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
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
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=mc2, 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.)