations.

    DR. HAMILTON:  So, is there anything stopping a dentist from using a consumer glove?

    DR. STRATMEYER:  Now you are getting into--

    DR. HAMILTON:  Practice?

    DR. STRATMEYER:  --the practice of medicine or dentistry, and that is not part of FDA's role.  I think that most dentists would not do that because, first of all, the reason they are doing it is to protect themselves, and I think they would want the satisfaction that they are using something that has been tested and approved.

    DR. HAMILTON:  So, we can safely say there is a consumer glove entity and a medical glove entity, and they are distinct, but they can cross over just based on the user's preference.

    DR. STRATMEYER:  Yes.

    DR. HAMILTON:  If I could, I would like to address the question that Dr. Gaspari brought up, which is the issue of do we have actual data that supports the validity of the use of powder-free versus powdered latex gloves, and their use in terms of reducing exposure.

    I think we have several levels of studies that have been done based on what I have gleaned from the literature.  In 1994, John Yunginger initially started by measuring allergenic levels in powder and powder-free latex gloves by extracting them and doing in vitro testing with RAST inhibition analysis.

    He showed very clearly in his paper, in 1994, that while there are exceptions, that the general rule is that powdered latex gloves tend to have higher level of allergen extractable than powder-free gloves, but there were the exceptions.

    Then, as time went on, there are a variety of clinical studies that, as Dr. Stratmeyer said, are very difficult to do in terms of documentation of exposure, that have looked at populations that have been exposed to powder-free and powdered latex gloves, either small studies where they have looked at a dental office, like Charous' study, or the study in Canada with Tarlow, where they have looked at hospital with powder-free versus powdered latex gloves, and, in general, the gestalt is that in the environment where powder-free latex gloves have been used, there has been less tendency to develop latex allergy than in environments where powdered latex gloves have been used, but that is a soft set of studies because there are a lot of difficulties with interpretation of those studies.  They are very difficult to do.

    DR. GASPARI:  So, it is evidence, but it's not the highest quality evidence in support, in terms of scientific data to support a rationale.  The other question that I had attached to that was the protein content.  You didn't address that yet.

    DR. HAMILTON:  We will hear from Dr. Tomazac on this issue next, but, yes, there are definitive studies that looked at general allergenic potency by RAST inhibition analysis back in the early '90s.

    Most recently, we have more sophisticated methods for measuring allergenic content of rubber products that are extractable.  I am not sure I answered your question.

    DR. GASPARI:  Really, what I was getting at was the prevention issue, prevention of sensitization and lowering the incidence by using higher quality gloves, and that is really the heart of my question was again related to whether these two measures have been proven to lower the rate of sensitization in a prospective study.

    That would be the highest quality of outcome and also the most difficult kind of study to do, time and large number of patients, but that would be the best evidence, in my mind, the scientific evidence that there is a benefit to these measures.

    DR. HAMILTON:  In our packet, we don't have those papers, but there are a whole cadre of papers that have looked at those questions.  Some of them have flaws, aren't perfect, but as a group, they speak to the issue of powder-free latex is the direction that we should move at least in my opinion.

    DR. DWYER:  Are there specific papers that you wish the committee to have distributed?

    DR. HAMILTON:  Tomorrow, I can bring some and give them to the Secretary.

    DR. DWYER:  It will be helpful.

    DR. HAMILTON:  As at least suggested model papers in this area.

    DR. DWYER:  I have one last question and then I would like Dr. Johnson, and then we will go all around the table.

    I am puzzled because if you powder a latex glove, the powder apparently sort of absorbs compounds from the glove, so it would seem to me the ideal, and then it could get in the air and you could breathe it or it could get into food or the catheter that you showed us, and so forth, but it seems to me that the glove itself, if you got rid of the powder, should therefore have less of those proteins, because they have been leached out or absorbed.

    So, the ideal would be a glove where you put a lot of powder on it, get all of the proteins leached out, rinse the proteins off, and then went about your business.  To a naive nutritionist, that would seem logical.

    What is wrong with the logic there?  How does this work, is it an inhalation that we are talking about with the powder, or is it simply both?

    DR. STRATMEYER:  It depends on whether you are talking about the patient or the healthcare worker.  With the healthcare worker, it would probably be inhalation.  With the patient, that is a different matter.  That would be tissue contact.

    The issue of what you are talking about, you can do the same thing by washing the glove without adding, and then add the powder later, you know, because that is one of the things that we thought perhaps had happened, when all of a sudden glove production went from a few billion up to, you know, 20 billion in a very short period of time, because universal precautions, that is when we started noticing a lot of things, and it could be that they were just running lines faster, not emptying the water as fast, because remember how these things are made, they are dipped and then a mandrel goes through a wash.  If you don't clean that water out, you are going to get a lot of protein there, and it is going to end up coming off with the glove.

    Like I say, we have seen the levels--and Vesna will be getting into this, this afternoon--we have seen the levels of protein go down.

    DR. DWYER:  Thank you.

    Dr. Johnson.

    DR. JOHNSON:  My question is probably equally as naive, but I am just wondering anecdotally, if you ask workers to use the powder-free gloves, is there any evidence that they then powder it themselves?  I mean if they are difficult to get on, it seems as if the workers are constantly putting them on.

