> U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES
>
> FOOD AND DRUG ADMINISTRATION
>
> CENTER FOR FOOD SAFETY AND APPLIED NUTRITION
>
> FOOD ADVISORY COMMITTEE
>
> MEETING
>
> METHYLMERCURY
>
> **(VOLUME I)**
>
> Wednesday, December 10, 2003
>
> 9:10 a.m.
>
> Hotel Washington
>
> 515 Fifteenth Street, N.W.
>
> Washington, D.C.
>
> PARTICIPANTS
>
> SANFORD A. MILLER, Ph.D., Chair
>
> LINDA REED, Acting Executive Secretary
>
> MEMBERS:
>
> ALEX D.W. ACHOLONU, Ph.D.
>
> MARION H. ALLER, D.V.M.
>
> H. VAS APOSHIAN, Ph.D.
>
> DOUGLAS L. ARCHER, Ph.D.
>
> FRANCIS FREDRICK BUSTA, Ph.D.
>
> PATRICK S. CALLERY, Ph.D.
>
> ANNETTE DICKINSON, Ph.D.
>
> GOULDA A. DOWNER, Ph.D.
>
> RICHARD A. DURST, Ph.D.
>
> JOHANNA DWYER, Ph.D.
>
> JEAN M. HALLORAN
>
> DOUGLAS C. HEIMBURGER, M.D., M.S.
>
> NORMAL KRINSKY, M.D.
>
> DARYL B. LUND, Ph.D.
>
> MARK F. NELSON, Ph.D.
>
> ROBERT M. RUSSELL, M.D.
>
> CLIFFORD SCHERER, Ph.D.
>
> CAROL WASLIEN, Ph.D., R.D.
>
> C O N T E N T S
>
> [PAGE]{.underline}
>
> **Welcome and Introductions:**
>
> Dr. Sanford Miller 5
>
> **Conflict of Interest Statement:**
>
> Ms. Linda Reed 10
>
> **Opening Remarks:**
>
> Dr. Robert Buchanan 13
>
> **Subcommittee Reports** 17
>
> **Infant Formula**: Ms. Jeanne Latham
>
> Questions of Clarification 19
>
> Public Comment
>
> Roger Clemens, Dr.PH 21
>
> FAC Discussion and Comment 39
>
> **Contaminants and Natural Toxicants,**
>
> **Enterobacter sakazakii:** Dr. Frank Busta,
>
> Ms. Jeanne Latham 44
>
> Questions of Clarification 48
>
> Public Comment
>
> William C. MacLean, Jr., M.D. 58
>
> FAC Discussion and Comment
>
> **More Opening Comments:**
>
> Joseph A. Levitt 69
>
> Dr. Robert Brackett 81
>
> **More Subcommittee Reports**
>
> **Dietary Supplements:** Dr. Johanna Dwyer,
>
> Ms. Jeanne Latham 83
>
> Questions of Clarification 87
>
> **Additives and Ingredients:** Dr. Johanna Dwyer,
>
> Mr. Richard Bonnette 97
>
> Questions of Clarification 102
>
> **Food Biotechnology:** Dr. Frank Busta,
>
> Dr. Michael Watson 110
>
> Questions of Clarification 114
>
> C O N T E N T S (CONTINUED):
>
> [PAGE]{.underline}
>
> **Status Report and Response to Food Advisory**
>
> **Committee\'s Recommendations on Methylmercury**
>
> **in Fish and Shellfish** 129
>
> **FDA and EPA Development of Joint Advisory:**
>
> Dr. David Acheson, CFSAN 129
>
> Ms. Denise Keehner, EPA 135
>
> Dr. David Acheson, CFSAN 142
>
> Questions of Clarification 157
>
> **Exposure Assessment and Peer Review:**
>
> **Peer Review:** Rita Schoeny 177
>
> **Exposure Assessment:** Dr. Michael Bolger 188
>
> Dr. Clark Carrington
>
> Questions of Clarification 198
>
> P R O C E E D I N G S
>
> **Welcome and Introductions**
>
> DR. MILLER: Good morning. I would like to take this opportunity to
> thank you all for coming today, the members of the advisory committee,
> of which I think there are some eight new members.
>
> We have several topics to be discussed today including reports of
> several subcommittees that function in relationship to the senior
> committee, of which this is it. There are a couple of things. First, I
> intend to be ruthless in terms of time. I have said this the last time
> the committee met and I will say it again; there are too many people
> on the agenda and, if we don\'t be rigorous in terms of the amount of
> time that each person uses, we will be here next Tuesday.
>
> I think that is not what all of us want. I have a suspicion that, by
> tomorrow afternoon, people are going to be sneaking out and that
> wouldn\'t be fair to the people that still have time to make
> presentations. So I will use the gavel,
>
> the presentation gavel, which is an inside joke, ruthlessly. So,
> please, I really beg of you, please stick to your times.
>
> Second of all, the function of these meetings is to inform the
> committee. So the only questions that will be asked will be asked by
> members of the committee. The audience will not be called upon to
> provide questions to members of the committee or people making
> presentations. So, only the committee will be called upon to ask
> questions, if they have them.
>
> I also ask the committee if, when you do ask a question, let\'s keep
> the questions as brief as we can make them but at least make them as
> informative as possible because the function of the committee is going
> to be to come up with a report for CFSAN based on the outcome of this
> committee.
>
> Thirdly, one of the topics being discussed today is infant formula.
> There are two of us that have worked in this area before with industry
> and we have recused ourselves for these issues. I have asked Bob
> Russell to chair because I am one of the
>
> ones that is recused. Doug Archer is the other one.
>
> I think that is all of the announcements.
>
> Before we begin, I wonder if I could take a few minutes here and have
> the committee introduce themselves. Let\'s start with Dr. Scherer.
>
> DR. SCHERER: Clifford Scherer, Cornell University.
>
> MS. HALLORAN: I am Jean Halloran from Consumers Union.
>
> DR. ACHOLONU: Alex Acholonu from Alcorn State University, Mississippi.
>
> DR. APOSHIAN: Vas Aposhian, University of Arizona.
>
> DR. WASLIEN: Carol Waslien, University of Hawaii.
>
> DR. DOWNER: Goulda Downer, Metroplex Health and Nutrition Services
> here in Washington, D.C.
>
> DR. KRINSKY: Norman Krinsky, Tufts University, School of Medicine,
> Boston.
>
> DR. CALLERY: Patrick Callery, West
>
> Virginia University.
>
> DR. RUSSELL: Robert Russell, Nutrition Research Center, Tufts, Boston.
>
> MS. REED: Linda Reed, Center for Center for Food Safety and Applied
> Nutrition.
>
> DR. MILLER: Sandy Miller, Virginia Tech University.
>
> DR. LUND: Daryl Lund, University of Wisconsin, Madison.
>
> DR. DICKINSON: Annette Dickinson, Council for Responsible Nutrition.
>
> DR. ARCHER: Doug Archer, University of Florida.
>
> DR. BUSTA: Frank Busta, University of Minnesota.
>
> DR. DURST: Richard Durst, Cornell University.
>
> DR. ALLER: Marion Aller, Florida Department of Agriculture and
> Consumer Services.
>
> DR. NELSON: Mark Nelson, Grocery Manufacturers of America.
>
> DR. DWYER: Johanna Dwyer, Tufts New
>
> England Medical Center.
>
> DR. HEIMBURGER: Doug Heimburger, University of Alabama at Birmingham.
>
> DR. MILLER: Thank you. There is one more thing that I think I would
> rather say now than later. This is the last meeting that Catherine
> DeRoever, who has acted as the Executive Secretary of this
> committee\--I was going to say almost since its inception. I think it
> was since its inception. So, to a large extent, the committee and the
> way it works has been the result of Catherine\'s kind but firm
> directions, particularly the way she controls the Chairman. It always
> ends up the way she wants it to be, somehow, and everybody agrees that
> is the way it should have been in the first place.
>
> In any case, this is her last meeting and I would like to offer to her
> the thanks of the committee for doing a sensation job. Her successor,
> Linda Reed, whom you have already met,I am sure will be a worthy
> successor.
>
> Thank you, Catherine.
>
> (Applause.)
>
> Slight change on the agenda. Joe Levitt, the Director of the Center,
> who also is retiring\--I am just wondering if I have anything to do
> with it. We need to think about that\--will not join us until just
> before lunch. He will have with him the new Director of the Center to
> meet the committee and to be introduced to the committee.
>
> Bob Buchanan of the Center will make some opening remarks about where
> CFSAN would like us to go on these discussions. So, the first item on
> the agenda today is the additional Conflict of Interest Statement.
> Linda Reed will provide that.
>
> **Conflict of Interest Statement**
>
> MS. REED: Good morning, as Chairman Miller indicated, I am Linda Reed,
> the Acting Executive Secretary for this Food Advisory Committee
> Meeting. I would like to welcome everyone, our members and our
> temporary voting members. Thank you very much for being here today.
>
> With that, I would like to read the conflict of interest statement
> into the meeting record. The authority to appoint temporary voting
>
> members is granted to the Center Director. Relying on that authority,
> Mr. Levitt, Director, Center for Food Safety and Applied Nutrition,
> has signed letters stating, by the authority granted under the Food
> Advisory Committee Charter, I hereby appoint Dr. Aposhian, Dr. Russell
> and Dr. Scherer as temporary voting members of the Food Advisory
> Committee for December 10 and 11, 2003, committee meeting.
>
> All members and temporary voting members have been screened for
> financial conflicts of interest. Because of the breadth of topics to
> be discussed at this meeting, all of the members and temporary voting
> members have been screened for any and all financial interest
> associated with the regulated industry.
>
> Based on this review, FDA has determined, in accordance with 18.USC
> Section 208(b)(3), to grant general-matters waivers to Dr. Marion
> Aller, Dr. Douglas Archer, Dr. Francis Busta, Dr. Richard Durst, Dr.
> Johanna Dwyer, Dr. Douglas Heimburger, Dr. Normal Krinsky, Dr. Sanford
> Miller, and Dr.
>
> Carol Waslien that permits them to participate fully in the matters
> before this committee.
>
> Copies of the waiver statements may be obtained by submitting a
> written request to the Agency\'s Freedom of Information Office, Room
>
> 12A-30, of the Parklawn Building. However, as Dr. Miller stated, he
> requests that I inform the committee that he is voluntarily recusing
> himself from all discussions relating to the Infant Formula Committee.
>
> Similarly, Dr. Douglas Archer has asked that I inform the committee
> that he is also recusing himself from all discussions relating to the
> Contaminants and Natural Toxicants Subcommittee on Enterobacter
> sakazakii.
>
> In an effort to enhance consistency within FDA, the agency has
> recently adopted a policy whereby all public commenters will be asked
> to report any personal financial interests that could be affected by
> the committee\'s deliberations. A copy of this policy was provided to
> all the individuals who registered to make a public
>
> comment. I believe that additional copies of the policy may be
> obtained from the registration desk.
>
> I have one additional administrative announcement. We have received
> two written submissions for individuals that were not able to appear
> at the meeting. The submissions are from Dr. Jane Hightower and Dr.
> Philippe Grandjean.
>
> The submissions have been provided to our members and copies are
> available at the registration desk.
>
> With that, I would like to welcome everyone and turn the meeting back
> over to Dr. Miller.
>
> DR. MILLER: Thank you, Linda.
>
> The next item on the agenda is some opening remarks which will be made
> by Bob Buchanan.
>
> **Opening Remarks**
>
> DR. BUCHANAN: Thank you, Sandy. As Sandy already sort of let the cat
> out of the bag, I am not Mr. Levitt. Joe sends his regrets for not
> being able to be here first thing in the morning. He does intend to be
> here just before the noon break and will be making a few comments at
> that
>
> time.
>
> I did want to take this time to just make a couple of opening remarks
> and sort of to set the stage for the next deliberations that will be
> taking place. I want to emphasize the fact that FDA faces challenges
> in the area of foods and applied nutrition that are diverse, often
> highly complex and affect the American consumers, every American
> consumer every day.
>
> FDA prides itself on basing its programs and its decisions and
> continually striving to bring the best science it can to these
> questions and working through a process of effective risk management.
> An integral part of being able to achieve that goal of sound science
> is seeking opinions and advice and expertise from outside.
>
> We do this in many manners. We deal effectively with our stakeholders.
> We establish collaborative research and scientific programs. As you
> know, being here today, we rely heavily on our advisory committee.
>
> We will be throwing to you today some very
>
> highly complex issues and we appreciate, and I want to thank you ahead
> of time for the attention and efforts that you are going to bring to
> bear.
>
> I might note also that is a
>
> precedent-setting meeting because this is the first meeting we have
> had where we have completed on full cycle of our new structure of the
> parent committee and six standing subcommittees. You will be hearing
> reports from those subcommittees this morning.
>
> I want to note also that the committee has been rechartered for its
> next two-year cycle and we are looking forward to your activities over
> that next two years. I was also asked to let everyone know that there
> are still several vacancies available on our subcommittees. So, as you
> are listening to the activities of this morning of those
> subcommittees, if you have suggestions on people that would be
> appropriate and interested in serving in that capacity, please let
> Linda Reed know. That also goes for the people in the audience, or
> pass the word back to other interested
>
> parties. We are looking for the best scientists that can be brought to
> bear in those areas.
>
> With that, again, I want to express our sincere thanks for devoting
> your time and efforts and substantial grey matter to the issues at
> hand and, if there is anything that we can do to make your activities
> easier during the next several days, please do not hesitate to ask the
> staff to identify how we can help you through this process.
>
> With that, I also want to express my sincere thanks to Sandy for his
> continuing activities and also to Cathy DeRoever for her activities on
> behalf of the committee for the last nine years.
>
> So let\'s get on with the show. Thank you.
>
> DR. MILLER: Thank you, Bob.
>
> The next item on the agenda has to do with the Subcommittee Report on
> Infant Formula. Since we need to make a changeover in the
> Chairmanship, we will take a really quick five-minute break and
> reassemble for this discussion.
>
> (Break.)
>
> **Subcommittee Reports**
>
> **Infant Formula**
>
> DR. RUSSELL: We are at the point of hearing the first subcommittee
> report, the Report on Infant Formula. To give that report is Ms.
> Jeanne Latham who is the Executive Secretary of Infant Formula and
> Dietary Supplements Subcommittees.
>
> DR. LATHAM: Good morning, everyone. I am Jeanne Latham, the Executive
> Secretary for the Infant Formula Subcommittee. I am standing in for
> Dr. Cutberto Garza who chaired the November 2002 Food Advisory Meeting
> on Infant Formula. I will very, very briefly review the minutes of the
> meeting.
>
> In your briefing package for today\'s meeting, you received, among
> other things, a copy of these minutes for the November 18 to 10, 2002,
> Food Advisory Committee Meeting on Infant Formula.
>
> As a matter of background, the Food Advisory Committee met in April of
> 2002 to begin discussions related to the general question, what
>
> components constitute an appropriate and complete general
> science-based set of guiding principles for clinical studies used in
> the context of providing assurances that a particular infant formula
> supports normal physical growth under its intended conditions of use.
>
> The November 18 to 19, 2002 meeting was a follow-up to that April,
> 2002 meeting and addressed questions relating to that general
> question. The purpose of the November, 2002 meeting was to consider
> seven questions under two issues; criteria for the adequate evaluation
> of normal physical growth during the first six months as an indicator
> of the nutritional adequacy of new infant formulas and the types of
> changes in infant formulas that should be accompanied by a clinical
> study in order to provide assurances of normal physical growth.
>
> Questions 1 through 6\--again, these are in your minutes in your
> package\--address the specific criteria covered under the first issue
> about criteria for evaluating normal physical growth and the types of
> changes in infant formulas that should
>
> be accompanied by the clinical study were addressed in Question 7.
>
> The committee reached consensus on all seven questions and made
> recommendations to the agency. I was not going to go into the details
> because you have that before you and, if you had any comments or
> questions, I will try my best to respond to you.
>
> **Questions of Clarification**
>
> DR. RUSSELL: This is the time for questions of clarification from the
> Food Advisory Committee members if you have any questions at that
> point.
>
> **Public Comment**
>
> If there are no questions from the committee of Ms. Latham, we will go
> ahead with regard to the public comment on the Infant Formula Report.
> Before we do that, I need to read to you this statement that, both the
> Food and Drug Administration and the public believe in a transparent
> process for information-gathering and decision-making.
>
> To ensure such transparency at the Open Public Hearing Session of the
> Advisory Committee Meeting, FDA believes that it is important to
> understand the context of an individual\'s presentation. For this
> reason, FDA encourages you, the Open Public Hearing speaker, at the
> beginning of your written or oral statement, to advise the committee
> of any financial relationship that you may have with the sponsor, its
> product and, if known, its direct competitors.
>
> For example, this financial information may include the sponsor\'s
> payment of your travel, lodging or other expenses in connection with
> your attendance at the meeting. Likewise, the Food and Drug
> Administration encourages you, at the beginning of your statement, to
> advise the committee if you do not any such financial relationships.
> If you choose not to address this issue of financial relationships at
> the beginning of your statement, it will not preclude you from
> speaking, however.
>
> The first speaker is Roger Clemens from
>
> the University of Southern California who is the Industry Rep on the
> Infant Formula Subcommittee.
>
> You have eight minutes, Dr. Clemens.
>
> DR. CLEMENS: Thank you, Mr. Chairman. Roger Clemens with the
> University of Southern California School of Pharmacy and the Infant
> Formula Council, International Infant Formula Council, has paid my way
> here to serve as consultant on this topic.
>
> On behalf of the International Infant Formula Council and its
> membership, I would like to thank you for this opportunity to address
> the question posed to this advisory committee just moments ago by Ms.
> Latham.
>
> Historically, researchers in the
>
> infant-formula industry have conducted clinical studies in infants
> prior to the introduction of a new formula or whenever an existing
> formula underwent a change that might call into question the
> formula\'s continued ability to support growth. In the process,
> researchers follow ICH and American Academy of Pediatric Guidelines.
>
> It should be emphasized that, during the past ten years, approximately
> 50 growth studies among 6,000 infants have been performed for new
> infant-formula introductions characterized by what the FDA and the
> Academy have termed as major change in formulation. Based on these
> practices, no infant formula has been introduced into the marketplace
> that has been later withdrawn due to failure to support normal growth
> of infants. This confirms that the clinical process currently followed
> in assessing growth adequacy are practical and appropriate.
>
> We believe there are several areas, general areas, of the
> subcommittee\'s charge that deserve particularly emphasis. Changes are
> frequently made in the manufacture of infant formula in the interest
> of continuous improvement and not every change is a major change, and
> not every major change justifies a clinical study.
>
> Guidelines incorporated into law in the 1986 Amendments to the Infant
> Formula Act specify the types of changes that require clinical study.
>
> These guidelines highlight the need for individual case assessment
> before making any decision to subject babies to clinical trials. The
> recommendations before you are not final. The agency has advised that
> the Infant Growth Report on your desk is, in fact, a work in progress
> and we look forward to continually working with the subcommittee in
> the future on these issues.
>
> Current systems are firmly in place by the industry and they are
> working. Practical and definitive outcomes need to be defined for any
> growth studies when considered necessary. Certainly, there is little
> point in having collected data unless there is a recognized measure by
> which to evaluate those data.
>
> Industry experience in this arena is rich and valuable to this
> subcommittee and to these deliberations. Even industry assistance in
> framing questions for future FAC meetings should be very helpful to
> the FDA in eliciting answers that provide truly practical guidance for
> the agency\'s review process.
>
> Each of you has this flow diagram in the packet before you. Some of
> you have seen this industry-provided decision tree before, such as the
> last meeting. It is key to understanding the process that industry
> routinely goes through in determining the nature of a given change and
> whether, in light of the nature of the change, clinical data are
> necessary to confirm growth support.
>
> This decision tree reflects a process that has served the public well.
> This FAC has been asked by the FDA to assess and respond to seven
> fundamental questions. Upon review of the FAC responses, we offer the
> following summary comments.
>
> Formulation changes; it is clear that not all change trigger the need
> for a clinical study. As indicated in the decision tree, there are
> multiple factors to be considered when documenting the nutritional
> adequacy of infant formula. In many cases, a clinical-growth study may
> be warranted. In other cases, not. For example, when clinical growth
> studies are not justified include
>
> taking into account previously published information.
>
> Control population; the reported FAC response to this key topic is
> there should be a comparison in addition to some reference source
> based on breast-fed infants to try to understand deviations, if any,
> between growth patterns exhibited by breast-fed infants and
> formula-fed infants targeted for the study.
>
> Breast-fed infants are not mentioned in the question posed to the FAC.
> Breast-fed infants do not represent a concurrent control and there is
> not a well-recognized growth database for
>
> breast-fed infants.
>
> Clinical comparators; if a reference is used to help interpret the
> results of a randomized controlled parallel-designed clinical study,
> the CDC-NCHS reference data published in 2000 reflect the most recent
> information and should serve as the comparator for these kinds of
> clinical studies.
>
> Essential anthropometrics; at issue is the need for anthropometric
> assessment from birth to
>
> six months of age for infants implying that this need applies to
> studies for both term and pre-term infants. Historically, for term
> infants, the Academy recommended that growth studies went from birth
> to four months of age. There is no rationale for an extra two months
> of follow up, particularly when extending the growth evaluation beyond
> four months of age is confounded by the introduction of solid foods.
>
> With respect to preterm infants, formula for this population is
> provided during the initial hospitalization after birth and is usually
> discontinued post-discharge. Therefore, to demonstrate adequate growth
> in preterm infants, the study period can be no longer than from near
> the time that enteral feedings were introduced until the approximate
> hospital discharge.
>
> Value of metrics; given the circumstances surrounding anthropometric
> measure obtained at birth, trace measurements are not reliable
> baseline measurements. Recording body weight and recumbent length data
> provides sufficient data for
>
> evaluation.
>
> Reference groups; in evaluating normal physical growth for term and
> preterm infants, the FAC noted the comparison should be the population
> intended to consume the formula. We do not believe that the
> subcommittee\'s comments were meant, or should be interpreted to mean,
> to preclude conducting growth studies outside of the United States.
> What is most important is the health status of the intended population
> and not its geographical location.
>
> Growth assessment endpoints; consistent with our experience and the
> extensive data collected and published, body weight, alone, is the
> most reproducible and the most reliable measure to assess body growth
> and, thus, the most important factor to evaluate.
