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]{.underline}
>
> **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]{.underline} [SESSION]{.underline}
>
> \[1:00 p.m.\]
>
> 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 pointed out this morning, there is a number of adverse
> reactions that can happen as a result of wearing latex gloves. One is
> irritant contact dermatitis. Irritant contact dermatitis is a
> breakdown of the skin that is exposed to the NRL. It is confined to
> the area of contact with the NRL glove, and it is not mediated by the
> immune system.
>
> Delay type hypersensitivity reactions are T-cell mediated reactions.
> They are usually caused by chemicals in the glove that are used in the
> compounding of the rubber into a useful product, for example, it is
> not uncommon for people to react to the accelerators that are used to
> hasten the vulcanization or the cross-linking of the rubber polymer in
> the natural rubber matrix.
>
> Now, although together, these two reactions comprise perhaps 80 to 90
> percent of all the adverse reactions associated with latex gloves,
> they are not the reactions that are the subject of this meeting.
>
> The reactions that are the subject of this meeting are the immediate
> type hypersensitivity reactions. Immediate type hypersensitivity
> reactions are IgE mediated and therefore they are systemic reactions.
> They are a reaction to certain proteins that are found in the natural
> rubber, and they present with symptoms such as urticaria or hives,
> rhinoconjunctivitis, asthma, and sometimes anaphylaxis.
>
> They require previous sensitization, usually prolonged cumulative
> exposure to the natural rubber latex proteins, although genetic
> predisposition does play a role in sensitization.
>
> So, for the rest of this meeting, anytime we refer to latex allergy,
> it is these immediate type hypersensitivity reactions that we are
> referring to.
>
> Now, because FDA\'s involvement or Center for Food Safety and Applied
> Nutrition\'s involvement with this issue begins with the food code, I
> am going to describe briefly what the food code is.
>
> The food code contains FDA\'s recommendations for safe food handling
> and sanitation procedures that FDA offers for use in the retail food
> industry. It is offered to state and local agencies as guidance in the
> hopes that they will adopt it. This guidance is neither federal law,
> nor is it federal regulation, however, FDA does encourage the states
> to adopt the food code as part of their state codes.
>
> The food code is developed in cooperation with state and local
> governments, consumers, industry, and academia at the Conference for
> Food Protection. The Conference for Food Protection has in place,
> procedures that ensure that everyone who has a stake in setting food
> safety standards has a chance to be heard before any changes are made
> to the food code.
>
> Now, FDA\'s involvement probably begins in 1993 or the Center for Food
> Safety\'s involvement begins in \'93, when FDA added Section 3-301.11
> to the food code. This section of the food code recommends that bare
> hands contact with most ready-to-eat foods be prohibited. It further
> states that suitable utensils should be used instead of bare hands.
>
> This provision was added to the food code as a result of a number of
> outbreaks of foodborne illnesses that resulted from the transmission
> of pathogens from the food worker\'s hands to the food, and was
> intended to address that issue.
>
> This provision was not adopted or accepted by many states initially,
> but in time, more and more states began to adopt it, and by 1997, many
> states had adopted the provision as state law, and this resulted in a
> noticeable increase in the number or in the use of all kinds of food
> service gloves. Latex happened to be an alternative to other materials
> for food service gloves.
>
> The Center for Food Safety, this should say, first learned that latex
> food service gloves were a concern to many people who have been
> sensitized to latex allergy in the occupational setting.
>
> We learned that the concerns centered around the possible migration of
> allergenic proteins to food as a result of contact with these food
> service gloves, and the subsequent possibility that such proteins
> could cause an allergic reaction in consumers when that food is
> consumed by someone who is latex allergic.
>
> By this time, however, the subject of latex allergy, as it relates to
> medical gloves, had been the subject of review in the Center for
> Devices and Radiologic Health, as you know.
>
> They made several findings which are important and relevant. Those
> include that certain NRL proteins can be allergenic, NRL proteins bind
> to the cornstarch that is used as donning powder, and that aerosolized
> donning powder is allergenic and may be an agent for sensitization of
> non-allergic individuals, although again, usually, prolonged chronic
> exposure is required for sensitization.
>
> So, as a result of the expressed concern about the use of latex food
> service gloves, the findings of the Center for Devices and Radiologic
> Health, and the recommendations of the National Institute for
> Occupational Safety and Health, the Occupational Safety and Health
> Administration, the American Academy of Allergy, Asthma, and
> Immunology, who all recommended that food service workers not use
> latex food service gloves, FDA published a caution in the food code
> that basically stated that information relating to latex allergy
> should be considered by those retail food establishments who were
> choosing food service gloves.
>
> At the same time, FDA began gathering information that relates latex
> allergy directly to food safety.
>
> In 2002, FDA reported its findings to the Conference for Food
> Protection, and the findings that we reported at the Conference for
> Food Protection won\'t be different from the findings that we are
> reporting here today, so I won\'t tell you exactly what we said to
> them, we will get to that soon enough.
>
> FDA also indicated to the Conference that natural rubber is the
> subject of federal food additive regulation, and therefore, the safety
> of such use is most appropriately reviewed under Section 409 of the
> Federal Food, Drug, and Cosmetic Act, and not within the context of
> the food code.
>
> Now, we get to the interesting part, data that relates latex allergy
> directly to food safety. This does not include several things. One, it
> is important to acknowledge that there is an enormous body of
> information, scientific information relating to latex allergy, and one
> author was able to show that the number of publications, scientific
> publications relating to latex allergy increased exponentially during
> the 1990s.
>
> However, most of that relates to occupational use of latex gloves in
> the clinical setting, and for our purposes, it is important to
> separate those uses from the food safety issues, so I won\'t be
> presenting the bulk of that information that relates to worker
> exposure and occupational safety.
>
> In addition, when we review the safety of a food additive use, as Dr.
> Shanklin stated, under Section 409 of the Federal Food, Drug, and
> Cosmetic Act, we are required to consider the safety of the additive
> itself, and we don\'t have authority to consider risks and benefits
> relative to alternative materials.
>
> If an alternative material is safe, if we have evaluated it and
> determined it to be safe, and latex is safe, one can\'t be more safe
> than the other. They both meet the safety standard. So, information
> relating to risks and benefits associated with alternative materials
> really won\'t answer any questions about the safety of latex in this
> use, so I won\'t be presenting any information about vinyl gloves or
> nitrile gloves, just the information that relates to latex.
>
> We have a number of publications from the literature. Most of them are
> Letters to the Editor describing either case reports or experiments
> that were done that are not exactly the quality in terms of design and
> control of the experiments that you would like in a study that you
> would use for a decisionmaking process.
>
> However, this is one paper that is a full research report. It is
> reported in Allergy Asthma Proceedings in the year 2000. Dr. Beezhold
> is in the audience today, and I think he will talk more about this
> later on today.
>
> The authors reported study to determine whether natural rubber
> proteins can be transferred to foods following contact with latex
> gloves. The results of this study were that the direct transfer of
> natural rubber protein to cheese was visualized using a modified
> immunoblot method. That is, they took a latex glove and they applied
> it to a slice of cheese, and then used an immunoblot method to lift
> the fingerprint and visualize the fingerprints that represented the
> latex protein that was transferred to the cheese.
>
> Another thing that they did in this paper was they measured the direct
> transfer of natural rubber protein to lettuce, and they quantified
> that using an inhibition ELISA specific to natural rubber.
>
> The results of their study, one of the conclusions was that an average
> of 50 nanograms of protein was found to transfer per finger contact.
> These are the authors\' results, and the nice thing about a full
> research paper is that you get to see the context by which they
> arrived at those results.
>
> The context is shown on this slide. The authors report using a
> specific lot of gloves with an expiration date of 1993, which means
> that they were manufactured well before 1993. During the 1990s, it is
> important to note that the protein content in such gloves dramatically
> decreased.
>
> This is evidenced by, among other things, Table 1 in that publication,
> which shows the most recent powdered latex gloves that were examined
> by the authors had 33 times less protein in it than the gloves that
> they used for the transfer experiments.
>
> The newest powder-free gloves, that had an expiration date of 2003,
> had a total antigenic protein content below the detection limit of the
> method. In addition, the authors report that 80 percent of the total
> protein was on the inside of the glove.
>
> This is not unusual to have most of the protein on the inside of the
> glove for two reasons. One, as the glove is being cured on the mold,
> the aqueous part of the latex is being driven to the outside of the
> mold, and that is going to carry the water-soluble proteins with it.
>
> In addition, of those proteins aren\'t removed from the glove by
> extraction before the donning powder slurry is applied, the proteins
> can accumulate in the donning powder slurry. Then, when you apply the
> powder, it is possible for you to apply additional proteins at the
> same time.
>
> Well, the outside of the glove on the mold is the inside of the glove
> as you use the glove. The author reports that the experiments were
> done with such gloves turned inside-out to make it easier to detect
> the protein that transferred.
>
> These experiments demonstrate the physical possibility of detecting a
> transfer under certain circumstances, but those circumstances are
> different from what would be encountered in the use of a food service
> glove today.
>
> The next bit of information we found was published in the Journal of
> Allergy and Clinical Immunology. It was an abstract and subsequently
> published in the European Journal of Allergy as a Letter to the
> Editor.
>
> The authors described a double-blind, placebo-controlled challenge
> study with latex glove extract on patients allergic to NRL. The
> purpose of the study was to determine if latex-contaminated food can
> provoke an allergic symptom in an NRL-sensitized individual.
>
> The protocol was at 30-minute intervals, the subjects being identified
> as being latex allergic receive 10 ml of sugar water followed by 0.2
> or 0.5 ml of an aqueous solution NRL glove extracts.
>
> The results were that three of the test subjects experienced reactions
> to the challenge, and those reactions were pharyngeal itching and
> congestion, and one subject experienced dysphonia.
>
> That was all that was reported. Dysphonia could be anything from a
> generalized sensation of hearing impairment to a loss of hearing, but
> it wasn\'t explained in the report.
>
> They also reported that none of the four in the control group reacted
> to the challenge. Now, the four in the control group were four people
> who were not latex allergic.
>
> The positive responses were found at doses of 5 micrograms, 50
> micrograms, and 20 milligrams, and it would be interesting to compare
> the nature of these reactions and the dose with what could be arguably
> an exaggerated dose from the experiment that tried to quantify the
> amount of protein that does transfer to food. That is, these doses
> are, at the lowest, 100 times higher than what was found in the
> previous paper.
>
> It is also important to note here that three of the subjects who were
> latex allergic did not respond to an oral challenge of up to 50
> milligrams of latex glove extract.
>
> The next paper is the paper that came up earlier today. Printed as an
> abstract in the Journal of Allergy and Clinical Immunology, and
> subsequently in the Canadian Journal of Allergy and Clinical
> Immunology is a report on the oral desensitization experiments in NRL
> allergic patients.
>
> The patients were subjected to oral challenges beginning at does of
> 1/10,000th, the lowest skin prick positive concentration, doubling
> those doses every 15 minutes until the patients received the 2 mg dose
> of latex extract.
>
> Thereafter, the subjects ingested 1 mg two or three times a day. The
> authors reported diminished skin prick test response, and they also
> reported that all subjects returned to their jobs involving heavy NRL
> exposure without symptoms. They didn\'t say what heavy NRL exposure
> meant, but they did say that the workers were healthcare workers, so
> they were in a healthcare environment.
>
> The information may suggest that the ingestion of allergen does not
> necessarily induce systemic reactions in latex allergic subjects. One
> of the authors on this report is also Dr. Beezhold, so he may be able
> to comment more directly on that.
>
> Also, reported in the Journal of Allergy and Clinical Immunology in
> 2002, a case report of a patient who had anaphylactic reaction 10
> minutes after eating a doughnut at a shop that used latex food service
> gloves.
>
> The patient had previously eaten similar doughnuts at a shop that did
> not use latex food service gloves, and never had an adverse reaction
> to those doughnuts. The patient was then diagnosed with latex allergy,
> and he was also tested for the major ingredients in cream-filled
> doughnuts.
>
> The authors reported administering with consent piece of doughnuts
> obtained from the shop using latex gloves every 30 minutes until the
> patient experienced urticaria, conjunctivitis, and lip edema. They
> report that the patient experienced no symptoms upon consuming a
> doughnut obtained from the shop that did not use latex gloves.
>
> Based on this result, the authors conclude that the latex
> contaminating the doughnut was the cause of the original anaphylactic
> reaction. However, they did not measure latex in the doughnut that the
> subject reacted to, and other than testing for the major components
> that are generally in a cream-filled doughnut, they didn\'t establish
> that there wasn\'t there some other ingredient in the doughnut from
> the shop that used the latex glove that the child may have been
> allergic to.
>
> In the New England Journal of Medicine, 1999, healthcare was reported
> to have developed latex allergy after five years of using latex gloves
> in her work. The authors conducted double-blind tests where the
> patient was asked to drink orange juice that was stirred with a latex
> glove and on another occasion drink orange juice that was not stirred
> with a latex glove.
>
> The patient experienced allergenic symptoms within 35 minutes of
> drinking the orange juice stirred with the glove, and she was treated
> and the symptoms cleared. No symptoms were experienced after drinking
> orange juice that was not stirred with the latex glove.
>
> Howard Schwartz reported in the Journal of Allergy and Clinical
> Immunology in 1995, two patients who experienced severe reactions to
> food eaten at restaurants. In both cases, food handlers were said to
> have been wearing latex gloves.
>
> Both patients had long histories of allergies and both tested positive
> to skin prick tests with a crude latex preparation, and one had been
> previously diagnosed with latex allergy. The authors conclude that
> although the clinical experiences of the two patients could not be
> confirmed, it is suggestive that latex may be a hidden food allergen
> in this food.
>
> Nixon and Lee reported in the Medical Journal of Australian 2001, a
> healthcare worker with a history of eczema, hay fever, and asthma
> developed angioedema, bronchospasm within 10 minutes of eating in a
> restaurant. The patient was treated and had an uncomplicated recovery.
> The cause of the episode remained unknown.
>
> Several months later, she was diagnosed with latex allergy on the
> basis of a positive RAST, and after developing a skin reaction to
> latex gloves at work. Subsequent inquiry confirmed that the restaurant
> generally used latex gloves to handle salad, vegetables, and seafood.
>
> Adverse event reports. What I am going to say here is going to differ
> from what you got in your background report, because there was a
> mistake in your background report, so this is the part you need to pay
> attention to.
>
> CFSAN began receiving some adverse event reports of food mediated
> latex allergic reactions from consumers in 1999. A total of 79
> consumers contacted FDA in 2000 following placement of the name and
> address of an FDA contact on a web site run by the National Latex
> Allergy Network.
>
> Approximately 12 additional reports were received after 2001. This is
> the total of all the adverse event reports that we have gotten from
> any channel, so the question about how long our Adverse Event
> Monitoring System has been in place, I guess gets to the point were
> there adverse event reports that we missed in that system.
>
> That system had a predecessor. That system is relatively new, but it
> had a predecessor, and not all of the adverse events that FDA receives
> came in through those channels. This basically documents all the
> adverse event reports that we have received.
>
> The consumers reported their recollection of allergenic reactions
> followed by consumption of foods purportedly handled by food workers
> wearing latex gloves. These reported allergic reactions occurred over
> a wide period of time, most having taken place in the past 10 years,
> and all consumers reported developing latex allergy prior to
> experiencing what they believed was their first food mediated latex
> allergic reaction.
>
> Finally, there is the issue of cross-reacting food allergies. The
> appendix to your background report lists an awful lot of foods that
> have cross-reacting potential with latex-specific IgE.
>
> The cross-reactivity issue raises two very important questions. One is
> the possibility that the reaction was due to food that has
> cross-reacting potential to latex specific IgE.