    DR. STRATMEYER:  There are ways to make the gloves easier to get on without powder.  A lot of it is going to be preference, so anything I have is anecdotal.  I think there are still a lot of surgeons that still like powdered gloves because they can get a nice, thin glove with a lot o tactile sensation, and surgeons' gloves are longer and tighter, they are harder to get on.

    But again, if you want good, solid information, I don't have any.  I don't know, Wava Truscott, do you have any solid information?

    DR. DWYER:  I am sorry, you will have to come up to the microphone and identify yourself if you wish to speak.

    DR. TRUSCOTT:  I am sorry, I am Dr. Wava Truscott,  Kimberly Clark.

    DR. DWYER:  Go ahead.

    DR. TRUSCOTT:  As far as reports, there are some hospitals where surgeons in preference to having a powdered glove, will add their own powder.  Basically, all gloves do start off as powdered because they just stick together and crumple in manufacturing.  So, then, you take off the powder and you are almost right, because you start off with powder and that washing takes the protein down.

    They are adding, as Dr. Stratmeyer was indicating, other things, like lubricant type things, to make it easier and easier to put on than the other types of gloves, or coatings, and thus to facilitate it.  Unfortunately, there are still some people that want more of the ball-bearing type effect of a powder, so they will add it after it has been removed.

    DR. DWYER:  Thank you for your informative comment.

    Dr. Gaspari.

    DR. GASPARI:  I had a couple of comments related to local effects of powder on the skin that are potentially of relevance.  First of all, the cornstarch powder or really any kind of particulate material, when held against the skin, will damage the stratum corneum, which really supplies the barrier function to the skin.  When held under occlusion for a prolonged period of times, like under a rubber glove, this is theoretically a basis for enhanced percutaneous exposure, percutaneous penetration of polypeptides that are stuck onto those cornstarch particles.

    So, that is one issue, enhanced penetration of things that are sticking to the cornstarch because of the alterations in barrier function.

    Secondly, there has been a couple studies that suggested that--these are animal model studies--that if you co-administer an antigen with cornstarch particles, that it is acting like an immunologic adjuvant, so there is an immunologic basis for potentially adjuvancy of the cornstarch particles themselves.

    So, an adjuvant means that it induces inflammation and enhances the immune response to a foreign antigen, boosting, like an IgE response, and alters the way the immune system sees an antigen.

    So, those are two issues related to cornstarch particles.

    DR. DWYER:  Thank you.  More good news.

    Could we now go around the table, just finish, and have lunch.  Remember that this gentleman may not be here tomorrow, so this is your chance to get your shots in.

    Dr. Torres, any more questions?  Dr. Fischer.  Dr. Hamilton.  Dr. Taylor, you have been uncharacteristically silent today.  Dr. Blumberg.

    DR. BLUMBERG:  It is really a question and it relates to some of the issue about the availability of the protein to deliver that antigenic stimulus.  The reports that we were given by Beezhold, they said that there is more protein inside the glove and it may have to do with some of this issue of occlusion and the powder, and so on.

    In his study, he actually turned the glove inside-out to get more protein when they delivered it.  Now, that is not how a food handler presumably would use it if they are using medical gloves and those regulations, so I guess my question is--maybe you can address that manufacturing issue--is there a difference between the availability of the protein on the inside and the outside of the glove, or does it have to do with the fact that you just have your hand inside the glove and there is the contact that is involved, because that is going to affect it.

    DR. STRATMEYER:  Again, I think the manufacturers can probably this better than me, but there is a difference I think because of the fact of the way, again, a mandrel is dipped in there, and then it's pulled off, so what you have got, it is turned inside-out when it comes off.

    So, the side that was next to the tank that it was going through, the latex it was going through, would then be the inside of the glove.

    DR. BLUMBERG:  Thank you for clarifying that.

    DR. DWYER:  Thank you.

    Dr. Gaspari.  Dr. Johnson.  Dr. Downer.  Dr. Scholz.

    Well, we have learned more about this particular product's manufacture than we ever thought we would know.

    DR. STRATMEYER:  So did I.

    DR. DWYER:  At this point, I think we are going to adjourn for lunch.  Is that appropriate for the committee, adjourning now and coming back at 1:30?  Is that your pleasure or do you want to start at 1 o'clock?

    I think the committee prefers, unless I hear otherwise, to reunite at 1 o'clock.

    Thank you.

    [Whereupon, at 12:10 p.m., the meeting was recessed, to reconvene at 1:00 p.m., this same day.]

AFTERNOON SESSION

[1:00 p.m.]

    DR. DWYER:  Over the lunch, it became apparent that two committee members may have to leave tomorrow evening, therefore, if the committee is willing, we would like to plow ahead today and we would hope to try to go until 5 o'clock or thereabouts, 5:00, 5:15, and then what we are trying to do, and we should know in about an hour, is to get two speakers to move up, so that more speakers will be today, and we will have fewer speakers tomorrow.

    There are some people who are not here and there are other people who cannot be changed, the public comment time cannot be changed, but we will try to move up those who can be moved up, and then Mr. Bonnette and I will work together to see if we can move up some of the other things in the afternoon tomorrow to give us enough time to finish in a deliberative and considered fashion by tomorrow evening, so we have the benefit of the entire committee.