>
> In conclusion, our experience and data reveal that the current
> clinical practices in assessing adequacy to support growth are
> practical and appropriate. Therefore, any proposed changes to these
> practices must be carefully considered and
>
> evaluated in the context of whether they would truly improve the
> quality of infant formula.
>
> Thank you for your time.
>
> DR. RUSSELL: Thank you very much. Are there any questions at this time
> from the Food Advisory Committee members? Dr. Dwyer?
>
> DR. DWYER: Roger, I wasn\'t sure what your point was on breast milk.
>
> DR. CLEMENS: Thank you, Johanna, for the comment. It was thought that
> we should run a concurrent \"control\" to gain additional data and our
> experience has indicated that we know\--I believe it was the FAC had
> indicated that they wanted additional data on the deviations or any
> changes in kids that were breast-fed.
>
> In fact, we know quite well that the growth velocities of breast-fed
> kids do differ from those which are formula-fed. We know that the
> growth patterns are not identical between these two groups. It has
> been well established. Despite these apparent differences, there
> isn\'t any information whatsoever to say that these
>
> differences are clinically significant.
>
> MS. HALLORAN: Did the committee give any consideration to indicators
> considering developmental indicators as opposed to just physical
> growth and weight gain?
>
> DR. CLEMENS: I defer that question back to the committee.
>
> DR. RUSSELL: Can you repeat the question, Ms. Halloran?
>
> MS. HALLORAN: The question was was there any consideration given to
> whether one should look at developmental indicators as well as
> physical growth.
>
> DR. RUSSELL: It would have to be referred back to the subcommittee?
>
> DR. CLEMENS: It was deferred. The point was discussed, but no
> consensus was established.
>
> DR. RUSSELL: Other questions or clarification or discussion?
>
> DR. CLEMENS: Thank you.
>
> DR. RUSSELL: Thank you very much, Dr. Clemens.
>
> The next speaker is Ms. Sally Fallon, Westin Price Foundation in
> Washington who has requested fifteen minutes.
>
> MS. FALLON: Thank you very much for allowing me to present this
> morning. My name is Sally Fallon. I am the President of the Westin A.
> Price Foundation, a nonprofit nutrition education foundation based in
> Washington, D.C. We, myself and members of the Board of Directors of
> this foundation, have no ties with any food industry, certainly not
> with the infant-formula industry. We serve as volunteers.
>
> Our concern is the use of soy infant formula. About 25 percent of
> formula-fed babies in the United States receive soy infant formula.
>
> Our first concern centers on the major ingredient, soy protein
> isolate. This is a highly processed protein powder derived from soy
> that is processed using many chemicals and at very high temperatures
> in order to reduce the levels of antinutrients that naturally occur in
> the soy bean. There is always a tradeoff. In order to reduce the
>
> antinutrients as much as possible, there is also the overdenaturing of
> many of the proteins in soy.
>
> In feeding experiments with rats, soy protein isolate caused increased
> requirements for Vitamins E, K, D and B12 and deficiency symptoms of
> calcium, magnesium, manganese, molybdenum, copper, iron and zinc.
>
> As far as we can determine, soy protein isolate does not have GRAS
> status and we have not been able to ascertain whether it has gotten
> premarket approval for soy infant formula.
>
> We are also concerned about toxins that are added or produced during
> processing, nitrates and lysinoalanine, which were the concerns
> expressed by the FDA in the early 1970s when GRAS status was sought
> for protein isolate, higher than normal levels of aluminum, fluoride
> and MSG, free glutamic acid.
>
> The second concern is the lack of cholesterol in soy infant formula.
> Dietary cholesterol is vital for the development, optimal development,
> of the infant, particularly
>
> neurological development. This is why mother\'s milk is very rich in
> cholesterol and contains a special enzyme that ensures the complete
> assimilation of the cholesterol. Soy infant formula does not contain
> cholesterol.
>
> Our third concern is the phytoestrogens, the high levels of
> phytoestrogens, in soy infant formula. These have been associated with
> many conditions, endocrine disruption, depression of the immune system
> and thyroid dysfunction. Animals fed high levels of phytoestrogens
> have shown infertility, reproductive problems, thyroid disease and
> liver disease. This has been observed in many species including mice,
> rats, cheetah, sturgeon, quail, sheep, pigs and marmoset monkeys.
>
> Children on soy-based formula have levels of estrogens 13,000 to
> 22,000 times higher than the levels in children on milk-based formula.
>
> This indicates a comparison. We are looking here at the\--on a
> body-weight basis, we have three surveys from Japan showing a range of
> 0.17 to 0.47 milligrams per kilogram of body weight
>
> daily. This is what you find in the Asian diet. Getting above that at
> 0.60 to 0.75, you start to see thyroid problems, endocrine disruption,
> hormonal changes. The FDA recommended amounts comes out to be about
> 0.42 milligrams per kilogram of body weight.
>
> An infant on soy infant formula because of its small size\--and this
> is an average\--is about 0.625 milligrams per kilogram of body weight,
> so this is an order of magnitudes greater than any thing that we see
> in traditional diets or that is causing problems in adults. You have
> to remember the infant is particularly vulnerable to the effects of
> these isoflavins.
>
> Just to go over a few studies from the literature. This is 1981, soy
> formula fed to premature babies caused increase in digestive enzymes
> indicating very low digestibility of soy infant formula.
>
> Gastrointestinal damage was observed in two infants\--this was
> published in 1983\--this was consistent with celiac disease and
> lectin-induced
>
> toxicity.
>
> Aluminum, this was 1986, was found to be ten to twenty-fold greater in
> cow\'s mild formula compared to breast milk but a hundred-fold greater
> in the soy infant formula.
>
> The things that I am pointing out here would not necessarily affect
> growth. In fact, the estrogens promote growth. In animals, they give
> estrogens to promote growth. So the protocols that you are suggesting,
> just six months looking at weight and height, are not going to see the
> neurological effects of some of these other components of soy formula.
>
> Fort, 1986, found that twice as many
>
> soy-fed children developed diabetes as those in the control group that
> was breast-fed or received
>
> milk-based formula. Once again, this was not show up in the first six
> months of life.
>
> Early puberty in girls; this was the Puerto Rican study, 1986. Soy
> infant formula was associated with higher rates of early development
> in girls including breast development and pubic
>
> hair before the age of eight and sometimes before the age of three.
>
> 1987, soy-based or milk-free formulas contain eight to fifteen times
> more cadmium than milk-based formulas as well as high amounts of
> fluoride.
>
> Dr. Fort, once again, 1990; he documented associative soy formula in
> infancy with autoimmune thyroid problems. Once again, these types of
> problems would not necessarily show up in the first six months of
> life.
>
> The JAMA study, published in 2001, widely reported as a vindication of
> soy formula, actually found more reproductive problems and more asthma
> in the adults who had been fed soy formula. It was also an indication
> of higher weight and thyroid problems.
>
> Now, this was a study on marmoset monkeys that is very important to
> our discussion, published in 2002. They fed marmoset monkeys soy
> infant formula for the first few months of life. There was a decrease
> in the testosterone surge of 70
>
> percent and the levels of soy given to these monkeys were actually
> less than what is given to human infants on soy formula.
>
> As you may be aware, the testosterone surge in little boys in the
> first six months of life programs the child to express male
> characteristics at puberty. So, once again, you are not going to see
> the effects of this until much later.
>
> Thymic and immune changes in mice due to exposure to genistein in
> utero or after birth; the authors caution\--in the conclusion, these
> results raise the possibility that serum genistein concentrations
> found in soy-fed infants may be capable of producing thymic and immune
> abnormalities.
>
> This is another recent study, 2002. Infant mice given genistein
> developed cancer of the uterus later in life. They said the data
> suggest that genistein is carcinogenic if exposure occurs during
> critical periods in the young animal\'s development.
>
> Changes in the ovaries. This was another recent study. Once again,
> these are, I believe it is mice. The authors concluded that, given
> that human infants are exposed to high levels of genistein in
> soy-based foods, this study indicates that the effects of such
> exposure on the developing reproductive tract warrant further
> investigation.
>
> Another study, quite recently, 2003, when female rats were given low,
> medium and high doses of genistein, they found persistent
> demasculinization of male infants even at the low doses.
>
> Finally, another one in 2003, infant rats exposed to phytoestrogens
> exhibited much higher levels of anxiety and stress and much less
> contact with the other animals. This is consistent with the anecdotal
> reports that we get on a weekly basis of extreme emotional behavior
> and difficulty in social adaption on soy-fed infants. Once again, this
> is not going to show up in looking at growth in the first six months
> of life.
>
> Our recommendations; we urge the FDA to
>
> follow the cautionary principle and take soy formula off the market,
> make it available only by doctor\'s prescription and to provide
> pediatricians with the recent studies indicating the dangers of high
> levels of isoflavins in the diets of infants.
>
> We think that the promotion and development of a meat-based formula
> should be a top priority. Gerber used to produce a meat-based formula.
> Finally, we encourage renewed emphasis on breast feeding and healthy
> diets for breast-feeding mothers.
>
> We are a nonprofit nutrition education foundation. We encourage you to
> visit our website. We promote a return to traditional foods and
> nutrient-dense diets, especially for our pregnant women, nursing women
> and growing children.
>
> Thank you very much for the opportunity to testify today.
>
> DR. RUSSELL: Thank you. Your talk was not provided to the committee
> members in the briefing materials. I wonder if you are planning to do
> that for us or if your talk is on your
>
> website that you have posted up there.
>
> MS. FALLON: I can get it on the website right away. I do have notes
> here. We also provided about 60 or 70 pages of testimony. I don\'t
> know if it is in your packet, but we certainly submitted a lot of
> testimony.
>
> DR. RUSSELL: It is not in the packet that this committee received. But
> a copy of your talk would be very helpful.
>
> MS. FALLON: I have it here. I will leave it with Linda.
>
> DR. RUSSELL: Thank you. If you wouldn\'t mind staying up there for a
> little bit. If the committee has any discussion or comment on this,
> this is time to ask questions or to get clarifications or comments.
>
> **FAC Discussion and Comment**
>
> DR. RUSSELL: Dr. Aller?
>
> DR. ALLER: Not so much a question for our speaker but rather for the
> committee, or for the subcommittee, was this topic discussed at the
> subcommittee at all? Again, I am just curious.
>
> MS. LATHAM: We did not single out any specific types of\--infant
> formulas were not singled out such as this. They were groups of
> different types of formulas were discussed as a whole.
>
> MS. FALLON: We did submit testimony to both committee meetings, both
> times.
>
> DR. RUSSELL: Any other questions?
>
> DR. CALLERY: This is Pat Callery. A follow up of your question. Did
> the subcommittee discuss developmental measures beyond just the weight
> and height that would be more in the neurological area and in the
> reproductive area that were described here?
>
> MS. LATHAM: I believe we were just basically talking about the
> physical growth factors and we primarily talked about the
> anthropometrics. I believe that there was some very brief discussion
> about neurologic, but that was the focus of the meeting.
>
> DR. RUSSELL: Dr. Dwyer?
>
> DR. DWYER: I haven\'t had a chance to read it yet, but the Committee
> on Nutrition of the
>
> American Academy of Pediatrics periodically puts out a Yellow Book
> that reviews a lot of topics on infant feeding. I don\'t remember the
> past Yellow Books singling this out after they have all of the looks
> at all the evidence.
>
> Could you, perhaps, tell us why you think that the studies you have
> suggested come to such a different conclusion?
>
> MS. FALLON: I hate to speculate. The concerns have been expressed by
> public groups only in the last few years. We have actually been trying
> to get a meeting with the American Academy of Pediatrics. Our phone
> calls are never returned.
>
> We were just founded in 1999 and kind of got going in 2000. Our
> Director of Public Affairs has attended all of the meetings on infant
> formula and we have presented a large number of studies that we urge
> the committees to look at. We would very much like to open a dialogue
> with the American Academy of Pediatrics. Our Director of Public
> Affairs was in Chicago just recently but was unable to get a meeting.
>
> DR. RUSSELL: Dr. Durst?
>
> DR. DURST: I am not a nutritionist, but I think studies such as this
> point out the importance of not only considering growth but that
> long-term effects are very critical. I can imagine there are a number
> of infant formulations that can provide growth but may actually have
> other deleterious effects that don\'t show up until later in life.
>
> DR. DOWNER: Goulda Downer. I think what we really need, though, would
> be to get a plethora of data to suggest what she has presented today.
> Clearly, there may be a potential for long-term effects of not just
> soy but other products. But just one or two pieces of research is not
> enough. And I am a nutritionist.
>
> DR. RUSSELL: I have a question. Dr. Russell. With regard to the JAMA
> study that you talked about, I actually forget whether\--you mention
> the higher rates of the asthma and reproductive abnormalities in
> adults who have been fed soy infant formulas. Were those results
> actually statistically significant?
>
> MS. FALLON: No; they were not. It was not a very large study, either.
> It would have been very hard to get statistical significance. There
> were many flaws in that study and I can send you an analysis that we
> did of the study. Just the way the questions were asked and the
> parameters that they used, we felt that the study was very superficial
> and very flawed.
>
> I would be happy to provide you with our analysis of that.
>
> DR. RUSSELL: I think that would be helpful, yes. Thank you.
>
> Any other questions or comments? If not, thank you very much.
>
> MS. FALLON: Thank you.
>
> DR. RUSSELL: At this point, while we reorganize again, another very
> short break of five minutes while Dr. Miller resumes the Chair here.
> Thank you.
>
> (Break.)
>
> DR. MILLER: I want to thank Dr. Russell for taking over the Chair.
> What I am going to do
>
> is to ask certain members of the committee to take some notes on the
> discussion so that we will have some kind of record when the meeting
> is over to make some recommendations, if necessary, to CFSAN.
>
> The next topic is from the Contaminants and Natural Products
> Subcommittee which has to do with Enterobacter sakazakii. The
> presenter will be Dr. Frank Busta who is the Chairman of the
> Committee.
>
> Frank?
>
> **Contaminants and Natural Toxicants**
>
> **Enterobacter sakazakii**
>
> DR. BUSTA: Thank you, Sandy. As you heard, I am Frank Busta. The
> committee had a very interesting and comprehensive meeting. As you can
> see in the report, we had a series of presentations from guest
> speakers including the marketing and use of powdered infant formula, a
> review of the case of a Tennessee outbreak as well as case reports
> from British outbreak situations.
>
> Then the medical consequences of Enterobacter sakazakii, and I will
> just say E. sak
>
> for all of our ease. It is a lot faster. Infections as well as the
> general microbiology, the detection methodology, thermal and other
> resistances by the organism, and then some field studies that FDA
> conducted.
>
> There were a series of public comments from a number of individuals
> representing industries as well as the International Formula Council
> and an individual from a medical college.
>
> As you can see in your report, the questions that we received as a
> charge was, one, characterize the infants at risk. We were asked is
> there a risk and, if so, identify the infants that are at risk. Here
> is a situation where we actually voted unanimously on the answer to
> that question and saying that, yes, there is a risk.
>
> We identified, and you can see the comprehensive identification of the
> infants that would be at risk, mainly the preemies, immunocompromised
> infants and those in neonatal intensive-care units. The subcommittee
> thought that there was probably a low but yet unquantified
>
> risk to healthy term infants and really couldn\'t describe that at the
> point.
>
> Our second charge was, if there is a meaningful risk, how can the risk
> be addressed. As you see, the first question is intervention
> strategies in manufacturing. We discussed that extensively, methods to
> reduce bacterial presence in the manufacturing process. There is a
> series of interventions that were identified.
>
> The development of microbiological sampling programs was also
> discussed and it was indicated that FDA and the industry formally
> assess the contribution of a microbiological testing program, whether
> it would help with the intervention.
>
> In discussing the currently available processing technologies, it
> appears that E. sak cannot be completely eliminated for the at-risk
> populations. We really don\'t know if the indicated interventions will
> actually improve the situation.
>
> Continuing on in other intervention strategies in handling practices
> and other aspects,
>
> it was recommended that the FDA, with input from the industry, prepare
> educational documents and distribute those and get those to the
> healthcare users because it was apparently some healthcare users do
> not understand that powdered infant formula is not sterile and,
> consequently, there can be some mishandling and, if it is possible,
> based on available information, specify allowable lower limits for the
> microbial detection of E. sak. The subcommittee said there was not
> sufficient information to make that kind of judgment at the present
> time.
>
> Finally, the subcommittee identified a series of information gaps, a
> lot of them ideal research and surveillance needs including
> inactivation post-drying of E. sak. If I were to do this again, I
> would separate the first bullet into two. The second one is continuing
> the methods to detect E. sak.
>
> Number three there is to document the occurrence of the organism in
> powdered infant formula, develop means of sterilizing powdered
>
> infant formula, develop sterile liquid products for use in the at-risk
> populations, identify pathogenic factors in the organism that result
> in the disease, do continued population surveillance on the incidence
> of the infection, assure that
>
> clinical-laboratory procedures are available to identify the organism
> and the last, but far from least, determine and develop the optimal
> therapy for infected infants.
>
> Thank you.
>
> DR. MILLER: Thank you, Frank.
>
> Any questions from the committee?
>
> DR. DURST: Frank, is there any information available on the resistance
> of E. sak to sterilization? Is it especially robust or is it something
> that could be easily sterilizable.
>
> DR. BUSTA: We obviously have one of the experts sitting over here to
> my right, but, as I recall, it appears that some of the E. sak is more
> resistant to dehydration, may have a fair amount of resistance, but
> the normal handling of
>
> infant-formula components, it would appear that at
>
> least some of the processes would inactivate the organism in it. So,
> post-processing contamination appears to be one of the major sources.
>
> Bob, am I still on the right track?
>
> DR. BUCHANAN: It is not a particularly heat-resistant organism but,
> within the Enterobacteriaceae, at least some of the strains have some
> fairly substantial heat resistance at non-boiling temperatures. It
> does survive quite nicely in dehydrated products. We have it surviving
> for well over a year now in infant formula. It does also have the
> characteristic of coming out of the dry state and growing quite
> aggressively so it does represent some unique challenges.
>
> But, in the greater scheme of things; no, it is not a heat-resistant
> organism though it is relatively heat resistant to close cousins, E.
> coli, Salmonella, et cetera.
>
> DR. MILLER: Would everybody identify themselves for the record,
> please.
>
> DR. BUCHANAN: Sorry. Bob Buchanan, FDA.
>
> DR. DURST: That was Richard Durst asking the question.
>
> DR. MILLER: Thank you. Dr. Dwyer?
>
> DR. DWYER: I was just wondering where it came from, and I think it is
> not just
>
> post-production. It is in the raw materials as well, or isn\'t that
> known?
>
> DR. BUSTA: I am not sure that the comprehensive investigation of that
> is complete. I think it has been found in the environment in the plant
> and its origin, I am not sure it has been highly traced as to the
> origin. I am waiting to see\--am I, again, interpreting that right? I
> got a nod from Dr. Buchanan.
>
> But, as I recall, it has been identified in the processing-plant
> environments and, consequently, that is one of the interventions that
> is being worked on.
>
> DR. DWYER: May I ask a follow-up question?
>
> DR. MILLER: Of course.
>
> DR. BUSTA: Yes.
>
> DR. DWYER: If it is true that what you say is that every effort should
> be made to avoid feeding powdered infant formula to at-risk infants
> who include immunocompromised infants at any age, does that mean
> that\--what do you do with powdered formula in Africa, for example,
> where are lot of very sick babies are being fed and I assume they are
> being fed powdered.
>
> DR. BUSTA: That is probably a larger question than I can answer, but I
> know that, for clinical situations or neonatal situations where the
> infants are ill or preemies, it was suggested, I think by some of the
> committee, that they might just use sterilized liquid formula. Then
> the concern was that the individualized needs for each of these
> situations is such that the production of sterile liquid infant
> formula for each of those groups is at least not yet feasible.
>
> There was also a concern about rehydrating with very hot water so that
> you would inactivate the organism with the heat treatment of just
> rehydrating. The concern that I recall expressed
>
> was hazardous situations of using boiling water to rehydrate the
> formula and possibly losing some of the nutrients in the rehydration
> of that hot water.
>
> For international use in immunocompromised populations such as in
> Africa, I don\'t recall that being surfaced at the meeting that we
> had.
>
> DR. MILLER: Dr. Lund?
>
> DR. LUND: I was going to ask a procedural question on this. What does
> this committee do with the report from the subcommittee? Do we take an
> action on this report?
>
> DR. MILLER: The major function of this meeting is for the
> subcommittees to report back to the parent committee to provide
> information. Our role is to ask questions that maybe should be
> rediscussed or relooked at, or not. If we are satisfied with the
> report, then that is okay, too.
>
> DR. LUND: I guess that leads to the question, Frank, there are
> recommendations in here with regard to specific things that should be
> done. With regard to the information that Dr. Durst asked with regard
> to its susceptibility to various
>
> treatments, et cetera, that is also one of the recommendations from
> this committee?
>
> DR. BUSTA: Yes. As I recall, the study of the organism and the study
> of interventions are, I think, ongoing but encouraged by the
> subcommittee.
>
> DR. MILLER: Members of the committee ought to be prepared when we come
> to the end of the meeting to indicate where they disagree with the
> subcommittee reports. I would like you to raise that question now, now
> that we are discussing it. But, when all is said and done, the
> committee is going to have to sign their names to a report that says
> that we can find no area of disagreement, not because they are
> necessarily experts, but based on our general knowledge of the area.
>
> What I am also going to do is to ask some of you to serve as kind of a
> monitor and to prepare a brief note of discussion as it goes on, not
> of the report, itself, because that we have copies of, but a brief
> note of the discussion and any important points that came out of the
> discussion
>
> that we think ought to be highlighted in the final report.
>
> DR. KRINSKY: Krinsky, Tufts. I just wanted to know if there was any
> follow up to the recommendation that the FDA should prepare
> educational documents. Has that been carried out in the nine months
> since the subcommittee reported?
>
> MS. LATHAM: This is Jeanne Latham. That is something that is in
> process with that process.
>
> DR. MILLER: Any other comments or questions?
>
> DR. DOWNER: Yes. Goulda Downer. How long would something like that
> take before the public becomes aware of the recommendations, the
> educational materials?
>
> DR. MILLER: How long does it take the recommendations of the
> committee?
