ATDEPARTMENT
OF HEALTH AND HUMAN SERVICES
FOOD AND DRUG ADMINISTRATION
CENTER FOR FOOD SAFETY AND
APPLIED NUTRITION
DIETARY SUPPLEMENT SUBCOMMITTEE MEETING
A DISCUSSION OF THE TERM "METABOLITE"
AS CONTAINED IN THE STATUTORY DEFINITION
OF A DIETARY INGREDIENT
Tuesday, March 25, 2003
8:45 a.m.
This transcript has not been edited or corrected, but appears as
received from the commercial transcribing service. Accordingly the Food and
Drug Administration makes no representation as to its accuracy.
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PARTICIPANTS
Johanna
Dwyer, D.Sc., R.D., Chair
Constance
J. Hardy, FDA
MEMBERS:
Nancy M. Childs, Ph.D.
Harihara M. Mehendale, Ph.D.
Michael Wayne Shannon, M.D., M.P.H.
TEMPORARY
VOTING MEMBERS:
Eric P. Brass, M.D., Ph.D.
Paul L. Schiff, Jr., Ph.D.
CONSUMER
REPRESENTATIVE:
Edward Blonz, Ph.D., M.S., C.N.S., F.A.C.N.
NON-VOTING
ACTING INDUSTRY REPRESENTATIVE:
Annette Dickinson, Ph.D.
C O N T E N T S
Regulatory
Perspective and Challenges,
Christine Taylor, Ph.D. 4
Robert J. Moore, Ph.D. 16
Administration
Issues, Constance J. Hardy 22
Remarks
by Chairperson, Johanna Dwyer, D.Sc., R.D. 33
Biochemical
Facts Behind the Definition and Properties of Metabolites, Edward D. Harris,
Ph.D. 38
Questions
and Discussion by Subcommittee Members
on Dr.
Edward Harris' Presentation 65
Public
Comment:
Philip Harvey, Ph.D. 111
Steven Dentali, Ph.D. 122
Discussion
of Charge and Questions by the Subcommittee 130
P R
O C E E D I N G S
Welcome
DR.
TAYLOR: Good morning and welcome to
FDA's Food Advisory Subcommittee for Dietary Supplements. This is the first meeting of this particular
subcommittee. I do want to extend my
personal appreciation to the members of the committee. They are not only experts of renown, but
they come from quite far away from us.
Thank you for agreeing to participate in this particular subcommittee.
The
subcommittee is, as we have mentioned, under the auspices of the Food and Drug
Administration, particularly the Office of Nutritional Products, Labeling and
Dietary Supplements.
My
welcome is not only on my behalf, Christine Taylor--I am the Director of the
Office--but I also am extending a welcome for Mr. Joseph Levitt, who is the
Center Director. He ordinarily does
attend the first meeting of every subcommittee. Today, he was unable to attend so I bring his apologies but also
his best wishes for a very good meeting.
Basically,
the session agenda starts this morning with the overview, which is inclusive of
some advisory logistics as well as an overview put together both by Mr. Levitt
and myself, what he calls "the dietary supplement state of
play." Again because this is the
first meeting of the subcommittee, we will spend just a few moments on that.
We will
then put up the charge to the subcommittee for this particular meeting and,
from there, we will move to a presentation from one of the FDA staff on the
regulatory process which will consider again those charges. We will then do an
official handoff to your Chairperson, Dr. Johanna Dwyer. From there, she will introduce the members
or you can introduce yourselves, however Johanna prefers to do it. There will
be a "white paper" presentation on the topic today and then you will
move to your discussion and your recommendations.
Just a
little bit of a reason for the existence, now, of subcommittees. Many of you may remember that for many years
the Center for Food Safety and Applied Nutrition had a food advisory committee. That one food advisory committee handled all
of the issues within the Center for Food Safety and Applied Nutrition.
A few
things have happened in the last couple of years that have made us look at a
way of enhancing that particular process.
One is that there is clearly an increased need for scientific input on
the part of the Center. What is
envisioned is a chance for the agency to make the possible regulatory decisions
based on scientific input and one way to get that kind of scientific input is
through advisory subcommittees.
But also
over the last couple of years there has been an increased need for a notion
that a more broad food advisory committee could revive that kind of input for a
variety or topics that became increasingly difficult. So, several years ago the agency began to work to develop
subcommittees of the Food Advisory Committee and there are now six official
subcommittees. There is a contaminants
and toxicology one. There is a
biotechnology one. There will be one
for infant formula. There is now one
for food additives. There will be one
for nutrition and this is the sixth subcommittee, dietary supplements.
From our
perspective, the establishment of these subcommittees is extremely useful
because you will have the chance to develop what I call a standing
relationship. That is, the folks who
are members of the subcommittee will come together perhaps once, twice or three
times a year, depending on the topics at hand, and begin to develop a relationship
with the regulatory issues that they are providing scientific advice for.
There
also will an effort to stagger rotations on these subcommittees so that it is
not as if a whole new committee meets each and every time, but people have
various lengths of their terms and, therefore, people are integrated in and
then rotated out.
The
general theme for these kinds of advisory committees is that the focus is on
scientific input. Regulatory matters,
as you would expect are retained by the agency and what we are seeking is
scientific input that can better inform our regulatory decisions. It is very important that the FDA staff
present here in the room do not influence or lead the discussion. We do kick it off. We do present charges to you, but then we are available at a side
table to clarify questions but not to participate in your discussion per
se. We are always available to try and
answer your questions but we don't want to influence or lead you in any way.
We do
have several FDA scientists present and I will introduce them at this point in
time. We have Dr. Susan Walker, who is
the Acting Director of our Division of Dietary Supplement Programs. She is here, on the end. Very shortly Dr. Beth Yetley will be joining
us. She is the Center's lead scientist
for nutrition. Then, we have available
Dr. Robert Moore, who is the Branch Chief of one of our organizations within
the Dietary Supplement Division. As I
have mentioned before, I am Christine Taylor and I am the Director of the
Office of Nutritional Products, Labeling and Dietary Supplements.
We also
have an FDA Executive Secretary in the form of Connie Hardy, who is sitting
with the Chair to help with the logistics of the meeting. I do believe our ethics representative, Mary
Anne Kelley, might be coming today. We
do have an ethics representative with us today.