    Is there anyone on the committee who will find it a hardship to work until 5:00 tonight?  Yes.

    DR. DOWNER:  I may, I will have to make a call.

    DR. DWYER:  Very good.  Anyone else?

    With that, if you will let us know, Dr. Downer, that will be nice.

    Let's get started then and resume our deliberations with those questions, those key three questions.  That is what we are expected to do and what we will have to do tomorrow is to answer those three questions, not everything about latex and latex allergy, but those three specific questions must be answered by tomorrow.  So, it is a good idea to just keep them at top of mind as we go through the rest of the discussion.

    For more substance now, we are turning to Dr. Shanklin, who is at the Office of Food Additive Safety at the Food and Drug Administration.  She is going to speak to us on Safety Assessment of Food Additives.

    We are grateful, Dr. Shanklin, for your presence.

Safety Assessment of Food Additives

    DR. SHANKLIN:  Thank you.

    Good afternoon.  As was stated, my name is Anna Shanklin.  I am from the U.S. Food and Drug Administration, FDA.

    FDA's mission, pure and simple, is to promote and protect the public health by helping safe and effective products reach the marketplace and monitoring those substances while they are still on the market.

    Today, we will discuss a very important aspect of our agency's mission, food additives, and today's presentation, Safety Assessment of Food Additives, how FDA regulates food additives.

    Additives provide a variety of useful functions, as you are aware, in foods, such as keeping them wholesome and appealing in transport.  Additives also help to improve food's taste, texture, consistency, color, and even nutritional value.

    In this presentation, we will review aspects of the food and drug law, to learn about the legal framework in place for food additive approvals.  We will discuss the food additive review process outlined in the law, and gain more understanding on the safety evaluation of food additives and how we should apply these provisions in the law to evaluate natural rubber latex, a food additive, and its implications in food mediated latex allergic reactions.

    As you have heard earlier, CFSAN's mission is to promote and protect the public health by ensuring that the food supply is safe and wholesome and that cosmetics are safe, and that food and cosmetic products are honestly and accurately labeled.

    The Office of Food Additive Safety within CFSAN has the task of ensuring that the use of food ingredients is safe.

    In review of OFAS's vast universe of food ingredients covered by Dr. Pauli this morning, for the purposes of today's presentation, we want to focus on food packaging and food contact substances for deliberation.

    Now, foods and food ingredients, as well as substances for use in, on, or in contact with food, fall under the jurisdiction of the Federal Food, Drug, and Cosmetic Act, often referred to as "The Act" or the FFDCA.  It is the basic food and drug law of the United States.

    The FDA is the federal agency mainly responsible for administering the main part of the FFDCA.  The law gives FDA authority over foods and food ingredients, and is intended to assure the consumer that foods are pure and wholesome, safe to eat, and produced under sanitary conditions.

    The Office of Food Additive Safety is mainly responsible for administering the food additive provisions of the Act, found in Section 409.  Our administration of Section 409 focuses on the evaluation of the proposed uses and safety information of the new food additive, and once a safety determination has been made, writing regulations stipulating safe conditions of use for the food additive.

    Now, regulations are not law, but a regulation is the standard requirement based on the law.  However, a regulation does have full force of the law.  U.S. federal regulations are compiled in the Code of Federal Regulations, CFR, and specifically Part 21 contains FDA regulations.

    Although our food additive regulations are not law, they are intended to be written such that noncompliance with the regulation would violate some section of the law, and in our case, the FFDCA.

    The law provides a framework for assuring the safe use of these additives or chemicals on or in food.  Under this framework, the agency must approve new food additives before they can be used in a manner and whereby they may be become components of foods.

    This is in accordance with the 1958 Food Additives Amendment to the Act, which requires FDA approval of new food additives prior to their inclusion of food, thus, the term "pre-market approval."

    What i a food additive?  You have also visited this definition earlier.  In Section 201(s) of the Act, a food additive is any substance, the intended use of which results or may reasonably be expected to result, directly or indirectly, in its becoming a component or otherwise affecting any characteristics of any food.

    This includes any substance intended for use in producing, manufacturing, packing, processing, preparing, treating, packaging, transporting, or holding food if such use is not generally recognized as safe.  Yes, even food contact articles or food packaging is considered to be a food additive if it is expected to become a component or migrate into food.

    The definition excludes substances that are generally recognized as safe, or GRAS, by qualified experts. Examples of these would be items, such as salt, glass, and stainless steel, among a few.

    In short, in the broadest sense, a food additive is any substance that is reasonably expected to become a component of food as a result of its intended use, if such use is not generally recognized as safe.

    In addition to the definition of food additive found in the Act, there are also other important provisions provided in the law relating to how we regulate food additives.

    Section 409 defines an unsafe food additive. "The use of a food additive is unsafe, unless that use conforms to a regulation, notification, or an exemption issued by FDA under Section 409."

    Section 402 speaks about adulterated food.  "A food is adulterated if it is or if it contains any food additive that is unsafe."

    Section 301 defines prohibited acts.  "The introduction or delivery into interstate commerce of any food that is adulterated or misbranded."

    Together, these mechanisms or these provisions provide a mechanism for FDA to enforce the law.  Let's look at an example.