>
> DR. DOWNER: For the educational materials to be developed. As I think
> about Johanna\'s question, and she talked about Africa, I am also
> thinking about, as the consumer rep, those resource-poor communities
> in this country and those
>
> communities that have a lot of migrant populations that prefer to use
> the powdered formula than the liquid ones.
>
> So, based on that, I am asking how soon will those recommendations be
> available for the public?
>
> DR. MILLER: Bob has an answer?
>
> DR. BUCHANAN: This is Bob Buchanan from the FDA. The questions that
> were posed to the subcommittee were specifically oriented to the
> situation here in the United States. In addition, the Food and Drug
> Administration has brought this issue up through the Codex
> Alimentarius system and has requested that the Codex Alimentarius Food
> Hygiene Committee reexamine the current code of practice for powdered
> infant formulas. This is an agenda item currently being considered at
> that level.
>
> In addition, at our request, we have gone to WHO-FAO to request an
> expert consultation on this subject matter looking not just at the
> situation here in the United States but infant
>
> formula on a broader framework, or that is what Codex Food Hygiene
> would like.
>
> It is my understanding that that consultation workshop is going to
> take place in early February. We have yet to receive the official
> notice, but I understand it is on its way out. So this is being dealt
> with at two different levels but the specific request to the
> subcommittee was oriented towards the condition here in the United
> States.
>
> DR. MILLER: Johanna?
>
> DR. DWYER: Just to follow up again, Dr. Buchanan, to make your life
> more difficult, I guess both Dr. Downer and I were thinking about
> at-risk populations such as the infants of HIV-positive mothers who
> often are immunosuppressed. It seems to me that any information
> activities would have to involve somehow getting information to those
> healthcare providers and, perhaps, also to federal programs that were
> providing food or formula to these folks.
>
> Has the committee made any recommendations
>
> with respect to that, immunosuppressed populations here within the
> United States?
>
> DR. BUCHANAN: Working in conjunction with CDC, when we start to have
> outbreaks associated with this organism, we have already communicated
> some public-health messages out during and with that process. As
> Jeanne indicated, we are looking further into additional methods and
> different vehicles for those messages currently.
>
> We have also looked at the international front in terms of our
> activities associated with the International Code. So we are looking
> at it at multiple functions. We did, immediately, working with CDC, as
> soon as we started having outbreaks, get public-health messages out.
> We always refine those over time.
>
> DR. WASLIEN: This is Carol Waslien from the University of Hawaii. This
> brings to mind some of the things the U.S. ran into with problems of
> Vitamin A in infant formula that the U.S. was distributing through its
> AID Program. Even though this is a question for consideration inside
> the
>
> U.S., the fact that U.S. is essentially distributing a product that
> might be dangerous out for other countries puts it into the framework
> of something that the U.S. should consider even though it might be
> that the target audience is not U.S.
>
> DR. MILLER: Would it be fair to say that there is a general consensus
> on the committee that CFSAN ought to pay increased attention to making
> sure that educational materials are provided on the international.
>
> DR. WASLIEN: Yes.
>
> Any other questions before we move on?
>
> Thank you.
>
> Dr. William MacLean of Ohio State University has a public comment.
>
> Dr. MacLean?
>
> **Public Comment**
>
> DR. MacLEAN: Thank you, Mr. Chairman. My name is Bill MacLean. I am
> here as a paid consultant on behalf of the International Formula
> Council which represents the formula manufacturers in the U.S. I
> should also note that I recently
>
> retired as Head of Medical and Regulatory Affairs at the Ross Products
> Division of Abbott and am a stockholder of Abbott Laboratories.
>
> On behalf of the IFC and its members, I want to thank you for this
> opportunity to speak to you on issues related to, as we will refer to
> it, the E. sak issue and powdered infant formula.
>
> The subcommittee has recommended a number of intervention strategies
> to reduce the risk of E. sak infections, including the development of
> a microbiological testing program as well as the development of
> educational materials. Since these recommendations were released, the
> infant-formula industry has provided FDA with a number of proposals
> and discussion documents to address these intervention strategies.
>
> We are also providing you today with a preliminary brochure that
> addresses one of the issues you have been talking about. This is
> entitled Infant Feeding; Safety issues for Healthcare Professionals.
> If you don\'t have it, it is available for you at the table outside, I
>
> believe.
>
> We also understand that FDA acknowledges the interim nature of the
> subcommittee review and we strongly concur with the FDA\'s plans to
> continue to work in combination with industry to further address these
> issues.
>
> Today, I would like to speak about two unresolved issues, specifically
> the population at risk for E. sak infection and the microbiological
> and sampling program. Let me take the infants at risk first.
>
> We agree with the subcommittee that preterm infants born at less than
> 36 weeks gestational age and up to a post-term age of four to six
> weeks, that immunocompromised infants at any age and term infants
> hospitalized in Level 2 and Level 3 neonatal intensive-care units are
> at risk and that this risk is low but unquantified.
>
> As the subcommittee suggests, we do not believe that this low but
> unquantified risk extends to healthy term infants. The presence of
> extremely low levels of the organism as reported by the FDA,
>
> the group in Canada, the group in Holland, does not begin to suggest
> that an infant formula used as recommended is unsafe for term infants.
>
> There is a near absence of reported cases of E. sak-related illness
> despite feedings to millions of full-term infants each year. The only
> reported occurrence of disease in healthy term infants in which
> reconstituted formula has been contaminated also had evidence of
> external contamination or mishandling of the reconstituted product.
>
> Furthermore, these infections are almost exclusively associated with
> preparation and use of reconstituted powder formula in hospital. Thus,
> FDA should not extrapolate to term infants any assessment of risk
> derived from disease among immunocompromised and low-birth-weight
> infants.
>
> The subcommittee recommended, and we agree, that \"Every effort should
> be made to avoid feeding powdered infant formula to these at-risk
> infants.\" However, as Dr. Thureen commented during the
> subcommittee\'s deliberation, it is important to
>
> maintain perspective on the low risk of E. sak infection relative to
> all the other more common pathogens and other hazards to which preterm
> infants are exposed in the neonatal intensive-care unit.
>
> We would like to reemphasize that, in many cases, there is a medical
> need for powdered products. Powdered products offer a significant
> benefit to the 10 to 15 percent of babies who are born prematurely
> and/or with low birth weight. Powered human milk fortifier is a prime
> example of this.
>
> Human milk is known to offer significant advantages to preterm infants
> yet it is nutritionally inadequate for preterm infants unless it is
> supplemented. The availability of these and other powders offer
> neonatologists flexibility to provide individual nutrition to these
> low-birth-weight infants that simultaneously accommodates things such
> as fluid-restricted diets, delivery of specific nutrients and desired
> improvements in growth.
>
> These medical benefits must be weighed against the very low risk of E.
> sak-related disease in the at-risk population. Any decision to remove
> powder from the NICU would place neonatologists in an untenable
> position.
>
> Risk management should focus on formula handling, especially after
> reconstitution, not the elimination of powdered infant-formula.
> Despite continuous improvements in manufacturing, it is important to
> recognize that manufacturing changes are going to play a relatively
> limited role in risk management.
>
> FDA also charged its surrogate to identify intervention strategies
> that can be used in
>
> infant-formula manufacturing processes and plants. The subcommittee
> encouraged the development of a microbiological sampling and testing
> program through joint efforts by industry and FDA. The infant-formula
> industry has provided FDA with two possible options to assess
> microbiological control.
>
> A workshop was held on November 7 of this year in which some
> differences in laboratory
>
> procedures used by FDA and industry were identified. Alignment of
> testing methodology in use by both FDA and industry is essential.
> Pooled industry data revealed about a ten-fold lower prevalence rate
> of E. sak than FDA\'s 2002 field survey.
>
> There is no validated method to test for E. sak in powdered infant
> formula. The current FDA methodology detection limits are inconsistent
> with its zero-tolerance policy. Newer methodology, for example, for
> conformation of isolates using DNA showed that 39 percent of 77
> samples identified using conventional testing methods were, in fact,
> not E. sak.
>
> Thus FDA and industry\'s employing a common validated methodology will
> ensure that E. sak in powdered infant formula is consistently and
> accurately monitored and reported.
>
> It is essential that we continue to further define and reduce, to the
> extent possible, any potential risk posed from powdered infant formula
> while assuring that this product, which is
>
> essential for the health of infants remains available. Efforts by
> industry, academics, practitioners and regulators should continue to
> include actively collecting information about the organism, itself,
> including all the possible ways infants might be exposed to the
> microorganism and the frequency and incidence of its occurrence. A
> sound risk assessment can only be conducted once the infectious dose
> is known.
>
> Mr. Chairman, if I might, it was not part of my original remarks but
> there has been a lot of discussion and comments about the issue of
> powdered formula in Africa. If I might, I would offer an answer, a
> personal answer, as a pediatrician who has worked in malnutrition
> outside the U.S.
>
> DR. MILLER: If you can do it two minutes.
>
> DR. MacLEAN: I can do it in two minutes. Dr. Dwyer raised the
> issue\--my understanding, Dr. Dwyer, is that most of the powdered
> formula that is used in AIDS in Africa, for example, is infants who
> have been born to HIV-positive mothers, most of whom, or many of whom,
> have been dosed with drugs
>
> at or around the time of delivery and, therefore, the goal is to
> prevent vertical transaction to these infants through breast feeding.
> In other words, these babies are, in fact, generally healthy term
> infants who do not yet have HIV.
>
> The second point I would make is that the risk of using any formula
> but, in particular, powdered formula, be it in these infants or normal
> infants in developing countries, the risk of contamination through
> water and reconstitution is far, far greater than the risk of E. sak.
> Just to put that in perspective for you, the detection of E. sak in
> powdered infant formula in this country is about 0.36 colony-forming
> units per 100 grams which means that, in two-and-a-half to three days
> of feeding, an infant would get one organism which is many log orders
> below what they would need based on what we know for infection rates.
>
> The key thing is, after it is reconstituted, to feed it before the
> organism can go into a growth phase. If that is done, my view is that
> the risk would be relatively low. The
>
> issue for formula for any of the pathogens is dirty water, improper
> reconstitution and then storage without refrigeration.
>
> Thank you, sir.
>
> DR. MILLER: Thank you.
>
> Are there any questions for Dr. MacLean?
>
> DR. DURST: Durst. Can you provide the reference on this new
> methodology for confirmation of the isolates? It is 16SR RNA. This is
> not always the most specific methodology and I was just curious is
> there is a reference available on that.
>
> DR. MacLEAN: I believe there is. We will certainly provide you what we
> have.
>
> DR. DURST: Thank you.
>
> DR. MacLEAN: I am not a microbiologist so I cannot answer your
> question beyond that.
>
> DR. MILLER: Dr. Dwyer?
>
> DR. DWYER: Thank you for those clarifications, Bill. I certainly think
> you are absolutely right about getting validated and agreed-upon
> methods.
>
> The other issue that you spoke to and we
>
> got a chance to at least glance at the brochure is how important it is
> to have education of everyone in the NICU, at least in this country,
> where many of those babies are residing. I think it is very useful
> that you went with the dieticians who are especially concerned about
> food and see that as sort of their function.
>
> It is also important, of course, to reach the NICU nurses and the
> neonatologists. It seems to me that the detail people who go around to
> these places all the time anyway from the different companies are
> particularly good a delivering messages like this. Maybe that is a
> useful partnership for the public health.
>
> DR. MacLEAN: Yes. I agree with you entirely.
>
> DR. MILLER: Other comments or questions? If not, thank you.
>
> DR. MacLEAN: Thank you.
>
> DR. MILLER: That completes our discussion of the report of the
> Contaminants and Natural Toxicants Committee.
>
> Before we move on, I understand that Mr. Levitt is here and is going
> to make his delayed opening remarks. Just make sure you put it in the
> right place in your notes.
>
> **More Opening Remarks**
>
> MR. LEVITT: Thank you very much. It is a pleasure to be here and to
> see so many of you. It was just a couple of weeks ago where we were
> very pleased to send around, and I hope people got copies, our
> end-of-year accomplishments for CFSAN for 2003 where, again, we were
> pleased that we not only reached but exceeded our goal of completing
> over 90 percent of our priorities for the year.
>
> That is not only the second year in a row we were able to do that,
> but, as we went back and looked at the actual number, not percentage,
> we actually mapped out that, over the last five years, we have
> actually gotten more done each year and we feel very good about that.
>
> But I gather that news got a little bit foreshadowed a week later when
> I announced that I had decided to retire from the federal government
>
> and go back to my roots and be a lawyer. Hard to imagine, by some, I
> guess. But I will be retiring at the end of this month and begin a new
> career in January.
>
> So I am particularly pleased, as I try to go around and reach closure
> in different forums, that Food Advisory Committee was meeting this
> month because it gives me an opportunity to directly thank you, say
> good bye and give you a few thoughts of my own.
>
> Over the last six years, one of the things we really set out to
> accomplish was to strengthen the scientific base underpinning and
> stature of the Center for Food Safety and Applied Nutrition. I
> remember, just after I got appointed, one of the first people I spoke
> to was Sandy Miller. Sandy was frank, as always, and said, \"Joe;
> it\'s the science. It\'s the science.\" Right, Sandy? That\'s what he
> said.
>
> DR. MILLER: You were a lawyer, you see.
>
> MR. LEVITT: That\'s right. You see, it all kind of comes in a nice
> circle. We have, I
>
> think, made very, very good progress in that area. We started this
> fiscal year about 200 people above the number we had when I started.
> When I came, it was about 750 people in CFSAN. We started this fall,
> this fiscal year, at about 960.
>
> That is the net increase. The actual number of new people, because a
> lot of people left who retired, it is more like 300, 350. We have been
> able to recruit a wide cadre of people with strong scientific
> expertise, a high number right out of college or out of graduate
> school, a number of others with much more experience. We, I feel, have
> infused a strong level of science throughout the organization.
>
> Dr. David Acheson, who you will be seeing this afternoon, is certainly
> one of those and I think is an excellent example of the kind cadre of
> people we have been able to attract to CFSAN. I feel good about that.
> Together with the scientific stature goes with the importance of
> follow-through and productivity. As I said, with our accomplishments,
> I feel we have been able to do
>
> that.
>
> Part of all this, of course, is the work of the Food Advisory
> Committee. I believe that the work this committee does is critically
> important. It helps in adding openness and transparency to the work we
> do. It certainly strengthens even further the scientific expertise
> that we bring to our decision-making and it provides an additional
> level of independent advice, which we need and we value.
>
> We have also, as you know, greatly expanded the Food Advisory
> Committee. When I came, there was one standing advisory committee. I
> remember my first meeting was on Olestra, so we got a good initiation
> on that but really saw that there was a value in greatly expanding the
> reach of the advisory committee and went out and have established six
> subcommittees a number of which a number of you chair. I want to thank
> all of you who are already giving reports on today. But we have
> subcommittees on Infant Formula, Contaminants and Natural Toxicants,
> Food Biotechnology, Food Additives and Dietary Supplements and a new
> one
>
> which we have just established and will be meeting this year, we hope,
> in Nutrition.
>
> So, again, I thank everybody for your work on there. I really believe
> that the role of this kind of committee and the subcommittees and the
> public discussion of the very important issues we face is an enormous
> benefit to the FDA and to the public.
>
> We have, just within the last year, taken on, or a couple of years, a
> number of very important issues, as you all know, and have
> participated in. Methylmercury, which was probably one of the, I
> think, most visible in watershed meetings on the Food Advisory
> Committee and I think it is appropriate that the last meeting I am
> able to address is also revisiting methylmercury.
>
> I will those this afternoon go into the details of it but we did very
> much take your recommendations to heart and have gone back and tried
> to answer those questions in terms of what does it mean to eat a
> variety of foods and what is the contribution and the role that tuna,
> in
>
> particular, plays and what are the scientific exposure and risk
> assessments, what is the best advice to children.
>
> I think you will see we have come back and done our best to try to
> answer those questions, work them into advice and probably, maybe even
> most importantly, work hand-in-hand with EPA. I remember that was one
> of the significant recommendations that came out and I think you will
> see FDA and EPA standing up here together.
>
> As before, we will continue to welcome additional advice you have. It
> is hard to get an issue of that level of complexity exactly right. I
> have no doubt that people will have additional thoughts as we try and
> provide the very best advice to women that we possibly can.
>
> We have also taken on other issues; acrylamide, E. sakazakii, that I
> just heard some discussion about, latex, food biotechnology, dietary
> supplements. These are all issues that are ongoing and we will need
> your continued advice and counsel. And I thank you for that.
>
> I want to give particular thanks to our distinguished Chair, Dr. Sandy
> Miller. Sandy has provided, for me, personally as well the Center, a
> number a important roles. When I first came to FDA, Sandy, was, of
> course, a Director of the Center for Food Safety and Applied
> Nutrition, or I guess it was the Bureau of Foods, at the time and
> actually renamed it Center for Food Safety and Applied Nutrition.
>
> So, when I first came to FDA, that was my model of what the Food
> Center ought to be and what the Director ought to be. While I doubt I
> have been able to measure up entirely, I have tried to at least follow
> with the degree of trying to engage on the issues that I know Sandy
> always brought when he was at FDA, and has ever since, and, as Chair
> of this committee, you have brought just the right level of, again,
> continued candor, focus, scientific expertise and discussion of the
> issues in an open form and I thank you so very much, as I know does
> the entire Center.
>
> DR. MILLER: Thank you, Joe.
>
> MR. LEVITT: I want to extend thanks to the different subcommittee
> chairs. You may not have known what you quite signed up for but,
> again, I think you will find the time invigorating and rewarding and
> probably a little frustrating, too. That is okay. That is part of the
> picture.
>
> One thing you are also finding at FDA is, while I, as an individual,
> am retiring it is also a time at FDA where there is a significant
> turnover for a number of different administrative reasons. Actually,
> with CFSAN, there are about 50 people that are retiring at the end of
> this month or during this month.
>
> One of those people I want to recognize here that has been very close
> to the members on the Food Advisory Committee is Cathy DeRoever. Cathy
> has been serving as the Exec Sec kind of since time immemorial, it
> seems. But, as you know, there isn\'t anything of this magnitude that
> happens simply. Putting together an advisory committee is a tough job.
>
> You have got to, first of all, find the
>
> right people and do all the right background checks and be sure that
> we have the right expertise and the right balance and the right focus
> from lots of different quarters. You have got to put together these
> meetings which are no mean feat. Just getting a date for the meetings,
> itself, deserves a Nobel Prize, I think. But to try to get the
> facilities and the hotels and the accommodations and the schedules for
> everyone is no small feat. And Cathy has done it with extraordinary
> capability and with grace and I want to publicly thank you, Cathy, for
> your contributions here and in many other areas throughout your career
> at CFSAN. So I want to extend our personal thanks to you, also.
>
> Finally, I will want to do here what I am trying to do in as many fora
> as I can which is to help what I hope will be a very smooth transition
> at the helm of CFSAN. When the Commissioner, Mark McClellan, came out
> the day that we announced my retirement to CFSAN, had four main themes
> that he tried to enunciate and which I will try to reiterate and try
> reinforce.
>
> The first is that the Food Center is doing well, that we have amassed
> a strong record of accomplishment and he feels very good about that.
> As you know, I feel very good about it, as well, as I think do many of
> our stakeholders and staff members. So it feels good for me kind of
> going out when the program is at least, I can\'t say on top because I
> expect it to be even butter, but certainly doing well.
>
> Second, and, again, this is a good feeling for me but I think an
> important message for everyone that his charge to the Center was
> continuity, continuity of priorities, continuity of the way we have
> been conducting business. The FDA announced this past summer a
> Strategic Action Plan which goes to a number of cross-cutting areas
> and the Food Center is heavily involved in virtually every single one
> of those. So I think the theme of continuity is also important.
>
> Third is smooth transition. I am working with Dr. Bob Brackett very
> closely\--he is here. I am going to announce and introduce him in a
> minute
>
> and give him a chance to stand up and say hello and introduce
> himself\--ut working very hard within and without so that continuity a
> priority, to have that continuity of leadership. I think people know
> that I was very involved with bringing Bob to CFSAN. So, for us, that
> smooth transition feels very comfortable.
>
> But I want to be sure we are reinforcing it. In keeping with that,
> finally, I think the future\--and I know the Commissioner shares
>
> this\--the future of CFSAN and foods programs at FDA is a bright one.
> We have put in place a lot of things built on strong traditions in the
> past, strength in the science and sheer productivity, bringing in
> outside advisors. I think I look forward, in my new capacity, to both
> viewing that and contributing in different ways.
>
> With that, I just want to take a moment and introduce and invite up to
> the podium so you can meet him directly Dr. Robert Brackett who will
> be the new CFSAN Director starting January 1. Bob is already here but
> he is going to have to wait and
>
> let me just introduce him for a second.
>
> Bob came to CFSAN in the spring of 2000. Before that, he was actually
> a member of the Food Advisory Committee and those who are on the
> committee, then, for a short time. He didn\'t last long because we
> gobbled him up. Sometimes you see somebody and you say, this guy is
> too good. We can\'t let him get away. We knew that he was one of them.
>
> Bob has a Ph.D. in microbiology from the University of Wisconsin. He
> came most recently from the University of Georgia, Center for Food
> Safety, under Michael Doyle\'s operation there. I am sure many of you
> know him. He has co-chaired, over the last couple of years, in his
> capacity as Director of Food Safety in our Center, the Joint Advisory
> Committee that we have with USDA, what is called the National Advisory
> Committee for Microbiological Criteria for Foods. Somehow, somebody
> came up with the acronym NACMIF. I first said, what is a NACMIF?
>
> But it is a strong joint committee and Bob
>
> brings his expertise in co-chairing it. Within the Center, he began as
> a senior microbiologist within our Office of Plant and Dairy Foods and
> Beverages, what we finally referred to as Landfood.
>
> He quickly moved up to be Director of Food Safety. Last spring, as the
> issues of counterterrorism rose to the fore, we added to his
> responsibilities to make him also Director for Food Security as well
> as Food Safety.
>
> In my dealings with him, Bob has, I think, simply exemplified the very
> best of what we have tried to recruit into CFSAN and bring strong
> science, strong integrity, clarity of thinking and, above all, a
> desire to do what is good for the public good.
>
> So, while everybody knows no one is allowed to choose your successor,
> but you are allowed to take a great pride in one when someone such as
> Bob is named. So, please, give a warm welcome to Dr. Bob Bracket.
>
> (Applause.)