I will
just spend a minute or two talking about our perspective of the dietary
supplement state of play. In our
parlance, legislation that happened in 1994 is really relatively new
legislation. At the time DSHEA occurred
there were a number of studies within the agency that looked at implementing
legislation, and the rule of thumb was that it takes almost ten to twenty years
before a new piece, a major piece of legislation really becomes a comfortable
vehicle for the agency to operate in.
I think
it is fair with DSHEA to characterize it as a primarily post-marketing set of
provisions, and what anyone can tell you at FDA is that a post-marketing
paradigm is not easier than a pre-marketing paradigm. There is a great deal of work in either paradigm and it is
important to recognize that DSHEA was a switch for the agency and, therefore,
it is taking us some time to better understand kind of what the boxes are that
we operate in. The government does bear
a considerable burden in a post-marketing world and has a considerable amount
of responsibility. As you can probably
tell, this is leading up to the need for an advisory committee.
Because
the statute happened in 1994, was passed by Congress in 1994, we are in the
stage of interpreting and implementing the statute. Clearly, the notion of what Congress intended by the statute is
foremost on our plate. When the statute
was enacted all legislative history, that is, the background discussion of the
committees, was struck from the record so we don't have the advantage of
legislative history to help clarify some of the phrases and the meanings of the
provisions in that Act.
No matter
what kind of statute you are dealing with, you do rely heavily on precedent
actions and case law, and that is why it is a ten- to twenty-year process to
fully implement the statute. We are in
that process now.
The
feeling that Mr. Levitt wanted us to sound today is that building a foundation
for implementation is slow work. From
his perspective, he is having to muster resources. DSHEA did not come with resources and, therefore, he is working
to put in place resources to implement the statute. Then, there is a whole series of policy questions in terms of
what do you address as precedent issues.
Where do you want to put your efforts in order to better clarify the
intention of the statute? That is
highlighted in yellow, here. An
important role is clarifying the science that drives that implementation. That is one of the purposes of having the
advisory committee, to help with that particular set of issues.
In many
ways, some of the plans that were put in place three or four years ago, as you
would expect, have been overtaken by other issues and pressures, and dietary
supplements are in a state of flux at the moment in terms of implementing the
statute, interpreting the statute and defining it.
One
important evolving issue is the notion of fraudulent claims. For those of you who have followed FDA's
activities in the area of the Dietary Supplement Health and Education Act,
given the resource limitations, much of the effort, the focus on the limited
resources was what Mr. Levitt termed safety first. He will be perfectly frank about his lack of resources to deal with
the issue of fraudulent claims.
This
really did change last December when our new Commissioner put in place an
initiative. He entitled it
"Consumer Health Information for Better Health" and one of the
aspects of that initiative was to enhance enforcement against false or
misleading claims or otherwise unapproved drug claims. So, you will now see FDA in a much more
active mode in terms of not only safety but this whole issue of fraudulent
claims and labels on dietary supplements.
As I look
to the future, I am sure that there will be some need for guidance on
substantiating these claims clearly if you expect the claims to be truthful and
not misleading. The agency does have
some responsibility to clarify what that basis is. So, I do see us in the future seeking some input.
The
evolving safety standard is the whole question of significant and unreasonable
risk. The statute is clear that dietary
ingredients can be removed from the market if they present significant and
unreasonable risk. The big question is
how do you determine when something has reached the threshold of a significant
and unreasonable risk? What is the
standard? What is the role of adverse
events or sentinel events versus a cause and effect relationship?
Some of
you may have noticed recently that in the Federal Register there were some
provisions for some warning statements, as well as a series of I think very
important questions. The agency is
seeking comment on whether evidence of significant concerns, short of a
definitive demonstration of a risk profile, is sufficient to declare
significant and unreasonable risk. So,
again, the agency is going to have to look for clarification and definition on
the standard and I think again, we will be seeking input.
A third
one is the whole issue of manufacturing standards that are known as GMPs, good
manufacturing standards. Less than two
weeks ago the agency published a proposed rule for dietary supplement GMPs
which did focus on the quality and purity of the products. The idea here is to ensure that the product
is what it says it is and contains amounts of what it is supposed to contain
and that manufacturers of ingredients know what they are putting in their
particular products.
This
particular proposal has a phenomenal amount of technical interpretive aspects,
as well as questions about appropriateness.
This will be an important process for the agency as it works to a final
rule and, again, I think we will be seeking input.
Finally,
where we are today--an evolving issue of definitions. Let me tell you that a plan for dietary supplements was put in
place in the year 2000. Quite a bit of
space was given to the concept that you need to define boundaries for dietary
supplements. Congress gave us words as
to what dietary supplements are but, as I think you will see from your discussions
today, a lot of that evolves around what do these words mean. As I have mentioned, we don't have
legislative history which is important for clearly having a good handle on what
these definitions are. But it is very
important that these definitions be grounded in sound science and that is one
of the purposes of having an advisory committee.
Part of
today's overall umbrella though is what is the definition of a dietary
supplement. So among other things
today, you will find out that a dietary supplement is defined as a metabolite
of a vitamin, mineral, amino acid, herb or other botanical, or dietary
substance for use by man to supplement the diet, and the word that is the issue
today is metabolite. We are asking
consideration of the meaning and the application of that word, metabolite. What substances are or are not metabolites
of other substances is the key question.
In a few
moments you will get the regulatory context from Dr. Moore, who will then
revisit the notion of the charges to the committee, but I will just highlight
them now before I turn over the microphone to Dr. Moore.
There are
basically three charges to the committee for your discussion today. The first is, is it possible to identify
particular scientific criteria, principles or conventions that enable a
determination to be made about when a substance is or is not a metabolite of
another dietary ingredient? Again, Dr.
Moore will review this.
Second,
consider and discuss the scientific strengths and weaknesses of the following
concepts with respect to their usefulness in identifying whether a substance is
or is not a metabolite of another dietary ingredient. As you will see, there are four components that we have asked you
to consider and, again, these will be reviewed in some detail.
The third
charge to the subcommittee is to discuss the scientific validity and likely
usefulness for identifying when a substance is or is not a metabolite of
another dietary ingredient. If so, what
characteristics associated with the criterion makes it valid or useful?