    The presence of an unsafe food additive renders a food adulterated, and when that food enters into interstate commerce, a violation of the FFDCA occurs.  FDA can then proceed with enforcement actions under the law against the person introducing the adulterated food into interstate commerce.

    The same applies for food packaging.  Here, we have the example of a candy bar wrapper using or containing a new antioxidant that is not approved.  If that antioxidant then migrates into the candy bar, that is an adulterated food.  When that food enters into interstate commerce, a violation of the Act occurs and FDA can take enforcement measures.

    Again, food additives are regulated because the Act prohibits the interstate distribution in the U.S. or importation of any food or articles that are adulterated.

    Points to Remember.  An unsafe food additive in a food renders that food adulterated.  An unapproved additive is the same as an unsafe food additive.  Therefore, the presence of an unapproved food additive renders a food adulterated.

    The 1958 Amendment to the Act, in addition to defining the food additive and establishing pre-market review of food additives, also established two key concepts we want to focus on today - the standard of review and the standard of safety for food additive approvals.

    The Amendment also published formal rulemaking procedures.  Under the general safety standard of the Act, a food additive cannot be approved for a particular use unless a fair evaluation of the data available to FDA establishes that the additive is safe for that use.

    Thus, the Standard of Review criterion requires a fair evaluation of the data, and not infiltration of personal attitudes or preferences or beliefs of administrative officials.

    The 1958 report states that, "The committee has endeavored to prescribe a new criterion requiring a high standard of fairness be observed in administrative rulemaking, and again that personal attitudes or preferences of administrative officials could not prevail on the basis of being supported by substantial evidence picked from the record without regard to other evidence of value in the record."

    Furthermore, the House of Representatives report from 1958 states that, "The committee feels that the Secretary's findings of fact and orders should not be based on isolated evidence in the record, which evidence in and of itself may be considered substantial without taking account of the contradictory evidence of equal or greater substance."  Thus, there must be a fair evaluation of all the available data.

    The Standard of Safety relies on the concept of reasonable certainty of no harm.  You have heard that also earlier.  "Reasonable certainty of no harm," with equal emphasis on each word, as stated by Commissioner David Kessler of 1995.

    "Safe" is defined in the Code of Federal Regulations as a "Reasonable certainty in the minds of competent scientists that the additive or substance is not harmful under its intended conditions of use."  This is the standard.

    "Harm," what is harm?  Harm refers to health of man or animal.

    The Standard of Safety set forth by the law requires the petitioner to demonstrate a reasonable certainty of no harm from the intended use of its substance. FDA will then assess whether it has received adequate documentation to appropriate questions regarding the safety of the proposed use of the additive.

    It is very clear from the legislative history what the concept of reasonable certainty means.  From the 1958 congressional report, it states that, "The concept of safety used in this legislation involves the question of whether a substance is hazardous to the health of man or animal.  Safety then requires proof of a reasonable certainty that no harm will result from the proposed use of an additive."

    In prescribing these standards, Congress recognized that absolute certainty of any substance can never be proven, and in the report it indicates that the concept of safety as outlined in the legislative history does not, and cannot, require proof beyond any possible doubt that no harm will result under any conceivable circumstance.

    In Section 409, the law provides a legal framework for regulating the safe use of food additives.  Let's review this legal framework more closely.

    Under Section 409, any person may petition FDA to issue a regulation prescribing safe conditions of use of an additive, and this is formally known as the Food Additive Petition Process.

    Keeping in mind our Standard of Review, fair evaluation of the data, and our Standard of Safety, reasonable certainty of no harm, let's clarify or examine the petition process more intimately.

    Our safety decision regarding the approval of food additives is solely a safety decision.  Our evaluation is not intended to ensure, nor is it possible to ensure, safety with absolute certainty.  Our standard is the reasonable certainty of no harm rather than a certainty of no theoretical possibility of harm.

    Our evaluation is not a risk-benefit analysis relative to other available options.  Our evaluation is not intended to enforce or limit consumer choices.  However, our decision does, in fact, ensure safety.

    It is a consensus decision made with residual certainty that provides a fair evaluation of all the data of record.  It must protect the public health, and this data of record will be able to withstand scientific, procedural, and legal challenges from all sides.

    Thus, our evaluation is a science-based decision in a well-documented record.

    So, the approval of food additives again are solely based on safety, under the safety standard, reasonable certainty of no harm where harm refers to health of man or animal.  The Standard of Review is the fair evaluation of the entire record, and benefits are not to be weighed in our safety decision.

    Let's review the process and the key players.  With the submission of a petition, the safe use of a substance is determined through a series of reviews of the relevant scientific data and information submitted by the petitioner.

    A typical submission will undergo chemistry, toxicology, and environmental science reviews, and the review is managed and coordinated by a consumer safety officer.

    In order for FDA's key players to evaluate the safety of a substance under its proposed use, certain scientific information is needed - the complete identity of the chemical substance, conditions of proposed use, the intended technical effect with the petitioner submitting to FDA, data establishing the minimum amount required to achieve this technical effect, the method for quantifying how much of the additive is available, full reports of safety studies, manufacturing methods, as well as environmental information in accordance with the National Environmental Policy Act.

    We want to stop and emphasize here that a full-blown, exhaustive safety evaluation of all the appropriate studies with agency ownership of the safety decision occurs under the safety evaluation of a food additive.