>
> The second issue is to what extent could the reaction be due to food
> that has been contaminated by proteins from a different food that
> either has cross-reacting potential to latex specific IgE or to which
> the individual may already be allergic.
>
> Contamination with another food protein could simply result from
> handling one type of food that the consumer might have been allergic
> to before preparing that consumer\'s food, and then transferring that
> protein to the food prepared for the consumer who reacted.
>
> This brings us back to the charging questions. The questions that we
> are asking the committee to consider in light of that information are:
> Does this information establish a positive relationship between the
> use of natural rubber latex gloves in food service and allergenic
> reactions to food served in food establishments or sold at food
> markets?
>
> If that relationship does exist, what is the strength of it, and can
> it be shown to be causative? If a positive relationship has been
> established here in No. 1, and shown to be causative, can you suggest
> science-based options to mitigate food mediated latex allergy risks?
>
> If the current evidence is not sufficient to establish a relationship,
> what additional questions need to be addressed to adequately
> understand this issue?
>
> I will be happy to take questions.
>
> DR. DWYER: Thank you very much for your presentation.
>
> **Questions of Clarification**
>
> DR. DWYER: I have a question to lead off. I was puzzled in going
> through the list that you so kindly provided us of the various foods
> that seem to cross-react. I am not clear as to the botanical families
> of these various things, like celery, loquat, kumquat, kiwi, and so
> forth.
>
> I wonder if you or someone at the agency could give us a list of the
> botanical families of these various foods, so that we could see if
> they fall in any pattern.
>
> DR. HEPP: We can try to generate that information.
>
> DR. DWYER: Dr. Gaspari.
>
> DR. GASPARI: I have a question about the consumer reports to your
> office during 2000 and 2001. You said there were a total of 91 reports
> from consumers that they self-reported. They had knowledge of a
> registry? Tell me a little bit more about your registry for the
> consumer self-reporting of the food reactions that are postulated to
> be related to latex.
>
> DR. HEPP: At one point, the name of an FDA contact was put on the web
> site of the National Latex Allergy Network, and adverse event reports
> that people wanted to report would go directly to that contact person
> rather than through the Adverse Event Reporting System.
>
> Does that answer your question?
>
> DR. GASPARI: The next question, was there any follow-up interactions
> with those patients to verify whether they had been to an allergist or
> whether they were really latex allergic or not, or just whether they
> thought they are latex allergic, or whether they thought that latex
> gloves were being used in the restaurant? In other words, what
> follow-up contacts happened after these self-reported incidents came
> in to the Bureau, what kind of verification was done, and were any
> site visits made to restaurants to find out whether there were latex
> gloves actually being used in the restaurants or not?
>
> DR. HEPP: I think we have Carl Klontz in the audience. Carl was the
> contact person on the web site. He is probably the best person to
> answer that question.
>
> DR. DWYER: Would the committee be willing to have this gentleman come
> up and answer this question?
>
> DR. KLONTZ: My name is Carl Klontz. I am a medical officer,
> epidemiologist at the Center for Food Safety and Applied Nutrition.
>
> A little bit of history on this. As Mark said, about late 1999, we
> began receiving reports spontaneously at the Food and Drug
> Administration from consumers who reported experiencing reactions that
> they attributed to food eaten at retail food establishments wherein
> latex gloves had been used.
>
> There was some frustration and concern among these people that there
> was no single reporting site in the Center for Food Safety where these
> reports could be sent, so I had volunteered to have my name and
> contact information put on the web site you have seen there.
>
> So, in 2000, about 79 reports came in directly to me as a result of my
> name and contact information being placed on that web site, and in
> about 2001, about 12 more. No, we did not follow up with site visits
> to the food establishments. This was strictly a system of receiving
> spontaneous reports or reports that came in as a result of the posting
> on the web site.
>
> I will say, though, that 88 percent of the 79 individuals, 88 percent
> had indicated they had a positive RAST test, that they had IgE, that a
> physician had diagnosed not only latex allergy, but IgE antibodies to
> latex through the RAST test.
>
> There were a few that just had a clinical history compatible with
> latex allergy and then a couple with a positive skin prick test.
>
> DR. DWYER: Thank you.
>
> DR. GASPARI: Could I ask one more question?
>
> DR. DWYER: Yes, one.
>
> DR. GASPARI: When you analyzed those reports after you had information
> from these consumers, did you analyze them individually and draw some
> kind of conclusion as to whether this is feasible versus this patient
> is totally mistaken and this self-report has no validity? Did you
> place any value to their reports based on the information that you
> were able to get from them, and any medical records or basically
> whatever information that you had, or did you just record the reports
> and leave it as that?
>
> DR. KLONTZ: You have several complements to your question there.
> Number one is no medical records were obtained. We did not go back and
> obtain medical records. We did not verify, in fact, that physicians
> had made the diagnosis of latex allergy. We took what we received in
> the reports.
>
> Now, having said that, let me tell you about the population that
> reported to us, because I personally put a lot of credibility into
> this group, this cohort of individuals. A highly educated group of
> individuals. Most of them were healthcare workers. They understand the
> biology of allergies in general and latex allergy in specific.
>
> About half of them were R.N.\'s. They were dentists, they were
> physicians, allied healthcare workers composed about 85 percent of the
> cohort, so a highly educated group of individuals.
>
> The other thing I would like to say is that we have to qualify these
> results. This is a case series. In the world of epidemiology, that is
> at the bottom in terms of persuasiveness. We don\'t have
> case-controlled studies, we don\'t have clinical trials, that\'s for
> sure, don\'t even have cohort studies. Nevertheless, my own opinion is
> that this is a highly believable groups of individuals.
>
> Can I prove it? No, I don\'t have the kinds of studies, but I put a
> fair amount of merit into this group.
>
> DR. DWYER: Thank you.
>
> Dr. Torres had a question. I think it was for Dr. Hepp, though.
>
> DR. TORRES: On the study report from Beezhold, I haven\'t read the
> full paper, but you said it was lettuce and cheese, there was the same
> amount, it didn\'t matter what the substrate was?
>
> DR. HEPP: I think with the experiments on cheese, they used a method
> that they didn\'t quantify the amount of protein that transferred. The
> method that they used to detect the protein on the lettuce, that
> transferred to lettuce, they could quantify the amount. So, 50
> nanograms per finger touch would refer to the amount of protein that
> transferred in his experiments to the lettuce.
>
> DR. TORRES: The same study, you said that reversing the glove was
> required to do the study meaning that if they had done it the other
> way around, it would have given no response?
>
> DR. HEPP: There is a good chance that the amount of transfer would
> have been below the detection limit. I don\'t know that for sure, but
> you are going to be approaching the detection limit of the method. In
> the paper, it states that he did it to facilitate detecting the
> protein.
>
> DR. DWYER: Thank you.
>
> Mr. Scholz, you had a question?
>
> MR. SCHOLZ: Yes, thanks. Back to the self-reporting, you had cases in
> \'99 and 2000 and 2001, there is nothing in 2002?
>
> DR. KLONTZ: The web site, as I understand it, was disbanded in 2002
> because of a lack of funding, so, no, that current channel does not
> exist for further reports.
>
> MR. SCHOLZ: Was there any follow-up inquiries to where they said they
> were at restaurants or where they thought\--I mean on your end, did
> you follow up to confirm where they were, or it was just on their
> recall?
>
> DR. KLONTZ: No. Again, all the information was on their recall. The
> vast majority indicated that the reactions had occurred in association
> with consuming food at restaurants.
>
> DR. DWYER: Thank you.
>
> Dr. Johnson had a question.
>
> DR. JOHNSON: I just wanted to clarify about the web site, it wasn\'t
> clear to me. Your name and contact information was on the Latex
> Allergy Network.
>
> DR. KLONTZ: Yes.
>
> DR. JOHNSON: Not an FDA web site.
>
> DR. KLONTZ: That\'s correct, it was not an FDA web site, it was the
> National Latex Allergy Network, my name, telephone number, and
> address.
>
> DR. JOHNSON: Thanks.
>
> DR. DWYER: Thank you.
>
> Dr. Hamilton and then Dr. Taylor.
>
> DR. HAMILTON: Again, the self-reporting. All the reactions that were
> reported to you occurred during the short time interval after
> which\--occurred in that year of, what, 2000 basically or 1999, 2000.
> In other words, no reports came to you of previous experiences back in
> the mid-1990\'s, because that is when the latex allergen levels and
> gloves were really super-high, and it is at least a gestalt that it
> began dropping down about the time that you started collecting
> reports.
>
> So, if anything, I would have expected that you probably would have
> gotten the tail end of a lot of the reports that might have occurred
> and might have been reported to you.
>
> DR. KLONTZ: Right. One of the deficiencies of the questionnaire is
> that we did not ask specifically what the dates of each of the\--in
> many cases, multiple reactions that these individuals experienced was,
> so I have no tabular list of a chronology there in terms of dates of
> reactions for any given individual, however, the median number of
> reactions reported by this cohort was 6 in their lifetime, ranging
> from 1 to actually, one person more than 100 episodes, which she
> believed had occurred of this sort of reaction, but I don\'t have the
> dates. It was a deficiency of the questionnaire.
>
> DR. HAMILTON: Did you get information on other allergenic
> specificities that the individual was sensitized to, such as other
> foods, or not?
>
> DR. KLONTZ: Yes, we asked about food histories both before and after
> development of latex allergies; prior to developing latex allergies,
> about 28 percent of the cohort said they had pre-existing food
> allergies.
>
> Once latex allergy came to their attention via diagnosis or symptoms,
> that number jumped up very high, to about 70 percent indicated they
> had allergies to foods.
>
> DR. HAMILTON: How many individuals actually went back to the
> restaurant to confirm or validate that they actually had latex gloves
> in the restaurant?
>
> DR. KLONTZ: I can\'t tell you that. We didn\'t specifically ask that.
> The understanding on the basis of reporting was that they attributed
> the reaction to consuming food at a retail foods where latex gloves
> were used. A number of them indicated in a narrative fashion that they
> had called back after experiencing the reaction and documented or
> through a telephone call learned that indeed latex gloves were used
> there.
>
> DR. HAMILTON: Did they specify whether they were powdered and
> unpowdered?
>
> DR. KLONTZ: No, not to that level, no.
>
> DR. DWYER: Dr. Taylor.
>
> DR. TAYLOR: I have several questions for Dr. Hepp actually. You made a
> number of comments about various dosage levels of exposure to NRL from
> some of these case reports and studies, but is there a well-validated
> analytical procedure that can be used by investigators and researchers
> to determine the amount of natural rubber latex proteins in foods?
>
> I mean can we put faith in the numbers from the analytical procedures
> in several different laboratories where they have done with different
> methods that might not be comparable to one another directly?
>
> DR. HEPP: Different methods will be measuring different things. There
> are definitely certain standard methods, and those methods don\'t
> necessarily always measure the same thing. It is important to know,
> when you are reporting a number, the method that is used to determine
> that number.
>
> DR. TAYLOR: I just wondered if 5 micrograms by one method could be 50
> nanograms by another method.
>
> DR. HEPP: Sure. Dr. Tomazac is going to speak to this issue, I
> believe.
>
> It may be that they are not even measuring the same thing. In one
> case, they might be measuring total protein, and in other case\--
>
> DR. TAYLOR: Dr. Beezhold\'s experiment in particular seemed to be sort
> of a real world experiment, you know, handling the lettuce with gloves
> even though he turned them inside-out first, but the one where they
> stirred the orange juice with the glove seemed to me to be a little
> bit contrived because I could visualize that these proteins might have
> different degrees of solubility in different kind of materials, and
> that that could alter the level that might be found in the product.
>
> DR. HEPP: Like I said, most of the information that we have available
> is not a part of a well-designed and controlled experiment, but this
> is what we have.
>
> DR. TAYLOR: Now, I have a question about the food codes. You mentioned
> the food code pretty prominently, so I am going back to the charge to
> this committee again. We are primarily charged to come up with
> recommendations about the use of natural rubber latex gloves, but are
> we also restricted to food service, because of the focus on the food
> code?
>
> DR. HEPP: I guess I wouldn\'t say that you were even restricted to
> gloves. What I have reported is information that relates to gloves
> because that\'s the information that is available. People are looking
> at gloves. But most of the background report is not referring
> necessarily to gloves, but the use of natural rubber in contact food.
>
> DR. TAYLOR: Gloves could be used by food processing establishments in
> addition to food service establishments, so I am wondering why the
> focus is on the retail segment of the industry when a processor might
> use the very same gloves at a different level.
>
> How do I know if I am an affected individual and go to a restaurant
> and get sick, that it was because the restaurant used the glove or
> maybe it was because the pre-chopped lettuce came in a great big bag
> and the processor of that lettuce used the latex gloves?
>
> DR. HEPP: You absolutely don\'t. The only reason I brought up the food
> code is to basically the issue of latex allergies and food service
> gloves started with the food code, but we are interested in any
> information that relates for use of natural rubber, and it is actually
> natural rubber allergy, although it is often referred to as latex
> allergy, that relates to food safety.
>
> So, yes, any way that impacts the foods processing industry, as well
> as the retail food and food service industries, it is all on the
> table. The reason we keep focusing on food service gloves in the
> retail establishments is that that is the information that we have.
>
> DR. TAYLOR: I appreciate that. Thank you.
>
> DR. DWYER: Dr. Downer had a question.
>
> DR. DOWNER: Back to self-reporting. I wanted to find out if your
> questionnaire addressed whether or not there were any family members
> that had an allergy. I am trying to get at possible genetic
> redisposition.
>
> DR. KLONTZ: Was the question whether there are family members?
>
> DR. DOWNER: Whether or not your questionnaires for the self-reporting
> indicated whether or not family members or the persons reporting, if
> they had any problem with possible allergies.
>
> DR. KLONTZ: No, the questionnaire did not.
>
> DR. DOWNER: You did not ask that question.
>
> DR. KLONTZ: No.
>
> DR. DWYER: Thank you.
>
> Let me just go around the table one final time before we finish.
>
> Mr. Scholz, any questions? Dr. Johnson, Dr. Gaspari, Dr. Blumberg.
>
> DR. HAMILTON: I have a question. Is it correct that Dr. Beezhold will
> be giving a presentation or not?
>
> DR. DWYER: Yes.
>
> DR. HAMILTON: Excellent. I will wait until then.
>
> DR. DWYER: Dr. Fischer, any questions? Dr. Torres.
>
> DR. TORRES: I am thinking about the comment made by Dr. Taylor about
> the difference between food service and food processing. One
> difference I can imagine would be that in the food service
> environment, the worker may use a glove on a limited volume of food,
> while in a processing environment, the worker may use on a much, much
> larger volume of food, therefore, whatever protein was found on the
> glove get much more diluted in the mass of food, and therefore, being
> less of a problem, but without having data to show it, it is just a
> belief at this point.
>
> DR. DWYER: Dr. Hamilton.
>
> DR. HAMILTON: I have one last question. How do you deal with the issue
> that it has been shown, to the best of my knowledge, but bananas in
> the United States are actually taken to a site where they are gassed
> with ethylene gas, and in the process of maturing the bananas, a
> protein, cross-reactive with natural rubber latex, Hevea, Hev b 6
> related protein actually is created or developed in the banana,
> whereas, the child can eat a banana from Brazil that is not processed
> in this way, a latex allergic child can eat a banana from Brazil, but
> not a banana from America, and a person who also has a cross-reactive
> sensitivity to the components Hevean, which is cross-reactive with
> banana, the component of banana.
>
> So, the question is how do we deal with the development or the actual
> production of a cross-reactive allergenic protein by the distributor
> that really doesn\'t relate to natural rubber latex gloves, but is
> clearly a problem to the latex allergic sensitized individual.