Those are
basically FDA's charges or questions to the advisory subcommittee, and we very
much look forward to your discussion and appreciate the chance to hear from
you. Dr. Moore? I know at one point we are going to turn it
over to the exec. sec. but I think right now we will move right into Dr.
Moore's presentation and then turn it over to Connie.
Regulatory Context
DR.
MOORE: Thank you. What I am going to cover is just briefly,
you know, a brief summary of the legal framework that applies.
As Chris
has already said, in 1994 the law was amended and among other requirements that
DSHEA added was a definition for dietary supplements that really forms the
basic element of the statute from which everything else flows.
In
general, in implementing any provision the issues that are raised fall into two
categories, the nice, simple, straightforward ones, for example with DSHEA that
required us to withdraw an advanced notice of proposed notice of rule-making
that doesn't require a great deal of thought or insight. Then, there are more complicated provisions
that ask us to interpret an ambiguous phrase within the statute in a way that
fairly and even-handedly applies that provision to the marketplace.
Today's
purpose is one of those ambiguous phrases in the statute. It is important to recognize that what we
are considering is not so much defining the term metabolite; we are looking for
principles or conventions that allow us to determine when something that may be
a metabolite is a metabolite of something, of another substance. I will walk through the definition that is
in the statute and will make it more clear why that sort of parsing of the
phrase is important.
I don't
know if you heard that in the back, but Dr. Dwyer was mentioning that there is
sort of a one-page summary of my discussion somewhere in that book.
One of
the things that DSHEA did was define what dietary supplements are. The statutory definition defines them as a
product, other than tobacco, intended to supplement the diet that contains one
or more "dietary ingredients."
It then went on to define the universe of substances that would be
eligible to be used as dietary ingredients.
It defined dietary ingredients as a vitamin, a mineral, an amino acid,
an herb or other botanical, a dietary substance for use by man to increase
total dietary intake. Then, in the last
provision, it included a category that was a metabolite, a constituent, a
concentrate, an extract or a combination of any preceding dietary ingredient
and that brings us to the point we are at today.
As Dr.
Taylor mentioned, the statement of agreement that constitutes the legislative
history for DSHEA doesn't directly address the issue of metabolite. It is not defined elsewhere in the statute
and the plain language is simply ambiguous.
Clearly, it envisions not just any metabolite because it redirects to
metabolites related to other substances.
So the
question, is in the face of ambiguity, of no legislative history and the lack
of a definition in the statute, how does one go about interpreting and adding
meaning to this phrase? The basic
question then is because only metabolites that are metabolites, if you will, of
something previously named in the statute, what we have to do to decide which
substances may or may not be lawfully used in ingredients is find out when is a
substance or is not a substance a metabolite of something else.
The
reason that is important, just to reemphasize what I just said, is that the
statute doesn't say any metabolite necessarily is a dietary ingredient but only
those substances that are metabolites of something else that has been
previously named.
In trying
to reach a starting point to parse out a definition when the legislative
history is silent, one generally looks to the plain language of the
statute. Again, the term metabolite is
ambiguous so one looks to the ordinary meaning of the term that one finds in
authoritative references, in dictionaries and in other types of texts, and what
one comes up with is a series of potential definitions of a metabolite, but all
sort of condensed down as largely a substance that is consumed or produced in
metabolism.
That sort
of general plain meaning of the term then leads you to the conclusion that
anything is a metabolite and yet, as I have mentioned, it doesn't address the
basic question of when or if a particular substance is a metabolite of some
other substance and that is the basic question that we need to consider.
"Anything
goes" is meaningless. The agency
has an obligation, under general rules of statutory construction, to interpret
portions of the Act in a way that gives them meaning and so to interpret
metabolite in a way that renders the phrase meaningless or reads it out of the
Act simply isn't an option available to us.
More
importantly, if it is undefined and is undefined in such a general or
meaningless way, it provides no basis or guidance to firms trying to make good
faith efforts to decide whether a novel substance may or may not be a dietary
ingredient. So, this adds certainty to
the marketplace that is obviously a necessary requirement for firms that are
trying to make business decisions for the long-term.
If one
looks at is there even a need, and I am not going to go through any of these in
any detail because that is why Dr. Harris is here, but there are a series of
things in the marketplace that when one looks at them, it raises or begs the
question as to are they metabolites of some other dietary ingredient. Some of these examples are many of the
hormones and bioactive molecules, some of which may be simple one- or
two-reaction steps from the parent compound; others may reside at the end of
very multi-level branched metabolic pathways.
The
question is from the time we start the cholesterol or arachidonic acid and
reach steroid hormone or prostaglandin if there are twenty steps in there, is
there a way to tell how one approaches that and say this is or isn't a
metabolite of all of the things that preceded it? In a very general way that is setting the stage, hopefully, for
what Dr. Harris will address.
So, the
basic question that we come back to is that the issue at hand isn't defining
metabolite per se. What it is, is
looking at how a scientist looks at a substance and reaches a conclusion that
it is or is not a metabolite of some substance that may have preceded it in
that metabolic pathway.
Real
briefly since Dr. Taylor mentioned it, what we are really looking for is not so
much to reach a conclusion necessarily today, but to explore the thought
process and the principles, the scientific principles that biochemists and
metabolic physiologists, and the like, would apply to reaching these types of
conclusions and then weigh the usefulness and the merits or the arguments
against relying on one or more of these principles, and how useful they are in
the context of what we are required to do in the statutory framework to decide
these things are or are not metabolites of some other substance that preceded
them in the pathway. I will leave it at
that.
DR.
TAYLOR: Thank you, Bob. As I mentioned, we will be available to
answer clarifying questions from the committee but at this point we do need to
begin our hand-off to the chair of the committee, and it begins with some input
from the executive secretary on how the meeting is managed logistically as one
aspect, and there are also some ethical and procedural concerns that Ms. Connie
Hardy will now present to the committee.
At that point we will turn it over to Johanna Dwyer who will introduce
the committee and begin the discussion.
Thanks.
Administrative Issues
MS.