>
> DR. BRACKETT: Thank you, Joe. I would
>
> like to say hello to all of you. Many of you I know quite well. Many
> of you I don\'t know yet but I do look forward to getting to know you
> better on this committee.
>
> As Joe said, I was a member of the advisory committee about the time
> that they tried recruiting me. In fact, Cathy DeRoever and I spent
> time in the hallways between some of the meetings talking about things
> that we might do. So I am very, very supportive of the advisory
> committees. I think the scientific advisory committees are to our
> policies and to our science what the journal management and editorial
> boards are to scientific journals and I think that is very important,
> as Joe mentioned.
>
> So I will say that I will look forward to meeting all of you. Please
> feel free to call on my if there are things that I can do in my new
> capacity. Joe has left a very big set of shoes to fill but, at the
> same time, he has done everything he can to make it as smooth for me
> as he possibly could and I do thank him for that.
>
> DR. MILLER: Thank you, Bob. Thank you, Joe. The torch passes on.
>
> I was going to ask to see if anybody had any questions for the new
> Director, but I decided discretion was the better part of valor in
> this case. Let\'s keep everybody friendly for the moment.
>
> The next report is on Dietary Supplements. Johanna Dwyer is going to
> make a presentation. What I normally do is try to ask somebody to make
> a brief note of the discussion. I have asked Daryl Lund to make the
> one on Contaminants and Natural Toxicants. But I think it might be
> useful if we ask the Chairman of the subcommittee to do that for us.
> So, Johanna?
>
> **Dietary Supplements**
>
> DR. DWYER: This committee had a very interesting challenge. We met in
> March. If you look in Tab 1, you will see all of the details of the
> meeting. But the basic question had to do about the definition of
> metabolite.
>
> The first question we were asked to answer
>
> was whether it was possible to identify a particular set of scientific
> criteria or principles to determine whether a substance was or was not
> a metabolite of another dietary ingredient.
>
> Dr. Dickinson was there. I had a wonderful committee to think about
> this with but I have to tell you, Dr. Miller, all through this
> meeting, I kept thinking about you from many, many years ago when you
> were a Professor at MIT and I was privileged, or whatever, to take
> your course. You always asked us questions like this; what is a
> metabolite.
>
> Thanks to several members of the committee, we did come up with a
> definition. It is a wonderful question for those of you who have to do
> oral exams for Doctoral students. We decided that X is a metabolite of
> Y if ingestion of Y by humans results in net production of or
> increased flux of X incorporating structural elements of Y. Now, if
> that doesn\'t sound like E=mc^2^, I don\'t know what does.
>
> But if you think about it and reason about
>
> it, you will see that it pretty much does cover the questions that we
> were asked to answer. We do have a few caveats there that we have
> listed in depth in the report.
>
> The second question we were asked
>
> to\--there is one interesting one that I call to your attention and
> that is whether human ingestion included or did not include changes in
> substances by the microflora of the gut. We decided we thought it did.
>
> The second question we were asked, again focusing on what is a
> metabolite, was whether the strengths and weaknesses of the concepts,
> whether there were some concepts that were necessary to consider with
> respect to their usefulness in identifying whether a substance was or
> was not a metabolite of another dietary ingredient.
>
> One criterion was direct or indirect participation in catabolic or
> anabolic sequences or pathways. The second issue we were asked to
> consider was proximity. The third, in terms of semblance to another
> dietary ingredient with
>
> respect to structure, function or a combination of them and, finally,
> qualities or similarities to another dietary ingredient relative to
> speed or rates of different sorts, compartmentalization or fate.
>
> Going back to that definition, we agreed that the items that were just
> mentioned did seem to be adequately addressed by our definition. We
> didn\'t agree as to whether metabolites, at least in common parlance
> in the science that most of us were familiar with, were both catabolic
> and anabolic. There was some question about whether you called things
> that were products of anabolism and metabolites. But basically we did
> come to agreement on that, too.
>
> Then the third and final question we were asked was about the
> scientific validity and likely utility of the concepts that we had
> discussed when identifying when a substance wasn\'t a metabolite or
> was of another dietary ingredient and what characteristics associated
> with the criterion made it valid or useful.
>
> We agreed that the definition we sort of forged emphasized product
> precursor relationships, metabolite formation as a result of human
> ingestion, net production of the product from the precursor and also
> it incorporated structural elements. So we were quite pleased with our
> definition.
>
> I would like to recognize Dr. Bonnette who was our officer on this and
> who helped us enormously and see if he wants to add anything to the
> report or if Dr. Dickinson who was present at the meeting does.
>
> DR. DICKINSON: I do not. I think that is very complete. Thank you.
> That was Dickinson.
>
> DR. MILLER: Does that complete your report?
>
> DR. DWYER: That completes it.
>
> **Questions of Clarification**
>
> DR. RUSSELL: Johanna, this is Dr. Russell. I noticed there was this
> criterion that had been requested about the safety component and then
> several members, it says at the last
>
> paragraph, repeated reservations about lack of a safety component and
> the definition. Can you expand on that a little bit more, what the
> arguments revolved around?
>
> DR. DWYER: Yes. I defer to Rich Bonnette who is very well familiar
> with this. I was one of the persons who raised those concerns, as I
> remember from the transcript. I believe the issue there had to do with
> whether\--it really was a legal question more than anything else. As I
> understood it, the answer we were given by the experts who were there
> was that other parts of the FD&C Act and other regulations would cover
> the safety issue and, therefore, we didn\'t need to be as concerned
> about it for this specific thing. Dr. Bonnette, do you want to add
> anything?
>
> You don\'t look like Dr. Bonnette.
>
> MS. LATHAM: No. This is Jeanne Latham. I am actually now the new
> Dietary Supplement Executive Secretary. The Executive Secretary who
> was there was Constance Hardy.
>
> DR. DWYER: Oh; I\'m sorry. I\'m all mixed
>
> up.
>
> MS. LATHAM: You are exactly correct. The discussion points at the
> meeting included the fact that the safety is part of another section
> of the Act and we were specifically focused on the definition of what
> is a dietary supplement or a dietary ingredient.
>
> DR. MILLER: Dr. Callery?
>
> DR. CALLERY: Callery. I wonder if we could get a little more
> background as to maybe beyond what was just said about why the
> question was asked of what is a metabolite. I have a follow-up to
> that.
>
> DR. MILLER: Annette?
>
> DR. DICKINSON: The reason the question comes up is that, under the
> Food, Drug and Cosmetic Act, the definition of a dietary supplement
> includes a specification of what kinds of ingredients it might
> contain. These include vitamins, minerals, botanicals, various other
> ingredients or metabolites of those or concentrates and other kinds of
> things.
>
> So the question for the committee was how broad is that. What does
> that mean, or metabolites of those? So, for purposes of qualifying as
> a dietary supplement, the issue was what is the scope of term
> metabolite.
>
> A second question which Johanna mentioned and which is mentioned in
> the minutes, was we also have other concerns about those ingredients;
> for example, are they safe, are they beneficial, and so forth. The
> nature of this discussion, however, was to answer the definition
> question and there are other sections of the Act that relate to\--even
> if you accept that it meets the definition of an ingredient, there are
> still other criteria about whether it is safe to use and whether it
> may be used.
>
> DR. CALLERY: Then let me add this comment to it. I come from a
> drug-metabolism background. Much of this definition seems to follow
> that type of thinking, what happens to the substance once ingested in
> the body, or what does the body do to the substance.
>
> I have colleagues in phytochemistry and botany and drug-discovery
> people who think of secondary metabolites in plants as a research for
> biologically active substances so that the whole definition of
> metabolite to them is quite different from the human conversion type
> of thinking.
>
> I will give you an example. Out of opium are metabolites\--well,
> morphine is one of them but codeine is another metabolite. Here is an
> indication that, in fact, if you said that that was only one
> substance, then you would not have the definition that they are
> looking for.
>
> So I am wondering if the definition wants to be expanded to other
> metabolites of known ingredients that you can still follow the same
> definition that it is enzymatically formed, et cetera, but it may be
> the enzyme that was in a plant, for example, rather than in the human.
>
> DR. DICKINSON: Right. There was discussion of the fact that we had to
> take into account that there are also plant metabolites of components
> in those plants. But this had to do
>
> with an actual ingredient that is added to a supplement. First of all,
> the ingredient that is added must meet one of the criterion in the
> definition; that is, it must be a vitamin, mineral, botanical, et
> cetera.
>
> The further question then would be what kind of metabolite of that
> ingredient could also be added as an ingredient of a supplement. In
> other words, the metabolite you are talking about would be a
> metabolite already produced by the plant.
>
> DR. CALLERY: Right.
>
> DR. DICKINSON: And, therefore, theoretically, would already be
> eligible for use before you take into account the other restrictions
> on what can be used. The question here is if you took a substance like
> that and, perhaps, in a laboratory created another metabolite of it,
> what would the scope of that term metabolite be? In other words, the
> ingredient that is the metabolite of the plant is already an eligible
> ingredient.
>
> DR. CALLERY: As a botanical.
>
> DR. DICKINSON: As a botanical.
>
> DR. CALLERY: Maybe you want to call it human metabolite.
>
> DR. DICKINSON: We did specify that it is a human\--that metabolite
> for\--
>
> DR. CALLERY: That metabolite means human metabolite. Then another is
> the toxicology part is the conversion of metabolites that make toxic
> products where the precursor is not toxic. Is that now part of your
> definition of metabolite for the conversion to a reactive species that
> may not be necessarily identified?
>
> DR. DICKINSON: And that might be toxic?
>
> DR. CALLERY: Like you have a metabolic pathway.
>
> DR. DWYER: I don\'t think we got into that, did we, Annette? I believe
> that we didn\'t specify whether something was \"good\" or \"bad,\" but
> rather the process.
>
> DR. DICKINSON: That\'s exactly why we got into the safety question
> because, obviously, there would be metabolites of some components that
> would be clearly unsafe. The charge to the committee was
>
> not necessarily to draw those distinctions but to, in the first place,
> say what is a metabolite and then it would be subject to other
> provisions regarding safety as to whether it could actually be used.
> In other word, its safety or non-safety did not affect whether it was
> a metabolite.
>
> DR. MILLER: Do you think it would be worthwhile to recommend to the
> subcommittee to review the definition and clarify it?
>
> DR. CALLERY: I think that it would cause confusion to the plant
> metabolite people if you don\'t say that it human metabolite and maybe
> just adding metabolite by making it clear up front or always that it
> is a human metabolite that you are referring to.
>
> DR. DICKINSON: I think that is included in the definition where it
> says, if ingestion by humans results in\--
>
> DR. DWYER: If the Chairman would allow us\--if I could get your ideas
> on the definition, we can certainly put that in the report.
>
> DR. MILLER: Okay. Other comments?
>
> DR. DURST: Durst. Just a curiosity on the definition why it is
> necessary to have net production and increased flux of X. What is the
> significance of that distinction?
>
> DR. DICKINSON: We had a guy there who knew that but it is not
> necessarily one of us.
>
> DR. DWYER: I can tell you, your questions are very perceptive. One of
> the leading lights in terms of thinking this through and arguing it
> through was Dr. Eric Brass who is a pharmacologist. I believe that the
> transcript, the complete transcript, will get at those points and
> which part of the discussion led us to specify both increased
> production and the increased flux.
>
> DR. MILLER: Dr. Waslien?
>
> DR. WASLIEN: One of the questions is efficacy; correct\--because then
> you would say it had to have an increased production, if you were
> looking at efficacy. But if all you are looking at is a source, you
> wouldn\'t have to have that flux, that increased production. Waslien.
>
> DR. CALLERY: Callery again. Since we got
>
> involved in editing a little bit here, I would like to add another
> need for clarification when you ask, does not violate principles of
> stereospecificity makes little sense. I would recommend that that one
> be deleted.
>
> DR. DWYER: Just share your deletions and emendations with me and I
> will put it into the report.
>
> DR. MILLER: These are all useful recommendations to go back to the
> committee. I assume that this would have to go back to the committee
> for their agreement. Any other comments or questions?
>
> DR. CALLERY: I am not sure we have to hold it up. If that holds it up
> to do these, which I think are minor changes\--
>
> DR. MILLER: I am not prepared to tell the staff how to handle this,
> but one way of doing this is by mail. The committee signed off on a
> particular report and we are making changes and they don\'t seem to do
> violent damage to what they were trying to do. It is a question of
>
> clarification. I think it can be easily done by mail.
>
> That, I think, is one of the functions of this committee. Our role is,
> I think, not to begin debating the science, although that is what the
> subcommittee did. There is no point in repeating it when it is just
> kind to oversee this to make sure that their results are clear and are
> doable and useful.
>
> If there are no other questions, we are going to move on to the next
> presentation which is Additives and Ingredients. Dr. Johanna Dwyer,
> again. You will take some notes on this? Again, I am going to ask to
> inform you all that please identify yourself for the record before
> speaking.
>
> **Additive and Ingredients**
>
> DR. DWYER: Thank you. This is also under Tab 1. This is Dr. Bonnette.
> I finally got it right. This was in August and it was on
>
> food-mediated latex allergy which is a very interesting issue.
>
> The questions we were asked in this
>
> meeting were, first of all, has a positive relationship been
> demonstrated between the use of natural rubber latex gloves in food
> service and allergenic reactions to food served in food
> establishments\--in other words, in the eaters, not in the people that
> are wearing the gloves\--or sold at the market based on available
> data. Then, if it did exist, what was the strength of the relationship
> and was the relationship causative.
>
> We heard a lot of testimony and listened to a number of different
> people. We concluded and agreed that the scientific evidence
> demonstrates that natural rubber latex allergens, and there are
> several of them, can be transferred to food from natural rubber latex
> gloves.
>
> However, we also agreed that evidence was very weak whether these
> allergens were transferred to foods in amounts that were sufficient to
> elicit systematic allergic reactions in variably sensitive
> individuals.
>
> We also felt that the absence of any good information about dose\--we
> didn\'t hear very much
>
> about dose\--that was required to elicit allergic reactions in
> sensitized people made it awfully difficult to extrapolate whether
> such a transfer would have any clinical significance. So, yes; we
> thought that it could be transferred but we weren\'t sure that it was
> clinically meaningful.
>
> So we suggested a weak positive relationship between the use of these
> natural rubber latex gloves and food-mediated latex allergic
> reactions. We felt that the data linking the presence of these
> proteins, these allergens in food to allergic reactions, was based
> primarily on anecdotal evidence and was weak.
>
> That brings us to the second question which was whether a positive
> relationship had been established. If it had and been shown to be
> causative, then could we suggest some science-based options to
> mitigate food-mediated latex allergy risk.
>
> As I have already said, we really felt that the evidence was
> sufficiently weak to preclude us recommending a ban on latex gloves.
> In other
>
> words, several people suggested that we do that but we didn\'t think
> that was warranted because of the level of evidence being weak.
>
> However, we did agree that there existed other evidence suggesting
> that the cornstarch, which is called donning powder\--if you use these
> gloves, you know that a lot of times, you use cornstarch\--serving as
> the vehicle for the transmission of allergenic proteins. So the
> donning powder gets a lot of the proteins in it.
>
> Then, if you could eliminate that powder, it would eliminate a lot of
> the exposure to the allergen. So we suggested adoption of a
>
> food-service glove standard that specified glove powder or protein
> limits on food-service gloves. We also acknowledge, though, that the
> data to properly establish such limits really didn\'t exist.
>
> We thought, also, that this kind of standard should apply to all
> producers of food and it shouldn\'t be limited to retail food outlets
> and food service. In other words, if this is true, what\'s sauce for
> the goose is sauce for the gander
>
> and it also applies in processing for frozen foods or something like
> that.
>
> We suggested that, perhaps, there was a need for a public
> education-project to heighten public awareness of this problem.
>
> Our third question was if the evidence wasn\'t sufficient to establish
> a relationship, what other kinds of questions did we need to ask to
> understand the issue. What we felt very strongly about was that a
> well-designed, double-blind, clinical, placebo-controlled, low-dose,
>
> oral-challenge study would be necessary to really find out the
> threshold doses for the kinds of reactions that people were talking
> about and to better understand what percentage of the latex allergic
> population was really at risk of a reaction to food contaminated with
> the gloves.
>
> So we suggested that that be done as well.
>
> I think that is about all I have got to say on that. Does anyone have
> any other suggestions or comments?
>
> **Questions of Clarification**
>
> DR. LUND: Daryl Lund. Johanna, is the only allergic reaction to the
> latex gloves caused by the donning powder?
>
> DR. DWYER: No; I don\'t believe so. I think it is\--
>
> DR. LUND: There are other allergenic constituents in the latex gloves,
> themselves, that cause the allergic reaction.
>
> DR. DWYER: Yes; it is just that it concentrates in the donning powder.
>
> DR. KRINSKY: Norman Krinsky. I am a little bit confused, Johanna,
> because it seems to me that your answer to the first question
> indicates that there is not adequate evidence. But your answer to the
> second question leads to making recommendations. That doesn\'t seem to
> make sense to me.
>
> DR. DWYER: Thank you, Dr. Krinsky. We felt that there was a positive
> relationship but that it was weak, that the positive relationship was
> weak but that there was a remedy to making it even weaker. Dr.
> Bonnette, do you want to speak
>
> with knowledge of the transcript?
>
> DR. HEPP: If I may, my name is Mark Hepp. I participated in this
> meeting. I think that most of the committee felt that allergic
> reactions elicited by people consuming food that was handled by latex
> gloves were plausible and that they also recognized that the data
> indicated that the main part of the exposure would result from the
>
> natural-rubber proteins combining with the donning powder and being
> transferred to the food.
>
> There was data presented at the meeting that showed that powder-free
> gloves transferred undetectable levels of protein. So, the committee,
> feeling that the relationship was weak but because some protein could
> be transferred to food made it somewhat plausible, they felt that, by
> recommending specifications on glove powder and protein levels that,
> although there wasn\'t sufficient data to take regulatory action, they
> could address a potential problem or something that seemed plausible,
> anyway.
>
> DR. DWYER: I think it is also true, and, again, my memory may fail me,
> that the gloves vary
>
> widely. There is some reason to think that, by source, by the
> manufacturer or the country of manufacturer, there are quite big
> differences in the amount of allergens present. Is that correct?
>
> DR. HEPP: That is correct.
>
> DR. DWYER: So we felt a standard that tried to get it down across the
> board would be helpful.
>
> DR. MILLER: Dr. Krinsky, do you want to continue?
>
> DR. KRINSKY: Norman Krinsky. I just wonder how industry has responded,
> then, to this recommendation.
>
> DR. DWYER: I am unaware of the response so I can\'t answer that, Dr.
> Krinsky.
>
> DR. MILLER: Jean?
>
> MS. HALLORAN: Jean Halloran. It is my understanding in the case of
> peanut allergies that the threshold dose varies enormously from one
> allergic individual to another. Some people are extraordinarily
> sensitive, others not so sensitive, by orders of magnitude. I was
> wondering if you had
>
> any discussion of that in terms of designing the oral-challenge study
> and getting a big enough sample or is there literature so that you
> could select a range of individuals or is there information on how
> to\--the percentage of individuals who are highly sensitive versus
> less sensitive? Or did you not get into that? Would that be part of
> the well designing?
>
> DR. DWYER: Those are very good questions. The thing is that the data,
> it didn\'t seem to me and I speak as someone who is more familiar with
> peanut allergy, that the databases were as well developed as they were
> for peanut allergy.
>
> We did hear from a number of very interesting\--much interesting
> testimony. We did hear from a few physicians who were dealing with a
> highly allergic population and who one would presume would be the
> people who were the most sensitive. Even there, the dose-response
> studies were not all that the committee felt were good ones. They were
> not as well developed.
>
> So the answer is there are a lot of
>
> unanswered questions here but the relationship didn\'t seem, after we
> looked at everything including a great deal of testimony from people
> who were among these individuals who were presumably highly sensitive,
> we felt that the relationship, if there was a weak one.
>
> DR. MILLER: Dr. Downer?
>
> DR. DOWNER: Goulda Downer. I participated in that meeting, also. I
> think one of the things that also clouded the discussion was that
> individuals who are allergic to natural rubber latex also had an
> allergy to kiwi fruit and bananas. So the challenge was how do we know
> exactly what they would be allergic to. We recognized then that they
> did have some allergy to the latex but that was something that made it
> even more confounding.
>
> We didn\'t have enough data. We did have some individuals who were
> very persuasive in explaining some of the challenges they had or
> patients had, becoming very ill. However, there were some other
> confounding variables clouding
>
> this.
>
> DR. MILLER: You mean that they were cross-sensitive to kiwi and
> bananas?
>
> DR. DOWNER: Yes; they all were.
>
> DR. MILLER: That is interesting, in itself.
>
> DR. DOWNER: Yes; it was.
>
> DR. DWYER: I think they are the same family, aren\'t they,
> botanically.
>
> DR. MILLER: Other comments or questions? Yes?
>
> DR. SCHERER: Cliff Scherer. I was just wondering, the committee
> recommended a
>
> public-education program. I was wondering whether any thought had been
> given to exactly what kind of message that might be and what the
> purpose of it would be.
>
> DR. DWYER: We didn\'t really get very specific beyond the issues, as I
> remember, and, again, Dr. Downer or others who were there may want to
> elaborate, certainly, this issue of the donning powder. To heighten
> public awareness, I think,
>
> also meant heightened food-service establishment awareness. So it was
> more of a suggestion to try to get people who were food-service
> handlers to be aware of these sorts of thing.
>
> DR. DOWNER: Goulda Downer. In addition to that, we had recommended for
> the manufacturers that restaurant establishments may want to
> voluntarily put up large signs says, we are
>
> latex-free, so the consumer would have a choice in assisting in doing
> that.
>
> DR. MILLER: Further comments?
>
> DR. WASLIEN: I always cringe when I hear somebody adding another thing
> to the list of\--oh; Waslien\--cringe when another thing is added to
> the list of free environments when the scientific support for any
> relationship is very weak. It would seem very, very premature to start
> talking about permitting manufacturers, or food establishments, to
> say, we are latex-free.
>
> I would think, and I also worry. I am not an immunologist, but I
> thought I would worry about the ethics of doing exposure in
> individuals who are
>
> highly sensitive to an antigen. I think the other studies that are
> listed on here further on have seen the amount of latex that goes into
> the donning powder and how much, actually\--what procedures would put
> it in foods\--would be first-order priority before any human studies;
> one, because of cost, and, two, because of ethics.