>
> That is an issue we are not dealing with, of course, here, but does
> that fall at all within the realm of the food code issue that we are
> dealing with? Am I making myself clear or not clear?
>
> DR. HEPP: I think you are, and I think the place to begin dealing with
> a question like that is gathering information, understanding the
> problem.
>
> DR. DWYER: Thank you. Any other questions? Is everybody finished?
>
> What we are going to do now, we have I think some good arrangements.
> We are going to take a short break, 15 minutes. We will have Dr.
> Tomazac and then Dr. Beezhold has kindly agreed to speak today, so we
> will have them and ask questions and then we will be finished.
>
> Tomorrow, what we are trying to do, Mr. Bonnette is trying very hard
> to move some of the other speakers up a little bit, so that we can
> have some time for deliberations when our two members, who otherwise
> would not be able to participate, will be involved.
>
> I think that will be very helpful because we really need everybody\'s
> wisdom around the table. So, 15 minutes, we need to get back here in
> 15 minutes, which is just 3 o\'clock according to my clock.
>
> \[Recess.\]
>
> Is it a problem tomorrow morning to start at 8:00 rather than 8:30 for
> anybody? We will revisit that but, basically, we will probably start
> at 8:00. This afternoon, we will go through Dr. Tomazac who can come
> up to the podium now. The second speaker will be Dr. Beezhold. We have
> kindly also got Mr. Heumann from the Oregon Department of Health
> Services. So this is a big help.
>
> Now, for dinner, you are on your own tonight. One of the things that
> we need to be careful of is not to discuss committee business except
> when we are here together. Some of us are going to dinner at 6:30 and
> if anybody wants to come and talk about bad football teams like the
> University of Wisconsin or Vermont and its various laws, whatever, if
> you want to talk about things other than food and drugs, let us know,
> and we will arrange to make the reservation for more. But no committee
> business will be discussed so that we don\'t violate the Federal
> Committee Act, or whatever it is called.
>
> At this point, we are going to turn back to our deliberations and hear
> about progress in the management of natural rubber latex allergy and
> its impact on food safety with Dr. Tomazac.
>
> Thank you for coming and doing this, Dr. Tomazac. She is also at the
> Center for Devices and Radiological Health.
>
> **Progress in the Management of NRL Allergy**
>
> DR. TOMAZAC: Good afternoon, whoever is still awake. It is very hard
> to be one of the last speakers because it looks to me like everything
> has been said already that I am planning to say. But I hope I will be
> able to, even if I will be a little bit redundant, to give a little
> bit different angle to what I am going to say.
>
> You heard a nice overview of what is latex allergy and why did it
> develop and how did it develop. Also, you had a number of
> presentations that clearly show you that FDA was actively involved in
> this process of trying to resolve this issue.
>
> FDA, and actually I am really talking about CDRH at this point in
> time, has been involved in various ways, as you heard, education and
> methods development and guidance documents and regulations. Certainly,
> that was a very important part of the progress, but the most important
> progress came from clinical and basic research because they told us
> what is involved in latex allergy, what are the allergens and how can
> we handle that.
>
> So I think we are grateful that we have this huge amount of data that
> can be used to make the changes because industry was also actively
> involved.
>
> Now, when we are discussing the issue of possible food contamination
> with latex proteins, it is very important to keep this in mind, what
> has been the situation and conditions at the time when latex allergy
> became a problem and when actually, transfer of the proteins from
> latex glove to food became a concern.
>
> In decision process making, it is very critical to include present
> status of the situation, what do we have now on the market and where
> are we going from there.
>
> The main things I will be talking about protein levels and powder
> levels. You also heard about that, but I will give you a little bit
> more details how they changed through years and, of course, that had
> effect on the prevalence of NRL sensitivity, and I will show you a
> little bit about that, and then also summarize technology that has
> been developed and different actions that have been taken through the
> years to actually help these changes to substantiate and also, among
> other things, the type of the glove that is being used today is
> different than what has been at the time when we didn\'t know anything
> about latex.
>
> Protein levels on the gloves were extremely high at the time when
> actually the use of gloves skyrocketed in the few years after the
> Universal Precaution Act and other things, and I tried to summarize
> just a few papers that actually through the years used the same method
> for measuring proteins, so at least we can compare this.
>
> If you look at the level that has been reported in \'93, which
> probably includes gloves at that time and earlier, was extremely high,
> and then you could see steady trend of protein levels going down. If
> you look at this two last studies where both of them are actually
> reported in the ASTM minutes because it was ASTM-associated study,
> studies were done in many labs on the same samples and they clearly
> indicate the drop in protein level in gloves that are presently
> marketed.
>
> With powder, there was also similar situation. At a time when the
> whole issue started, we had no controls of how much powder should be
> or was on the gloves. There were no methods also to measure that, and
> no regulations to control it.
>
> So, for example, we did one survey in our laboratory in the
> mid-sixties, and I saw the gloves, like some surgical gloves that had
> up to 600 milligrams of protein per glove, and this is a huge amount
> of protein.
>
> But that also changed because in the meantime, what we did, I mean
> ASTM developed method for measuring the powder level, and based on
> that, once when we had the method, ASTM could develop specifications
> for what should be a limit for powder on the gloves, and that is
> actually included in one of the ASTM standards.
>
> With this in mind, and also the large body of literature that
> indicated how bad powder can be, the level decreased, and also besides
> the lower level, manufacturers developed a number of technologies that
> can reduce or completely eliminate donning powder and some of them
> were mentioned, like chlorination or coating or whatever, but donning
> is there, and the powder doesn\'t have necessary to be present.
>
> With these changes that I just mentioned and the main culprits, which
> is protein and the powder, we also see clearly a decrease in the
> prevalence of latex allergy. This is very hard to document well
> because several people mentioned this morning the studies are done in
> different ways, studies include different populations of people, and
> also they use very different criteria to say what is allergy, what is
> not allergy.
>
> Now, if you notice maybe a little difference in the numbers between
> these and what Jay Slater presented this morning, that is because this
> is true allergy. I did not include any studies where serum antibodies
> was the only parameter, because that has been discussed also how
> unreliable this can be as a sole criteria for determining sensitivity.
>
> So, we are really having a nice trend and I am sure or I hope the
> trend will continue.
>
> DR. DWYER: Before you go on, could you please say what that is based
> on then, it is based on symptoms, signs, or is it based on\--
>
> DR. TOMAZAC: This is only related to healthcare workers and how this
> goes usually when they study healthcare workers, the first thing is
> they have symptoms, so medical history is usually number one, and
> then, of course, they are skin tested and then they have a serum test,
> so basically, allergy is confirmed with all these three symptoms, and
> then there are situations where actually you may find discrepancy
> between skin test and serum antibodies.
>
> This is due to the mechanism of how the allergies develop and stage in
> which sensitization is, so there are other tests that can apply, which
> is wear test and inhalation challenge test that actually Dr. Hamilton
> really worked hard on developing kind of standard procedure for that.
>
> So, basically, all these positively confirmed cases of latex allergy.
> So, now, how does that reflect to food contamination? I think when we
> discuss this issue, there are two main questions that we need to ask
> ourselves, how serious the problem indeed is, and how would these
> improvements in gloves today affect our thinking and our possible
> actions regarding to that.
>
> Why is the problem to know how big the problem is, the main issue is
> cross-sensitivity with other allergens. Now, you also heard a lot
> about that, but let me just say that most of the NRL, I mean of the
> latex sensitive individuals diagnosed as sensitive, they had other
> allergies, too, because as we know, genetic setup is very important
> factor in developing of allergies, so frequently, when someone has an
> allergy, it is actually predisposition and can easily develop other
> allergies.
>
> In latex sensitive population, there is a very high percentage of
> those who have a food allergy, and Dr. Klontz said that his
> questionnaire indicated 70 percent, and I think that some other
> studies are close to that.
>
> So, this is two-way street actually and most of the studies start with
> latex allergy and then they detect food allergy. I don\'t think that
> there are many studies or any that I am aware of that look for food
> sensitive individuals and then test for latex allergy, but this, too,
> phenomenon clearly associated with each other.
>
> Now, the similar thing is with reactions to supposedly contaminated
> food. Now, when there is a reaction, it is very hard to say is that
> reaction to ordinary component of the food or it is reaction to
> contaminant by handling with latex gloves.
>
> The only way how that possibly could be determined is to have these
> individuals who experience such reactions to really test them very
> carefully afterwards for all kinds of related food allergens as for
> latex allergen.
>
> From the reports that we heard from Mark Hepp and actually from Dr.
> Klontz, none of them actually provides these details. None of these
> patients have been tested subsequently for all kinds of food except
> the only testing was that in a doughnut shop, but as Mark said, there
> would have been other things besides these three basic protein
> sources.
>
> So, how hard it is I will just mention one anecdotal case, but it was
> highly publicized several years ago, and it was featured on 20-20. I
> think that some people will remember that. But this was a lady who I
> think was a healthcare worker and was highly sensitive to latex and
> aware of that.
>
> She started to avoid latex completely, and she did that successfully,
> and then one evening before going to bed, she ate a banana and
> experienced severe anaphylactic shock. So I think that indicates very
> clearly how cross-reactivity may be a very dangerous issue.
>
> So, now I would like actually to summarize things, actions, and
> activities that have been already done in order to help this whole
> issue of latex allergy to be reduced, minimized or resolved. There are
> different kinds of documents that exist today, and some of the
> documents are clearly informative and educative for consumer\'s
> safety, and besides the Medical Alert that our center issued right in
> the beginning of the whole thing, there are other documents that this
> is NIOSH Alert which was issued several years ago, and then Academy of
> Allergy issued their own position paper, and then OSHA issued a
> Technical Bulletin that I think is going to be revised and a new
> version will come out shortly.
>
> But anyway, all these three documents are similar in the sense that
> they all warn people to exercise caution when they use latex gloves
> and as Jay said in the morning, for those who are latex sensitive, the
> only way of preventing reaction is avoidance, avoidance, and
> avoidance.
>
> But for those who are not sensitized and they don\'t have clear
> indication that they may be sensitized, then, all the documents
> recommending use of low powder or no powder and low protein gloves, so
> in this respect, they are very similar.
>
> So, this type of a document, of course, had effect on the public, and
> here I tried to summarize a little bit of the market analysis that we
> have been using for our documents and for our proposed regulation. In
> the first column, you see how use of gloves in the United States has
> grown tremendously, and it is still going up and now with the threat
> of bioterrorism, I think it is going to go up again quite a bit.
>
> But look at the shift, how it is occurring from powdered gloves, latex
> powdered to non-powdered, and also increase in use of synthetic
> gloves. This is clear trend and I hope that this trend will also
> continue, so that everybody can use the glove, which is safe or
> relatively safe, and proper for the particular use.
>
> Besides this advisory document, we also have other documents that can
> help achieve these goals, and this is, as I said, we develop now
> standard methods for both powder and protein measurements, so there is
> good control of the amount there is on the gloves.
>
> We also have this ASTM specifications now for both protein limits and
> powder limits, so this is recommendation, of course, but we hope that
> it will be followed.
>
> Interestingly, there are also documents that actually are specifically
> designed for using the gloves in the food services and food
> processing, and this is a recommendation from NSF, National Sanitary
> Foundation, and the other one is just being developed by ASTM, is ASTM
> standard for specification for gloves in the food service.
>
> I can say that both of those documents are again in a way similar.
> They both are recommending the high quality gloves to be used in food
> service and actually they recommend that food service gloves should
> meet the criteria for medical gloves.
>
> I hope that ASTM one will be finalized relatively soon and also, as
> Dr. Stratmeyer mentioned before, in our proposed regulation, we did
> propose labeling\--I mean not propose\--we would require the labeling,
> but we would recommend also powder and protein limits in conjunction
> with the labeling.
>
> So, now, in conclusion, I think I can say that in more than the 10
> years that we are dealing with this issue and with involvement of
> everybody who is involved, who actually was affected by the issue,
> which is consumers, manufacturers, regulators, medical community, they
> all participated in one or the other way to resolve the issue, and I
> can say that what we see now it is significant improvement in the
> quality of gloves, and I think that it was confirmed by Jay Slater in
> the morning, who said that indeed, there are less new cases of latex
> allergy now, and I spoke privately with a number of clinical
> laboratories or clinicians who confirmed the same thing, that the
> number of new cases is much less than it used to be.
>
> Now, that doesn\'t mean that our work is finished because I think that
> many of the improvements came up already in the anticipation of the
> new regulation, because proposed regulation was published in 1999, and
> it will come out one day, I am sure, and manufacturers wants to be
> ready when it comes, that they actually are already to the level that
> they think will be asked from FDA.
>
> So, that will ensure that trend continues, but I think until it is
> completely resolved, I think we should all hang in and help.
>
> Thanks.
>
> **Questions of Clarification**
>
> DR. DWYER: Thank you very much, Dr. Tomazac, for a very interesting
> presentation. Can you tell us the difference between\--just tell us
> what they look like at least\--those surgical gloves and the food
> handler gloves.
>
> It seems to me they would all order the same gloves in a hospital. I
> work in a hospital.
>
> DR. TOMAZAC: This is the same question as actually was raised this
> morning. If I am talking about surgical and examination gloves in the
> medical environment, then, surgical gloves are just a little bit\--may
> be heavier in the sense of latex. They have slightly different
> requirements, and they usually have a longer cuff, and because the
> surgeons have gloves on their hands for much longer time, that was
> tendency that they had much more powder than examination gloves.
>
> Now, examination gloves, I mean inside the surgical gloves, you have a
> very different glove because orthopedic gloves are so different than
> some other gloves, which I don\'t know much since I am not in a
> clinical practice, but examination gloves also vary tremendously. It
> depend on the manufacture and so on, but how is that reflected to food
> gloves.
>
> Again, this question, we cannot answer. Maybe someone tomorrow from
> industry will be able to tell you a little bit more.
>
> DR. DWYER: It certainly would be very helpful if someone, either at
> the agency or elsewhere, could show the committee the difference
> between these gloves. Perhaps everyone else on the committee knows it.
>
> DR. TOMAZAC: The question is if it can be done because, see,
> manufacturers may send the same glove to hospital and sell it on the
> consumer market. They may sell a less good quality, but they also may
> make special gloves for consumer use, and we really cannot get this
> information.
>
> So, what has been used so far, it is hard to say.
>
> DR. DWYER: Thank you.
>
> Dr. Torres.
>
> DR. TORRES: Have there been any surveys on what the level of
> compliance with recommendations of products on the market? Since your
> expertise of your agency is on medical application, at least in the
> medical applications.
>
> DR. TOMAZAC: As far as I know, any glove that is on the market, and
> it\'s labeled as medical glove, has to meet requirements of the
> medical gloves. If it is not, I think our compliance usually makes
> inspection from time to time, and if something\--
>
> DR. TORRES: I mean specifically about powder and protein, because
> those have recommendations at this point.
>
> DR. TOMAZAC: Up to this point, there was no strict recommendation. The
> only recommendation that we had is if the manufacturer wanted to label
> a level of protein, they can, and also because of the limitation of
> the standard method, we also said in that guidance document that the
> lowest level they can label is 50 micrograms/gram of latex, because
> that was the limit of detection of the method.
>
> What we have observed on the market were gloves that said this product
> has less than 50 micrograms, which means they could not detect any
> proteins on their gloves, but any other gloves, we never saw any other
> number on that box, and they were not required to label, they just get
> this option. But we did not propose any limits on protein or powder at
> the same time.
>
> DR. GASPARI: I have two questions. The first one is related to the
> data slide and the trend in glove use in the U.S.A. In 1997, you have
> synthetic gloves representing about 10 percent of the total number of
> gloves being sold in the U.S. or in use, I guess, and in 2003, it is
> up to about 33 percent.