HARDY: Good morning. I am Constance Hardy, the Executive
Secretary of the Dietary Supplement Subcommittee of the Food Advisory
Committee. I want to welcome everybody
and take a few minutes to go over a few procedural rules in terms of advisory
committee operations since this is the first meeting of Dietary Supplement
Subcommittee.
Subsequent
to that, I will read into the record the conflict of interest statement. Each of the subcommittee members should have
received a copy of the committee member guide to the FDA advisory committees
and a video. The video's title is
"A Panel Member's Responsibility."
There are copies of the member guide available at the registration desk
for anyone who may be interested. The
committee member guide is in need of updating but, by and large, provides a
good operational overview.
As a
scientific regulatory agency, FDA needs access to highly qualified expert
external advisors who can provide scientific and technical advice. Thus, FDA uses advisory committees to
supplement the agency's internal expertise to help the agency staff stay
current with state-of-the-art technology.
Committee members participate in an advisory capacity and final
decisions are ultimately made by agency officials.
With
respect to the committee members, the chair of the committee presides at and
conducts the meeting. She may ask FDA
staff for clarification at any time during the meeting. Each committee member contributes their
unique scientific and technical background and education experience to the
committee process. The standing
committee members generally are voting members, including a consumer
representative who is voting and an industry representative who is non-voting,
as specified in the charter. All
members of advisory committees are appointed by the Commissioner. Voting members are appointed as special
government employees following a conflict of interest review.
Conflict
of interest reviews are also conducted immediately prior to each meeting to
determine whether a voting member might have a conflict based on the specific
topic to be addressed at a particular meeting.
Other
advisory committee participants may include guest speakers. A guest speaker will present pertinent
information to the committee and will not participate in the committee
discussions or vote. However, we do
request that in the interest of fairness, guest speakers report any financial
interest that may be affected by the committee's discussions.
Additionally,
the advisory committee process encourages public interaction with the agency in
arriving at decisions. Not only is
there a consumer representative, in this case a voting member, appointed to
serve on the committee, but the public is invited to appear before the
committee during the open public comment period.
FDA
participates in a listening mode and is available to respond to questions and
provide clarification if such service is requested by the chair. FDA relies on its advisory committees to
provide the best possible scientific advice available to assist us in making
complex decisions. Our goal is to do
this in as open and transparent manner as possible. Part of that openness carries with it a request for members to
try to avoid giving the appearance that issues are being decided or conclusions
are being reached outside the actual meeting.
We
understand that issues raised during the meeting may well lead to conversations
over breaks or during a meal. In fact,
we hope the discussions are thought provoking. We have had instances where members have come back from a break
and said, "well, you know, we were talking in the break and we would like
to request that FDA provide us some additional information so we can better
understand thus-and-such." This is
a perfectly acceptable thing that can occur.
What we don't want is to have a situation where, after a break, members
come back and say, "well, we were talking in the break and we decided that
the answer to question one is..."
From our perspective, that would be particularly troublesome because
neither the agency nor the public would have had the benefit of listening to
the entire discussion, the questions raised, the responses, etc.
In fact,
FDA has recently adopted a policy that only procedural matters can be decided
by a show of hands. For example, all
comments must be placed on the record, each being attributed to the member
making the statement. The policy goes
even further. If a member has to leave
a meeting early, the member waives the right to vote. You may wonder why a person loses their right
to vote and the answer is fairly simple.
FDA believes all parts of the meeting and the discussions are important. Consequently, voting on issues without
having the benefit of all the discussions would be premature.
The issue
of openness is larger than what transpires during the course of a meeting. I would like to call your attention to the
section in the member's guide entitled, "member interaction before, during
and after a meeting." In essence,
this section underscores the fact that all communication with the members
should be routed through the committee's executive secretary. No one, not even the FDA staff with the
exception of the executive secretary, should be contacting members about
upcoming meetings, topics, etc. The
same guidance applies to consultations between members prior to a meeting. If a member receives an inappropriate
contact, the member should feel free to notify the executive secretary and/or
refer the person making the contact to the executive secretary. All contacts should be routed through the
executive secretary so that we can minimize any situation that could be
misinterpreted.
Appearance
issues are always difficult because, as true of many things, appearances can be
deceiving. We ask that all members,
guest speakers and everyone attending the meeting be mindful of how an
interaction between a committee member and anyone might be perceived.
Please
let me be clear. It is not my intention
to question anyone's motives or integrity but, as you can imagine, we do not
want to see respected individuals becoming objects of negative attention based
on misperception and we wouldn't want anyone in this room to become such a
target. I am confident that everyone
here recognizes these issues and can appreciate that my comments are intended
as a general reminder.
Moving on
to the issue of conflict of interest, the following announcement addresses that
issue with respect to this meeting, and is made part of the record to preclude
even the appearance of such at this meeting.
By the
authority granted under the Food Advisory Committee Charter of July, 2002, the
following individuals have been appointed by Joseph A. Levitt, Director of the
Center for Food Safety and Applied Nutrition, as temporary voting members for
the March 25th meeting on the term metabolite as contained in the statutory
definition of a dietary ingredient:
Edward Blonz, Ph.D.; Eric Brass, M.D.,
Ph.D.; Paul L. Schiff, Jr., Ph.D.
The
issues to be discussed at this meeting are issues of broad applicability. Unlike issues in which a particular
sponsor's product is discussed, the matters on today's agenda do not have a
unique or distinct impact on any particular product or manufacturer but,
rather, have widespread applications with respect to all dietary supplement
ingredient products and/or manufacturers.
To preclude even the appearance of a conflict of interest, the
subcommittee participants have been screened for interests in dietary supplement
manufacturers or dietary supplement suppliers.
As a
result of this review, in accordance with 18 U.S.C., Section 208(b)(3), Dr.
Johanna Dwyer, Dr. Eric Brass, Dr. Nancy Childs and Dr. Harihara Mehendale have
been each granted a particular matter of general applicability waiver that permits
each of them to participate fully in the matters at issue.
With
respect to screening our guest speaker, Dr. Ed Harris, he has reported that he
has no financial interest related to today's meeting topic. Dr. Harris is employed by Texas A&M
University.
A copy of
the waiver statements for each of these individuals can be obtained by
submitting a written requirement to the agency's Freedom of Information Office,
room 12A-30 of the Parklawn Building.
