AT DEPARTMENT OF HEALTH AND HUMAN SERVICES

UNITED STATES FOOD AND DRUG ADMINISTRATION

CENTER FOR FOOD SAFETY AND APPLIED NUTRITION

ADDITIVES AND INGREDIENTS SUBCOMMITTEE

OF THE

FOOD ADVISORY COMMITTEE

LATEX ALLERGY

Tuesday, August 26, 2003

9:10 a.m.

St. Regis Hotel

923 16th Street, Northwest

Crystal Ballroom

Washington, D.C.

PARTICIPANTS

Johanna Dwyer, D. Sci., Chair

Richard Bonnette, Executive Secretary

MEMBERS

Jeffrey Blumberg, Ph.D.

Goulda Downer, Ph.D.

Lawrence Fischer, Ph.D.

Anthony Gaspari, M.D.

Robert Hamilton, Ph.D.

Rachel Johnson, Ph.D.

Brandon Scholz

Steve Taylor, Ph.D.

J. Antonio Torres, Ph.D.

C O N T E N T S

Welcome and Introductions

Committee Chair 5

Conflict of Interest Statements

Committee Executive Secretary 7

Welcome

Alan Rulis, Ph.D. 11

Overview of CFSAN's Office of Food Safety

George Pauli, Ph.D. 14

Charge and Questions

Laura Tarantino, Ph.D. 29

Basic Latex Allergy Background

Jay Slater, M.D. 39

Questions of Clarification 70

CDRH Proposal

Mel Stratmeyer, Ph.D. 96

Questions of Clarification 107

Safety Assessment of Food Additives

Anna Shanklin, Ph.D. 128

Questions of Clarification 151

Specific Background on Food Mediated Latex Reactions

Mark Hepp, Ph.D. 163

Questions of Clarification 183

Progress in the Management of NRL Allergy

Vesna Tomazac-Jezic, Ph.D. 200

Questions of Clarification 212

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

Invited Comment

Don Beezhold, Ph.D. 229

Questions of Clarification 243

Invited Comment from a State with Latex Food Service Glove Prohibition

Michael Heumann 260

Questions of Clarification 283

P R O C E E D I N G S

Welcome and Introductions

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

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

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

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

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

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

Mr. Bonnette.

Conflict of Interest Statements

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

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

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

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

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

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

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

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

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

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

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

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

MR. BONNETTE: Sure.

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

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

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

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

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

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

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

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

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

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

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

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

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

Welcome

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

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

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

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

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

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

Thank you.

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

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

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

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

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

Overview of CFSAN's Office of Food Additive Safety

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

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

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

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

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

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

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

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

Finally, our research wing on the far right.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

DR. DWYER: Thank you very much.

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

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

Thank you for setting this process in context.

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

Dr. Tarantino.

Charge and Questions

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Thank you, Dr. Tarantino.

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

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

[Recess.]

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

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

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

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

DR. SLATER: I think I am.

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

Basic Latex Allergy Background

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Questions of Clarification

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

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

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

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

DR. HAMILTON: Yes, from foods.

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

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

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

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

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

Did that answer your question?

DR. HAMILTON: Excellent.

DR. DWYER: Thank you.

Dr. Johnson and then Dr. Downer.

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

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

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

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

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

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

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

DR. DWYER: Thank you.

Any additional? Dr. Downer.

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

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

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

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

DR. DWYER: Thank you.

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

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

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

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

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

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

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

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

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

DR. SLATER: I am sorry?

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

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

DR. TORRES: Only from an allergy reason.

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

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

Dr. Gaspari.

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

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

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

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

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

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

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

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

DR. DWYER: Thank you.

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

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

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

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

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

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

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

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

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

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

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

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

DR. HAMILTON: They had positive skin tests.

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

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

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

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

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

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

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

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

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

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

Would this study help to answer that question?

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

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

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

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

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

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

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

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

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

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

Isn't there a cross-reactivity between those?

DR. SLATER: Between psyllium?

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

DR. SLATER: I am not aware of it.

DR. DWYER: No? Okay.

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

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

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

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

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

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

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

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

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

DR. DWYER: Thank you. What a surprise.

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

DR. SLATER: I haven't a clue.