>
> DR. DWYER: Thank you for those comments. I think the committee\'s
> judgment is reflected in the transcript. We did hear testimony from, I
> think, one state for sure and maybe a couple where they had already
> put some regulations in place. So it is critical to get a very good
> science-base on this before we go too much farther.
>
> DR. MILLER: Would it be worthwhile for this committee to recommend to
> the subcommittee that, in order of priority, that the studies done
> on\--the in vitro studies be done\--they will do that, anyway, but
> just to emphasize the ethical issues involved. Would that be
> worthwhile?
>
> DR. DWYER: We will do it. Thank you very much. Good questions.
>
> DR. MILLER: Any other? Yes?
>
> DR. SCHERER: Cliff Scherer, again. I just wanted to make one note of
> thought about the problem of beginning to alert the public. I think if
> we really talk about the public as different than food-service or
> whatever, but the idea of focusing them on what appears to be a
> relatively minor risk while we have others that we maybe do want them
> to focus on. I think that is the tradeoff.
>
> DR. DWYER: It is part of public education, too, so I am not sure our
> statement precluded that, that the risk might, in fact, be very low.
>
> But the point, again, is that there are already states that have done
> this. So this is all after the horse got out of the barn, so to speak.
>
> DR. MILLER: Okay. Then why don\'t we move on to the last topic for the
> morning, Food Biotechnology. Frank Busta, again.
>
> **Food Biotechnology**
>
> DR. BUSTA: Just to recognize that I will
>
> be going fast, good afternoon. The Food Biotechnology Subcommittee has
> met twice. You have the second of the meeting reports in front of you.
>
> The first meeting was on August 13 and 14. Basically, that was to
> discuss the science-based approaches to assessing whether new proteins
> or bioengineered foods are likely to cause allergic reactions in some
> individuals. There was a good discussion. It included looking at some
> of the Codex documents and recommending that the FDA work closely with
> them, with those documents, looking at some areas of allergenicity
> research and discussing some potential draft guidelines in
> allergenicity.
>
> The second meeting that you have the minutes on the report was in
> September of 2003. I was the Acting Chair at that meeting. We received
> reports on the current regulatory framework, policies and procedures
> going on as well as what Codex Alimentarius is doing in this regard
> and FDA\'s safety assessment process, specifically oriented toward
> molecular biology.
>
> If you note the questions looking at
>
> molecular biology data and whether\--to what extent sequencing
> information would contribute to the identification of newly expressed
> substances and especially how this information might contribute to the
> safety assessment.
>
> A lot of the subcommittee discussion was individualized. Generally,
> the subcommittee agreed that sequencing the DNA insert was helpful but
> they really didn\'t comment on how this information would be used in
> safety assessment. Some of the subcommittee believed that the data
> might be useful for safety assessment in certain situations but it was
> not highly specific.
>
> One of the subcommittee members thought that sequencing the extended
> regions flanking the insert site of every bioengineered food plant was
> useful but, again, didn\'t comment on how that would be phased into
> food safety assessment.
>
> Also, we were asked to look at the current approaches. The
> subcommittee continued to agree that the molecular biology data
> specified by FDA were appropriate as part of the characterization,
>
> that they should be consistent with the Codex Alimentarius process and
> they supported that approach.
>
> Some of the members of the committee stressed the importance of
> characterizing proteins expressed by the genetic-engineering process
> and several also recommended that the phenotype be the focus of the
> characterization.
>
> Finally, on the technicological advances, there was a great deal of
> discussion on the proteomics, metabolomics, approaches and that those
> newer techniques beyond genomics be introduced and utilized for the
> food safety assessment program.
>
> There was a letter introduced by several of the members of the
> committee specifically requesting information sooner, faster, and a
> report on\--this is the last paragraph in the
>
> report\--asking for updates on what FDA was doing with the
> subcommittee\'s recommendations. FDA indicated they would respond to
> the subcommittee, take that latter into consideration and respond to
> the subcommittee.
>
> DR. MILLER: Thank you, Frank.
>
> Comments, discussion?
>
> **Questions of Clarification**
>
> MS. HALLORAN: I was wondering about your bringing attention to the
> fact that, in the report, various members did not comment on how the
> information contributed to safety assessment in regards to two sets of
> information. I think, in the Codex document which I am quite familiar
> with, it is quite clear how they contribute to the safety assessment,
> that it gives you data on possible problems related to toxicity,
> allergenicity and unexpected effects.
>
> Do you think it was just sort of an oversight or a thought that
> everybody understood what the importance was so it wasn\'t necessary
> to discuss, or was there a\--it is a curious phrase. I am wondering
> why you included it.
>
> DR. BUSTA: My recommendation is that, in many situations\--for
> example, looking at the adjacent components, there was no indication
> of what the outcome of that assessment would mean. If
>
> you had those data, would it indicate that there was an additional
> component generated? Would it, actually, in fact, make any difference
> to the outcome of what is in the specific food?
>
> I think that was that was the reasoning behind not knowing how it
> would contribute to the food-safety assessment in that some
> differences in that sequence may make absolutely no difference in the
> subsequent food product. It may not demonstrate any change in protein.
> It may not demonstrate any change in the product. It may not
> demonstrate any differences as a result of a small change in the
> sequence. I think that is the reason why they said they didn\'t see
> how it would fit into the food-safety assessment.
>
> MS. HALLORAN: I believe the people who included this as well in the
> Codex document and who bring it up here do so because, indeed, in
> certain cases, you would not uncover anything interesting if you
> looked at the flanking sequences. But there is the possibility that
> you might uncover the existence of a gene for toxin production or
>
> allergen production that could, perhaps, be turned on by the promoter
> genes that you have inserted along with the insertion and that it is
> to rule out that possibility that you would want to do this piece of
> analysis.
>
> DR. BUSTA: Again, my understanding was that those discussions were
> generated by the concern by some people who think the flanking
> sequences should be assessed. But, as I recall, the conclusion by most
> of the people was that a difference there does not\--it would not be
> unusual to see changes that have no influence at all and that it would
> take a great deal of additional effort without any significant yield
> in the
>
> food-safety assessment.
>
> But that is the best of my recollection.
>
> DR. MILLER: I am a little curious as to why the committee did not also
> continue to explore that subject. It is quite true that, it is
> probably correct that, sequence changes don\'t necessarily mean that
> there are toxic responses that are going to come out, or any response
> at all.
>
> But, given the nature of the technology, it would seem to me that it
> would be worthwhile doing it and then using it as a basis for further
> study.
>
> DR. BUSTA: I think that is why individuals sort of emphasized the
> importance of characterizing the proteins, going down the proteomic,
> or the metabolomic, directions rather than just the genomics
> sequencing.
>
> DR. MILLER: The genetic sequencing, it would seem to me, would be
> equally important.
>
> DR. APOSHIAN: It might be of interest to some of you that there are
> now techniques available called DIGELP, difference in gel
> electrophoresis. About eight universities in the country have this
> kind of equipment. I happen to know we have one, too, and that is why
> I am aware of it.
>
> Many of believe that it is not important, or we are not going to be
> able to tell the meaning of what happens when a gene is turned on or
> turned off. What is more important is to know what the gene product
> is. This particular kind of equipment
>
> can now detect and differentiate a single protein from 25,000 other
> proteins. It is completely computerized. There is a central bank and
> so that, in the future, probably in a year or two\--we have begun
> using it already for our research, but in a year or two, it is going
> to be available to many, many more people.
>
> If you are concerned with allergens or toxic proteins, as you should
> be, the product of the gene is more important than the gene structure,
> itself.
>
> DR. ARCHER: Dr. Archer. I am surprised at the outcome that I am
> reading for a couple of a reasons. Number one, trying to remember back
> when I actually got involved in looking at these things, if, for no
> other reason, some of the sequence data, to me, was a precision index.
> It was sort of a scorecard as to what a company had done or an
> individual had done in terms of trying to understand what, in fact,
> they had accomplished by inserting a gene or deleting a gene, what
> else had happened. I used to call it a precision index.
>
> I guess my other question would be wouldn\'t a responsible individual
> or company know this anyway and, if that data is being generated in
> any event, why not put it out there. Even in those rare instances
> where it might be useful, I have a hard time, basically, right now,
> putting all my marbles with proteomics simply because, once the
> protein is there, the cat is out of the bag.
>
> If it is a harmful protein, it is going to be there. It is a heck of
> way to find out if there was a way to prevent that. Maybe you
> couldn\'t, but, if that data is available, why not use it.
>
> DR. BUSTA: As I recall, there was a great deal of discussion as to how
> much information various organizations submitted with their materials.
> Some offered a great deal of information, lots of sequencing, and some
> offered a minimal amount.
>
> We have got a comment here from someone who really knows this.
>
> DR. MILLER: All right.
>
> DR. JONES: Good afternoon. Kathleen
>
> Jones, Center for Food Safety and Applied Nutrition. I was involved in
> this particular meeting. I think the point that Dr. Busta was trying
> to make was that the committee agreed that sequencing information was
> helpful. It was helpful as part of the safety assessment.
>
> One of the individual committee members felt that not only sequencing
> the immediate flanking regions around the insert but sequencing
> enormous regions from the insertion site into the plant genome was
> also necessary to look for some of these translocation events. As
> other members of the committee informed us, translocation events
> happen\--they do happen in genetic engineering, but they also happen
> in regular plant breeding.
>
> They couldn\'t decide, or figure out, how that enormous amount of
> sequence data would contribute to the safety assessment. You would
> generate a lot of data but it wasn\'t sure how much that would
> actually tell you about the safety of that food product.
>
> DR. MILLER: The problem with that is that
>
> there are many things that happen during normal plant breeding, the
> same thing that happens in genetic modification . I think this is a
> question of\--my own feeling is that this data is generally available.
> Doug, did you say that? Somebody said that this data is available.
>
> It at least gives you an idea of where to look if you are doing your
> proteomics. It is one thing to be able to do 20,000, or 200,000,
> different products but, if you had someplace to look, you would be
> able to focus on a particular area.
>
> I, personally, don\'t think it is going to generate a lot of useful
> information. But, given the nature of debate, it would seem to me that
> the more data you could get, the better off you are going to be.
>
> DR. ACHOLONU: This is Alex Acholonu. My question is informational. In
> this report, the FDA is requested to update the activities,
> biotechnology activities. My question is is the FDA actively engaged
> in biotechnological
>
> activities?
>
> DR. JONES: FDA is engaged in both our own biotechnology activities,
> meaning the review of biotech notifications that are submitted by
> companies for new products derived through biotechnology, new
> bioengineered plants as foods.
>
> FDA has also been involved in the international community in working
> in the Codex Alimentarius Committee to generate guidances for the
> safety evaluation of bioengineered plants for food.
>
> DR. MILLER: Does that answer your question?
>
> DR. ACHOLONU: Yes.
>
> DR. MILLER: Jean, did you have another question? I saw your hand up.
>
> MS. HALLORAN: I was just going to make a suggestion. From the
> discussion we have had, it seems as though, perhaps, the committee
> report could be amended a bit because it doesn\'t seem quite accurate
> to say that there were no comments on whether the information
> contributed to the
>
> safety assessment.
>
> DR. JONES: There were no comments from the individual that was
> requesting that information.
>
> MS. HALLORAN: But it seems as though there was quite a bit of
> discussion about whether it would be useful or not.
>
> DR. JONES: There was an enormous amount of discussion
>
> MS. HALLORAN: So it is a little bit sort of unreflective of the
> meeting to word the report in this way. Perhaps, if you deleted those
> two phrases and substituted a sentence saying that there was
> considerable discussion and varying points of view about whether this
> information was useful or not.
>
> DR. JONES: Certainly. We will work on the meeting report.
>
> MS. HALLORAN: Okay.
>
> DR. BUSTA: Recognizing that you might get grilled, maybe that is why
> Mike Watson went to USDA.
>
> DR. MILLER: How about that suggestion?
>
> DR. BUSTA: Fine, being that the real Chair of this committee is taking
> notes on the comments, I am sure we can put something together and
> send it. Doug is the Chair.
>
> DR. MILLER: As I said, I wanted the Chairman of the committee if they
> would act as a kind of a rapporteur to make a brief note to report
> back to the committee on the nature of discussion. So I guess it is
> not the Chairman. It is going to be a member of the committee.
>
> DR. BUSTA: We will do our best to get that out to the subcommittee as
> quickly as possible because that subcommittee was very interested in
> high participation. So we will do our best to let them participate.
>
> DR. MILLER: Johanna?
>
> DR. DWYER: Just as a procedural issue, Dr. Miller, I would feel more
> comfortable as a subcommittee chair, myself, in working with FDA staff
> to circulate the gist of the discussion that we have had here and the
> very good suggestions I
>
> think to the two committees that I was involved in. But I feel very
> uncomfortable about changing the minutes or the things here.
>
> DR. MILLER: No; I am not suggesting we change the minutes. What I am
> suggesting is that, at the end of the meeting when it comes time to
> summarize the chief points that are being made, I am asking that the
> chairman of each to come up with a short note for this committee. The
> recommendations that we make are recommendations that go back to the
> subcommittee because you can\'t change the report unless they are
> willing to accept the changes.
>
> DR. DWYER: Thank you.
>
> DR. MILLER: Jean?
>
> MS. HALLORAN: One more procedural question. There is no report from
> the meeting on Allergenicity? Is one planned?
>
> DR. JONES: There is a report. The summary minutes are available on the
> FDA Food Advisory Committee website. It was an oversight that that
> information wasn\'t contained in your
>
> packet.
>
> DR. MILLER: Any other comments or questions before we break for lunch?
> That is one way of getting the discussion closed. Then we will meet
> again at 1:45.
>
> \[Whereupon, at 12:30 p.m., the meeting
>
> recessed, to reconvene at 1:45 p.m. this same
>
> day.\]
>
> A F T E R N O O N S E S S I O N
>
> \[1:50 p.m.\]
>
> DR. MILLER: We will get started with the afternoon session. There are
> a couple of things. First of all, for those of you who have pagers and
> wireless telephones, would you please put them on vibration. We have
> been hearing a few little notes. I think it is rude to other people
> who are trying to listen to the discussion and I would appreciate it
> if you would do that.
>
> Secondly, let me remind you again, and we did very well this morning
> sticking to the schedule and I am going to try to make certain we do
> the same for tonight and tomorrow morning as well. So let me remind
> you of that.
>
> For those people in the audience who have just joined us, the
> questioning will be by the committee. It is a function of these
> meetings to provide information to the committee for it to issue its
> report. We will be taking no questions from the audience. Maybe that
> is the reason why they set me up with my back to the audience.
>
> The last point I want to make is that tomorrow morning we are
> scheduled to start at 8:30. It would make life considerably easier for
> me if we could start at 9 o\'clock. Unless there is some objection, we
> will start tomorrow morning at 9 o\'clock.
>
> Do I see any objections? All I see is great big grins. Thank you very
> much.
>
> This afternoon and tomorrow we will be discussing methylmercury. This
> committee had the opportunity of reviewing the science, particularly
> the toxicology, and the derivation of the RFD for methylmercury back
> in November, I think it was. The committee at that time made several
> recommendations, six, I think there were.
>
> The function of this meeting is for this committee to hear from FDA
> and EPA what progress they have made in response to the comments and
> questions that were made by this committee the last time. In
> particular, the issue is the advisory concerning methylmercury in food
> and also one of the more important recommendations was the
>
> suggestion by the committee that EPA and FDA work much closer together
> on this issue than they have.
>
> Based on that, we have a number of people from both agencies, as you
> will see, reporting on progress in this area. The first issue is going
> to be the Status Report and Response to our Recommendations. The
> presentation is going to be made by Dr. David Acheson of CFSAN and
> Denise Keehner from EPA.
>
> **Status Report to Food Advisory Committee\'s**
>
> **Recommendations on Methylmercury in Fish and**
>
> **Shellfish**
>
> **FDA and EPA Development of Joint Advisory**
>
> DR. ACHESON: Thank you, Dr. Miller. First of all, I would like to
> thank the advisory committee for taking the time to spend the next day
> and a half with us discussing methylmercury issues in relation to
> fish. We certainly appreciate you doing that and we look forward to
> hearing your comments.
>
> The presentation that I am going to be giving is going to be a dual
> effort between myself
>
> and Denise Keehner. I am going to start off and then Denise is going
> to fill in some of the middle part and then I will come back and
> finish up talking specifically about our response to recommendations.
>
> First of all, before I get into this, I want to just emphasize three
> important points as we move forward in our development of our
> advisory. The three things that we have really tried to do here is to
> keep the advisory science-based, simple and protective of public
> health. That has been our goal and that is where we are striving to
> end up; science-based, simplicity and protective of public health.
>
> With that, what I am going to do is to move into the presentation and
> really just to iterate the purpose of the meeting which is to provide
> a report to the Food Advisory Committee on how FDA has responded to
> the committee\'s recommendations in developing a revised joint
> advisory with EPA that addresses both commercially and locally caught
> fish.
>
> The structure of the presentations over this afternoon and
> tomorrow\--I decided I would just put this in perspective for you so
> you could see where we were going\--right now, I am embarking on the
> first point, the status report of how FDA has responded to the
> previous recommendations. A portion of this will be a description of
> the process that we have used and that is where Denise Keehner is
> going to speak.
>
> That will be followed by a review of the exposure assessment by Clark
> Carrington. That will conclude today\'s presentations, obviously with
> appropriate questions. Then tomorrow we are going to begin with a
> discussion of the focus-group testing that we have undertaken on the
> revised advisory and that will be followed by a presentation of where
> we have ended up
>
> post-focus-group testing.
>
> So, moving into the status report, this presentation is going to,
> first of all, briefly cover the background of the relevant recent
> history in relation to the development of the current
>
> advisory. As I have already mentioned, we are going to go into the
> process that we used to get where we have ended up in relation to
> responding to the six primary recommendations from the 2002 committee
> meeting.
>
> I am going to go into more detail of the response to those
> recommendations and finally end up with the question that you already
> all have for the current committee.
>
> So, by means of background, and I will deliberately keep this brief,
> in 2001, FDA and EPA issued separate advisories on fish consumption.
> In July 2002, the FDA Food Advisory Committee was asked to evaluate
> this 2001 advisory.
>
> To summarize what was in these two advisories, this slide summarizes
> what was in the FDA advisory and it simply says, avoid shark,
> swordfish, king mackerel and tile fish. That part of the advisory was
> aimed at women of childbearing age and young children. It also advised
> to eat up to 12 ounces per week of a variety of other fish. That was
> primarily aimed at women of childbearing
>
> age.
>
> It recommended following EPA\'s advice for recreationally caught fish.
> There was obviously a lot more in it but this, essentially, is the
> primary substance.
>
> The 2001 EPA advisory issued at the same time had the following advice
> in it; to limit consumption of freshwater fish caught by family and
> friends to one meal per week. You can see that as specifics; in
> adults, 6 ounces cooked, 8 ounces uncooked; a child, 2 ounces cooked,
> 3 ounces uncooked. This should apply to areas where states have not
> provided advice about untested waters.
>
> The advice was to check with state or local health departments for
> advice on waters where friends and family fish. The target for EPA\'s
> advice was to women of childbearing age and children and the
> recommendation was that people follow FDA\'s advice for ocean and
> commercial fish.
>
> The charge to the committee in 2002, just to reiterate what that was,
> to put this in the context of the recommendations, the committee was
>
> asked to evaluate whether the FDA\'s Consumer Public Health Advisory
> on methylmercury provided adequate protection for pregnant and women
> of childbearing age who may become pregnant.
>
> Based on that charge, the committee came up with six major
> recommendations as to what FDA should do. I am going to go over them
> briefly here to put this in the context and then I will be handing
> over to Denise Keehner to talk about the process of how we approached
> it.
>
> The first was to better define what is meant by \"eat a variety of
> fish.\" Second, work with other federal and state agencies to bring
> commercial and recreational fish under the same umbrella. Third was to
> publish a quantitative exposure assessment used to develop the
> advisory. Fourth was to develop specific recommendations for canned
> tuna based on a detailed analysis of what contribution canned tuna
> makes to overall methylmercury levels in women. Fifthly, to address
> children more comprehensively in the advisory and, finally, to
> increase monitoring of methylmercury to
>
> include levels in fish and the use of human biomarkers.
>
> I am going to hand over now to Denise. She will go over more of the
> process that we have used to address these specific recommendations.
>
> MS. KEEHNER: Thank you, David. What I would like to do is to briefly
> walk through some of the key process-related steps that EPA and FDA
> followed in getting to the point that we are at today in developing a
> joint fish advisory.
>
> In the fall of 2002, the EPA Administrator at that time was Governor
> Whitman and the Secretary of HHS, Tommy Thompson, exchanged letters
> around the issue of EPA and FDA working in a more collaborative and
> joint manner in developing fish consumption advisories. The agreement
> that was reached at that time between these two individuals was that
> we would collaborate and bring commercial and recreational fish under
> the same umbrella advisory.
>
> After those letters were exchanged, there was a series of meetings.
> The first was between
>
> Dr. Levitt and Tracy Mehan. Tracy Mehan is the Assistant Administrator
> at EPA for the Office of Water. Dr. Levitt is the Director of FDA\'s
> Center for Food Safety and Applied Nutrition.
>
> Those two gentlemen got together and they talked about what needed to
> be done. The follow up to that in February of 2003 was the formation
> of a joint EPA and FDA working group/leadership group that consisted
> of both leadership representation from the two organizations as well
> as scientists and staff representatives that would form basically the
> team that would be working on the joint advisory.
>
> Starting 2002 and moving into 2003, FDA, Drs. Carrington and Bolger,
> were involved in developing an exposure assessment for fish
> consumption and mercury-related exposure. Between April of 2003 and
> today, we have been working very well together, the two agencies,
> including very, very frequent meetings. I think we meet at least once
> a week and staff are meeting even more frequently than that, many
> conference calls, many
>
> joint meetings, that have occurred.
>
> Some of the key milestones and accomplishments that we have achieved
> as a group, as a team, since April of 2003 including planning and
> completing an independent external scientific peer review of the
> exposure assessment and also some revisions to the draft exposure
> assessment based on that peer review as well as some other comments.
>
> We planned and we held four stakeholder meetings that brought in
> representatives from industry, from the consumer and health
> professional segment, states and tribes, to talk about where we were
> and to get some early input.