We would also like to note for the record that Dr. Annette Dickinson is
participating in this meeting as the acting industry representative and a
non-voting member of the committee.
In the
event that discussions involve any other issues not already on the agenda for
which FDA participants have a financial interest, the participants are aware of
the need to exclude themselves from such involvement and their exclusion will
be noted for the record. With respect
to all other meeting participants, and this will be our public commentors, we
ask in the interest of fairness that they address any current or previous
financial involvement with any firm that is involved with dietary ingredients
or dietary supplements.
As this
meeting is being transcribed, I would request that you please use your
microphone when speaking and that you clearly identify yourself for the record.
At this
point we will have a three minute presentation by Dr. Catherine McComus who is
here doing a survey on FDA advisory committees.
MS.
MCCOMUS: Good morning. My name is Catherine McComus and I am a
faculty member at the University of Maryland.
I am conducting a study with collaborators at the FDA on public
understanding of the procedures that the FDA uses to monitor and manage real or
potential conflicts of interest of its advisory committee members.
So, I am
responsible for the surveys that are on your chairs, and for the AC members I
have a special survey that I will be distributing to you also. Your participation is voluntary but, of
course, it is going to be appreciated because it will help us to accurately
portray what people perceive and understand about the conflict of interest
procedures that the FDA uses.
This
survey takes about 15 minutes to fill out.
It is anonymous. If you complete
it today, there will be a box on the registration desk and you can just drop it
in there. Otherwise, there is a
postage-paid envelope inside and you can drop it in the mail as soon as you can
once you leave this meeting.
Again, we
really appreciate your assistance in helping us to understand what the public
understands about the conflict of interest procedures. It is not for the FDA people to fill out at
this time. I will be contacting them
for another aspect. I will be around
today, as well as my research assistance, to answer any questions or provide
any sort of background on this questionnaire and research. Again, anybody is welcome to have a copy of
the results. There is a letter with my
contact information inside. Feel free
to contact me separately and, again, thank you very much for your time.
DR.
BRASS: Can you clarify who is the
sponsor?
MS.
MCCOMUS: Yes, it is being sponsored by
the Joint Institute for Food Safety and Applied Nutrition, which is a
collaborative research effort between the University of Maryland and the FDA. So, CFSAN actually provides some of the
funding for this.
DR.
DWYER: You are aware that this is the
first meeting?
MS.
MCCOMUS: Yes, I am.
DR.
DWYER: Fine, as long as you are aware.
MS.
MCCOMUS: And I appreciate it whether
you have gone to one meeting or fifty, I appreciate your feedback; your
perceptions.
DR.
DWYER: And you have IRB approval?
MS.
MCCOMUS: Yes, this has gone through the
University of Maryland Institutional Review Board.
DR.
DWYER: Just checking!
MS.
MCCOMUS: Definitely so. Thank you very much for your time.
MS.
HARDY: That should clear up all the
administrative matters at this point and I am going to turn the meeting over to
Dr. Johanna Dwyer.
DR.
TAYLOR: I would like to begin just by
introducing Dr. Dwyer. She is the chair
of this particular subcommittee. And,
to the extent that we need to discuss what just occurred, it was unknown to me
it was occurring, Johanna, so I will be glad to talk to you about that. Dr. Dwyer, the meeting is now yours and you
are free to introduce your members and begin the discussion.
Remarks by Chairperson Johanna Dwyer
DR.
DWYER: Thank you. Welcome to everybody on the committee. It has taken two years to get this together
but it is nice to finally be here.
Welcome to everyone who has come all the way out to the far reaches of
Maryland for this meeting.
What I
would like to do is just tell you that I am a professor at Tufts. I have just come back from a year, about a
year and a half, over at USCA where I was on IPA, interagency personnel acquisition,
working a fair amount of time there and also at Tufts. I was the assistant administrator for human
nutrition at the U.S. Department of Agriculture and have been back at Tufts
since the first of the year.
I am a
clinical nutritionist and I do a lot of work as well with databases that are
very much involved in some of the emerging components, trying to characterize
where they are in food and developing databases.
Why don't
we just go around the table and people can say why they are here. Annette, would you start, please?
DR.
DICKINSON: I am Annette Dickinson. I am president of the Council for
Responsible Nutrition, which is a trade association of dietary supplement
manufacturers and, as was mentioned earlier, I am the acting industry representative
on this subcommittee.
DR.
SHANNON: I am Michael Shannon. I am a pediatrician and a toxicologist at
Children's Hospital Boston and Harvard Medical School.
DR.
SCHIFF: I am Paul Schiff. I am a professor of Pharmaceutical Sciences
in the School of Pharmacy, University of Pittsburgh.
DR.
BLONZ: My name is Ed Blonz. I am a nutrition scientist. Currently I am the consumer representative
on the committee. I am a newspaper
columnist as well. I answer consumer
questions about nutrition, foods, food science, health, dietary supplements,
interpreting science and answering questions correctly for the consumers. This is a syndicated column and I work at
home. I have been doing this for twelve
years, and I am really pleased to be here.
MS.
HARDY: Connie Hardy, the executive
secretary. DR. MEHENDALE: Harihara
Mehendale, from the University of Louisiana, School of Pharmacy. I am interested in toxicology. I am interested in mixture of toxicology,
diet, caloric restriction and toxicities and mechanisms of toxicities in
general.
DR.
CHILDS: I am Nancy Childs, professor in
the Department of Food Marketing, St. Joseph's University.
DR.
BRASS: I am Eric Brass, from the
Department of Medicine at Harbor-UCLA Medical School.
DR.
DWYER: Thank you. Yes, Dr. Dickinson?
DR.
DICKINSON: Would you accept one or two
comments before Dr. Harris begins his presentation?
DR.
DWYER: Yes, I think we have time.
DR.
DICKINSON: I thank the FDA
representatives for a thorough summary of the definitional issues here, but I
would just like to add the notion that there are other aspects, of course, of
DSHEA that limit what ingredients can be used in dietary supplements.
I have
read Dr. Harris' excellent presentation that was distributed earlier, and I
just would like to make a comment so that everybody doesn't assume that
everything that is listed as part of the definition or any metabolite is
necessarily eligible to be sold as a dietary supplement. I am sure we will get into these other
aspects later, but there are requirements about whether the ingredient was
grandfathered, which means that it was on the market as a dietary supplement
prior to 1994.