    We also want to emphasize that in the safety evaluation of a substance, an important requirement is the estimation of the food additive's probably human exposure under its proposed conditions of use to determine whether its use or presence in food at a certain concentration is safe.

    The key determinant in the evaluation of the substance in or added to the diet is the relation of its human exposure to a level at which no adverse effects are observed in toxicological studies, or as a popular coined phrase states, "The dose makes the poison."

    The technical review process is very thorough.  FDA scientists provide free filing consultations to help petitioners.  FDA scientists review the data and evaluate the petitioner's safety argument.

    FDA communicates with the petitioner to resolve any questions and/or additional data needs it has.  FDA reviews the documentation and then FDA reaches a scientific conclusion and makes a recommendation.

    Section 409 also stipulates other required actions on food additive petitions after it has been submitted.  FDA must complete the review and establish a regulation or deny the petition and inform the petitioner.

    The FFDCA legal framework outlined in Section 409 also speaks to other provisions pertaining to the response of actions on food additive petitions.  FDA must allow for objections to the actions filed by any person and honor requests for public hearing.

    The Act also allows for judicial review of the objections that have been filed.  The requirement we want to focus on today is agency-initiated amendment or repeal of regulations.

    In amending or repeal of regulation, it is essential to understand that the process is equivalent to that of food additive approvals.  In the process of food additive approvals, there is a fair evaluation of the data under the Safety Standard, reasonable certainty of no harm, and an issuance of a regulation.

    In the process for amending or repealing a regulation, there should be a fair evaluation of the data under the Safety Standard, reasonable certainty of no harm, and the issuance of a regulation.  Simply put, if it comes in as a regulation, it goes out as a regulation.  It is FDA's responsibility under the law.

    So, the legal framework for food additive approvals provide that food additives again are unsafe until FDA makes a decision, and if FDA decides that the food additive is safe under its conditions of use, we write regulations stipulating an identify, specifications and conditions of safe use.  The detailed specifications may include types of food that the additive is permitted in, the manner of use, and any other special labeling requirements.

    FDA regulations do not provide for specific product approvals.  This process for review of additives is for those added directly into food, as well as for food contact substances, such as packaging.

    Specifically, the food additive regulations for indirect regulations are listed in Part 174 through 178 of the Code of Federal Regulations.

    We want to touch briefly on the fact that in 1997, the Food and Drug Administration and Modernization Act amended the Act more commonly referred to as FDAMA to establish a food contact notification process as the primary process by which FDA regulates food additives that are food contact substances.  The FCS process is outlined in Section 409 of the Act.

    FDAMA also gave us the statutory definition of a food contact substance.  And what is a food contact substance?  It is any substance intended for use as a component of materials used in manufacturing, packing, packaging, transporting, or holding food if such use is not intended to have any technical effect in the food, also known as indirect food additives.

    Thus, for the purposes of today's meeting, it is important to emphasize that under the legal framework established by the Act, a food additive that is the subject of an effective notification is also a safe food additive.

    So, food additive approvals in brief.  Section 409 gives FDA all the necessary tools for assuring the safe use of food additives regardless of whether FDA is petitioned or notified, the safe use of a substance is determined through a series of reviews of the relevant scientific data and information submitted.

    We review the safety of each substance under its proposed conditions of use, and this review is carried out by qualified and competent scientists.

    The safety assessment of the food additive is concluded by writing a regulation, allowing a notification to become effective or by granting an exemption.

    In reviewing roles and responsibility, the petitioner is responsible for demonstrating safety, and FDA is responsible for conducting a full and fair evaluation of the data and information, and issuing a regulation only if FDA scientists conclude that the requested use is safe.

    Now that we are well versed on how FDA evaluates the safety of food additives and the regulatory process for food additive approvals, let's examine a specific food additive, an indirect food additive, a food contact material, natural rubber.

    Let's review it based on the Act in Section 409 and the Standards of Review and Safety previously discussed. First, I would like to point out that natural rubber latex is approved in several places throughout the Code of Federal Regulations in Part 21.

    As we talked about earlier, a direct use is in 21 CFR 172.615, chewing gun base.  So, that is one of the regulated uses that Dr. Taylor mentioned earlier.  For indirect use, it is also listed in adhesives, pressure-sensitive adhesives, resinous and polymeric coatings, acrylic and modified acrylic plastics, both semirigid and rigid, cellophane, closures with sealing gaskets for food containers, and the one that we are concerned about, rubber articles intended for repeated use.

    So, natural rubber latex is listed along with its conditions of safe use in Section 177.2600, and this regulation was issued in 1963.  Therefore, it is an acceptable indirect food additive.  It is used in the production of latex food service gloves, thus, it is a food contact substance.

    FDA's current position is that provided that the compositional requirements of the regulation and its limitations and specifications are met, the use of natural rubber as a component of food service gloves is in compliance with 21 CFR 177.2600, and it is not an unsafe food additive.

    But we know that we have issues with natural rubber latex, and what are these issues?  As previously discussed, exposure to natural rubber latex has been shown to elicit a range of responses in sensitized people.  Of specific concerns are various allergic reactions responding to the natural rubber latex usually as a result of prolonged cumulative exposure to natural rubber latex.

    These allergic reactions have been linked to latex proteins.