>
> DR. TOMAZAC: No, no, this is the billions of gloves. The first column,
> right?
>
> DR. GASPARI: No, the total would be 33 in 2003.
>
> DR. TOMAZAC: Billion.
>
> DR. GASPARI: Thirty-three billion.
>
> DR. TOMAZAC: Can we have that slide back?
>
> DR. GASPARI: If you add up synthetic and powder and powder-free, that
> is about 13.4. 13.4 over 33 is about a 33 percent of the market share.
> Is that right?
>
> DR. TOMAZAC: I don\'t have a slide in front of me.
>
> DR. GASPARI: So, my question is, is that one of the reasons that latex
> allergy is declining, because of an increased use of synthetic gloves
> as opposed to a safer latex glove, or in addition to the fact that NRL
> gloves that are being manufactured now because they are low protein
> and low powder, or safe.
>
> DR. TOMAZAC: I think that this is combined effect of everything
> because you have less protein and less powder on the latex powder
> gloves. You have a higher percentage of other gloves that are on the
> market that the people use, so when you combine this effect, that all
> results in a decrease.
>
> DR. GASPARI: My second question is related to why do latex gloves
> continue to be the dominant glove product, is it a result of expense
> and glove production and barrier function, so what are all the factors
> that maintain natural latex glove industry and in the medical
> community as the dominant glove?
>
> DR. TOMAZAC: Well, I think that the majority of glove users would
> agree that latex has some superior qualities that synthetic materials
> only recently tried to reach. Earlier, synthetic products were
> extremely inferior in comparison with latex, but now it is a slightly
> different situation, but ductility, elasticity, and barrier properties
> were superior in latex.
>
> DR. GASPARI: What about the cost of, say, a surgeon\'s nitrile glove
> compared to a surgeon\'s natural rubber latex powder-free glove?
>
> DR. TOMAZAC: If I am not wrong, I think the nitrile gloves cost even a
> little bit more, a little bit more at this point in time, but other
> synthetic gloves would probably cost a little bit less, but I don\'t
> know if anyone else\--I am getting yes. But I don\'t think that cost
> was the main factor, because really, there are some recent studies,
> for example, that show in-use durability of latex versus synthetic
> materials, which before we didn\'t know really exactly how much better
> they are, but durability is definitely better, and when you are
> talking about the surgeon who has one glove on for several hours,
> certainly, that is an important factor.
>
> But some nitrile gloves tend to be equally good now in durability and
> barrier properties.
>
> DR. DWYER: Thank you.
>
> Dr. Blumberg.
>
> DR. BLUMBERG: I may have missed it, but I am a little confused. Did
> you state what the NSF or the ASTM standards were for protein content?
> You indicated that a 2002 figure, the number was 140 micrograms per
> gram, and then you talked about standards of 50 microgram per gram or
> less.
>
> DR. TOMAZAC: I know it may be confusing. 50 micrograms or less refers
> to our first guidance that we issued in \'95, which says the
> manufacturers are allowed to put the level of protein on the box of
> the gloves, but any number below 50 micrograms is not valid because
> the limit of the standard procedure that we had then for measuring
> total proteins could not measure less than 50.
>
> So, that was that guidance document and, as I said, some of them
> followed this. The number that I showed you here, those are just by
> random taking gloves from the market, and right now we do not have any
> other regulation that requires level of protein to be certain number.
>
> What we do have, we have ASTM specification, which is actually a
> guidance document, and so now what can happen in the future, you know,
> you or we can say, okay, we will say that this is what it should be,
> or we said we do not agree with ASTM standard, but we want this and
> this limits if you want, but we may not ever say that we really want
> to limit.
>
> DR. BLUMBERG: Thank you. In terms of those standards, is it the total
> protein number or is it the amount that is actually soluble or
> transferable, and with that, is it again total protein, or does it
> really relate to the antigenic proteins?
>
> DR. TOMAZAC: Numbers that showed you, it is total protein, because
> this was the only standard method that existed at that time, and if I
> wanted to compare, I had to use just those data, otherwise, I cannot
> compare.
>
> Also method measures only those proteins that can be extracted, water
> extracted from the glove. So, is there any protein that can be
> released from the glove in some other way. I don\'t think that is the
> question, but, you know, because the latex is pretty solid material
> and the proteins from matrix usually don\'t come out especially in the
> normal use.
>
> DR. BLUMBERG: Just one more question at least from me. Again, a point
> of clarification. What is the difference between NIOSH and AAAAI and
> OSHA guidelines and the NSF and ASTM guidelines, are one use and the
> other manufacture?
>
> DR. TOMAZAC: NSF is, I don\'t know, maybe somebody else can tell me
> what the function of NF\--can I just ask Mark?
>
> DR. HEPP: The National Sanitation Foundation is a private certifying
> organization. They develop standards, and then they allow people to
> certify their products against their standards, kind of like
> Underwriter Laboratories, it is certified by that certifying body.
>
> The National Sanitation Foundation is not a government organization,
> it\'s a private organization, however, they like to develop their
> standards, so that those standards comport with any federal
> requirements.
>
> DR. BLUMBERG: But in contrast, for example, I mean does NIOSH
> recommend or develop guidelines for protein content or powder content,
> or is that just issues of prevention and avoiding use of the gloves?
>
> DR. TOMAZAC: No, NIOSH is actually recommendation and information for
> the consumers, what to do and how to do. Now, OSHA, you also heard
> about OSHA before. OSHA is regulating medical practice, but also other
> worker practice, whatever, and they actually are making rules, what
> should and should not be done in a practice.
>
> ASTM, on the other side, is the organization that develops standards,
> any kind of standards, so when these standards exist, it is asset that
> whoever needs them can adopt them and say, you know, we want you to
> use this one because we want to compare your data with someone else
> who uses the same method, so having a standard method is very critical
> for any kind of regulations that are made.
>
> Then, with us, who else was there mentioned, oh, Academy also, that is
> also recommendation. But when we bring a regulation, then, that is a
> mandatory thing, whatever we put.
>
> DR. DWYER: Thank you. That is very helpful.
>
> I might add that 33 billion, I thought at first you meant million, but
> I guess you do mean billion.
>
> DR. TOMAZAC: Oh, I do mean billion.
>
> DR. DWYER: I must say I am under on my glove consumption this year.
>
> DR. TOMAZAC: Actually, I don\'t have, like I think that like \'89 was
> 2 billion, and then it went up to this number.
>
> DR. DWYER: It sounds like a lot of gloves.
>
> Dr. Torres, any question?
>
> DR. TORRES: Sure. Is that consumption data or production data?
>
> DR. TOMAZAC: Consumption, yes, what has been sold on the market.
>
> DR. DWYER: Dr. Fischer, any questions? Dr. Hamilton.
>
> DR. HAMILTON: Could you remind us of what the ASTM specifications are
> that are proposed by the ASTM for both protein and powder?
>
> DR. TOMAZAC: Well, I guess I can even if it\'s not final. If I
> remember correctly, ASTM proposed, first of all, calculation of both
> protein and powder, not per gram of latex or per device, but per
> surface area, because as I mentioned before, orthopedic gloves are
> extremely thick and heavy, but the surface is the same as the
> examination glove besides the size of the cuff.
>
> So, it will be very unfair if you say you have to have so much powder
> per gram of latex. So, it was suggested by ASTM to start expressing
> the concentration or level on surface. Proposal was in this stage, the
> proposal exists already for three years, and at this point in time,
> the level of powder for examination gloves is 10 microgram per
> decimeter squared, and for surgical gloves, it is 15.
>
> Then, we also have for protein, it is also about 10. I think maybe
> Ko-Kee will answer that question better.
>
> DR. DWYER: If the committee doesn\'t mind, this gentleman speaking?
>
> DR. HAN: Ko-Kee Han from ASTM Subcommittee on Consumer Rubber
> Products.
>
> I just want to clarify it\'s milligram, not microgram. You were saying
> 10 microgram, 15 microgram.
>
> DR. TOMAZAC: It is not 10 milligrams\--oh, for powder, yes, I am
> sorry. Powder is 10 milligrams for examination.
>
> DR. HAMILTON: So, I am totally confused. What are the levels again?
> Can you repeat them?
>
> DR. TOMAZAC: Say it again.
>
> DR. HAMILTON: What are the levels again for both protein\--
>
> DR. TOMAZAC: For powder, it is 10 milligrams per decimeter squared;
> for examination gloves, 15 milligrams; for surgical gloves and 2
> milligrams for powder-free gloves, which I did not mention before.
>
> DR. DWYER: And the protein?
>
> DR. TOMAZAC: And the protein would be 10 micrograms, but\--there we go
> again. When we were talking about total protein, there was one method,
> the first standard that ASTM developed, and that standard, based on
> this standard, ASTM recommended 200 micrograms per gram of latex at
> that time.
>
> Then, in the meantime, there was another method developed which was
> immunological method. It\'s ELISA assay that measures only
> biologically relevant proteins, those proteins that can cause immune
> response in rabbits, so we call it total antigen assay.
>
> Now, because it is so different in the mechanism, also, the levels are
> different, and for this method, ASTM suggested 10 micrograms per
> decimeter squared. So, you know, this was developing standard that
> included new methods and new thinking, but that is where they are
> right now.
>
> But that doesn\'t mean that 200 micrograms per gram of latex is 20
> times higher value, so please do not be confused with that. This is
> actually somehow equivalent value because we did study where we
> compared the levels of a 30 gloves measured by this classical, old
> protein method comparing with the levels that we were receiving with
> ELISA method, and then determined what will be equivalent level for
> the new method.
>
> DR. DWYER: Thank you.
>
> Dr. Hamilton, do you have further questions?
>
> DR. HAMILTON: Yes. Is it safe to say, then, that the allergen on the
> cornstarch is not represented in any of the measurements that we do
> for extractable protein and antigen?
>
> DR. TOMAZAC: It is.
>
> DR. HAMILTON: So, therefore, what we are dealing with in terms of
> transfer of allergen onto food products or onto surfaces may not be
> represented in the measurements that we are doing of glove products.
> So, it is very complicated.
>
> DR. TOMAZAC: It is very complicated and actually I just did some
> studies on that, so I can say a few words. You know, the dry powder, I
> think maybe you have been doing something with the dry powder and
> trying to determine how much protein is when you take the powder
> directly from the glove.
>
> What I did, I took powder and the proteins away from glove, extracted
> everything together, and then separated powder, and I assumed that
> from this powder, some of the protein has been also extracted, not
> only from glove, but also from powder.
>
> Up to recent time, we really didn\'t have any way of measuring this
> protein on the powder. We only measured clear water extract of all the
> proteins. So, I tried to develop a little modification of this ELISA
> test, so that we could include that powder, and, yes, even after
> extraction, there is protein that remains on powder.
>
> This is not very uniform, like 5 percent, 10 percent. It can vary from
> glove to glove. So, yes, at this point in time, that is not included
> in standard tests, but it may be included in a revision if we decide
> to do so.
>
> DR. HAMILTON: So, the ASTM method or recommendations may ultimately
> include also a specification for absorbed allergenic component on
> donning powder basically.
>
> DR. TOMAZAC: Theoretically, it may because there is a technical
> approach to it.
>
> DR. HAMILTON: Thank you.
>
> DR. DWYER: Thank you.
>
> Dr. Johnson.
>
> DR. JOHNSON: I have a question about the doughnut study. It seems like
> a couple of speakers have dismissed this because of the possibility
> that there were different ingredients in the two doughnuts, that there
> was a difference other than the fact that the one was prepared with
> latex gloves, and the other wasn\'t, even though the authors say that
> they tested for every ingredient used in the preparation of
> cream-filled doughnuts, and the child was negative.
>
> So, my question is, do you know, was this a chain type of doughnut,
> such that you would anticipate that they would be using the same
> recipe, or was it just two\--and I realize it was done in Italy\--but
> was it just two random doughnut shops that they bought a cream-filled
> doughnut from?
>
> DR. TOMAZAC: As Mark said this afternoon, all of these studies are so
> deficient in the details, that it is almost impossible to\--you know,
> you have more questions than answers in each of these. Now, they did
> test for three major components, which is egg\--
>
> DR. JOHNSON: They tested for milk.
>
> DR. TOMAZAC: \--wheat and milk. But there are other ingredients in
> doughnuts, and we cannot discount that. It could have been latex, but
> there is no proof that it was latex, because not all the appropriate
> studies have been done to eliminate all the possibilities of other
> things.
>
> DR. DWYER: But if it was an Italian doughnut, it probably wasn\'t a
> Krispy Creme or Dunkin. We have our suspicions.
>
> Mr. Scholz, do you have any questions for our colleague?
>
> Okay. Then, thank you so much. We have really put you through the
> wringer, and you can go and eat a doughnut without gloves.
>
> Thank you so much for that.
>
> We will go then to our colleague from NIOSH, Dr. Beezhold, who has
> been asked to comment for us from his agency\'s perspective. Thank you
> for accommodating the committee, Dr. Beezhold, we are most grateful to
> you.
>
> **Invited Comment**
>
> DR. BEEZHOLD: Thank you and I appreciate the invitation to come and
> talk to you. I must clarify, though, as a new government employee, I
> am really not here as an official NIOSH representative since I have
> just joined the agency in the last couple of months, and the work that
> I am presenting, which you have all seen several times already, was
> done prior to joining NIOSH.
>
> So, I am not here particularly as a NIOSH representative, but I do
> have NIOSH clearance to come and speak, and in that light, my opinions
> probably don\'t differ that much from NIOSH\'s opinions.
>
> You have seen the NIOSH Alert, I don\'t know if you have a copy of
> that. You should all get a copy of that. But I would just like to read
> for you the recommendations.
>
> They have recommendations for employers and employees, and their first
> recommendation for employers is to provide workers with non-latex
> gloves to use when there is little potential for contact with
> infectious materials, for example, in the food service industry. So,
> they are speaking particularly to that.
>
> Then, to workers, they also say use non-latex gloves for activities
> that are not likely to involve contact with infectious materials, for
> example, food preparation.
>
> So, I think the NIOSH stance is fairly clear, and think I want to move
> on from there to go and present what I will do. I am going to change
> my comments a little bit and try to move through because a lot of this
> stuff you have heard already.
>
> But what we are really dealing with, here is a slide that
> demonstrates\--
>
> DR. DWYER: The NIOSH recommendations, I am not sure they were included
> in our handouts, were they? If there is a way to get a copy of the
> NIOSH recommendations xeroxed to our desks tomorrow morning, that
> would be helpful.
>
> DR. BEEZHOLD: What I am going to direct my comments to is primarily
> the cross-sensitization\--I mean for inadvertent exposures. You have
> heard about cross-sensitization to foods as a potential complicating
> issue here, but I am really talking about inadvertent exposures, and I
> want to just point out the insidious nature of this where a latex
> allergic person has no idea the food is prepared and potentially
> contaminated with latex, so they are very unknowledgeable in what they
> are being exposed to, so it is very inadvertent and oftentimes a
> surprise for them.
>
> This is just some of the things that we came across with inadvertent
> exposures where people that were wearing gloves at work and were
> contaminated with latex proteins, and they actually carried them home
> on their clothes and on their hands and their hair.
>
> But then we have also\--the study I am going to present to you is the
> one from transferring the allergens to the foods by food service
> personnel.
>
> These are the reports in the literature that directly look at
> anaphylaxis or two latex glove contaminated food, and you have already
> heard some of these studies more documented and with all of the
> caveats that these are deficient studies, all of them in all of their
> designs and the information that they present, but I don\'t think that
> that means that what we are looking at doesn\'t actually occur. If you
> talk to allergists who have patients that are very sensitive to latex,
> most of them will tell you that they have had exposures in
> restaurants.