>
> We worked together to produce a draft advisory and we took it to eight
> focus groups in four different locations throughout the United States.
> We will talk about this a little bit later. Marjorie Davidson from FDA
> will discuss a little bit more and in more depth the results of the
> focus-group meetings. But, importantly, we were revising the advisory
> in real time as we heard
>
> what the response was of the focus groups to what our message was and
> what message we thought we were communicating versus what was
> received.
>
> We also planned and worked jointly together in putting together
> materials for this advisory committee meeting today and tomorrow.
>
> To briefly touch on some of the outcome of the stakeholder meetings,
> some of the key messages that we heard\--I\'m sorry. The stakeholder
> meetings, we held them, and I mentioned this just a moment ago, with
> industry, consumer and health professionals, states and tribes. We
> shared with the stakeholder group a tentative time line that included
> these focus-group meetings as well as a public meeting. This was
> shared with an idea that we would be going out with some type of
> public interaction in the fall of 2003.
>
> Some of the key messages that we heard at the stakeholder meetings
> included a message about needing to recognize that science would
> continue to evolve and new data would continue to be generated over
> time and that we needed to recognize that that
>
> new science and those new data needed to be part of planned future
> revisions to any type of advisory.
>
> But, importantly, from several sectors, there was a comment that we
> really did need to move forward with an updated advisory, a joint
> advisory, from the 2001 time frame. There was some concern that was
> expressed during the stakeholder meetings about the accuracy of some
> of the tissue data that was used in the model, the exposure model.
>
> There was some concern expressed about striking the right or the
> appropriate balance between not discouraging fish consumption because
> it is an important part of the diet while still maintaining an
> effective message on the risks posed and the concerns about mercury in
> fish.
>
> There were comments about the time line being too ambitious and there
> were concerns expressed about the need to make sure that the states
> were really brought into what we were doing because, in the end, there
> is a lot that occurs implementationwise that is at the state level.
>
> There were several comments that were
>
> expressed reinforcing the need for effective outreach and
> communication after the advisory is developed so that the message that
> we are communicating does get, in fact, to the people that need to
> receive the message and that that is an important part of achieving
> the public-health goal. Just developing the advisory is not the
> endpoint. It is, in fact, getting the message out.
>
> In September and October, we spent quite a bit of in-depth time
> working through\--taking all the input that we had heard, taking the
> different perspectives within each of the agencies and coming up with
> several different iterations of a draft advisory. We settled on an
> iteration that we thought was ready for focus-group testing and, in
> November, we started the focus-group testing of the draft advisory.
>
> The first focus group occurred in Calverton, Maryland. As I mentioned,
> Marjorie will be going into more depth and giving you more information
> on who was there and how those were conducted. The important message,
> processwise, is
>
> that, even though we thought we had a really good advisory, when we
> got to the focus group, the first focus-group meeting, it was clear
> that some of the messages that we were trying to communicate were not
> getting through and we had to go back and do a pretty major revision
> to what we had produced for subsequent testing in the subsequent focus
> groups.
>
> What we found was that, in the subsequent focus groups, we were making
> some refinements around the periphery but nothing as substantive as
> between the first focus group and the second.
>
> That brings us to this meeting here today. David has already mentioned
> what our objectives are in being here. We are basically here to
> present what we have come up with post-focus-group testing and to hear
> from you as to your thoughts and reflections and on how well it
> responds to the comments of this advisory committee and whether we are
> ready to move on to the next steps in the process.
>
> Now, David, you are next to come up again and talk about, in summary
> fashion, how we have
>
> responded to each of the six recommendations.
>
> DR. ACHESON: What I am going to do is just take these through just one
> at a time and go into a little more detail of how we have responded to
> them. Each slide, the format is the same. I have just repeated the
> question at the top there in the heading.
>
> The first one, to better define what is meant by \"eat a variety of
> fish.\" We approached this by considering a variety of different ways
> to get this message over. We considered putting in lists of fish to
> try to illustrate what we meant by variety and ran into some questions
> on that as to what to include and what to exclude.
>
> We then opted for more expanded language to try to explain what we
> meant by \"variety of fish.\" As Denise has pointed out, that didn\'t
> work. Focus group No. 1 told us that that didn\'t work. So we have
> sort of ended up with a shorter explicit language on what we mean by
> \"a variety of fish\" which you will see in the second rule on the
> revised advisory.
>
> In relation to the second recommendation which was to work with other
> federal and state agencies, you have obviously heard what our approach
> has been to that. There has been a very close collaboration between
> FDA and EPA to develop this singly joint advisory.
>
> Obviously, that has led to some changes in the advisory which we will
> go over in more detail tomorrow, but integrating the issue of the
> message of whether consumers can essentially eat the FDA allowance and
> then eat the EPA allowance. There was some concern that we had that
> that was part of the message that was getting out there so it was
> critical to try to meld these together.
>
> In so doing, not only have we just simply merged the language, but we
> have also gone to pains to try to point out that, under certain
> circumstances, once you have eaten a sports-caught or recreationally
> caught ration, that is it for the week. You are done\--which I don\'t
> think was coming through before.
>
> Part of the recommendation was to interact
>
> with states. We have done that through the stakeholder meetings and
> through our close involvement with EPA who interact with the states on
> a very regular basis.
>
> So the third recommendation was to publish a quantitative exposure
> assessment used to develop the advisory. You are going to hear a lot
> more about that in the next presentation from Clark Carrington. This
> was developed in the latter part of 2002, 2003. It was presented
> publicly as a poster in March, 2003.
>
> Following that, and following our initial dialogues with EPA, we all
> felt that it was critical to get this peer-reviewed which was done
> through the mechanism that you will hear from Rita Schoeny in the next
> presentation just exactly how that peer review was conducted and what
> the results of that were and how we reacted.
>
> Following the peer review and following some new data that I am going
> to come to in just a minute, the exposure assessment was further
> revised so that we have now ended up with another iteration
>
> of the exposure assessment that has really taken into account some new
> data, which I am going to share with you in a minute, and the comments
> from the peer review.
>
> The fourth recommendation was to develop specific recommendations for
> canned tuna. As you all know, canned tuna comprises two principle
> types, albacore or white, and light. We certainly learned\--we knew
> that canned tuna was one of the most frequently consumed fish in the
> United States.
>
> As you will hear from the exposure assessments, we have assessed
> different scenarios addressing tuna, albacore tuna, specifically, in
> terms of running scenarios where it is in or it is out and the impact
> of that on what it does to overall mercury levels.
>
> To try to get a sense as to what the effect, through
> exposure-assessment analysis, of including albacore in your diet,
> limiting albacore in your diet, taking it out. Part of this process
> was to develop new data on levels of mercury in canned tuna. There
> were some comments that the
>
> data that we were using was not particularly current.
>
> As you will see in a subsequent slide, we have addressed that. As I
> said, I am going to share those data with you in a minute.
>
> In the original 2001 advisory, there was no specific mention of tuna.
> We took the recommendation that there was a need to do that because it
> is one of the most frequently consumed fish and have addressed that by
> including a specific statement regarding canned tuna. I don\'t want to
> go into how we ended up there\--you will hear more about that
> tomorrow\--but we ended up with a Q&A approach and we now have a
> question and an answer regarding canned tuna.
>
> The fifth point was to address children more comprehensively in the
> advisory. As I pointed out when I summarized FDA\'s advisory and
> EPA\'s advisory, there were some differences there in the way we
> addressed children. What we did in our workgroup, or our joint
> workgroup, was we really determined that there was no scientific
> consensus
>
> to define a specific age or weight of a child in a revised advisory in
> terms of what constitutes a child by age, what constitutes a child by
> weight.
>
> The lack of scientific consensus on the that really limited us in
> terms of what we felt we should say in an advisory that was going to
> be a national advisory. However, what we have done in the revised
> advisory is put more emphasis on children in this joint advisory than
> there was in the previous FDA advisory.
>
> Young children are now mentioned specifically in the title as the
> target group of the advisory whereas previously they were not. They
> are now mentioned more frequently in the text. Previously, they were
> really mentioned only in the context of prudence in relation to
> avoiding certain types of fish, as in the third sub-bullet there. It
> is no longer limited to the \"Do Not Eat\" list which is really where
> we were in the 2001 advisory and a statement has been added, based on
> this lack of consensus that I discussed in the first bullet,
> indicating that children should eat less than the
>
> 12 ounces because they are smaller.
>
> Finally, in terms of increasing monitoring of methylmercury to include
> levels in fish and the use of human biomarkers\--I am not going to go
> into the human biomarkers issue. As you all probably know, there was
> data published recently from the NHANES study going back to the
> 1999-2000 NHANES study. I know that was presented extensively at the
> last Food Advisory Committee meeting.
>
> But we at FDA have done is we have embarked on two new assignments to
> measure mercury levels in fish in the U.S. These were completed in the
> latter part of 2003. These two
>
> assignments\--the first one was to look at twelve different species of
> fish with a total of 224 samples. The second assignment was focused
> exclusively on canned tuna. That comprised 170 samples of albacore or
> white and 119 samples of light tuna. I am going to expand on this in
> subsequent slides.
>
> This is a list of the twelve fish that were part of the general
> assignment. These were
>
> chosen because they were fish that we had limited amount of data on,
> fish that we felt that we just needed more information about. I am not
> going to go into detail here, but you can see that there was a wide
> range of fish that really wasn\'t focused on the fish that were most
> frequently consumed. That was not the purpose of this. It was to fill
> in data gaps. This assignment was initiated in 2002 and completed
> earlier this year.
>
> The assignment was set up so that it tested a mix of fresh,
> refrigerated and frozen fish. Approximately one-third were to be taken
> from domestic imports. These were from the places listed there,
> Baltimore, Chicago, Florida, Los Angeles, New York, San Francisco,
> Seattle and the Southwest. So it was pretty geographically diverse.
>
> The second part of this assignment which constituted about two-thirds
> of the samples were from domestic samples. These were, again,
> geographically diverse between Atlanta, Florida, Los Angeles, New
> Orleans, New England, New York and
>
> San Francisco.
>
> This slide summarizes the data that we obtained from this study. What
> I have done here is to, on the same slide, put the old data and the
> new data. Let me explain what I am talking about here.
>
> The new data, first of all, over on the right, is the data that was
> obtained from the assignment that I have just described to you. So
> that is the 224 fish. The old data are the same fish, the same twelve
> species. These data are from our website, which are a composite of
> older FDA data, some National Marine Fisheries data, and essentially
> are a composite of data that were used in the early exposure
> assessment and are the data that are currently on our website which
> will be subsequently updated with the new data.
>
> But I wanted to just put these up there for comparison. I am not going
> to go through each one line-by-line but I want to point out a couple
> of things. Some of these have got asterisks on them which indicate
> that there are questions about species in these old data that we just
> don\'t have
>
> information about.
>
> I want to illustrate this with tilefish. The new assignment in
> tilefish was specifically oriented towards golden tilefish. In this,
> we ended up with a mean of 0.208. Here is the range, 0.05 to 1.1, and
> a total of twenty samples. The old tilefish data, which was 60
> samples, there is no data on where these fish came from. There is no
> data on what species they were. But, clearly, they were very
> different. We had a mean here of 1.45 with a very different range,
> going much higher. This is largely why tilefish is in the \"Do Not
> Eat,\" the \"avoid\" list.
>
> What these data tell us is that there is a need for more testing to
> find out about tilefish. Is this a change in trend of tilefish or does
> golden tilefish not represent the tilefish in the United States. We
> are currently setting up further assignments to ask questions
> specifically in relation to more data that is needed to augment these
> new data over here on the right.
>
> The same applies, for example, to croaker.
>
> We don\'t see the big differences in the mean\--I beg your pardon;
> yes, we do\--0.28 to 0.054. Grouper, 0.27 to 0.569. The n\'s here are
> not very large and, really, what this is doing is it is asking more
> questions. But we don\'t know anything about the species of croaker
> that were looked at in this first set. We do know these are Atlantic
> croaker. Is that important? Is that an explanation? Don\'t know.
>
> These data are available in your packet so you can study it in more
> detail if you wish. But I don\'t propose to spend any more time going
> over the numbers here, but simply to point out that some of these
> differences between the old and the new data may well be related to
> sampling, geographic questions that we need to address further.
>
> The second major assignment was the tuna assignment. The tuna
> assignment which was initiated in the late summer, mid to late summer
> this year, looked at approximately 75 percent major brands of tuna, 25
> percent store brands, local brands and other brands. The goal here was
> that
>
> the sampling would be representative of the volume and type of major
> and local brands and in packing medium. So it was water, broth, oil
> that were available in the areas in which the testing was done.
>
> This was a market-basket type study so these were just cans off the
> shelf, so to speak. But, as you can see, we were shooting for 75
> percent major brands, 25 percent of the other type. Again, this was
> spread around the country; Los Angeles, San Franciso, Seattle,
> Chicago, Dallas, New England, New York and Florida.
>
> This slide shows the data that we obtained from that. Again, what I
> have tried to do is to compare old and new data. Previously, our old
> data for canned tuna was all lumped together as canned tuna with 248
> samples with an overall mean of 0.17. So this doesn\'t differentiate
> between white and light.
>
> Over here we have the new data, again 170 new white-tuna samples and
> 119 light-tuna samples. The old data, so to speak, had a paucity of
> white
>
> tuna, albacore, of only 17 samples. Here you can see that we have
> essentially the mean of 0.29 here, 0.358 there. Obviously, there is a
> huge difference in between those two which may to explain this.
>
> The highest that we found in the albacore was 0.85. The light
> tuna\--we already had 225 samples of light tuna in the dataset. We now
> have 119 more. Really, you can essentially say that the light tuna has
> not changed here and the ranges really are not that different either.
>
> DR. DWYER: Which is the main kind on the market, David?
>
> DR. ACHESON: The main kind that is consumed? Light. I don\'t have the
> specific split in my head, but I can certainly get that for you for
> tomorrow if you want to know as to what proportion of the market share
> goes to albacore and light. But there is more light consumed than
> albacore.
>
> So those are the new data from 2003. Again, we are not stopping there.
> There is a new assignment for 2004 that is about to be initiated
>
> that is going to continue to do this. We are going to continue to test
> canned tuna and light tuna along with all the other species plus some.
> Actually, the new 2004 assignment for the other species is going to be
> expanded to fifteen species including a lot more focus on the ones we
> need more data on, like the tilefish.
>
> So that concludes, really, the response to the recommendations and the
> new data. I just really want to end this presentation by just
> reiterating our question to the committee which is really broken down
> into three main bullets. I will just read these: \"Given the enormous
> interest and expectations from all perspectives in this issue, the one
> important point that we believe we all agree on is that we move
> forward and begin our education program.\"
>
> Certainly FDA and EPA feel very strongly that we want to embark on
> getting the word out. That is what we really want to try to do at this
> point. Clearly, as we move forward on this, new science will come
> along, as has already been
>
> mentioned by Denise, and that will cause us to review and to change
> and to rethink, but we want to move forward.
>
> This point is really brought out in the second one, \"As we learn more
> from scientific findings, population demographics, et cetera, and
> receive results from the education efforts on consumer behavior, we
> need to refine the approach.\" We learned some very important lessons
> with our focus-group testing. That was extremely valuable and that
> really illustrated to me, and this is the first time I have really
> been involved in focus-group testing from a personal perspective, was,
> wow; that didn\'t work. I understood it but the general public
> didn\'t. So we tried to fix it.
>
> Then, \"We believe that this activity is best conducted concurrently
> with an outreach and education program, \"hat is it in the interest of
> public health that we get on with this as soon as possible. Really,
> what we are looking for is the committee\'s concurrence and their
> feedback and comment on what we have done, where we have ended
>
> up, but with the goal of trying to move this forward as quickly as
> possible, again, with our focus on a scientifically sound, simple and
> public-health-oriented message.
>
> With that, my presentation is completed and I think I am open for
> questions. Is that right, Dr. Miller?
>
> DR. MILLER: That\'s fine, David. Thank you.
>
> **Questions of Clarification**
>
> DR. MILLER: Dr. Aller?
>
> DR. ALLER: Marion Aller. On the mercury testing in levels of fish, you
> mentioned that you were collecting species information on tilefish.
> What about the croaker and the grouper, on the new data. Was that
> information collected?
>
> DR. ACHESON: Yes; it was. The croaker were Atlantic. The grouper,
> there was a wide range of grouper that could have been in there. I
> don\'t have those data with me as to exactly what they were. But this
> was very clear to us that we need
>
> species information as we move forward. Just
>
> simply knowing that they are a croaker group or tilefish isn\'t
> enough.
>
> DR. ALLER: Thank you.
>
> DR. DURST: Durst. I just have a question on the tables with the
> analytical data; for example, the next to the last slide that you
> have. None of the tables that I see have any indication of what that
> mean is. I assume it is parts per million, or micrograms per gram,
> or\--
>
> DR. ACHESON: Oh; I do apologize. Yes; it is parts per million.
>
> DR. DURST: Then I am curious when you have, for example, 225
> datapoints, why the range has ND as the low limit on some of these.
>
> DR. ACHESON: It is non-detected.
>
> DR. DURST: There must be a lower limit of detection?
>
> DR. ACHESON: It is essentially the point of detection of the assay.
> The other one that says 0.00, I just simply dropped a number off to
> make it down to just two numbers, two decimal places.
>
> DR. DURST: Okay. Again, speaking as an
>
> analytical chemist, that looks a little curious when you see something
> like that without a number or some indication of why there isn\'t a
> number there.
>
> DR. ACHESON: I should point out that much of that data, 225, goes way
> back in time and were probably a mix of different analytical method
> some of which were probably less robust, less accurate, whatever\--I
> don\'t know the specifics\--than current methodologies. It is
> composite data from a variety of sources over a number of years.
>
> DR. MILLER: Dr. Waslien?
>
> DR. WASLIEN: When I look at these, I wonder something about frequency
> of distribution. Is there one value that is way out there all by
> itself and, if so, when you do your analysis, you can get batch number
> and find out if that is coming from one particular area. That is the
> chemist or research person in me.
>
> But I also prefer medians over means. If you have got one value that
> is very, very high and you have got all the rest low values, it gets
>
> distorted by a mean. I just don\'t know if maybe the means and the
> medians are the same, so it doesn\'t matter. But I do worry that there
> is one value out there that is your one value and that might be next
> to a contamination site, whatever.
>
> DR. ACHESON: That is a very good point. One of the reasons that I
> stuck with means is because all the old data were expressed in means.
> For example, with the tilefish, we tried to get back to the original
> data. Some of it goes back to the 1970s from the National Marine
> Fisheries and it wasn\'t available.
>
> So you are absolutely right. This is essentially a summary and the
> distribution is as important as what the overall mean and the range
> yes. Yes.
>
> DR. MILLER: Dr. Dwyer.
>
> DR. DWYER: Thank you, Dr. Miller. Thanks for an interesting
> presentation, David. A couple of questions. First of all, will the old
> values be included and merged with the new and, if so, what standard
> will you use for throwing values out\--for
>
> instance, you said the methods might have changed.
>
> Secondly, how will the data be transferred and used so that we can get
> exposure estimates from NHANES and other large-scale surveys?
>
> DR. ACHESON: First of all, to address your question of whether the
> data will be merged. Certainly, when we don\'t have specific data that
> is old, the feeling is to try to replace it with newer information,
> especially, to reiterate the tilefish issue where we don\'t know
> geographic distribution, we don\'t know species, that might be
> relevant, clearly, as we develop those data, we want to replace the
> old data with the new data.
>
> Where we have more recent, and we haven\'t defined what we mean by
> recent, but more recent data that is from FDA labs where we have the
> specific numbers, then, yes, I think we would attempt to pool it.
>
> The second part of your question in terms of how will these data be
> used to NHANES. I am not quite sure where you were going with that.
> Can you clarify what you are\--
>
> DR. DWYER: Is it going in any database that is accessible to people so
> that you can do the analysis.
>
> DR. ACHESON: Oh; absolutely.
>
> DR. DWYER: Or is it hidden someplace in FDA where nobody can find it?
>
> DR. ACHESON: The old data is already up on the website. Our intention
> is to update the old data, include the new data on the website.
> Certainly, we have already passed it out to interested parties who
> have requested through FOIA, the specific values. So it is going to be
> available.
>
> DR. DWYER: Just one final question, since the four baddie fish, shark,
> kingfish and so
>
> forth\--are we confident in those values or are they all old values,
> too? How old are the new values for those other fish that you didn\'t
> analyze, the ones that are supposed to be high in methylmercury?
>
> DR. ACHESON: There is more recent data on those that I am aware of.
>
> DR. DWYER: What does that mean; 1980,
>
> 1990?
>
> DR. ACHESON: No; 1990s. I can get you specifics if you need that on
> what data there is for those other ones. There is also a lot more of
> it than the tilefish. I think that it is a much clearer picture with
> shark and swordfish and king mackerel than it is with the tilefish.
> But you raise a good point, because the data is newer.
>
> DR. DWYER: Can I ask one more question, Dr. Miller, and then I will be
> quiet.
>
> DR. MILLER: Of course.
>
> DR. DWYER: I think that, for many foods, that sometimes industry
> produces their own data and, as long as it was done using standard
> techniques and the sampling frame was appropriate and so forth, these
> values are accepted\--at least, I think, in the USDA, they are
> accepted if they meet certain criteria.
>
> So, it is a private-sector effort that has public good coming from it
> because it all goes into the database. It sounds like this is all our
> tax dollars going to find out methylmercury in these
>
> various fish. Is there any effort on the part of the industry to
> produce similar data on methylmercury in these various fish?
>
> DR. ACHESON: I guess industry would have to speak specifically to
> that, but I do know that industry have generated data on certain types
> of fish which they have offered to share with us. Obviously, if it
> were to be included, we would have to be sure that the methods matched
> up and that it was scientifically sound. Having accepted those
> criteria, we would certainly be interested in seeing it
>
> DR. MILLER: Dr. Archer?
>
> DR. ARCHER: Doug Archer. It may be a minor point, but I noticed that,
> in some of your slides and in some of your explanatory text, you sort
> of used mercury as methylmercury. Is that intended?
>
> DR. ACHESON: The advisory is oriented towards methylmercury. The
> testing in the fish is actually mercury. It is total mercury that is
> tested for in fish. You are looking like I haven\'t
>
> answered your question.