    FDA has received reports of latex allergenic individuals, those who are already sensitized to latex, displaying allergic reactions to foods believed to have been handled by food service workers wearing natural rubber latex gloves.  Thus, the problem becomes food mediated latex allergic reactions.

    Remembering that part of our agency's mission, to monitor substances while they are still on the market, post-market surveillance, FDA understands, as Dr. Tarantino said, that since the approval of natural rubber latex in 1963, things have changed, and we want to state that we are dedicated to promoting and protecting the public health.

    With that, CFSAN has been gathering information relating to food mediated latex allergy in an effort to determine if there are data to support the claim that latex proteins are transferred to food as a result of the use of latex food service gloves, and if such use may trigger an allergic response in hypersensitive consumers, and if there is sufficient evidence to propose a regulatory action, such as amending or repealing the regulation currently in 21 CFR 177.2600.

    Let's look at the glove.  We know that latex food service gloves are used by the food service industry as a barrier to infectious agents that may be present on the hands of food service workers.  Thus, gloves are considered a food contact material, and they are subject to the law.

    Under the approval process, natural rubber latex was evaluated for use in repeat use articles with a fair evaluation of data, under the Safety Standard of reasonable certainty of no harm.

    However, it has been suggested that the latex food service gloves are responsible for introducing natural rubber latex allergens to food, thus rendering the food adulterated.  The proteins are components of food contact articles, the gloves, that may migrate to food as a result of their intended use in the food service gloves, thus, they are constituents of the food additives.  As such, they are subject to the safety requirements in the law, and their assessment of safety should be based on the law.

    So, evaluation and any regulatory actions on the use of natural rubber latex in food service gloves and other food contact articles should be based on the general safety standard.

    Again, the Safety Standard is reasonable certainty of no harm.  Our decision and actions regarding the use of NRL in contact with food has to be focused on this standard - does it or does it not meet the standard.  That is the question.

    So, food mediated latex allergic reactions, how do we address the problem from a public health standpoint?  In addressing the problem of food mediated latex allergic reactions, we must consider that safety is our first priority.  Before we act again, we must ask the question if the use of the additive would result in the production of unsafe food.

    FDA just operate under the law.  We must consider that food additive approvals result in the issuance of a regulation and that there is a legal framework in place.  We must remember that food additive regulations are issued based solely on safety data relating to the additive itself, that food additive provisions do not provide a mechanism for FDA to consider risk-benefit relative to other options when reviewing the safe use of a particular substance.

    In other words, we cannot ban latex for use in food service gloves based on the fact that there are other options available.

    We also want to remember that there is a legal framework in place for approvals and also for amending and repealing regulations, and that end with an issuance of a regulation.

    So, what did we learn regarding how FDA regulates food additives?  We learned again that there is a legal framework in place, and this is found in Section 409 of the Act, that this framework provides for a solid review process conducted by competent scientists, and that the Standard of Review is fair evaluation of data, and our Standard of Safety is reasonable certainty or no harm, remember safe meaning a reasonable certainty in the minds of competent scientists that no harm will result from the intended use of the additive, and harm again referring to harm to health.

    Also, currently, natural rubber latex is a safe food additive under Section 21 CFR 177.2600 as long as it is compliance with that regulation.

    Finally, we have reviewed the legal framework in place for food additive approvals, and we have reviewed the food additive process and the safety evaluation of food additives as outlined in the law.

    We have also reviewed the issue of food mediated latex allergic reactions, and hopefully, have gained a greater understanding of how to address the problem from a public health standpoint, understanding FDA's responsibility to operate under the law, promoting and protecting the public health.

    Are there any questions?

    DR. DWYER:  Thank you.

Questions of Clarification

    DR. DWYER:  While the committee deliberates, Dr. Hamilton, did you have a question?

    DR. HAMILTON:  Yes.  Could you, as a point of information for me, clarify whether powdered versus non-powdered gloves ever entered into the approval process with regard to this 21 CFR 177.2600?  In other words, there was no discussion of discriminating powdered versus non-powdered, it was just latex gloves were reviewed, right?

    DR. SHANKLIN:  Not that I am aware of, and in the regulation, it just says natural rubber latex.

    Would someone else from the agency care to comment on that?

    DR. PAULI:  Let me add a little bit, that when that regulation was issued, I think what people were mostly thinking about were hoses in factories, use of rubber in general, because cornstarch itself would be considered safe, and if natural rubber latex was safe, we often get mixes and matches in ways that one wouldn't have contemplated.

    DR. HAMILTON:  Thank you.

    DR. DWYER:  Dr. Taylor, you had a comment?

    DR. TAYLOR:  So, I asked this question once before this morning, but is our advisory committee restricted to the debate about natural rubber latex as approved under 21 CFR 177.2600?

    DR. SHANKLIN:  Yes.

    DR. TAYLOR:  So, we are not to comment upon--I mean it seems incredulous to me that we are being asked to comment on the use of latex gloves, when there is direct food additive approval for latex.  It seems very inconsistent.

    DR. SHANKLIN:  Dr. Tarantino wishes to comment on that.

    DR. DWYER:  Dr. Tarantino.

    DR. TARANTINO:  Again, I think as you have seen most of the information presented to us was about gloves, but as George said, the regulation is about natural rubber.  If you have any evidence that it is the hoses and the belts and the other things as opposed to gloves, we would be very interested in hearing that.