>
> It is just that physicians don\'t go on to document this very often in
> the literature. So, what I want to do is show you the work that we did
> to show the direct transfer of latex protein. This was kind of
> stimulated by one of my colleague\'s patients, Gordon Sussman in
> Toronto, who has a huge patient population of latex allergic
> individuals, and he has got a large number of them that have reactions
> to food service gloves.
>
> This one was particularly severe, and this was a dental hygienist who
> had been diagnosed with latex allergy, she was skin test positive, had
> a clear positive history. She had no known food allergies except she
> was skin test positive to potato, and potato is one of the weaker
> cross-reactors with latex.
>
> She went to a restaurant, ate a salad, a lettuce salad, and within 30
> minutes, she went into anaphylaxis. She actually blacked out. She was
> given an Epi-Pen. She was taken to the emergency room. She recovered
> okay, but it was a very severe reaction. Her eyes even swelled shut.
>
> So, that stimulated us to look at can proteins really be transferred
> from gloves to the food, so we embarked on this series of experiments,
> and we looked at a sampling of gloves that we had in the laboratory at
> a time in order to do this demonstration.
>
> As was pointed out, these were gloves that as the time went on, their
> protein value fell, and I would only point out to you that this is the
> Lowry total protein, it is an ASTM standard. This is the ASTM
> inhibition ELISA. We are talking about levels of less than 200 here or
> what should be on the market, and less than 10 here should be on the
> market.
>
> We chose this particular glove with a value of 258 because it had a
> large amount of protein on, and what we were attempting to do was
> going to be difficult technically in the laboratory.
>
> I would also point out that you see this level of 258 back a few years
> ago, and we have talked about a distinction between medical gloves and
> gloves in food service. My laboratory at Guthrie had a vast experience
> of testing gloves on the market, and we probably tested every latex
> glove that has been manufactured or presented on the market at one
> point or another.
>
> Just recently, in June, received a glove for testing that was labeled
> a food service glove, and it had a value, a Lowry value of 10, 140
> micrograms per gram, far exceeding the level of the glove that we used
> in this particular experiment.
>
> What we do with this fingerprint assay, it\'s a visual assay, it is
> not quantitative, but it\'s a visual, and it shows you what happens
> when you contact a surface with a latex glove. These are the different
> gloves that we used for this particular paper, and we chose\--
>
> DR. DWYER: By the way, while you have got this slide on, where did the
> glove come from, was it sent in a brown paper envelope?
>
> DR. BEEZHOLD: These were gloves that we had on store in our Testing
> Service. I do have the manufacturer, and I have given you the lot
> number, but they were packaged gloves. That is another thing, that we
> made sure they were packaged in their original packagings, so they
> weren\'t altered at all.
>
> But what this test does is just gives you a visual demonstration, and
> it\'s a modified immunoblot. We touched the surface of a membrane that
> combined protein with the glove. Each one of those touches is for 3
> seconds. Then, we processed the membrane with antibodies that detect
> latex proteins.
>
> You can as you see darker fingerprints, that means there is more latex
> protein that has come off of the glove and onto that surface. We have
> done this with numerous gloves, and we get a very pattern like this.
> You can do it with gloves on the market today, and you will see
> protein transfer like this.
>
> This is essentially the situation that we are looking at on foods.
> This is a moist surface that is being touched with the glove, and that
> is what is transferring and that is what is there. You are leaving
> fingerprints of protein behind when you touch.
>
> Yes, the lower the amount of protein on the glove, the less of a
> fingerprint you will see.
>
> To address that point, or the criticism of our study is that we turned
> the gloves inside-out, and really, the only reason we did that was so
> that we had enough protein there to actually detect it on these blots.
>
> But this is just to look at some gloves. You will see here we have a
> couple of different exam gloves that we have done this fingerprint
> test with the outside of the glove, and you see protein, and with the
> inside, and you see a little bit more protein.
>
> Here is a comparison of some surgical gloves that are on the market,
> that we actually extracted either the inside or the outside surface of
> the glove, and quantitated it in the ELISA assay. You will see here
> that some of the gloves have more on the outside than the inside. Some
> of the gloves have more on the inside than the outside.
>
> What happens is it is manufactured dependent, it depends on how the
> manufacturer processes the glove, how they strip it off the mold. Some
> strip it off and turn it inside-out, so the high protein level goes on
> the inside. Some of them blow it off with air, and so the outside
> stays the outside, and you have a higher protein on the outside.
>
> So, it is really you can\'t make the statement that gloves have most
> of their protein on the outside, it is variable, it depends. In
> general, it is usually on the outside, and we looked at it, and about,
> I think in the paper I report something like 65 percent of the protein
> is on the outside versus the inside. But again, it is dependent on the
> particular glove that is being used.
>
> So, a food service person doesn\'t know that they have got a glove
> with a low protein on the outside and have all the protein on the
> inside.
>
> This is a visualization of what happens when you contact food and the
> reason why we used the particular glove that we used, because what we
> are doing is touching a piece of cheese, then taking that
> nitrocellulose membrane and putting it on the cheese to pick up the
> protein, and you lose a lot of protein in each of these steps and/or
> the cheese blocks the ability of the antibody to recognize it.
>
> So, we needed a fair amount of protein there to actually visualize it,
> but again, you can see here that the protein in this lane is cheese
> lane, this is the glove directly contacting the membrane, which is
> what has actually occurred.
>
> This is what we were able to pick up off of that cheese. Again, this
> is not quantitative, and our controls over here were vinyl gloves
> that, of course, produced no fingerprints of latex protein, nor were
> we able to pick any up off the cheese.
>
> DR. HAMILTON: Could I stop?
>
> DR. BEEZHOLD: Sure.
>
> DR. HAMILTON: Could you go back? You are saying transfer of latex
> allergen. So, did you use human IgE containing sera?
>
> DR. BEEZHOLD: No, not in this particular situation. This is a rabbit
> polyclonal sera.
>
> DR. HAMILTON: So, it really is latex antigen instead of allergen?
>
> DR. BEEZHOLD: Correct. We have done this same technique with patient
> sera and see the identical same thing. It is a weaker reaction, but we
> have confirmed that we see the same thing with human IgE to latex.
>
> So, the next step we did, we actually quantitated the amount of
> protein that was on latex, and we did this just by taking a piece of
> lettuce and contacting it with a gloved hand. The technician counted
> the number of contacts, you see down at the bottom, number of
> contacts, and this is the total amount of protein that we are
> detecting.
>
> This is done with the inhibition ELISA. Here, we are reporting what we
> actually found. With 100 contacts here, we found 8.7 micrograms of
> protein transferred from glove to the lettuce. In all of these cases,
> that transferred to about 70 to 80 nanograms per contact, per finger
> contact.
>
> This is glove-specific, so it depends on the amount of protein now,
> but in this particular glove, we had 70 to 80 nanograms, and I have
> put down here, as we reported in the paper and in other papers, we
> have patients that react on skin testing to a solution containing 70
> picograms per milliliter of latex protein.
>
> So, a drop containing 70 picograms per ml is put on a patient\'s skin.
> They are pricked through that drop, and they have a positive reaction
> to the latex proteins. So, it gives you an indication of about what
> kind of level a patient can react to.
>
> Certainly, it doesn\'t translate to how much you need to ingest to
> react to.
>
> DR. TORRES: This is contacted with the same glove 100 times?
>
> DR. BEEZHOLD: Yes, the same glove contacted at one piece of lettuce
> 100 times, just going like that. They counted how many times they did
> it, and then put the lettuce in a tube and extracted the surface of
> the lettuce and tested it for latex protein.
>
> So, the point is that we are here seeing 100 or 1,000-fold more
> protein per fingerprint from this glove than a person can react to on
> a skin test, and with the caveat we don\'t know how much a person
> ingesting that can react to other than the comment that Dr. Hepp made
> earlier about a study we did with desensitizing patients and having
> them drink latex protein.
>
> We did that. That is a very, very different situation, it is really
> not the same thing, because what you are doing is we skin prick tested
> them, found out if they reacted to a microgram or a half a microgram
> or a nanogram.
>
> Depending on the patient\'s level of reactivity, we then diluted
> 10,000 times that, gave that person that to drink, so you reduced
> 10,000-fold the amount of protein that they react to on skin test, so
> you wouldn\'t expect a clinical reaction to that.
>
> Then, every 15 minutes you give them a two-fold higher dose than that,
> and immunologically, what is being done is you are hyposensitizing the
> patient and theoretically, you are depleting the IgE that is present,
> so it really gives you no indication whatsoever of how much protein a
> person can react to mucosally.
>
> DR. HAMILTON: Could I stop you for a second? In that study, because
> now you are here and you participated with the guys, you selected 2
> milligrams as the target dose for escalating up, and that was based,
> as I understand it, on an estimate of total, that that is the content
> of total protein extractable from average latex glove?
>
> DR. BEEZHOLD: At the time we started the study, we could, from a pair
> of gloves, we were seeing gloves at that time that would have a
> milligram of protein on their surface, so we reasoned that 2
> milligrams would be from both gloves, and we would have to reach that
> target dose.
>
> It was actually a similar target dose that has worked out for some
> other allergens that are used in hyposensitization techniques like
> that.
>
> DR. HAMILTON: Penicillin.
>
> DR. BEEZHOLD: Right. So, you try and reach a target dose that is in
> the milligram range.
>
> DR. DWYER: Was this work done in Toronto?
>
> DR. BEEZHOLD: This work was done in Philadelphia, with Steve
> McGadey\'s group.
>
> So, I just close with this slide and say that in my mind, in the
> experiments that we have done, there is really no question that if you
> contact the surface with a latex glove that has protein on the
> surface, that that protein is transferred to whatever surface is
> contacted.
>
> You can pick it off of lab benches and doorknobs and telephones, and
> we have actually done some of that work, and the presence of moisture
> increases the ability of that protein to transfer over.
>
> I don\'t know that we have talked about this a lot, but I don\'t know
> that this represents a route whereby people are actually being
> sensitized to latex. I don\'t think that it is. But it certainly is a
> route whereby people that are allergic to latex can be exposed and can
> have significant and life-threatening reactions.
>
> I think I have one more slide. This is just kind of a summary slide. I
> had my name on a list with actually some of the people from the FDA
> and ASTM, and various other organizations regarding a movement within
> the ASTM to actually ban latex or consider banning latex from food
> service, and this is just the letters\--I was named as one of maybe
> six or seven people on a list\--these are the letters that I received,
> or e-mails, that I received all supporting a ban or removal of latex
> gloves from food service.
>
> I would be happy to answer any more questions that you have.
>
> **Questions of Clarification**
>
> DR. DWYER: We have a number of questions. Dr. Taylor and then Dr.
> Hamilton.
>
> DR. TAYLOR: You indicated that the use of latex gloves in food service
> could be a significant cause of reactions. We have also heard today
> that that statement might have been more true in 1993 than it is in
> 2003.
>
> Based on your experience and your long experience with this issue, I
> guess I would just like your comments about that. You also presented
> us with this one result that here in June of 2003, you managed to
> analyze a glove with 1,000 micrograms of protein in it.
>
> DR. BEEZHOLD: There is no doubt that protein levels have come down on
> medical gloves. Clearly, I mean the data right there showed it to you
> visually and numerically, and we have looked at gloves, and they have
> come down 100- to 1,000-fold. That is medical gloves.
>
> My concern with food service gloves is that they are not in the
> medical regulation, and they are not necessarily covered by those same
> protein values.
>
> DR. TAYLOR: I have the same question. Have you had much experience
> with testing of, quote, unquote, \"food service gloves,\" or gloves
> not designated as medical gloves or examination gloves that would be
> covered by the other part of FDA?
>
> DR. BEEZHOLD: Sure, and just like with the examination gloves that are
> on the market, there is good ones and there is bad ones, and they span
> the gamut. We actually looked, after we did that study, we actually
> examined I think three food service gloves that were specifically sent
> to us by people that had gotten them from restaurants, and there was
> one that was very low protein, and there was kind of a medium one or
> two medium ones, I would say, and nothing off the charts, but they
> vary considerably by manufacturer.
>
> If all of the food service gloves came from the same place and you
> knew where they came from, and you knew that people were testing them,
> then, that would be one thing, but a restaurant doesn\'t have a
> particular supplier of food service gloves. They may get them from
> various sources, and you really don\'t know what you are getting.
>
> The other problem I see with food service gloves, and that is really
> not an issue here, but many of them are powdered. Those of you who are
> familiar with powder manufacture or the placing of powder on gloves,
> it is typically done in a slurry tank, and those slurry tanks are
> where large numbers of gloves get dipped into this tank, the proteins
> elute off of the glove into the slurry.
>
> They can reach very high concentrations in that slurry. The slurry has
> been tested for bacteria and many different bacteria can grow in that
> slurry, produce endotoxin, and then that material is left on the
> surface of the glove. Then, you are having your food contacted with
> that same material.
>
> It is just not something, personally, my own personal opinion is that
> it is not food that I want to be eating.
>
> DR. DWYER: Could you provide some references in the peer-reviewed
> literature that demonstrate those points?
>
> DR. BEEZHOLD: Brock Williams published a study looking at endotoxin
> levels, and endotoxin levels have been tested on gloves for a long
> time. In ancient literature, you know, 20, 30 years ago, there is
> levels of endotoxins on gloves.
>
> DR. TAYLOR: How about analytical values on food service gloves as far
> as protein levels or powder levels are concerned? We saw some data on
> medical gloves, and I know that there has been a lot of literature on
> that, and it has been monitored since the early \'90s, and you can
> document the drop.
>
> DR. BEEZHOLD: The concern has always been or the major concern has
> been medical gloves because of the outbreak of allergy among
> healthcare workers.
>
> DR. TAYLOR: So, we don\'t have a heck of a lot of published data on
> the food service gloves.
>
> DR. BEEZHOLD: No, we don\'t.
>
> DR. HAMILTON: But the real problem is what is a food service glove. I
> mean that is what I was trying to get at initially. I mean is it a
> consumer glove or is it a defective medical glove, medical examination
> glove? I mean we don\'t know.
>
> DR. BEEZHOLD: Some food service gloves are medical gloves that fail
> the standard, so they are passed on to the food service.
>
> DR. HAMILTON: How can Don, in running a laboratory that gets all these
> examination gloves, and one happens to be labeled \"food,\" but it
> could be an examination, consumer glove, whatever. I mean it\'s
> terminology that is so vague in the United States, that we really
> don\'t know what we are dealing with.
>
> I don\'t think it is even possible for us to know what is considered a
> food service glove, so we couldn\'t possibly answer that question.
>
> DR. TAYLOR: When I say \"food service glove,\" I am just meaning any
> analytical data on gloves that are not labeled as medical or
> examination gloves. If they are labeled in that fashion, then, they
> have to meet these other specifications. So, I would assume any glove
> that doesn\'t carry that designation isn\'t required to meet that
> standard either.
>
> DR. BEEZHOLD: That is correct. I think there are some other
> qualifications that they do have to meet for food services. Wava is
> shaking her head yes. But they have nothing to do with proteins. I
> think it is for\--is it for chemical additives?
>
> DR. DWYER: It sounds like there is a riffraff of the medical glove
> industry or something.
>
> DR. BEEZHOLD: Yes.
>
> DR. DWYER: Could we go around the table and get more questions out
> here?
>
> DR. DOWNER: Was what you are saying true, then, you are saying that if
> the medical gloves are defective, they are sent to the food industry,
> is that what I heard you say?