There are
also provisions that require that if it was not grandfathered, there are
certain safety provisions that have to be observed. In most cases this takes the form of a 75-day notice that a
manufacturer must submit to FDA providing information as to why the ingredient
would reasonably be expected to be safe.
In addition, if the ingredient--and some of the examples that Dr. Moore
and Dr. Taylor mentioned earlier are clearly pharmaceutical ingredients, that
is, the end metabolite in some cases is a pharmaceutical ingredient--there is a
provision in DSHEA that that prevents a pharmaceutical ingredient from being
marketed as a dietary supplement.
So, there
are a number of safeguards, that I am sure we will come to, that limit the
scope to some extent of the marketing of ingredients even if they are covered
by the definition.
DR.
DWYER: Thank you, Annette. Are there any other comments or questions
from the committee from the presentation we have heard so far?
I have
one, Dr. Moore. It will take a while so
you may want to think about it. On one
of your slides you mentioned examples and mentioned the number of steps, and I
wondered if later on you could give us a rough idea of the steps from
cholesterol to steroid hormones, arachidonic acid to prostaglandins, amino
acids to catecholamines and there was one more. I just don't have those pathways in my brain and I would like to
get whether it is two or 25, what the order of magnitude is.
Biochemical Facts Behind the Definition and
Properties of Metabolites
DR.
HARRIS: Good morning to the members of
the subcommittee. First let me say I am
very happy to be here, and work with you, and help you in arriving at a
definition of what in biochemistry is a very common word that we use almost on
a daily basis, and that is a metabolite.
I say it is a common word, implicating that it is almost invisible to
us, much the same as numbers are to a mathematician or words to a
grammarian. We simply use the term and
never really think about what its implications are.
So, in
addressing this assignment I really had to try to step back, keeping my profile
as a biochemist and, yet, try to arrive at a definition of what is and what is
not a metabolite. In my presentation I
hope to bring to you some historical perspective and some examples that will,
hopefully, help you see how these general principles have evolved.
I found
this quotation, which I found extremely interesting primarily for the date, and
that was 1839. This is a quotation that
was basically derived right after the realization that life was a process that
occurred within cells. We are looking
at a quotation by Theodor Schwann where he said, "one must first consider
the combination of molecules to form a cell and secondly those which result in
chemical change in the cell itself."
So, this is the first recognition, you might say, that we are dealing
with a process carried out by cells that are involved in chemical changes.
When we
think of a metabolite we have to think in a larger context. Certainly, it is an element of metabolism
but what do we mean when we say the word metabolism? That, again, is a syllabus for a historical search here and, as
you can see, we go down the list here and we can see that the word metabolism
was first introduced back around the turn of the nineteenth century. A German, Johann Reil, represented it as
something that said that matter is changing or stoffwechsel which is
changing components. The French
referred to this as le changement du materiel and that has again given
us the implication that chemistry is evolving in cells and in living
systems. Actually, the word metabolism,
which implies something happening after the fact in a changing context, was
introduced by Sir Michael Foster in a Textbook of Physiology for the first
time.
So, if we
are looking at the historical perspective here, we certainly want to be caught
up with today's interpretation.
Obviously, our earlier ancestors and pioneers in science did not have
the opportunity to see the things that we simply know today. Things happen inside cells certainly but
what are these things? Can we define
them in a more precise manner?
Let's take
a look at what textbook markers in biochemistry have to say. I think this will sort of fortify some of
the definitions that you have seen in the pamphlet that really came from
dictionaries. Here we can see a little
more in well-renowned textbooks on biochemistry. In this quotation, metabolites are the basis of metabolism. I will read a quotation from Bohinski who
wrote a very authoritative book on biochemistry: "metabolic expression is
due to the integration of individual reactions into a dynamic reaction
circuitry of intricate design controlled by sensitive regulatory checks and
balances." Wow! What does he mean?
Well, he
provides us with a picture. When I show
this to my class in Texas A&M to show them what metabolism is all about,
half of the class decides they want to be finance majors and the other half
want to know if it is going to be on the exam.
[Laughter]
What is a
metabolite? Well, if we look at some of
the definitions we see it is a chemical intermediate in the enzyme-catalyzed
reactions of metabolism. That was by
Lehninger who is probably one of the most authoritative authors in
biochemistry.
Here is a
more recent quote by Voet, Voet and Pratt: "a metabolite is a reactant,
intermediate, or product of a metabolic reaction." Well, they seem to be saying the same
thing. Here is a quotation I put in my
book: "a molecule considered an intermediate in a series of reactions
generally those in a pathway."
From each
of these definitions we can probably glean some very key words to help us reach
a definition. For instance,
enzyme-catalyzed--that means a metabolite has to be recognized by an
enzyme. It is a reactant or an
intermediate or a product. It means a
series of reactions. Finally, a series
of reactions that we would consider and define as a pathway. As I mentioned to you, a pathway is simply a
convenient way of putting some order and focus on different things that are
happening inside the cells.
Let me
give you some definitions that follow from this. Metabolites are products of metabolic events occurring within
cells. Metabolites are substrates,
products and intermediates in defined biochemical pathways; and metabolites
arise by the action of enzymes acting on defined precursors. If we want to put this in more simplistic
terms, let's just say that a metabolite is something that is made by the body,
used by the body, recognized by the body and is essential to body functions
and, of course, it is benign in its many ways.
Here is a
principle that I am going to elaborate a little bit later at the end of my
talk, but I want you, in arriving at this definition, to see it from many
different perspectives. The more
perspectives I can introduce to you, perhaps the more you can get a feeling of
what this is all about. So, let me give
you this thought, that only through chemical change can a molecule yield energy
to a cell or provide material that will be used for cell structure. Such molecules that are in the act of
changing chemically going out to something more global in cell function, these
are what we call metabolites.
Let's
address the question of when something is and when it is not to be considered a
metabolite. These are some factors for
you to consider. Most obvious, to be
considered a metabolite an unknown must have some semblance of structure to a
naturally occurring reference compound.
That is obvious; that is intuitive.
We can all see the relationship to that.