    It is clear that most of the information that came to us--and this is why the questions were phrased that way--pointed at gloves, but we are interested in hearing if you have something else to say about other forms of natural rubber latex used in food contact.

    DR. DWYER:  Dr. Taylor.

    DR. TAYLOR:  Does not the FDA also have authority to regulate the safety in food contact materials being applied to meat and poultry products under the purview of the U.S. Department of Agriculture?

    DR. TARANTINO:  The USDA defers to us about doing the safety review, and we coordinate with them.

    DR. TAYLOR:  So, it seems to me as though there may be some uses under Section 9 of the Code of Federal Regulations regarding meat and poultry applications, in particular, the netting materials that are used on corned beef and ham, and things like that, have a latex core.  That is what I am familiar with.  I don't know that there might not be others.

    DR. TARANTINO:  That is an issue, as well, in and of itself, but I think the underlying regulation that we are involved with here is the natural rubber latex per se in contact with food.

    DR. DWYER:  Dr. Gaspari.

    DR. GASPARI:  I have a question related to one of your slides with the quotation, "The dose makes the poison," and in terms of evaluating dosing with natural rubber latex exposures, number one, we don't know what the dose is that would elicit allergic response or allergic signs and symptoms in an NRL-allergic individual, and, two, we don't know the actual dose range of natural rubber latex that is carried over into the food that could potentially elicit, and what a safe level would be in an at-risk population.

    That is one question.  I guess the other question I have is in terms of what is a reasonable level of risk of this type of phenomenon occurring.  Obviously, there is millions of exposures of people in restaurants that food is prepared with handlers using natural rubber latex gloves, and there is probably, although I guess this is totally unknown, how much latex they are actually exposed to, and if basically, all we have is a handful of reports of severe reactions, it seems like a very rare event although we don't know what the exact denominator is.

    The other question, what is an acceptable rate of a very extremely rare reaction even though it may be potentially very serious to even fatal?

    So, those are my two questions.

    DR. DWYER:  Let's make sure we have got the questions.  One is what is an acceptable rate under the law of an adverse reaction, the kinds that have been described in the case reports for natural rubber latex, and the other question I had you ask is what dose elicits an allergic response.

    Could you speak to those?

    DR. SHANKLIN:  He wants to take it.

    DR. DWYER:  Okay, fine.

    DR. PAULI:  We want somebody near retirement to take a question like that.

    DR. DWYER:  Are you planning on identifying yourself?

    DR. PAULI:  This is George Pauli.  Actually, this is one of those questions we have to turn back, and that is why we are giving very general terms.  What is reasonable in terms of the real world?  That is where we are looking for your judgment and how much scientific data do you need to stand up to scrutiny.  That is where we are asking your input because our guidance is very general.

    As I mentioned this morning, we think of common food as the gold standard.  On the other hand, we don't want to see peanuts mixed in the chili as happened several years back and having someone die from it.

    This is a context where we are looking for wisdom, and we will give you the facts we have, and as you noticed, the questions, they were put together in a charge, had contingency clauses in there, because we don't know which can be answered.  But, frankly, this is what we are throwing to you to give us your best guidance in this area.

    DR. DWYER:  Thank you.

    Don't sit down, because we have another question. You didn't answer the question about what dose elicits an allergic response.

    DR. PAULI:  Then, again, I would say we don't know.  We don't know what amount would be transferred to food, we don't have any information on that.  You saw the papers that were given out.  That's all the information we have.

    Those are very legitimate questions, and it might point to a need for further quantification, but as you will also hear later, in reflecting from this morning, the framework is changing, too, of what was the amount that would have transferred 10 years ago compared to now may be different, so the exposure may be differing.

    I think for those of you in the allergy field, you know, one of the hot areas is how do you set a threshold and a threshold for whom, because there may be thresholds that vary with the individual, and just don't have answers on that, we are looking for feedback.

    DR. DWYER:  Thank you.

    One other question is, is the regulation really concerning natural rubber or natural rubber latex?

    DR. SHANKLIN:  Natural rubber latex.

    DR. DWYER:  Thank you.

    Dr. Hamilton.

    DR. HAMILTON:  I have one more question.  One of your slides you showed that candy wrapper adulterating a candy bar, and then it being transported with a truck across state lines, and then the FDA going after it.

    Is there a requirement to actually measure the adulterating component in the food before the FDA actually takes action, or is it just based on--

    DR. SHANKLIN:  In this case, since the antioxidant was unapproved, then, that automatically renders the food adulterated, and when it enters into interstate commerce, that is just a violation.

    DR. HAMILTON:  So, just the presence.

    DR. SHANKLIN:  Just the presence.

    DR. HAMILTON:  One doesn't have to quantify its absolute transfer to the food or anything of that nature?

    DR. SHANKLIN:  No.

    DR. HAMILTON:  Thank you.

    DR. DWYER:  Dr. Torres, Fischer?

    DR. FISCHER:  I would like to ask about chewing gum, because you brought that back up again.  Tell me what is in chewing gum, is it natural rubber or natural latex?

    DR. SHANKLIN:  Let's look it up right here.  I think it's natural rubber, if I am not mistaken, but I have the regulation right here.  It speaks to natural rubber, smokesheet and latex solids.