>
> DR. BEEZHOLD: In some cases, that is true, and defective for a medical
> glove might mean it didn\'t meet the whole specification or didn\'t
> meet the length specification or something like that. It is not
> necessarily a defective glove, but it didn\'t meet the standard for
> the medical glove, so it was put into the consumer glove market.
>
> DR. DWYER: Mr. Scholz.
>
> MR. SCHOLZ: Do you have any numbers that suggest how often that is
> done or how often that happens in the retail side, or is it anecdotal
> evidence?
>
> DR. BEEZHOLD: I can tell you that that is what manufacturers have told
> me is done; how often, I don\'t know, I have no clue.
>
> DR. DWYER: I am sure the manufacturers will be able to answer that
> tomorrow, because I suspect some of us will ask.
>
> Dr. Johnson.
>
> DR. JOHNSON: When you looked at the number of times of contact with
> the food, did you try at all to estimate in sort of typical or usual
> food handling practices? It seems to me, you know, I have seen food
> service workers where they have got their hands in the potato salad,
> and they likely are touching the item numerous times.
>
> DR. BEEZHOLD: The purpose of the paper was to try and demonstrate that
> it actually happens and sort of simulate, but we didn\'t really go
> into a detailed analysis of all of the ways foods manipulated with
> gloved hands, no. We were actually quite surprised that we were able
> to do it with the minimal contact that we did do.
>
> DR. DWYER: Dr. Fischer.
>
> DR. FISCHER: It looks like from your paper that if you use powder-free
> gloves, you get no transfer to the food in the small number of samples
> that you have done there. Would you say that if somebody in the food
> service position were to put on powdered gloves, and then rinsed their
> hands with the gloves on, or even washed them, that that would get rid
> of the problem?
>
> DR. BEEZHOLD: I think it may\--it would reduce the protein level
> somewhat, certainly if they used soap. I am not sure what that would
> do, what purpose that would do for the food industry wearing\--what is
> the difference of wearing a washed glove versus a washed hand, for
> instance.
>
> I do know that surgeons typically use a wiping method. We tested that
> years ago where they are required, when they go to surgery with a
> powdered glove, they are actually required to wipe the powder off with
> a sterile gauze soaked in saline.
>
> The compliance rate with that was less than 50 percent when we tested,
> but we also tested that it really didn\'t reduce the protein levels,
> and what it did do, the only thing you really saw was a clumping of
> the starch particles. It would have to be a really thorough wash to
> get it off.
>
> DR. FISCHER: I have a second quick question. The ELISA assay that you
> used to produce these results in the paper, are you still using the
> same ELISA assay today?
>
> DR. BEEZHOLD: That\'s the ELISA assay that has been standardized by
> the ASTM, and it is actually being used around the world, the same
> reagents.
>
> DR. FISCHER: Do you find it very reproducible, there is no problem?
>
> DR. BEEZHOLD: Yes. I mean it\'s not a monoclonal type assay
> reproducibility, there is variability in it, but it is an assay that
> we have had, we have sent out to labs around the world, and labs that
> haven\'t had a lot of experience doing ELISA assays, and they have
> come up with fairly similar results. So, it\'s a pretty reproducible
> technique.
>
> DR. FISCHER: And when you strip the protein off the lettuce, let\'s
> say, or cheese, there is no interference there?
>
> DR. BEEZHOLD: We tested for interference with lettuce because of
> cross-reactivities. You could potentially get lettuce proteins
> reacting, and we saw none of that.
>
> DR. DWYER: Dr. Torres, did you have a question?
>
> DR. TORRES: I am thinking about your 100 wash contact with the
> lettuce, then, thinking about washing your hands with the gloves in
> order to remove the proteins, when you said 100, when you did 50
> contacts, did you less protein?
>
> DR. BEEZHOLD: Yes, it was a very dose-dependent response or contact
> number dependent response. I could show you the slide again, but it is
> also in the paper. It was a linear response, which means that you are
> continually, each time you are contacting, you are continually
> releasing similar amounts of protein with each contact.
>
> DR. TORRES: So, every contact, you are releasing the same amount,
> meaning that if you wash it once, you remove some, if you wash it
> again, you love more?
>
> DR. BEEZHOLD: If you wash with large volumes of water and soap, say,
> although some soaps I understand are not good for latex gloves, but if
> you would wash large volumes of water and soap, you would remove\--I
> mean that is how, in manufacturing, that is how they lower the protein
> levels just by washing or leaching the gloves in large leaching vat.
>
> DR. DWYER: Mr. Scholz, you had a question?
>
> MR. SCHOLZ: Are you aware or do you know who may have done work with
> manufacturers to determine the different levels in their gloves, what
> we saw from you, and what you have said is a wide range, is there any
> research, is there any information on manufacturing process or
> information that you could give us that suggest as to why it varies so
> much?
>
> DR. BEEZHOLD: From what I know of manufacturing, and I am not a
> manufacturing expert, but I have toured manufacturing plants, and I
> have looked at protein levels from samples stripped off of the
> manufacturing line at various times.
>
> There is a point\--I don\'t know if we have time to go over
> manufacturing\--but the mold shaped like a hand is dipped into a vat.
> It then goes through some drying process. When it dries, the protein
> balloons to the surface, follows the water evaporating.
>
> It then can go to ovens. It depends on the manufacturer and the type
> of glove. If it\'s a surgical glove, it will receive a lot more
> processing. If it\'s an exam glove, it will receive less processing.
>
> At one point, exam gloves, my understanding was they went from the
> drying oven to the slurry tank, were dried off, and that was it. There
> was no leaching afterwards, and that is why we were seeing very, very
> high protein levels, but you can reduce the protein levels by washing
> and what is called leaching, and the glove is just dipped into a big
> tank with water.
>
> The more leaching beds that the manufacturer has, the lower the
> protein is. There is a major way they reduce proteins, is by
> chlorinating the glove, and that is a leach bath, in some places, a
> leach bath with bleach in it, so it is chlorinated.
>
> That tends to destroy the protein. Then, it has to be neutralized and
> rinsed, which reduces protein even more. So, depending on the
> manufacturer and how many of those steps that they have in there will
> determine the final outcome.
>
> Generalities, we know that chlorinated gloves have very low proteins
> on them. Powder-free gloves tend to be lower protein, and powdered
> gloves tend to be much higher protein.
>
> MR. SCHOLZ: That process, I assume it becomes more expensive as more
> steps are added, and the cost of surgical gloves versus exam gloves
> versus the lowest end of the gloves that the consumer could buy, I
> assume that the cost\--
>
> DR. BEEZHOLD: Yes, the manufacturers have different lines where they
> will make a surgical glove on one line, an exam glove on another line,
> and my understanding is they don\'t convert between those.
>
> To add something, intuitively, it says just add a leach bath to your
> line, or two leach baths to your line, you have to understand that
> these are huge conveyor belts, each one with a porcelain mold, so
> there is thousands of porcelain molds in this line, and it\'s a
> continuous loop, and they are just going along.
>
> So, my understanding is if you decide to increase the size of that
> line, so you can put another leach bath in, you have got a lot of
> expense, because you have got to buy more molds.
>
> DR. DWYER: Thank you. I think that\'s all we need about the
> manufacturing.
>
> How about Dr. Gaspari, because we are really focusing on the safety.
>
> DR. GASPARI: In some of your slides, you presented an estimate of how
> much antigen is transferred on the food, and you gave an estimate of
> how much it would take to elicit positive skin prick tests in a highly
> allergic individual, and I think you quoted, what, 70 picogram?
>
> DR. BEEZHOLD: That is what we have calculated.
>
> DR. GASPARI: So, the question is, one, based on that estimate, what
> spectrum of host reactivities would you expect to elicit, in other
> words, patients that are very highly allergic, moderately allergic,
> weakly allergic, that is one question.
>
> The second question is, is a skin prick test challenge dose the same
> as a mucosal challenge does?
>
> DR. BEEZHOLD: I will answer the second question first. I think I added
> that caveat it is certainly not. You know, the dynamics are different,
> how is it absorbed, is it reactive with proteases or other things in
> the mucosa.
>
> So, we really, they are too difficult to do to get\--I was just giving
> you kind of numbers to kind of put some perspective to it, but as far
> as how much allergen does it take to cause a mucosal reaction? I can
> tell you one thing, it will be different for different people and
> their level of sensitivity.
>
> We know that from our experience with the latex allergic individuals.
> We also know there are people out there that are exquisitely sensitive
> to latex, it just defies reason sometimes.
>
> DR. DWYER: Anybody else on this side have a question?
>
> DR. HAMILTON: We have a lot of experience with oral challenges with
> ragweed versus skin reactions, and we know that you have to add
> milligram quantities orally to get the same immune response that you
> get with nanogram quantities intradermally. That is just ragweed, that
> is a poor example because latex is probably more complex.
>
> DR. BEEZHOLD: In skin prick tests, you are actually breaching through
> the stratum corneum, it is almost a direct dermal inoculation. With a
> mucosal challenge, you are basically applying it intra-orally and
> allowing it, or do you prick the oral mucosa, as well?
>
> DR. HAMILTON: No.
>
> DR. BEEZHOLD: You breach the barrier. You just allow it to be
> absorbed\--
>
> DR. HAMILTON: Ingestion is my understanding of how the oral ragweed
> studies were done. So, you are dealing with digestive enzymes breaking
> down the proteins.
>
> Getting back to this oral challenge study, I actually talked to Dr.
> McGadey yesterday, and one question I did ask him, which sort of
> struck me a little, was in your opinion, now\--he has experience
> administering oral latex to latex allergic individuals\--in your
> opinion, can low levels of latex allergen elicit clinical symptoms
> that are severe, and in his general experience, his impression was
> that it probably did not or would not or could not.
>
> Now, that was the impression. Now, the question I have is we have
> talked about ammoniated latex being administered orally, but you have
> rightly reminded me over the years that we are dealing with a glove
> that goes through a process where it is treated with heat, so the
> proteins that are coming out are actually possibly even modified
> allergenic proteins.
>
> So, therefore, is that study representative or useful in terms of us
> interpreting what low levels of allergen will do orally?
>
> DR. BEEZHOLD: Well, actually, the material that was given to those
> patients orally was ammoniated latex, it was not heat treated, but it
> was broken down, peptides of the latex, so yes, there may be some more
> heat-induced type release of epitopes that might be opened up there,
> but we tried to use as close to the material that is on a glove as
> possible.
>
> DR. HAMILTON: Was it freshly collected, because we know that when
> latex allergen sits with ammonia, that it denatures the allergenic
> protein. That is, of course, one of the theories as to how this\--
>
> DR. BEEZHOLD: It was actually collected from ammoniated latex that was
> sent to our lab, and made a film of the latex and let it dry, and then
> extracted that film and lyophilized the material and stored it in the
> freezer until we were ready to use it.
>
> DR. DWYER: Thank you.
>
> Any other questions on this side? Anything else you wish to say?
>
> DR. BEEZHOLD: I am done.
>
> DR. DWYER: Thank you very much, appreciate it.
>
> We are almost finished here today, gang. We have got one more person
> and that\'s Michael Heumann from the Oregon Department of Health
> Services. Thank you for coming east to talk to us about some comments.
> This is a state, Oregon is a state with latex food service glove
> prohibition.
>
> We will hear from a couple of other states tomorrow, but first, we
> will hear from you. Thank you so much for coming east.
>
> **Invited Comment from a State with Latex Food**
>
> **Service Glove Prohibition**
>
> MR. HEUMANN: Thank you very much for having me. I would like to ask a
> favor of you. You have all been sitting here a very long time, and I
> don\'t want to give you a break, but I would like to ask you a stand
> up. When I stood up, I was as little numb, you have got to be numb, as
> well. Just stand up and sit back down again, please, just so that your
> brains will still function a little bit. It is pretty hard.
>
> DR. DWYER: Could the Secretary also get us copies of the slides that
> we don\'t have. There are several presentations that we don\'t have
> slides of, and we will need them tomorrow.
>
> MR. HEUMANN: Do you have copies of my slides in front of you? I
> presented them to FDA this morning, so they are here. All they need to
> do is hand them out. So, they are here and present.
>
> DR. DWYER: Why don\'t you go ahead and they will catch up.
>
> MR. HEUMANN: What I am going to do for the last talk this afternoon is
> something completely different than what you heard about so far today
> from the other speakers, and I do appreciate very much the opportunity
> to be able to come here to address this group.
>
> You have got one heck of a decision that you are struggling with and
> wrestling with, and, indeed, it is one that we have struggled with and
> made a decision about.
>
> So, what I want to talk to you about today rather than a scientific
> presentation, is rather share with you the steps that we took to apply
> the scientific data to make a similar decision to what you are facing,
> to what we believe is a public health problem.
>
> To do that, I want to talk about what it is that we did, I want to
> talk about how it is that we became aware of this situation in the
> first place. Then, I want to continue with why did we take the actions
> that we took, and then I want to conclude with the role of our
> partners in developing a response. You have already heard a lot about
> partnerships, but I want to go into a little bit in greater extent.
> Then, I will open it up to questions.
>
> So, what did we do? So, Oregon has the administrative rules that
> govern a whole variety of things that government does, and in January
> of 2002, Oregon\'s Food Code Agency, which is in my department,
> finally got around to adopting the 1999 FDA Food Code Rules. In our
> statutes, it is the Oregon Administrative Rule 333-150-0000.
>
> In that, we added a glove use limitation clause, and it says,
> \"Effective March 1, 2003, the use of latex gloves in food service
> establishments is prohibited.\" A simple sentence is all we wanted to
> go for. So, that\'s what we did.
>
> So, how did we become aware of this in the first place? Where did we
> get this from? This takes us back to the year 1992. I manage\--I
> should say by way of introduction\--I am an epidemiologist and I
> manage the environmental and occupational epidemiology programs for
> the Oregon Public Health Agency. So, I have in my bailiwick, if you
> will, a variety or programs that look at both workplace exposures and
> hazards, as well as those hazards that exist where people live and
> play. So, it is kind of the whole gamut of people\'s lives.
>
> So, what I focus on, though, are generally non-infectious or
> non-communicable disease issues. We have been partnering with NIOSH
> since 1992 to look at a variety of occupational illnesses and
> injuries, and most consistent during this time has been occupational
> skin diseases that we have been tracking.
>
> The way that we track those diseases, the way we started back in 1992,
> was to look at the State Worker\'s Compensation Claims Database. We
> have an open competitive state in Oregon, and that means that a
> variety of private companies, as well as public companies, sell,
> insure Worker\'s Compensation insurance to different employers, and
> they are required to report a portion of their information in a
> standardized fashion to the State to do their administrative work.
>
> So, we started looking at that and we realized that that data was
> very, very limited. It only had information on what are called
> \"disabling\" claims and also on denied claims. What was lacking from
> that a database was information on what are called \"non-disabling\"
> or \"medical-only\" claims, which is probably 85 percent of all of the
> Worker\'s Comp claims that are accepted.
>
> So, we had a problem there, and that was that we weren\'t getting good
> information, so we started partnering with some of the private
> insurance companies, so that we could get access to their information.
> So, these are administrative databases, they are not public health or
> epidemiologic databases, but they still have some very useful
> information in them.
>
> In particular, they have information on the antecedent causes of
> illnesses and injuries that are available in text fields, in uncoded
> text fields that are kind of just written down from the initial forms,
> which gives us a chance to look at that.
>
> So, since 1992, we were certainly quite aware of latex allergy issues
> in the healthcare industry and the healthcare field, and our response
> to that took the effect that we started when we first started seeing
> that this was a problem, and a very real problem in Oregon, is we
> started looking at the research that science and that researchers had
> come up with about the issues of latex allergy, so that we could get
> up to speed about it.