But we
have to be careful. I have to point
that out to you because I am going to add a few more statements to that. I am going to say it must also be a
substrate, product, or intermediate of a defined biochemical pathway in the
cells. It must arise from another
metabolite, which itself is a product of cellular activity. It must enter into enzyme-catalyzed reactions. Finally, it must be both a product and a
substrate of successive reactions. I
will point out to you why I feel that is important in the definition. The last point I want to leave you with is
that a metabolite has to undergo metabolic turnover. It cannot accumulate in a cell.
So, if
those are the definitions of what we would say would define an acceptable
realization of a metabolite, let's address the question of what is not a
metabolite and see the other perspective.
Obviously, a metabolite is a chemical that is not recognized by the cell
or has no connection with the living system; or any substance that is not
derived in the biochemical pathway; any substance that is not a product of a
substrate within a biochemical pathway; or any molecule that cannot be acted
upon by an enzyme; any substance that interacts unfavorably with a living
system; and any substance that is unable to undergo metabolic turnover. These, I would tend to feel, would be more
excluded from being considered as metabolites.
I am
going to address the question of metabolism itself. I am going to bring to your attention that metabolism occurs
inside cells. I have stressed the
importance of why metabolism requires enzymes and enzymes are only found inside
cells. Enzymes are functioning in
altering chemical structures. These are
cellular events.
Then, I
want to just bring something to your attention here just to show you what I am
getting at. Here we have a very
well-known cycle that occurs in physiology of biochemistry. It is called the Cori cycle. What it represents is an interplay between
the liver and the muscle. It is an
interplay because it shows an interdependence of these two organs on one
another. Liver, we know, can make
glucose. It can make it from smaller
precursors. It can pour the glucose
into the blood and provide the muscle, therefore, we a source of nourishment
for energy. Glucose. The muscle will take the glucose once it has
received it. It will metabolize it and
create lactate or lactic acid. Lactic
acid then is released back into the blood where it now again travels back to
the liver only to be reformed into glucose.
This is a Cori cycle, so defined in about 1935 or so, whose authors won
the Nobel Prize for recognition of this.
What does
this have to do with metabolism and metabolites? Well, we can see, if we look at this from a more careful
perspective, that all the chemical changes we are talking about, for instance
the making of the glucose all the way through to these intermediates here, and
all of these intermediates are metabolites, derived from preceding
intermediates, pouring into the blood.
In the blood we see pretty much a reversal of the trend, starting with
glucose-6-phosphate and going back up to lactate and so forth. So, we get a little better perspective of
just how this Cori cycle is operating and just where the role of metabolites
would be in this context.
I am
going to show you one more complicated slide here and it gets a little more
involved with biochemical pathways, but it basically is addressing the same
issues that I pointed out to you previously.
We are looking at what happens to a substance once it penetrates the
cells and become eligible to be considered a metabolite.
Here we
see glucose enter the cell and become glucose-6-phosphate. That is a biochemical intersection because
once it has formed glucose-6-phosphate it has many different fates ahead
depending upon whichever enzyme-determined need the cells has for it. For instance, if the cell needs to store the
glucose it alters the pathway in that direction. If the cell needs energy it will open a pathway down to
pyruvate. If the cell needs to make
nucleic acids it will open the pathway that way to DNA and RNA. So, you can see metabolites go every which
way, every which direction at once.
What a biochemist generally refers to when we look at these
opportunities for multiple directionality, a biochemist calls this carbon flux,
flow. If a cell needs energy the flow
is down toward pyruvate and into the mitochondria. If the cell doesn't need energy and needs to store the compound
the flow is toward the storage and so forth.
My point in pointing this out to you is that all these components that
get us from point A to point B, all of these components are metabolites.
Here is
another picture of that. Here we can
see that we are talking about directionality.
You basically have two different enzymes that are involved here in
controlling blood glucose. One enzyme
takes glucose into the cell and converts it into glucose-6-phosphate. The other enzyme actually takes the
glucose-6-phosphate and brings it back to glucose for release. Here I have put in just a few other little
things connecting pathways here. You
can see L-alanine, an amino acid, flowing to pyruvate, either down to carbon
dioxide and water or lactate can flow into pyruvate and then, of course, it can
go back the other way as we saw previously.
This is
what I mean when I say a defined biochemical pathway. We know precisely every step in that pathway; we know every
intermediate, and every intermediate that is part of that pathway we call a
metabolite.
Let's
look at this in a more focused way.
Let's say we have three metabolites that are in order, A, B, C, and for
the moment let's just focus on component B, here. To properly define B we would say that it is an intermediate in
the pathway from A to C. We would know
that there are enzymes that are involved in the conversion of A and B and
enzymes involved in the conversion of B to C.
But if we think in terms of B, relative to B we would call A a precursor
metabolite and we would call C a product metabolite.
The point
here is that B is a product of enzyme A and B is a substrate of the starting
component or enzyme 1--enzyme 1; enzyme 2.
So, you see, in that definition we can see that we formed B from A and
gave rise to C from B. That is a
metabolic sequence. We would very
easily define B as a metabolite.
Let's
look at the front of the picture now.
Again, we have A, B and C. Under
these conditions we see that enzyme 1 again catalyzes formation to B; enzyme 2
to C. But in this case A has no
precursor. So, we could consider A
something that has just entered the cell or has been in the cell for a while
and is now about to be chemically converted.
A, therefore, is a substrate of enzyme B and, in this regard, A is a
substrate, B is a product and A would be a precursor.
Here is
my take-home for you. In a biochemical
pathway a metabolite is typically the product of one reaction and the substrate
of a second successive reaction.
Take-home,
a compound that has no precursor can still be considered a metabolite but only
if ensuing metabolic changes occur via a known series of reactions. That is important because we could make
compound B, let's say, through some event and then stop at that point. So, would that say then that A is a
metabolite? We would say no because it
is not a successive series of events.
I am
going to give you some examples here, and I am going to draw some from some
arbitrary definitions here. Please
don't try to connect it with something that you already know, but basically it
is to illustrate some of the points that I am making here.
Let's
talk about compound X. Let's call it an
artificial sweetener. Let's say that X
has the unusual property, favorable really, of not yielding calories, which
makes it a very attractive sweetener.