>
> DR. ARCHER: You have answered my question. I don\'t have the
> background of having been here at the time so I guess my next question
> would be why.
>
> DR. ACHESON: The explanation for that is methylmercury is the form of
> the mercury that we are concerned about in fish with regard to the
> impacts on neurological development. Fish are the primary source of
> methylmercury. Virtually all of the mercury in fish is methyl. The
> methods for measuring total mercury are simpler than methylmercury.
>
> So, if you measure total mercury in fish, you have essentially got the
> methylmercury because it is virtually all methylmercury. So, arguably,
> the total mercury is a little bit higher, but very little.
>
> DR. MILLER: Dr. Aposhian.
>
> DR. APOSHIAN: I think it is appropriate to compliment the FDA and the
> EPA with coming out with a joint advisory. The White House Conference
>
> of 1999 was called specifically to try to get three government
> agencies to agree. For the FDA and EPA to do this, I think is quite
> remarkable and I think they should be complimented for it. I don\'t
> compliment people very often.
>
> I would also like to say I thought the two speakers did a very, very
> good job.
>
> DR. ACHESON: Thank you.
>
> DR. APOSHIAN: But I also have a question, namely, will we, at some
> time, have the opportunity to make suggestions or criticize this
> advisory or is that the appropriate thing to do now, or what?
>
> DR. MILLER: Why don\'t we wait until we get to the advisory.
>
> DR. APOSHIAN: Okay.
>
> DR. MILLER: It is kind of hard to criticize something that we haven\'t
> theoretically dealt with yet.
>
> DR. APOSHIAN: Okay.
>
> DR. MILLER: Although we could do it.
>
> DR. APOSHIAN: We can wait.
>
> DR. MILLER: Dr. Russell
>
> DR. RUSSELL: There is a fairly wide range when you look at the tuna
> with regard to the levels. Is there any geographical explanation for
> that? That goes for both the white and the light tuna.
>
> DR. ACHESON: We have not specifically looked at that. There may be
> data out there that gets at that but, obviously, when you pull a can
> of tuna off a supermarket in Washington versus one in Seattle, there
> is no way of telling from that can where that fish came from. So I
> don\'t have the answer to your question.
>
> It may be that there are other data sources that could get at the
> answer to that in terms of whether there are geographic differences. I
> would suspect that they are not huge because, essentially, tuna are
> from the ocean. The levels in the ocean are fairly even.
>
> DR. MILLER: Rob, does that answer your question?
>
> DR. RUSSELL: Yes. I guess I wondered, do you have levels for fresh
> tuna as well from various
>
> locations?
>
> DR. ACHESON: No; not in relation to recent testing. Fresh tuna is
> going to be part of our 2004 assignment.
>
> DR. ACHOLONU: Could you slow that slide again on mercury levels in
> various fish? I would like to see it again, please.
>
> DR. ACHESON: Okay.
>
> DR. ACHOLONU: There you have trout, fresh-water. And you have the mean
> as 0.42. Then you have the range, 1.22 maximum. Yet, under the next
> column, you have NA. How were you able to get the mean, the trout,
> fresh-water?
>
> DR. ACHESON: The trout, fresh-water, is the old data that is composite
> from a variety of sources. The next row, which is farm-raised trout,
> are the new data. So we did not have any old data on farm-raised trout
> specifically.
>
> DR. ACHOLONU: You got that from somewhere. What does N signify?
>
> DR. ACHESON: Not available.
>
> DR. ACHOLONU: So you don\'t have any
>
> number available but you have the mean for trout in fresh water. How
> did you get the mean? That is what I am trying to\--
>
> DR. ACHESON: I am a little\--
>
> DR. HEIMBURGER: It must have been reported by someone else.
>
> DR. ACHOLONU: So you got it from somewhere else?
>
> DR. ACHESON: Yes.
>
> DR. ACHOLONU: That is what I am trying to find out.
>
> DR. ACHESON: Okay. Like I tried to point out, the old data are from a
> variety of sources. Some of it, we had the specific numbers on and
> some of we didn\'t, which is one of the problems with the tilefish is
> we did not have the specific numbers, which is why we couldn\'t
> calculate medians and a variety of other dilemmas.
>
> DR. ACHOLONU: Thank you.
>
> DR. MILLER: Dr. Downer.
>
> DR. DOWNER: Goulda Downer. I, too, want to commend the two groups in
> working together and I
>
> am really very interested to get a little bit more information on the
> discussions you had with the focus groups. In preparation for this
> meeting, I asked just about every one of my patients last month, who
> would usually have tuna and soup for lunch, if they were still having
> it.
>
> And everybody, 100 percent, said they no longer ate tuna. I don\'t
> know if you are working with the media to make sure the message that
> comes out to the public is not one of, \"Don\'t eat the tuna,\" but,
> \"You can go ahead and have some.\" People were just so scared. They
> are saying to me, \"Dr. Downer, I don\'t know what to eat and what not
> to eat, so I am just not going to bother.\" These are not women of
> childbearing age, most of them, I might add. They are women past
> childbearing age but they are thinking, \"There may be some additional
> implications for me.\"
>
> DR. ACHESON: Right.
>
> DR. DOWNER: I am just curious to find out from you what kind of
> educational materials you have started to develop and how is that
> going?
>
> DR. MILLER: Let me just respond. As far as I can see, we haven\'t
> gotten to the advisory yet. Also, am I incorrect in saying that the
> distribution of the advisory hasn\'t taken place?
>
> DR. ACHESON: That\'s correct. The advisory is a draft. It is available
> for people to look at as a draft, but it is not\--subject to,
> obviously this meeting and other comments, it could change.
>
> One of the presentations tomorrow, the first one by Marjorie Davidson,
> is going to get much more into the focus groups. If it is okay to
> defer questions related to that until tomorrow, I think that might
> be\--
>
> DR. MILLER: Why don\'t we wait until the presentation tomorrow.
>
> Dr. Dwyer?
>
> DR. DWYER: Trouble again. Back to Dr. Russell\'s question. I just
> wanted to get this into the record and get somebody to answer it, and
> maybe it is you, Dr. Acheson. I think two years ago we heard from the
> halibut people about\--I think it was
>
> halibut\--huge differences between the Alaskan and New Zealand, I
> think it was, and other parts of the ocean. It was basically that
> there were certain parts of the ocean where the fish had almost no
> methylmercury in them even though they were the same species as fish
> in other parts of the ocean.
>
> Is it because the tuna are\--why wouldn\'t that also be true of tuna?
> I was just following up on Dr. Russell\'s\--is it because the halibut
> live in different places or what? I just don\'t know very much about
> fish.
>
> DR. ACHESON: I am not qualified to answer that question in relation to
> what the true data is on tuna. I speculated that tuna may not be that
> different, coming out of the same ocean, but I certainly could be
> wrong and subject to correction. I will try to find out the answer to
> that question for you in terms of what we know of the distributions of
> the levels in tuna as it relates to different parts of
> the\--geographic variation. I don\'t know. It was a speculative answer
> and I qualified as such.
>
> DR. DWYER: Am I incorrect? Didn\'t we hear a whole bunch of
> impassioned people from New Zealand and Alaska saying that they had
> been maligned because their fish didn\'t have any in it?
>
> DR. WASLIEN: Wasn\'t it salmon, which spends a lot of its life out of
> the ocean.
>
> DR. MILLER: There are a lot of fish that are called by the same name
> that are different species, actually. That is part of the problem. So
> some fish that are called halibut, two fish, both called halibut,
> could be two quite different species. There is a commercial advantage
> to calling the fish by these names.
>
> DR. ARCHER: If I may add just one other point in relation to that, the
> one thing that we do know is that the size of the fish has an impact
> on the amount of mercury in it. Certainly, that can affect, depending
> on how big the fish is that goes in the 6-ounce can, would have an
> impact, outside of geography.
>
> DR. MILLER: Dr. Callery.
>
> DR. CALLERY: This is a follow up
>
> analytical question about the tuna. The light tuna is substantially
> lower than the albacore but I believe the albacore is often, or
> usually, packed in water and the light in packed in oil?
>
> DR. DOWNER: Goulda Downer. You can get them in both, water or oil.
>
> DR. CALLERY: You can get them in both but I am wondering why, if there
> is a known reason why, the light tuna would be half the amount as the
> albacore and just wondering out loud if, in fact, the mercury is in
> the oil.
>
> DR. ACHESON: No. I think the differences are related to the size of
> the fish. Bigger fish generally have more methylmercury than smaller
> fish, and the smaller fish are typically the ones that wind up being
> as light tuna and the larger fish as white or albacore. It is not as
> straightforward as that but, in essence, that is the explanation.
>
> DR. MILLER: Dr. Lund?
>
> DR. LUND: Daryl Lund. A couple of questions. One is the tuna were all
> canned; is
>
> that correct?
>
> DR. ACHESON: The tuna in the new data were all canned; correct.
>
> DR. LUND: So you could get from the can code\--if you recorded those,
> you could get at least some location information about where those
> tuna might have come from, if you recorded the can code on the lid.
>
> DR. ACHESON: Theoretically, yes; if you recorded the can code and then
> went back to the manufacturer, I am sure you gather more information
> about that. We have not done that.
>
> DR. LUND: Then, secondly, on the other fish, under the new data, those
> were all processed in some way? Are they frozen or are they fresh out
> of the ocean or out of the lake or out of wherever you took them?
>
> DR. ACHESON: They are a mixture. They are a mixture of fresh,
> refrigerated and frozen.
>
> DR. LUND: Okay. I understand.
>
> DR. ACHESON: I don\'t have a breakdown as to how much fresh, but they
> were a mixture.
>
> DR. LUND: Thank you.
>
> DR. MILLER: Dr. Krinsky?
>
> DR. KRINSKY: Norman Krinsky. May I just ask why salmon is not included
> on your list?
>
> DR. ACHESON: On the list of the fish that were tested?
>
> DR. KRINSKY: Yes.
>
> DR. ACHESON: That list of twelve was developed based on the fish that
> we had a paucity of data on or there was some specific need to get
> more information about, and it was essentially a resource-limitation
> issue and salmon was not a fish that we needed more data on last year.
> So that list is not meant to include all the fish that we are
> interested in. It was a subset that we tested with new data in
> 2002-2003.
>
> DR. MILLER: Dr. Heimburger?
>
> DR. HEIMBURGER: Heimburger. A follow up to that. So the eventual
> posting of data will be a comprehensive list including salmon and
> other fish that were not tested in this time period.
>
> DR. ACHESON: Absolutely. The old dataset
>
> that is up there is a piece that I took out of what is already posted
> which includes salmon and a whole range of fish. I just, for purposes
> of comparison, and not to sort of have a slide that was
> uncomprehensible, stuck to the comparison with the new data. That is
> the reason. Please don\'t get the impression that if they are not on
> that list, we don\'t care about them. We do.
>
> DR. MILLER: Any other questions? Some of these issues can be re-raised
> again at the end of the session. Right now, it is supposed to be time
> for a break. Why don\'t we just take minutes.
>
> (Break.)
>
> DR. MILLER: The next series of presentations are on Exposure
> Assessment and Peer Review. Rita Shoeny from EPA.
>
> **Exposure Assessment and Peer Review**
>
> **Peer Review**
>
> DR. SCHOENY: Thank you. We are going to spend the rest of the
> afternoon, I believe, talking about the exposure assessment. I am
> going to begin the discussion with some brief remarks about the
>
> peer review that was conducted by EPA and FDA on this exposure
> assessment.
>
> The main reason why the exposure assessment was done was in response
> to the recommendations that were made by the Food Advisory Committee
> in 2002. That was recommendations on our fish advice, which Dr.
> Acheson has already addressed.
>
> There were at least two of your recommendations that were specifically
> addressed in the exposure assessment. The first one, of course, was to
> do an exposure assessment. But, as was also pointed out, the exposure
> assessment deals with some scenarios for fish consumption limiting
> either the amount of fish or the types of fish consumed, and that is
> where we specifically talk about canned tuna and some other fish
> varieties as well.
>
> We had available to us at the beginning of our discussions about the
> advisory the poster presentation and an earlier paper that were put
> together by Drs. Bolger and Carrington. We began using that exposure
> assessment as a tool to help
>
> focus our discussions on what could reasonable go into an advisory.
>
> We also discussed some of our conclusions with the stakeholder
> meeting. At the stakeholder meetings, we presented some of our early
> conclusions about the exposure assessment. At the time that we were
> addressing the stakeholders, we felt, as a group of scientists, that
> the model that is described in the exposure assessment closely
> predicted the NHANES data that you have referred to already. In
> particular, we were referring to the publication by some of the NHANES
> investigators that remarked that about 8 percent of women of
> childbearing age in the United States are at a blood level for mercury
> either at the reference dose that has been published by EPA or in
> excess of that reference dose.
>
> We felt that the fish scenario model, the fish exposure assessment
> that had been done by FDA, closely approximated the results that were
> presented in the NHANES paper. We thus felt that this was a useful
> tool in establishing the
>
> scientific background for specific advice. We felt that it was a way
> to inform our risk-management decisions and we also told our
> stakeholders at that time that we were submitting the exposure
> assessment to peer review.
>
> What was reviewed was a poster presentation that was publicly given at
> the Society of Toxicology Meeting last year. We provided, as well, an
> earlier publication by Drs. Carrington and Bolger which described the
> development of the model that was used and modified somewhat in the
> poster presentation.
>
> The poster abstract has been published. It has been published in The
> Toxicologist. We also have the citation here for the earlier paper.
>
> The review was done using an existing EPA peer-review contract. It is
> what we call a letter review or a pass-around review. This is a
> situation where we send out the documents to be reviewed to the
> reviewers. They submit their comments back in writing. There is a
> written report. This is as opposed to a public meeting
>
> such as the Food Advisory Committee or a Science Advisory Board
> meetings in EPA.
>
> EPA and FDA scientists describe the expertise that we felt was
> required to provide an appropriate review of this assessment. The
> contractor selected three reviewers. EPA, as the holder of the
> contract, approved the entire list of reviewers as having the
> requisite credentials. Then the contractor provided the material to
> the reviewers, collected the written comments from the reviewers and
> then, ultimately, compiled the peer-review report.
>
> EPA and FDA wrote the charge to the reviewers jointly and I will go
> over this briefly. As with any sort of review that we do of a piece of
> work that is going to be available to the public, we wanted to know if
> the document was logically written, if the arguments were clear and
> concise and presented in an understandable manner.
>
> We certainly wanted to know of all the appropriate literature had been
> cited and if there were other publications that we should be
>
> considering. As this exposure assessment is dependent upon a model, we
> wanted to ensure that the model was clearly described and, as there
> were modifications made between the time of the publication of the
> model and the poster and subsequently, what we were requesting is
> comment on the modifications that were made. Were they supportable by
> existing data?
>
> Here are some of the modifications that were made; expansion of fish
> categories, fitted distributions, addition of an amount of mercury to
> the predicted blood levels to account for exposure that was not fish
> related\--for example, from amalgams, medications and so forth.
>
> A keystone of the inputs are the data from the continuing study of
> food intake by individuals. The exposure assessment used the data from
> 1989 through 1991. There are more recent data\--that is, from 1994
> through 1996\--or I should say the FDA chose to use the three-day
> survey data that were somewhat older. We asked for comments on that
> use of data and also comments on adjustments made to
>
> compensate for likely underreporting in this short time-frame sample.
>
> We also requested comment on the range of ages that were used for
> women of childbearing age and for children.
>
> We asked of the fish scenarios were logically and clearly described.
> We had two questions, actually, asking whether or not some cutoff
> points that were set categorizing the fish as either low, medium or
> high mercury for purposes of the fish scenarios, whether this were
> appropriate characterizations and cutoffs.
>
> What we received back in response was a 37-page report that we felt
> was responsive to the charge questions and also addressed a number of
> additional issues. The contractor compiled the report. There was no
> summary\--that is to say, they were not looking, the contractor,
> themselves, for consensus across the reviewers. In our response to the
> reviewers, however, we do some summarization of review comments,
> particularly as they addressed the charge questions. I will go over
> those briefly.
>
> We were gratified to note that they thought the documents were well
> written and clear. There were some suggestions of additional
> literature that were made. The model was well described in the
> published paper. The reviewers felt that some of the modifications and
> adjustments were made and others they critiqued; for example, the
> adjustment of the three-day data for long-term exposure. Dr.
> Carrington will talk a bit more about some of these adjustments.
>
> Two of our reviewers felt that the use of the older three-day data
> were more appropriate than the use of the two-day survey data. All the
> reviewers commented that we were likely to be underestimating the
> number of fish consumers using the CSFII data.
>
> The definition of women of childbearing age was considered to be a
> policy choice by all of our reviewers. That having been said, though,
> they at least felt that these were reasonable age ranges to use for
> the scenarios and exposure assessment.
>
> All of the reviewers suggested
>
> improvements in our description of the fish scenarios. Many reviewers
> suggested additional scenarios to be run. Some of these have been run.
> All of the reviewers thought that cutoff and categorization of the
> fish species as high, medium or low mercury was appropriate.
>
> EPA and FDA provided a written response to the reviewers, and I
> understand you have that in your package. The review report, itself,
> as well as our responses, are available on the EPA and FDA websites.
> As you look at our response to reviewers, you will see that this
> describes revisions to the assessments and some of those will be
> subject of Dr. Carrington\'s remarks.
>
> We also feel it necessary to comment on areas where we disagreed with
> the reviewers to lay out our position on that disagreement. You will
> find that in the response to the reviewers as well. These were very
> voluminously and comprehensively written reviews for which we were
> very grateful. However, some of the comments that were made we felt
> were outside the scope of the assessment that
>
> we were doing now.
>
> There were a lot of comments made by our reviewers in terms of what
> additional items one should address for fish advice of various sorts.
> Should we be talking about other persistent bioaccumulative toxicants
> in this fish advice. You will see that we addressed some of those. And
> we also said, yes, some of these comments that you have made we think
> are fertile areas for future work.
>
> There were a lot of recommendations made in terms of, well, if you
> spent the next nine months, you could also model thus and such. You
> could make these enhancements and so forth. Given the fact that we
> think it is really useful to put out some advice in a relatively short
> time frame, we have not ignored those comments but we consider those
> as being some things to approach for the future.
>
> The exposure assessment has been modified. Drs. Bolger and Carrington
> have been refining the exposure assessments since they first gave
> their
>
> poster presentation. They have been using newer data on tissue
> concentrates of mercury in various fish species, as we mentioned
> earlier this afternoon, and they have also made some changes. Again,
> Dr. Carrington will explain. These include more categories of fish,
> some correction for food preparation, changing some of our parameters
> to reflect the NHANES data more closely, variations in consumer fish
> choice. I think Dr. Carrington is going to go over this.
>
> Some of the scenarios were changed to reflect both the limit on the
> amount of fish consumed and the type of fish consumed and combinations
> of both. Our reviewers commented to us that there are many areas in
> the country or many fish consumers where one species or a limited
> number of species are being consumed. That is something we should talk
> about.
>
> Some of these consumption scenarios addressed. And also the
> body-weight scaling was changed.
>
> At this point, I will stop and ask if
>
> there are any questions for clarification on the peer review.
>
> DR. MILLER: We can come back to this later on. I guess next is Clark
> Carrington. Why don\'t we move on to the Exposure Assessment.
>
> **Exposure Assessment**
>
> DR. CARRINGTON: I guess first I will warn you that there is a lot of
> stuff that I am not going to explain. I am going to start out talking
> about my model and I am mainly going to talk about the changes that
> were made since the last publication. If you are not familiar with the
> model, there is a lot that is going to go unexplained.
>
> I do have another set of slides that has some technical issues that I
> could go through, but I will only go through those if somebody asks me
> to.
>
> After going through the model and the changes I made, I am going to
> briefly compare the output of the model to the NHANES survey as a
> validation exercise. Finally, I am going to talk
>
> about some simulations for some putative advisories that can be used
> to evaluate what the expected impact of the advisories is, assuming
> that they are followed as specified.
>
> I have broken down the changes that were made to the model. These are
> all changes that were made in basically the last year. I have actually
> be working on\--I have had some form of this model since 1994 when I
> actually published an early version of this model. So I have been
> working on it for a long time. I have been working on it more lately,
> but, still, this has been an iterative development process and these
> are the most recent changes.
>
> First of all, the number of categories actually stands at 41. I think
> Rita said was expanded from 24 to 28, which was actually\--that was
> the expansion going from the paper to the poster. But, since the
> poster, I have actually expanded it to 41.
>
> A lot of that expansion occurred as a result of getting new data. But
> I also expanded it
>
> in order to try and make it match up with the NHANES categories
> because I think, in the future, I am going to try and use more of the
> NHANES data. So I am trying to get the concentration data to match up
> with the NHANES consumption categories as best I can.
>
> Finally, the biggest change in the model, at least in terms of what
> the average predicted level of exposure is, came about from
> introducing a correction factor for weight loss during cooking. This,
> on the average, is about a 20 percent factor so it resulted in a 20
> percent increase in predicted blood levels.
>
> Then I also made some changes on the part of the model which predicts
> consumption frequency for each individual in the survey. I am still
> using the same equation that I used before which is an exponential
> function which adjusts the frequency observed in the CSFII survey to
> generate the predicted long-term frequency.
>
> However, I have changed the parameters of the equation so now it is
> consistent with the
>
> consumption frequency observed in NHANES. Then I also increased the
> range of my estimated number of total seafood consumers to make it
> consistent with the number of consumers reported in the NHANES seafood
> survey.
>
> Finally, I made some changes in the way the model selects species for
> each individual
>
> for\--I have changed the way the model picks the species that each
> individual consumes over the course of a year. In the previous version
> of the model, I treated this value as a population variable so that
> somewhere between 20 and 80 percent of the time, I would use the CSFII
> survey to select the fish and then the rest would come from a
> market-share distribution.
>
> But, regardless of where it was between 20 and 80 percent, every
> individual in the survey had the same number. I have changed that so
> that is now an individual variable so that each person in the survey
> has a different number. Some people are eating the same fish all the
> time and other ones aren\'t and I am using a different range which is
>
> based on the NHANES survey.
>
> To sort of make a very long story short, this is what the output of
> the model currently looks like. It is still a pretty good fit but,
> instead of slightly underpredicting blood levels, now I am slightly
> overpredicting blood levels. It is off, depending on what percentile
> you look at, by about 15 to 30 percent. It is closer at the high end
> than it is at the lower percentiles.