>
> Once we had done that, we began the process of educating those people
> who are affected by the hazards and educating them about these
> hazards, as well as alternatives.
>
> Our goal was to try to encourage, on a voluntary basis, the creation
> of latex-safe environments. To do this work, we developed partnerships
> with hospitals and other employers, as well as employees and employee
> groups who were affected by this, so this is all in healthcare.
>
> The other partnerships were with the Worker\'s Compensation insurers,
> and then also with NIOSH. Our funding again came from NIOSH. The
> reason that Worker\'s Compensation insurers were a big partner, not
> only were the source of the initial information, but here were the
> entities that were responsible for paying out very large claims
> potentially when a highly trained healthcare provider, a physician, a
> nurse, a dentist may lose their career because of latex allergy, and
> no longer be able to function in the environment to which they had
> been trained.
>
> Some of the insurers in Oregon were paying out claims of \$500,000,
> and they don\'t take that very lightly, so they were a very willing
> partner to help find ways to encourage alternatives.
>
> Obviously, the other parties, the hospitals, the other employers and
> the employees were also partners willing, to one degree or another. I
> should say that we had been quite successful, certainly on a national
> level, the change was already happening, and we played, I am sure,
> just a small role in this, but we, by the late 1990s, had done a lot
> to help most hospitals in Oregon become latex-safe.
>
> One hospital had become completely latex-free and those hospitals that
> first became latex-safe agreed with us that they would serve as
> consultants for those other hospitals and employers that were just
> starting the process, so that somebody who had already created the
> wheel could share that information with others.
>
> So, we were pretty happy with ourselves that we were making inroads
> and being successful. In late 1998, our review of the Worker\'s
> Compensation data identified the first cluster of cases of latex glove
> dermatitis among food care workers in Oregon.
>
> Again, this was from the Worker\'s Compensation data, and I mentioned
> to you earlier the uniqueness of the private industry data is that it
> has certain text fields, so here is an example of some of the
> descriptions of the accident description, allergic reaction to wearing
> latex gloves. Another one said received severe rash on both hands due
> to latex gloves, and these were among workers in food service
> industries - cooks, chefs, food preparers, and others.
>
> Then, there is also the text of the injury description itself,
> describing respiratory disorders of the lungs in relation to an
> allergic reaction to wearing latex gloves or dermatitis on the hands.
> So, you can see there is a certain richness of data that we couldn\'t
> get when we looked at the State summary data, which just\--actually,
> the State summary data would say that there was either a disabling
> claim or a denied claim that was the result of clothing or glove
> material. It wouldn\'t get any more specific than that.
>
> So, we sought this kind of information and indeed found something that
> we hadn\'t seen before. This surprised us greatly because this was a
> new trend. Here, the numbers of cases of healthcare workers were going
> down, and all of a sudden, a new cluster.
>
> By the way, by \"cluster,\" I am saying we only saw five accepted
> claims by the end of 1998, but that was five claims in an industry
> that we had never seen before, so it surprised us.
>
> Well, we got another surprise just around that same time. As part of
> the training that we do, in the industry at this time, in the
> healthcare industry, we would call local representatives of various
> glove manufacturers and ask for samples of different kinds of gloves,
> so that we could use them in our training, both the latex gloves, as
> well as alternative gloves.
>
> So, when I did this, and this is not meant to be an endorsement of any
> manufacturer, but when I did that, this is what I received when the
> glove representative came to my office. I wanted medical exam gloves,
> and this gentleman brought to me a product that says, Food Mates
> Natural, and it was a lightly powdered latex exam glove, and the other
> was a powder-free latex exam glove, both with the name on them, Food
> Mates Natural, and the image that you can see there\--it may be hard
> for some of you to see\--is a hand with a latex glove on reaching in
> and picking up a strawberry out of a bowl of strawberries.
>
> I said what is this, I didn\'t ask for some other glove, I wanted
> medical exam gloves. He said, well, that is what they are because the
> demand for powdered latex gloves is going down, we are now marketing
> them to the food service industry. So, this was confirmation of where
> this trend was coming from, indeed, there was a shift in marketing of
> the companies.
>
> So, during the first two years, that is to say, 1998 and 1999, we saw
> 12 cases among workers. Not all of them were accepted claims, some of
> them were denied claims, but these were all among food service
> workers, and we also started to receive unsolicited reports of
> allergic reactions among restaurant customers.
>
> There were people who, of course, as was mentioned by Dr. Klontz
> earlier, are people who had a prior history of latex sensitivity, but
> we started getting reports from citizens who were consumers in
> restaurants that started having anaphylactic and other reactions while
> they were still in the restaurant. So, there was a range of symptoms
> certainly.
>
> Some only had throat tightness, some only had difficulty breathing,
> wheezing, and the like. Some had tickling in their chest and their
> throat, and others had an anaphylactic reaction and they needed to
> call 911 and have an Epi-Pen, et cetera, and be taken to an emergency
> department.
>
> So, we wanted to confirm what we were seeing. This was all very new to
> us and while we thought we were winning in one area, it is kind of
> like poking into a balloon, you push in one side and a bulge comes out
> on another side.
>
> So, we tried to confirm the cases with the Worker\'s Compensation
> insurer, and basically, they were as surprised as we were, because
> they don\'t review their data the same way that we do, so we were kind
> of educating them, and they would indeed go back to the employers
> where these cases had happened, and were confirming with them that
> these were taking place in food service now.
>
> We also confirmed with restaurants whether or not latex gloves were
> actually used. We would go out and visit and kind of go into the
> kitchen and ask, even though we are not sanitarians, we are
> epidemiologists, and, sure enough, we found latex gloves being used in
> restaurants almost everywhere that we went.
>
> Also, we would try to confirm as best we could with customers, but we
> didn\'t do anything nearly as extensive with an organized
> questionnaire as FDA did from their cases, so we just were receiving
> the cases.
>
> At this point, we started to identify who are the partners that we
> need to work with to address this issue, and we identified the Oregon
> Restaurant Association, which is an industry representative group that
> probably has a membership that represents maybe a quarter of all
> restaurants. There is over 30,000 restaurants in Oregon, so this
> represents about a quarter of those entities.
>
> We also wanted to find Labor if we could, and there was only one large
> union, the United Food and Commercial Workers Union, that represents
> food process workers and food industry workers.
>
> Also, we partnered with local health departments because they are the
> sanitarians that go out and license restaurants to operate. Then, of
> course, our primary insurance partner continued to be the largest
> carrier, which is Liberty Northwest Insurance.
>
> So, briefly, what happened with these relationships is that it turns
> out that Liberty Northwest insured the Oregon Restaurant Association.
> That was convenient because we were able to get Liberty to call a
> meeting with the leadership of the Oregon Restaurant Association
> allowed us to come and present our findings to them, and they
> immediately understood the severity of the potential issue and agreed
> to collaborate and agreed that this was something that they weren\'t
> looking forward to and didn\'t want to have happen.
>
> We also had contact with some of the large national and even some of
> the international corporations that have chain restaurants in Oregon,
> as well as elsewhere, and when we would bring this to their attention,
> they were usually very surprised. In the beginning they kind of said,
> oh, what is the issue here, why are you bothering us with this, but
> when we explained it to them and showed them the information of what
> we were seeing, they also recognized the importance of this and agreed
> to make changes immediately.
>
> So, we were feeling relatively successful. The Oregon Restaurant
> Association agreed to put out newsletter articles out to their
> membership, and our goal here was one of voluntary change. I should
> say here this was similar to what we wanted to do, and I think largely
> achieved, in the healthcare industry.
>
> One slight digression. In two different legislative sessions\--our
> legislature, thank goodness, only meets every other year\--but in two
> different sessions, we had bills that were introduced into our state
> legislature that would have prohibited latex glove use in healthcare,
> and we were adamantly opposed to that.
>
> We felt that this was a marketplace change and the industry was
> collaborating and that you didn\'t need to go that way, and, thank
> goodness, I think we all prevailed in that way.
>
> So, we wanted to do the same thing. Our goal is a voluntary change
> here. We would educate people, they would get on-board, and we would
> have no problem. Likewise, when we worked with the labor union, they
> agreed to collaborate. They published an article in their union
> newsletter, and the with local health departments, we ended up getting
> collaboration from five counties that wanted to help us with the pilot
> intervention.
>
> We did training for all county health departments. We have meetings
> with them on an annual basis, and so we did a large training where we
> trained all the sanitarians about the hazards associated with latex
> allergy and glove use and what were some of the alternatives, what to
> look for, and how they could get the information out.
>
> We also developed a latex Alert for restaurants, which is on the last
> page of your handout is the text of it. It is too large to fit on a
> slide, so I gave it to you as the last\--should be the last page of
> your handout.
>
> So, the five counties agreed to do a pilot assessment. They agreed to
> gather information to find out how commonly were latex gloves used in
> restaurants. They agreed then to provide education and to distribute
> our flyers both in English and in Spanish.
>
> So, this all seemed pretty good, so why did we need to take any action
> beyond that? Here we were, we had a positive response from
> restaurants. We also contacted suppliers, restaurant supply houses to
> let them know of the potential hazard in the products that they were
> selling to restaurants, and many of them agreed, some of them chose
> not to agree, but quite frankly, what got both suppliers and
> restaurant owners to make a change had less to do with what we were
> seeing more of, which was worker health and safety issues, that
> wasn\'t such a motivating factor.
>
> The motivating factor was the potential liability from a customer who,
> God forbid, should have an anaphylactic reaction or other reaction in
> their restaurant, causing a scene, and potentially leading to a
> lawsuit.
>
> Around that time, by the way, we were also getting calls from
> attorneys from other states wanting to know if we would give them
> information about these citizens, so that they could potentially build
> a lawsuit in Oregon.
>
> Needless to say, we don\'t do that, we don\'t give out that
> information, but that actually shocked us also. We were really worried
> that here was a new problem, an eminently preventable problem that
> could and should be prevented, and in our mind, there was no reason
> whatsoever that a lawsuit should ever have to happen in Oregon if we
> all acted together. We were a little naive perhaps, or idealistic I
> should say.
>
> So, even though we were doing this and having a positive response when
> we would go out and take our action, cases were still coming in, and
> the reality was there are over 30,000 restaurants, and we couldn\'t
> reach everybody quick enough.
>
> So, around this time, we wanted to find another way to do a statewide
> solution to address the problem. It needed to be simple, that would
> allow us to help prevent cases. Our goal again was to protect
> customers, employees, and employers, as well as suppliers. So, we were
> trying to create a multiple win-win situation here.
>
> Around this time, in late 2001, we learned that our colleagues in the
> Food Protection Office of our agency, were about to adopt a 1999 Food
> Code, and so that means that they were opening the food code to
> amendments and to changes, and indeed they were planning a few
> amendments, they didn\'t adopt the entire code. We are a little
> independent out in Oregon, I guess.
>
> But we saw it as our opportunity to act, and I should mention here
> also that Oregon\'s rules, unlike the FDA recommended rules, does not
> require the use of gloves. It requires hand washing. We require that
> all restaurant workers wash their hands and wash their hands
> frequently. They may also use other utensils, and a glove can be seen
> as a utensil as it was defined earlier this morning in FDA.
>
> But I think it is important because there are some states that
> require, in their statutes, glove use, that mandate no hand contact
> with foods that are no longer to be prepared or cooked, but are ready
> to serve foods. We don\'t do that, we are a little different.
>
> Tomorrow, you will hear from Rhode Island and Arizona about their bans
> and what they entail and how they got there. I can\'t speak for them,
> but you will hear from them tomorrow, but we found that their language
> was far more complex and went on for pages, and as I say, we wanted to
> have something simple, so we proposed that one sentence that the use
> of latex gloves in food service establishment be prohibited.
>
> The Oregon Restaurant Association prevailed upon us to delay that by
> about seven months and have it implemented on March 1st of 2003. We
> agreed because there should be time for everybody to make the
> changeover. Suppliers need to be able to get rid of product, the
> restaurants need to be able to get rid of product.
>
> So, the Food Code was finally adopted in August of 2002. This received
> major media coverage, and what received major media coverage was the
> latex glove ban. The rest of it was kind of old news and was a
> sleeper. But this issue received a lot of coverage in the media.
>
> In addition to that, which we helped foster because we wanted to get
> the word out, we advised restaurants and suppliers of the change
> through letters, as well as articles and a variety of methods.
>
> We also encouraged them to adopt the change before the March deadline,
> so that they could get on-board because now that they knew about it,
> we wanted to head off any potential lawsuits before the curtain came
> down.
>
> Also, the local health departments, which do routine inspections of
> all restaurants, agreed to carry out the word and provide letters. So,
> the information went out. This resulted in many, many questions, but,
> in general, we got very good support from the restaurants.
>
> Some of them called us very hostile and said what are you doing, why
> are you making me do this, you know, my workers love latex gloves, and
> when we would explain what we were doing and why, at the end they
> would generally say thank you for doing this.
>
> So, we had a lot of collaboration. There was really no unified
> opposition to this in Oregon.
>
> So, now I want to just switch to the concluding remarks here. From our
> perspective, it is important, as you all know, and this is why you are
> having industry and a variety of folks come here, to cultivate wide
> support among the people who are affected, indeed, you want to bring
> them together and find who is it that is at stake, provide them with
> information and education about the issues.
>
> From my perspective, it is important to involve them in the
> decisionmaking, to have them on-board, to have them in agreement with
> what is happening as much as possible.
>
> So, I want to conclude here and basically summarize what I had said,
> and that is that our actions were based on initially identifying the
> problem through our occupational disease tracking system, and that is
> how we identified a new pattern.
>
> By the way, I want to say here, you are separating it out, you are
> kind of having independent stove pipes, not looking at worker health
> and safety, but only looking at that which happens to customers.
>
> I have to tell, each and every worker that converts to become latex
> allergic is also a customer of restaurants, and many people are
> feeling that they can\'t go to restaurants safely without having the
> risk of developing a reaction, and if not at this restaurant, maybe
> another one, they always have to ask, so workers are affected equally,
> and the changes that you may recommend will improve potentially in the
> prevention efforts that will affect workers\' health and safety, as
> well as that of the consumers, and the more that we can do activities
> to prevent a problem from coming to a new industry, I think the better
> off we are.
>
> We got up to speed and then it was our effort to apply this science,
> tried to do it in a voluntary way and when it wasn\'t happening
> quickly enough, we did do the formal rule change.
>
> I do want to just conclude by saying that we agree with everybody I
> think in this room, and that is that natural rubber latex does have an
> important place in the protection against exposures to bloodborne
> pathogens, but this is primarily a healthcare issue. We don\'t know of
> any restaurants that are performing surgery or should have exposure to
> bloodborne pathogens or other bodily fluids as part of the food
> services that they supply.
>
> We also, though, agree that low protein, powder-free gloves are the
> safest option for people who are not yet latex allergic, however, for
> people who already have a latex allergy, I think the data is showing
> that even a low protein, powder-free glove, if they come in contact
> with it, can still trigger one level of a reaction or another.
>
> Also, as you all know, there are many alternative glove materials that
> exist and it is very important that we select gloves to the specific
> use that we have.
>
> I also want to mention something that was not talked about earlier. We
> talked about the fact that some people can have an irritant contact
> dermatitis reaction to latex gloves, perhaps from the mechanical
> presence of the powders that are occluded and held next to the skin,
> that can abrade the skin and actually even push the powders and
> proteins into the skin.
>
> Then, you could also have the delayed hypersensitivity reaction, and
> then we have, thank goodness just the small tip of the iceberg, are
> those people who have the immediate reaction.
>
> But there is some evidence, I think a good bit of evidence, that
> suggests that people who may only begin with either an irritant
> reaction or a delayed reaction, can indeed in many cases do progress
> on to an immediate hypersensitivity reaction. So, we should not
> exclude them out of hand as saying they don\'t matter. They may not
> matter now, but they may matter tomorrow or the next day.