    DR. FISCHER:  Well, that helps.

    [Laughter.]

    DR. DWYER:  No wonder the teachers told us not to chew it.

    DR. FISCHER:  My next question, to follow that up, would be are there any reports of allergies from chewing gum?

    DR. SHANKLIN:  Not that I am aware of.

    DR. FISCHER:  So, nobody has ever questioned that.

    DR. TAYLOR:  Is the FDA aware of whether any chewing gum manufacturers are actually using this material as chewing gum based today?

    DR. SHANKLIN:  I think Dr. Stratmeyer may want to comment on that question.

    DR. STRATMEYER:  I don't know about whether they are using it for chewing gum, but actually, what you are talking about is really not natural rubber latex, and I don't know for sure.  There are some people out here that can probably answer that, but one of the problems you have got is definitions.

    We ran into that when we wrote our first rule on labeling natural rubber-containing medical devices.  So, in the rule, we put down definitions for everything that there was.  We considered natural rubber to cover two different things, natural rubber latex and dry natural rubber.

    There is a lot of difference in how the proteins that are available from dry natural rubber are a lot less than the proteins that are available from natural rubber latex.  We also defined natural latex, and we had trouble doing this, because you could go to different places and find it.

    We worked with ASTM and some of the people in V-11, which is the rubber group, and we got definitions and nailed them down, and without those definitions, it is very difficult to identify what material you were talking about, particularly when you go back several years.

    Do you want to say something about the chewing gum?

    DR. DWYER:  Shall we recognize this person, and would the person please come up and identify themselves.

    DR. BOREL:  I am Dr. Lisa Borel of Consumer Advocates, Latex Allergy.  Over seven years we have investigated many products for natural rubber content or natural rubber latex content.  Chewing gum does not contain natural rubber which is made here in the United States.  It is all synthetics at this point and makes bigger bubbles, I was told.

    DR. DWYER:  Thank you.

    Dr. Blumberg, any questions?  How about Dr. Downer?

    DR. DOWNER:  Thank you for a very interesting presentation.  You mentioned with respect to food additives, amendment and repeal, that regulations in equals regulations out.  Can you tell me what happens within that process, because it seems as if there is no need for discussion or deliberations then?

    DR. SHANKLIN:  What I mean by that is that under the food additive approval process, there is a formal regulation or formal regulatory process, whereas, the data is submitted, FDA reviews the data, and it issues a regulation.  So, in order to have an amendment or a change to the regulation or repeal a regulation, that data or information has to be submitted and reviewed under the same standards and a regulation issued.

    DR. DOWNER:  Thank you.

    DR. DWYER:  Any others?  Dr. Hamilton.

    DR. HAMILTON:  May I make a recommendation that this committee use the definitions that have been already defined in the document that Dr. Stratmeyer just described because I got a little puzzled and confused when natural rubber and natural rubber latex were used all of a sudden, and it wasn't really well defined.  It was defined just a moment ago, but I think if we use the definitions that already have been through scrutiny, it would be helpful to all of us.

    DR. DWYER:  Does the committee agree to that?  If so, it might be helpful for the agency to provide us with the definitions if they are not already provided.  Could we get that maybe by the break?  Perhaps it's in our materials and we just don't know it.  So, someone from the agency will provide that to the committee by the break.

    Thank you very much, Dr. Shanklin, appreciate your help.

    Just recap, at the break, we should know how many speakers we can get moved up, but it is my intention as chair, unless the committee objects, to continue this meeting until 5 o'clock tonight.  Is that all right with everybody?  Dr. Downer is going to check and make sure that her other engagement can be changed.

    The purpose of this is to get the benefit of all committee in the discussion because two members may have to leave tomorrow night.  Thank you.

    Let's go on then to the next speaker, who is Dr. Hepp.  Dr. Hepp is at the Office of Food Additive Safety, and his topic is the Specific Background on Food Mediated Latex Reactions.  This should be some interesting science.

Specific Background on Food Mediated Latex Reactions

    DR. HEPP:  Good afternoon and thank you for the introduction.

    The information presented so far was, for the most part, background in that it was describing latex allergy as a problem that exists in the clinical setting.  It also described the steps that FDA's Center for Devices and Radiologic Health have taken to address that problem in the clinical setting, and as Anna just described, FDA's authority as it relates to the regulation of food additives.

    The purpose of bringing this Additives and Ingredients Subcommittee together is to provide you with all the information that relates latex allergy directly to food safety, and another reason is to collect any additional information that FDA may not be aware of from people participating in the meeting, and then to get independent consideration from this committee about all of the information.

    DR. TORRES:  Are there any slides in the handouts?  I don't see it in my set.

    DR. DWYER:  Is there a handout?

    DR. HEPP:  There is no handout at the moment.  We will provide that later.

    DR. DWYER:  Good.  It would be helpful before the end of the day.

    DR. HEPP:  Okay.  The third reason for getting the committee together is to get some independent consideration of all the data that we have collected or that we can collect at this meeting, and to get answers to the questions that we have presented the committee with in the charging questions.

    So, to that end, I intend to highlight the Center for Food Safety and Applied Nutrition's involvement with this issue and then catalog all the information that we found that relates latex allergy directly to food safety.

    As Dr. Slater