>
> Now, I will go through the advisory scenarios. I have gotten them
> broken into three scenarios. The first category is a series of
> scenarios where we are just limiting the amount of seafood consumed. I
> have got three different scenarios which correspond to limits of 18,
> 12 and 6 ounces.
>
> Then I have got a series where we are just limiting which species are
> consumed without limiting the amount. That revolves around dividing
> the fish into different groups. On the next slide, I will show you
> what those groups are. But, the way the simulation runs is that
> whenever a consumer
>
> encounters a fish that is prohibited, that fish is replaced with
> another\--I guess that item of seafood is replaced with an item from a
> market-share distribution from the low-mercury group. So it replaced
> with a low-mercury fish or shellfish.
>
> Here are the groups. There is a high, medium and low group. The high
> group basically corresponds to what our current prohibited list is.
> Tilefish isn\'t on the list because I wasn\'t sure where to put it
> because we have conflicting data.
>
> The middle group is basically defined\--the low group is largely
> defined by light tuna; in other words, in order to keep the market
> share at a reasonable level, we had to keep light tuna in
>
> the\--or we felt like we had to keep light tuna in the low-mercury
> group. So anything that is significantly higher than light tuna and is
> not in the prohibited list is in the middle group.
>
> Where the levels end up with those criteria is anything between about
> 0.15 and 0.6 ppm is in the middle group. If it is below that, it is in
> the low group. If it is above that, it is in
>
> the high group.
>
> Finally, we ran some scenarios with combinations of limits on the
> amount of seafood consumed and limits on the species consumed. The
> first one we ran, which basically corresponds to our existing advice,
> which I am going to refer to as the 12-ounce No High scenario,
> eliminate the high group and then has a total of 12 ounces from the
> remaining two groups without any restriction whether that 12 ounces
> comes from the low or the middle group.
>
> The next scenario which we are calling the 12-ounce Variety scenario
> has a 6-ounce limit from the medium group with a 12-ounce total, so up
> to 6 ounces can come from the middle group and the rest of the 12
> ounces has to come from the low group.
>
> Then the next two scenarios are similar to the 12-ounce Variety
> scenario except that is an actual reduction in the total amount that
> can be consumed which corresponds to the amount that is consumed from
> either albacore in the first case or the middle group in the second
> case.
>
> I will just give you an example of how it works for the medium group.
> In the 12-6 Medium scenario, if someone eats 6 ounces of medium, then
> they are done. So they can\'t eat any lower. I guess another example
> is you could eat 3 ounces of medium and 6 ounces of low. So, as far as
> the total is concerned, the medium counts double.
>
> Then the last scenario is the 12-ounce Low Only scenario where a
> person can eat 12 ounces and it all has to come from the low group.
>
> Here are the results of the first series, and I will only
> briefly\--there are a lot of numbers on there and so the most
> important ones to show or look at\--the predicted levels that are
> above the reference dose, which is given down here, are all going to
> be in the upper\--the 90th percentile and above. On the other hand, if
> you have significant reductions in seafood consumption, it is going to
> show up in the average, which I think is the best number to look at.
>
> So if you are reducing the average, you are reducing seafood
> consumption which is not
>
> necessarily something you want to do. On the other hand, if you are
> reducing the mercury levels in the 99th percentile, then you are
> accomplishing your goal. This last number is the predicted percentage
> of the population above the RFD. You will note that a restriction of
> 18 ounces per week has relatively little effect. A restriction of 12
> ounces has a slight effect, but it is still a relatively small
> reduction.
>
> Finally, you will see a pretty substantial reduction with 6 ounces per
> week.
>
> This is the series with species limits. The baseline is the same as
> before. It is also the same as we have plotted in that graph I showed.
> I guess the main conclusion from this is taking just the high group
> out has next-to-no effect whereas restricting it to the Low Only group
> has a substantial effect.
>
> Finally, I have got this list. I think I have got this graph, but the
> main thing to point out from this table is these three groups in the
> middle where you are adjusting the amount coming
>
> from the medium group are not substantially different. There is a
> reduction seen in the 12-ounce No High scenario but there is not much
> of a further reduction in the 12-ounce Variety, Albacore or Medium
> scenarios but there is a much greater reduction with the Low Only
> scenario.
>
> I guess the other thing I would like to show before I move the graphs,
> which you can\'t tell from the graphs, is that the numbers in
> parentheses are confidence intervals and the confidence intervals go
> up dramatically as you move out to the tail of the distribution. So
> the uncertainty estimates at the 99.9th percentile are pretty wide.
> That is one of the reasons I am not going out any farther than that.
>
> Here is a graph which is plotting the median values from the table I
> just showed you. This one on the far right is the baseline. Then there
> is another group of three here which are all the 12-ounce various
> combinations of the scenarios that have 12-ounce limits and eliminate
> the high group. They are all fairly similar. You will
>
> notice, they do eliminate most of the area beyond the reference dose
> but they don\'t completely eliminate it whereas the 12-ounce Low
> scenario does, in fact, come pretty close to the goal of getting
> everybody below the reference dose.
>
> Just as a summary, numerous revisions have been made to the model
> since the last time I published a description of it. Instead of
> slightly underpredicting NHANES, the model now slightly overpredicts
> NHANES. Finally, the percentage of individuals about the reference
> dose can be reduced by either limiting seafood consumption or by
> limiting the species consumed, and the degree to which the exposure is
> reduced is entirely dependent on how aggressive the limits are.
>
> And I will stop there and take questions.
>
> DR. MILLER: Thank you, Dr. Carrington.
>
> **Questions of Clarification**
>
> DR. MILLER: Comments?
>
> DR. APOSHIAN: I think we have to more or less view this with a few
> words of\--or a few fears. The risk assessment and model-making, I
> think most
>
> people would agree involves a total population. It does not involve a
> population that is hypersensitive, in this case to methylmercury, a
> population that cannot get rid of methylmercury from its cells.
>
> A perfect example in medicine of this situation with another metal is
> Wilson\'s disease or hepatolenticular degeneration where humans die of
> this because they don\'t have the mechanism to transport copper
> outside their cells. The only way of keeping these people alive, and
> we can do this now, is by giving them a chelating agent.
>
> I am passing around to you something. I would like you to look at the
> figure of the table on the top right-hand side. This deals with
> autism. I am not getting involved in what is causing autism. That is
> not what I want to speak about. What I want to show you here is that
> when the first baby hair of autistic children was analyzed for mercury
> and for methylmercury, particularly, and compared to the hair of
> normal children, it was very surprising to find the hair
>
> of normal children was much higher as far as mercury content than the
> hair of autistic children.
>
> The mercury in the hair is a reflection of the mercury in the blood.
> The reflection of the mercury in the blood is whether the mercury gets
> into the blood. On top of this, there is a paper coming out very soon,
> if it is not out already, in which, when they gave a chelating agent,
> gave a substance that would increase the excretion of mercury, get
> mercury out of the cells\--this was done by very reputable
> people\--when they gave a chelating agent, DMSA, to the autistic
> children and the normal children, it was found that the autistic
> children excreted six times more mercury than the normal children.
>
> Again, I am not saying that autism is caused by mercury, whether this
> is a result of the autism or the cause of autism is the beside the
> point. What I want to point out to you is that here is the first group
> of people that we know, now, who are unable to excrete methylmercury.
> Therefore, the amount of methylmercury in their
>
> tissues is higher and, therefore, is toxic.
>
> Models don\'t take this into account. Risk assessment does not take
> this into account. The only thing I want to do is caution this
> committee to consider that not everyone is a normal human being. Not
> everyone can get rid of the mercury. For those people who cannot get
> rid of the mercury, and this is just the tip of ice berg\--for those
> people who cannot get rid of mercury, the amount of fish, the amount
> of methylmercury in the fish that they are going to eat, is going to
> be very, very crucial.
>
> I hope you just take this\--what I handed out was the datasheet and
> the reference to the publication. The title page is attached to it for
> anyone who wants to look at it. I think that this is really the first
> example now of probably a deficit in the transport mechanism, the
> efflux mechanism, for getting methylmercury out of the cell.
>
> Thank you.
>
> DR. MILLER: Are you arguing that the
>
> levels that should be set for consumption of mercury be based upon
> these hypersensitive people?
>
> DR. APOSHIAN: Are you asking me?
>
> DR. MILLER: Yes.
>
> DR. APOSHIAN: What I am saying is that we cannot ignore a subset of
> the population that cannot excrete methylmercury and that most models
> have to take into account only the majority of the population.
>
> DR. MILLER: That\'s right. So the question is, if we try to take into
> account that segment of the population that may be hypersensitive, for
> one reason or another, how do we do that?
>
> DR. APOSHIAN: You have got to issue a word of caution. You have got to
> issue a word of caution that\--it is sort of like\--to me, the
> methylmercury story is very similar to the alcohol story. Almost every
> bottle of wine you buy now will say that excessive consumption of this
> material may cause a defect or a problem in the child that is going to
> be born, or have
>
> reproductive effects.
>
> No one has yet found out, although there is an Indian population that
> is very susceptible to alcohol, but no one has tried to just point out
> that certain people in the population are more susceptible to alcohol,
> pregnant women are more susceptible to alcohol than others.
>
> I am just saying that we have to take this into account in our warning
> system.
>
> DR. DURST: Durst. With respect to that, I guess my concern is that,
> for example, in this autistic case, how do they know they are in that
> risk group? Giving a warning, in this particular case, anyway, would
> not do any good except to frighten a lot of people from eating fish.
>
> DR. APOSHIAN: No one says that you shouldn\'t eat fish. We are not
> saying that. Just like no one says you shouldn\'t drink wine. It is
> like the State of California does have a cautionary statement on many
> of the products that are sold over the counter. They don\'t try to
> identify the groups but they just point out that there is a
>
> problem.
>
> I know that the fish manufacturers would, obviously, never agree to
> putting on a can of tuna fish that one should eat this very, very
> carefully. I just wanted to make you aware of some of the latest
> studies being done which really have amazed many of us. They are very
> good studies.
>
> I am sorry I didn\'t answer your question very well, Sandy, because I
> don\'t know the answer to your question about how we take care of
> everyone.
>
> DR. MILLER: I think whatever the outcome is, I think that the process
> by which these advisories are made can always be modified as data
> becomes available. In other words, whatever the presentation, whatever
> approach is presented by the agency tomorrow can be modified. But I
> think that the problem that FDA faces and, in fact, all regulatory
> agencies face, is how to deal with the bulk of the population versus
> those parts of the population that may be ultrasensitive and do it in
> such a way that the positive aspects of the food
>
> involved are not lost.
>
> DR. APOSHIAN: With all of your experience with the FDA on this matter,
> how would you suggest that this\--
>
> DR. MILLER: I don\'t know.
>
> DR. APOSHIAN: Okay.
>
> DR. MILLER: I don\'t know. Jean has got an answer.
>
> MS. HALLORAN: I have a suggestion. This is reminding me of how certain
> products have\--there is a sweetener that is a problem for people with
> a certain metabolic deficiency that has letters that stand for it.
> PKU; there we go. If there is a special group, it could be labeled in
> a way similar to people with that problem.
>
> DR. MILLER: Yes. But I wouldn\'t want to see a general recommendation
> to the population be ignored and base it on the population of
> ultrasensitive people.
>
> MS. HALLORAN: No; my only point would you would could special labeling
> for that purpose and also having the general advice.
>
> DR. MILLER: I agree. That is an approach. Dr. Russell?
>
> DR. RUSSELL: This is actually not on that particular topic, but in the
> slides, it says exposure assessment has been revised and expanded.
> Your last point was body-weight scaling changed. Can you explain that,
> how that was done?
>
> DR. CARRINGTON: It actually didn\'t change since the paper. That was a
> change I made right before the paper, as a matter of fact. I did it
> primarily to get the model to fit children better. Anyway, the change
> was I used body weight to the power of one-third which actually fit
> not only the adult data better but it also makes the model fit
> children better. So it is not straight body weight as a function of
> dose, it is body weight to the power of a third.
>
> DR. RUSSELL: Okay. Thanks for that clarification. The other thing was,
> in the table you have with the high, middle and low mercury
> concentration groups of fish, I noticed that there are several
> fish\--for example, like fresh tuna,
>
> that we were just told a little while ago that that actually was going
> to be done in 2005 or something like that but that you don\'t actually
> have those figures.
>
> So I was wondering how you placed those fish in that table.
>
> DR. CARRINGTON: We do have fresh tuna data. In fact, we have lots of
> it. That is one of the\--
>
> DR. RUSSELL: Then I guess we were told that you didn\'t.
>
> DR. CARRINGTON: That was a list of the stuff we had done last year.
> Actually, we did other stuff\--like, actually, I have gotten FDA data
> sort of in three parts. For a long time, we have had shark, swordfish
> and canned tuna. Then, actually, one of the differences between the
> paper and the poster is I got data for maybe 20 species that we had
> accumulated in the last four years, I believe. In that data was fresh
> tuna, so we do have fresh tuna data. it is just that it is not
> brand-new data.
>
> DR. ACHESON: Dr. Miller, may I just clarify that point?
>
> DR. MILLER: Sure.
>
> DR. ACHESON: Just to make sure that the committee understands that the
> data I showed was the new data. It was the new 2003 data. We didn\'t
> test fresh tuna as part of that assignment. Therefore, it wasn\'t
> included in my data table. I don\'t want to imply that if it wasn\'t
> on that table that I showed, we don\'t have data on it.
>
> DR. CARRINGTON: Actually, we, in fact, have something like 80 percent
> of the market covered at this point. There is still about\--I would
> say the biggest categories we don\'t have data for\--the biggest
> single category we don\'t have data for is crabs. That is something we
> are still using the National Marine Fisheries Service data. I guess
> that would be number one on my list of what we don\'t have data on.
>
> DR. MILLER: Dr. Dwyer?
>
> DR. DWYER: Thank you for a very interesting presentation. I had two
> questions,
>
> three, actually. The first was was the model you presented today
> published in the peer-reviewed literature or is it the old model and
> are you planning on publishing the new model in the
>
> peer-reviewed literature?
>
> DR. CARRINGTON: The answer is\--well, the answer to the first
> question, it is a modified version of the published model so, as it
> now stands, it has not been published although I think we are planning
> on doing so; yes.
>
> DR. DWYER: You are.
>
> DR. CARRINGTON: Yes. We will; yes.
>
> DR. DWYER: Thank you. The other question was, I guess, to our
> colleagues at FDA. It is my impression, and I may have the name wrong,
> that the Institute of Medicine of the National Academy of Sciences has
> just published, I think, several volumes on the whole issue of
> vaccines and neurodevelopmental and a whole bunch of other hazards. I
> wondered if it would be possible to get those volumes and bring them
> in tomorrow. I assume that this issue was also reviewed in those
> volumes
>
> and I would like to know what the Academy says about this issue as
> well, the issue of reduced levels of mercury in autistic children.
>
> DR. CARRINGTON: Is that a question?
>
> DR. MILLER: Let\'s get an answer to that. Can we get\--
>
> DR. CARRINGTON: The vaccine issue is inorganic mercury, isn\'t it? I
> guess it is ethyl mercury. That\'s right. Actually, it not that
> different. Its pharmacokinetics are different but it is\--
>
> DR. MILLER: David, do you want to respond to that?
>
> DR. ACHESON: That is really the Chairman\'s prerogative. Certainly,
> our goal was to keep this restricted to methylmercury in fish.
>
> DR. DWYER: Fair enough.
>
> DR. ACHESON: I am sure we could find the data that you want but it is
> taking us beyond methylmercury in fish.
>
> DR. MILLER: But the issue concerning what happens when you have a
> specially selected
>
> population is\--I think that there is a level of data that you need to
> do this and, if you are going to do something like you did with PKU
> and asparatame, you need to be able to clearly define what your
> endpoint is so you can identify which of the children are going to
> respond inappropriately.
>
> For the kids with PKU, they are identified at birth. It is very
> straightforward which kids are phenylketonuric and which are not.
> Autism is a much more complicated issue, I suspect.
>
> DR. HEIMBURGER: Heimburger. I have a question. Just to follow up
> exactly on that, unless I am misunderstanding the abstract in this
> paper that you presented relating to autism, or autistic children,
> unless I misunderstand autism, it is a diagnosis that is made well
> after birth. There is no way to identify, in utero, or reduce prenatal
> exposures to anything in a child who is destined to be diagnosed as
> autistic later on.
>
> Just to clarify, I would think any impact that it might have on any
> advisory would have to be\--there would be no way that I could see to
>
> reduce prenatal exposure to mercury.
>
> DR. APOSHIAN: No. Please understand. I was not trying to say in any
> way that autism is caused by mercury. That is an entirely different
> question and it is one that is unsolved. But the point I am bringing
> up is that, once these children are born, they are going to have diets
> of fish. If they can\'t get rid of the methylmercury, they are just
> going to be made sicker. That\'s all.
>
> The point I want to make also is we know that about autistic children
> and studies are just beginning now about other populations.
>
> DR. MILLER: Perhaps it would be fair to say that the committee might
> want to consider a statement such as the agencies ought to be advised
> to continue reviewing the literature as it changes and make
> modifications in the advisory where appropriate and to take into
> account new data. I think that is the best that you can say for that.
>
> Dr. Durst?
>
> DR. DURST: Durst. Dr. Carrington, I am curious about your comment that
> the body mass is to
>
> the third power in your model. I am not familiar with the model or how
> many variables you have in it and so on, but I am curious, does that
> number, the third power, come from biological or physical relevant
> matter or is this a number you put in to tweak it to fit the NHANES
> data.
>
> DR. CARRINGTON: I actually got it
>
> from\--the data I used to build the model on is a U.K. study which is
> Sherlock, et al., 1984 in Human Toxicology. It was 20 subjects with
> controlled fish diets. In that paper, they actually\--first of all, if
> you look at the data\--I have a slide of this. Can we pull it up?
> Okay. Somewhere, I have another slide. I guess the bottom line is that
> if you plot the blood diet ratio as a function of body weight, there
> is a correlation there but it is not directly proportional to body
> weight. They suggested that the best fit is one-third power which, I
> believe is\--they didn\'t how they got that. They just suggested that
> that was a good number.
>
> I actually recently went back and analyzed it myself and I got as my
> optimum power of 0.43; in
>
> other words, a body weight of the power of 0.45 provides the
> optimum\--you can account for the most variance possible out of the
> total variance as a function of body weight with a body weight to the
> power of 0.43.
>
> DR. MILLER: There is a relationship called metabolic mass which is
> approximately to the one-third. I don\'t remember what the exact
> number is, but that is a very old concept. It goes back to the days of
> people who were dealing with mathematical biology and energy
> metabolism.
>
> DR. CARRINGTON: Also, a lot of it has to do with how the compound is
> partitioned between fat and blood.
>
> DR. MILLER: Metabolic mass is supposed to take that all into account.
> The only animal that doesn\'t fit on the curve is the rabbit and it
> does if you take its ears off.
>
> Dr. Lund?
>
> DR. LUND: Daryl Lund. This question about identifying unique subgroups
> within the population and how you take those into account,
>
> obviously, we are going to gain a great deal more information as
> individuals have more information on their genetics, on their genes
> generated. So I assume\--I don\'t think we need to tell FDA that, in
> fact, as information becomes available on subsets of the population,
> that you will take this into account in advising the population as to
> its diet, or as to limits on its diet.
>
> Clearly, with the identification of PKU, and once you know, or even in
> the case of autism, once you know that an individual is susceptible to
> a particular accumulation in this case or disease state or something,
> then you can make advice. I assume that goes without saying to the
> FDA, that they would take into account that information, that new
> information on our population.
>
> DR. APOSHIAN: That isn\'t the experience that some of us have had with
> the FDA during the last 20 years.
>
> DR. HEIMBURGER(?): But we have had a change, also, in the FDA now.
>
> DR. APOSHIAN: Good for you.
>
> DR. ACHESON: May I answer that question, Dr. Miller?
>
> DR. MILLER: Of course.
>
> DR. ACHESON: Certainly, as new science is published in relation to
> methylmercury, genomics, proteomics, unquestionably, we would take
> that into account. I think the PKU model is a great one, but that is
> essentially a one-gene issue. You can diagnose it. You know early. You
> have got the therapy.
>
> If we could find the methylmercury gene, believe me, I would love to
> know what it is.
>
> DR. MILLER: Dr. Krinsky?
>
> DR. KRINSKY: Norman Krinsky. I am concerned about the consumer
> response to an advisory that suggests limitation of a certain food
> type and how that would be interpreted by the public, whether, in
> fact, as we have heard earlier, that a class of individuals have
> totally given up tuna consumption, whether, in fact, people might not
> totally give up fish consumption because of an advisory recommending
> limitation.
>
> What comes to my mind is fat consumption in this country. Despite the
> commercial success of the Adkins Diet, there is still a huge
> proportion of the population that believes that fat is bad for you
> and, therefore, are seeking out non-fat foods, fat-free foods. The
> impact of this is that it limits their Vitamin E consumption.
>
> If they take a multivitamin that contains the RDA for Vitamin E, they
> are going to be okay. But that doesn\'t necessarily go hand-in-hand
> that people limit their fat consumption and try to replace a missing
> nutrient.
>
> There are good things in fish. I don\'t know how to address this but I
> do have a concern that the public might, in fact, move towards
> eliminating fish as a food source.
>
> DR. MILLER: We are going to discuss this at much greater length
> tomorrow when it comes up.
>
> DR. KRINSKY: Okay.
>
> DR. MILLER: Jean?
>
> MS. HALLORAN: I have a question for Mr. Carrington. I am just trying
> to make sure I have
>
> understood your analysis. So let me read this back to you in another
> form and you can tell me if I have got it right.
>
> If you define success as having less than 2 percent of the population
> with greater than the RFD in their blood of mercury, you would have to
> have them eating\--limiting their consumption either to 6 ounces a
> week or to 12 ounces a week with the low fish consumption group?
>
> DR. CARRINGTON: Of the scenarios I presented, I think that is right.
> You could probably devise other scenarios that would\--or some
> combinations of those.
>
> DR. MILLER: Anybody have anything else? If not, then we come to the
> end of today\'s work. We meet again tomorrow morning at 9 o\'clock.
>
> (Whereupon, at 4:00 p.m., the meeting
>
> recessed, to reconvene at 9:00 a.m., Thursday,
>
> December 11, 2003.)