>
> Finally, we have found as a result of our work that we are doing that
> powdered natural latex gloves are being promoted in many other
> settings, and we are worried, not only about food care workers, but
> child care workers and children being exposed in child care when they
> either eat food, when their diapers are changed, or when their noses
> are wiped, being exposed to powdered latex gloves, janitorial service,
> a whole variety of other occupations and industries are likewise being
> exposed now because you have a large body of lesser quality gloves
> that are still being manufactured and are now being just promoted for
> use elsewhere.
>
> So, my final words are latex allergies are real, but they are also
> preventable and we have an opportunity.
>
> With that, I will be happy to take any questions.
>
> **Questions of Clarification**
>
> DR. DWYER: Thank you so much for coming and thank you for
> accommodating us. Now, we will ask some questions.
>
> Dr. Gaspari.
>
> DR. GASPARI: I would like to know when you started tracking the
> Workmen\'s Comp files, basically, from your slide, I see that on page
> 2, in 1998, the first case reports identified with latex glove
> dermatitis data, and then a second slide later on, 12 cases among
> workers in the first two years.
>
> So, what I would like to know is in those Workmen\'s Comp files, were
> those patients evaluated by a dermatologist or an allergist to
> determine the etiology of their hand dermatitis, because as you have
> already alluded, and we have heard repeatedly today, that actually,
> there are wide variety of causes of hand dermatitis and, of course, of
> the three major causes that latex allergy is probably the least
> common, so please respond.
>
> MR. HEUMANN: That is an excellent question. I agree, as mentioned
> earlier, few cases actually get into the Worker\'s Comp system for a
> variety of reasons. One is because the worker may not recognize the
> association; two, the worker may not go to the doctor; three, the
> worker may be afraid of filing a claim because, although it\'s wrong,
> they may be afraid that their job is in jeopardy.
>
> The fourth reason, and there may be even others, is the physician, who
> they may actually end up going and seeing, may not either ask or
> recognize whether or not this could be a work-related etiology.
>
> So, that\'s I think an important caveat to state, so, if anything,
> this is a major underreporting.
>
> But your question as to whether or not a case is seen by a
> dermatologist or not, most claims that are accepted usually are
> adjudicated. Worker\'s Comp claims, at least in Oregon, are not easily
> accepted without a hard body of evidence, and, indeed, we have seen
> more claims filed that are denied than we have seen that are accepted.
>
> So, those that we have seen that are disabling claims that are
> accepted, while we have only gone back to look at some of those data,
> because that is a separate database in the Worker\'s Comp system, we
> have identified a smaller number of those cases where they actually
> have been confirmed by dermatologists.
>
> Indeed, Dr. Franz Stors, who is probably the preeminent dermatologist
> in Oregon at least, sees most of those cases. She is our only tertiary
> care dermatologist, so any hard case gets kind of funneled to her from
> general practitioners and other dermatologists, as well. So, a number
> of the cases that were filed and accepted claims have come through
> her, and she is actually a sentinel provider for us. So, yes, some
> number of them have been, but certainly not all. It\'s a long answer.
>
> DR. DWYER: Other questions? Dr. Hamilton and Dr. Taylor.
>
> DR. HAMILTON: First, I would like to ask you\--I am a little confused
> because at one moment you indicated that on the issue of the use of
> latex gloves in medical applications, you were opposed to that notion,
> and yet I got exactly the opposite perspective when you started
> dealing with food handling.
>
> MR. HEUMANN: Isn\'t that funny, yes. Do you want me to explain that?
>
> DR. HAMILTON: Can you clarify a little bit on that issue?
>
> MR. HEUMANN: Sure. With healthcare, we believed that the change was
> coming by itself. We believed that there was motivation on the part of
> the medical industry, both employers and employees, because you have
> highly-trained, high-end, highly-educated employees who don\'t want to
> suffer from this allergy, because it is career threatening and they
> have a lot invested in that career.
>
> You also have the employers, the hospitals and others, who don\'t want
> to have, one, patients who are having problems as a result of a
> latex-contaminated environment. So, there was a lot of incentive
> there, a lot of awareness, a lot of momentum on the national level to
> identify other glove products, to identify and push for higher quality
> latex glove products in addition to the other non-latex glove
> products.
>
> So, that was happening already, I thought, by itself. When you go to
> make a rule change or a law change, oftentimes what happens is you
> polarize an argument, and people who you could otherwise have on your
> side and find ways to build agreement, tend to polarize and dig their
> heels in and say you are not going to tell me what to do.
>
> So, in this situation where we found ourselves in food services, we
> initially had the exact same attitude, this is a no-brainer. It\'s
> clear, you know, we are seeing cases that we didn\'t see before, they
> are matching temporally with an influx in marketing of these gloves to
> food industry.
>
> We thought we will teach them, no problem, and indeed in the early
> couple of years that we were doing this, every contact we had for the
> most part resulted in a positive change. It wasn\'t fast enough. We
> were seeing more cases coming in of workers who worked in other
> restaurants that we had not yet contacted.
>
> There is not the same unified industry within food care. You have got
> lots and lots and lots of small mom and pop restaurants and food
> stands and catering services that don\'t communicate with others and
> are pretty much out of the loop.
>
> So, because of that, we felt we were striving in a losing battle, that
> we were still running into more cases of both customers, as well as
> workers, and that we saw the opportunity of a rule change, which
> didn\'t have to go through the legislature.
>
> That\'s the other thing. A rule change can happen within the agency
> level, and because we had the main party to be affected, the Oregon
> Restaurant Association, who would be our, quote, unquote \"enemy,\"
> already on our side, we thought that this would be easier, and indeed
> it was.
>
> We didn\'t have any opposition, any real opposition from within the
> state. The only opposition, the Oregon Restaurant Association wanted
> was that they wanted to delay in the implementation.
>
> DR. HAMILTON: Could you clarify for me what role the liability issue
> played in this whole argument?
>
> MR. HEUMANN: Sure. The role of the liability issue is the Sword of
> Damocles, that threat that hangs over people that, one, restaurants
> don\'t like the idea of bad publicity, of the word of mouth getting
> out that somebody went down in a restaurant and had a horrendous
> reaction to the food, so there is bad publicity there.
>
> It becomes a news story. Then, secondly, we were hearing of, and
> hopefully, you guys are also aware of the fact that there have been
> numerous lawsuits in states all over the United States about customers
> who have gone into restaurants and had anaphylactic reactions and then
> sued.
>
> I should say that to date, no customer has won a lawsuit that has been
> finally settled. There was one I believe in San Diego where the
> customer actually did win, but, of course, that is going to be
> appealed and it will be years.
>
> But besides the win or the loss, there is the publicity issue and
> there is the tremendous dollars that go into legal cases.
>
> DR. HAMILTON: So, the issue of hard science supporting the notion that
> latex allergen and food can actually induce a reaction was not a
> consideration ultimately.
>
> MR. HEUMANN: Sure, it was the underlying consideration that I think
> convinced the restaurant folks that the lawyers from the other side
> would win the case. I mean I think that is how the science\--it played
> out for us way back when we were working in the healthcare area, but
> it certainly played out with worker health and safety that the science
> is the reason that we wanted them to make a change. That is not the
> reason that they wanted to make a change.
>
> Do you see what I am saying? Okay.
>
> DR. DWYER: Any other questions? Mr. Scholz and Dr. Gaspari.
>
> MR. SCHOLZ: What did you do with the Oregon Food Code in terms of
> requiring\--the food service folks cannot wear latex gloves\--does the
> code require\--
>
> MR. HEUMANN: Right, it was just that one sentence that say you can\'t
> wear.
>
> MR. SCHOLZ: Right. Does the code require that they wear other types of
> gloves?
>
> MR. HEUMANN: No. As I said earlier, our code requires them to hand
> wash, hand wash, and hand wash is what our code requires of food
> service workers. They have the option, in addition to hand washing, of
> using other utensils to augment their handling of foods that will not
> be further processed before serving.
>
> MR. SCHOLZ: I mean did you get as specific as saying you have to wash
> your hands six times a day?
>
> MR. HEUMANN: I am not a sanitarian, and I don\'t administer those
> rules, but they are very specific. I can call up and find out for you
> by tomorrow what the code says, but I believe that it says that when
> you change from one task to another, you have to wash your hands. So,
> if you are making salad one minute, and then you are going to make a
> sandwich, you have to wash your hands.
>
> If you are going to make food and then handle money, you have to wash
> your hands both before and after, like going to the bathroom, those
> sorts of things. I don\'t know if it is a specified number.
>
> DR. GASPARI: My question was along the same line, so I still don\'t
> understand why you decided to do away with gloves completely and not
> intervene like a vinyl glove or non-latex glove. That is one question.
>
> The second question is perhaps related to Dr. Shanklin\'s presentation
> about\--I am getting a little foggy about some of the earlier
> presentations\--about the transfer of pathogens from the hands into
> the food, and apparently what is happening at the Oregon State level
> seems to contradict what we heard from the FDA earlier about pathogens
> and direct handling of foodstuffs.
>
> Can you comment about how this\--
>
> MR. HEUMANN: Why don\'t I take a stab at it first and then they can
> fill in.
>
> DR. GASPARI: Go ahead, sure.
>
> MR. HEUMANN: So, you asked two questions. The first question, I am
> trying to remember back, about non-latex gloves. Indeed, the rule says
> that you can use\--under the other optional utensils, they include
> non-latex gloves, so they do include a vinyl glove or a nitrile glove,
> as well as wraps, as well as tongs, as well as other utensils.
>
> So, other gloves are allowable. We did not prohibit the use of gloves
> per se, just prohibiting the use of latex gloves in any way, shape, or
> form, which means dishwashers can\'t use latex gloves to wash dishes,
> janitors in restaurants can\'t use latex gloves to clean up, that
> everybody has to use a non-latex product or some other means to do
> their work. So, that one simple sentence was a little broader than we
> had even imagined, but it was or it is.
>
> DR. GASPARI: But the option of the direct hands on the foodstuffs,
> that is what I need to have clear.
>
> MR. HEUMANN: That is an option, direct hand contact in Oregon is a
> voluntary option in Oregon, it is not a recommended option at the FDA
> level. So, there is a difference there, but their food code is a
> recommended guideline, it is not a requirement. As I said, we do
> things a little differently out in Oregon.
>
> So, the other question you had
>
> DR. GASPARI: Would you state that directly to us for the record, as
> well? And you agree with that?
>
> DR. TARANTINO: The people who can address this more have left, but, in
> general, the food code which, as you said, is a recommendation, says
> no bare hand contact. It doesn\'t say you have to use gloves, it
> certainly doesn\'t say you have to use latex gloves. You can also use
> utensils, you can use tongs, but it does say no bare hands contact.
>
> What I am hearing here is that they are saying bare hands contact is
> an option, you wash your hands.
>
> DR. GASPARI: Let me ask you, then, how does the FDA respond to when a
> state basically doesn\'t follow recommendations, what is your response
> to that other than saying\--well, you tell me what you are going to
> say.
>
> DR. TARANTINO: It is clearly a recommendation, the states have the
> option to make their own recommendations or requirements, and
> presumably, they have a justification for doing it differently. This
> is an area where there is definitely differences of opinion on what
> the best route to food safety is.
>
> MR. HEUMANN: I don\'t believe that Oregon\'s rate or incidence of
> foodborne outbreaks that are restaurant-associated is any greater in
> Oregon than elsewhere, because one of the things to recall is just
> because you are wearing a glove, doesn\'t mean that you change the
> glove as often as you should, and indeed, people have observed glove
> users and have seen them to from getting a bagel off the shelf to
> handling money without changing gloves, to handling food again. That
> is a violation. You need to change your glove in between those
> activities. You shouldn\'t be handling different things.
>
> Likewise, they have observed people going into the bathroom with the
> gloves on, going to the bathroom, and coming out again with the same
> gloves on and going back to work.
>
> There is a potential for a false sense of security in gloves.
> Certainly, gloves can do a great job, but it takes the commitment of
> the worker to do what they need to be doing correctly with the glove,
> but they shouldn\'t have a false sense of security, and foodborne
> outbreaks still happen, folks, even in states where glove use is
> required.
>
> DR. DWYER: Are there any other questions?
>
> Dr. Hamilton and then Dr. Fischer.
>
> DR. HAMILTON: Could I just go back to the issue you raised at the very
> end? That is, you suggested that the scientific evidence was a
> consideration for Oregon initially, right?
>
> MR. HEUMANN: For the Public Health Agency.
>
> DR. HAMILTON: What data did you use to convince yourselves that there
> is absolute credibility, there is a link between the presence of
> allergen, latex allergen and a food, and the induction of a reaction
> in an individual in that restaurant?
>
> MR. HEUMANN: I would say that we used the same evidence that you have
> been citing today. We certainly because we worked closely with NIOSH,
> we were involved with them actively as they were developing their
> recommendations. We certainly appreciated and use as a reference the
> AAAAI recommendations that they had, the FDA Fact Sheet or Advisory,
> as well as the OSHA Advisories, as well as all of the published
> literature, Dr. Beezhold\'s work and all of the other literature.
>
> We would actively go and do lit searches to find out. We would
> actively contact all the different glove manufacturers that we could
> and invite them to come to speak with us about what the processes
> were, what went into it, what was involved, what were the weaknesses,
> what were the strengths, et cetera, et cetera, whether they were a
> latex glove manufacturer, a vinyl glove manufacturer, nitrile glove
> manufacturer, or other synthetic materials.
>
> We tried to absorb as much information as we could because we knew
> that we are a small state, we don\'t have the budget and the resources
> nor the time to be able to do these studies ourselves, so we have to
> rely on the work of others, and we try to learn it, understand it, and
> see how it applies, and it was for the reason of the literature that
> we decided that we needed to take action.
>
> How we took that action was to educate, to advise, and to build
> partnerships. We would try to share the science.
>
> DR. DWYER: Thank you. That was fine.
>
> Anybody else? No others?
>
> DR. TORRES: Is it correct, my impression is that you made the
> decision, the food service worker and the food service case based on
> the worker safety? That, you emphasized the most, because you went to
> the Workmen\'s Comp files, and there was a source of your decision
> data more than whether there were consumers being affected by the
> transfer of allergens.
>
> MR. HEUMANN: Correct. That is what we learned about first. That is
> where we observed a cluster of cases. The first cluster of cases were
> among workers, because that is part of the surveillance or tracking
> that we do, and because we are so involved with worker health and
> safety in our state, and we have been doing a lot in the area of other
> dermatologic issues, such as poison oak and other derm issues that we
> are trying to reduce that.
>
> So, yes, it is certainly not workers along, but we think workers are
> equally at risk.
>
> DR. DWYER: Thank you for an interesting presentation. I think all the
> questions have been asked.
>
> What we plan to do tomorrow, just for the committee, is we will be
> starting at 8:00 a.m., there will be food there earlier, and at what
> point we are going to be able to for a time certain for finishing, we
> are not quite sure, but we should know early tomorrow morning because
> it depends on getting an arrangement for some people who are scheduled
> fairly late.
>
> I think probably 4:00 is fairly safe. It depends on how fast we move
> along, but we will try very hard to get done tomorrow. I am going to
> try to get done by about 4:00 p.m. It depends on the deliberations, it
> could go until 5:00, but we will try to get some specifics to you
> before the break, so we can tell our planes, and so forth, when we are
> going to be coming.
>
> Thank you very much.
>
> \[Whereupon, at 5:15 p.m., the meeting was recessed to reconvene at
> 8:00 a.m., Wednesday, August 27, 2003.\]