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

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

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

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

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

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

DR. DWYER: Interesting.

Dr. Downer.

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

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

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

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

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

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

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

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

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

DR. DWYER: Thank you.

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

Dr. Torres? Dr. Fischer?

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

What is your interpretation of those results?

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

I think it is just a matter of exposure.

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

DR. SLATER: I think it's exposure.

DR. FISCHER: To the different allergens.

DR. SLATER: That's right.

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

Dr. Hamilton? Dr. Taylor?

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

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

DR. SLATER: No.

DR. DWYER: Thank you.

Dr. Blumberg? Dr. Gaspari?

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

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

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

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

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

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

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

Dr. Stratmeyer.

CDRH Proposal

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Thank you.

DR. DWYER: Thank you, Dr. Stratmeyer.

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

Questions of Clarification

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

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

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

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

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

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

DR. DWYER: Thank you, Dr. Stratmeyer.

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

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

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

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

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

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

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

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

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

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

MR. SCHOLZ: Drugstore, restaurant, grocery store.

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

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

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

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

DR. STRATMEYER: No.

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

DR. STRATMEYER: No.

DR. DWYER: Dr. Torres.

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

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

DR. TORRES: Right.

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

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

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

DR. STRATMEYER: Pardon?

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

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

DR. DWYER: Thank you.

Dr. Johnson has a question.

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

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

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

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

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

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

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

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

DR. DWYER: Thank you, Dr. Stratmeyer.

Dr. Hamilton had a question.

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

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

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

DR. STRATMEYER: Now you are getting into--

DR. HAMILTON: Practice?

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

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

DR. STRATMEYER: Yes.

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

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

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

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

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

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

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

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

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

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

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

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

DR. DWYER: It will be helpful.

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

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

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

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

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

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

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

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

DR. DWYER: Thank you.

Dr. Johnson.

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

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

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

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

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

DR. DWYER: Go ahead.

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

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

DR. DWYER: Thank you for your informative comment.

Dr. Gaspari.

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

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

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

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

So, those are two issues related to cornstarch particles.

DR. DWYER: Thank you. More good news.

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

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

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

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

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

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

DR. BLUMBERG: Thank you for clarifying that.

DR. DWYER: Thank you.

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

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

DR. STRATMEYER: So did I.

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

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

Thank you.

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

AFTERNOON SESSION

[1:00 p.m.]

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

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

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

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

DR. DWYER: Very good. Anyone else?

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

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

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

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

Safety Assessment of Food Additives

DR. SHANKLIN: Thank you.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

These allergic reactions have been linked to latex proteins.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Are there any questions?

DR. DWYER: Thank you.

Questions of Clarification

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

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

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

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

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

DR. HAMILTON: Thank you.

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

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

DR. SHANKLIN: Yes.

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

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

DR. DWYER: Dr. Tarantino.

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

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

DR. DWYER: Dr. Taylor.

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

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

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

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

DR. DWYER: Dr. Gaspari.

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

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

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

So, those are my two questions.

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

Could you speak to those?

DR. SHANKLIN: He wants to take it.

DR. DWYER: Okay, fine.

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

DR. DWYER: Are you planning on identifying yourself?

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

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

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

DR. DWYER: Thank you.

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

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

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

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

DR. DWYER: Thank you.

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

DR. SHANKLIN: Natural rubber latex.

DR. DWYER: Thank you.

Dr. Hamilton.

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

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

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

DR. HAMILTON: So, just the presence.

DR. SHANKLIN: Just the presence.

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

DR. SHANKLIN: No.

DR. HAMILTON: Thank you.

DR. DWYER: Dr. Torres, Fischer?

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

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

DR. FISCHER: Well, that helps.

[Laughter.]

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

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

DR. SHANKLIN: Not that I am aware of.

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

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

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

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

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

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

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

Do you want to say something about the chewing gum?

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

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

DR. DWYER: Thank you.

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

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

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

DR. DOWNER: Thank you.

DR. DWYER: Any others? Dr. Hamilton.

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

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

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

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

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

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

Specific Background on Food Mediated Latex Reactions

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

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

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

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

DR. DWYER: Is there a handout?

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

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

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

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

As Dr. Slater 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.]