Compound X has the basic formula of sucrose with the exception that in
that structure it contains three chlorine atoms. The question is, is compound X to be considered a
metabolite? Well, if compound X is to
be considered a metabolite, we know that as mentioned from the previous talk it
has to have a precursor and it has to be converted into a product. All right, so we need two enzymes to do
that. Reminding you again of that basic
principle, to be considered a metabolite, a compound must be the product of one
enzyme and the substrate of a second.
So, let's
look at what we would consider favorable in calling compound X a
metabolite. First of all, it resembles sucrose
structurally, and has biological function that emulates sucrose. So, in this regard it appears to have the
functionality and the structure that we would desire if we limited our
definition to those two parameters. But
let's look at the non-favorable factor here.
The non-favorable is that because it does not generate any calories
compound X is not metabolized. Compound
X, therefore, is not being treated as a sucrose in the system.
The other
thing we would call to your attention is that compound X has chlorine atoms in
its structure. If we look back into
biochemical pathways and biochemical events that occur in all different cells,
we will see that the ability of the cell to put chloride onto a sucrose molecule
does not exist by any known biochemical mechanism, any known biochemical
system. Therefore, compound X cannot be
considered a metabolite in that regard.
It is not a product of a metabolic event. I put enzymes very strongly into your perspective here. I want to make sure you are very clear on
this. This is really what is going to
determine or put real boundaries around what we would call a metabolite and
what is not a metabolite.
As I
said, there are substrates for enzymes that cross over products. Let me make sure you understand what I am
referring to. Here we have a chemical
reaction. Like all chemical reactions
that occur in a cell, this reaction requires an enzyme so let's bring that into
the picture. Let's say that in this
chemical reaction our goal is to add this component to this structure,
here. Let's call this structure
glucose; let's call that phosphate.
Let's say our goal is to make glucose-6-phosphate. Here is an enzyme that does that. Now, the enzyme has catalytic sites that you
see here. They are designed to interact
with the substrate and in the process of doing that they form what we call an
enzyme-substrate complex. This is an
intermediate. This can only be formed
when a substrate has found a proper recognition site on the surface of the
enzyme. Once that has occurred, we can
now bring in the second substrate, carry out a catalytic event and produce a
product.
After
that has taken place, the enzyme, once it has freed the product, is now a free
enzyme, capable of recycling back into the system again for another go-around. So, here we can see how enzymes typically
work in the living system.
Here is a
caveat that we have to bring to our attention.
Enzymes in many respects are stereospecific. What do I mean by that?
It simply means that if the substrate is going to engage that enzyme, it
has to do so in a stereospecific manner, stereo meaning in spatial relationship
to the structure of the enzyme. If you
will, a key and lock type fit here tends to occur. So, there has to be proper orientation.
Stereospecificity
can also be very subtle. For instance,
your left hand is different from your right hand and no matter how hard you try
you can't superimpose your right hand on your left hand. This is the principle of handedness that we
talk about. We find that when we are
dealing with molecules that have four different constituents attached to a
central carbon. We call these
stereoisomers, isomer implicating that they are similar in structure but, yet,
have slightly different properties. For
purposes of designation we call one a D-isomer and one an L-isomer. What I want to convince you of is that these
are not the same molecule. You might
look at them and say, oh, they are the same but let me make sure that you see
what the enzyme is seeing.
Here we
have a molecule. Let's make this a
duplicate image, and that would look like this. So, you would agree with me that these are now identical
molecules. But suppose I put a mirror
up here and I brought this other molecule so it now looks in the mirror and it
sees itself. The question that we would
ask is, is this molecule and the one in the mirror the same? Let's see if we can answer that question by
putting the molecule into the mirror.
You can see that the yellow matches up with the blue; the blue matches
up with the yellow--it doesn't fit. So,
the mirror image is not the same molecule.
How does
this apply a little more realistically to what we can consider? Let's talk about D- and L-glucose. Here is D-glucose. Here is a mirror. Here is
L-glucose, the mirror image. If you
look closely, it does look like this molecule is looking at itself in the
mirror. All right, if we look at some
of the parameters, chemical parameters, we would see that they both have the
same chemical formula. They both have
the same chemical properties. They both
have the same molecular weight. Yet,
the molecule on the left is a nutrient and the molecule on the right is not a
nutrient. On that basis we can call
this molecule a metabolite and this molecule, even though it has all the same
parameters, except for this handedness here, we would have to say that it is
not a metabolite.
Here is
our take-home for that, stereospecificity must be observed for those
metabolites that engage enzymes that have the capacity to select specific stereoisomers. The bottom line here is you just can't put
your left shoe on your right foot.
Dr. Moore
alluded to the point that metabolism can be an event where as a molecule it is
away from its parent compound loses its visibility. It loses its identity to its parent structure. This is a very true principle in
biochemical. The further down the
metabolic pathway you go, the more your molecule becomes mixed in with the
cell, and mixed in with metabolites from many other different sources. So, I would give you a little rubric here to
remember and just say that metabolism is an explosive process. When we see a metabolic event taking place,
we see the molecule scattering every which way. You might say, well, in that context does that actually
occur? The answer is yes.
Let's
look at a fatty acid for instance. This
is a fatty acid that is about to undergo metabolism. You can see it has eight carbons to its chain. Well, during the course of metabolism, that
gorgeous, beautiful looking, well-structured, long chain fatty acid is going to
be clipped in three different positions.
The explosion comes when the molecule completely dissipates, disappears
from sight and becomes four acetyl-CoA units.
These acetyl-CoA units could be derived from amino acids. These acetyl-CoA units could be derived from
carbohydrates. They don't have to be
fats. So, we can see that these
molecules would just blend into the general maven of the cell, what I would
call a mixed pool.
Let's
examine this idea that there may be structural similarity which is the real
criteria that we need to observe at the top of our list. I am going to show you a molecule of
cholesterol. You can see this is a very
complicated molecule. It contains a
series of fused rings of different sizes.
This molecule contains 27 carbons.
It is assembled from those acetyl-CoA units that you saw previously in a
series of well-defined--and I can assure you cholesterol metabolism is very
well understood in biochemical--well-defined metabolic steps.
If we
wanted to put the molecule of cholesterol together, let's go ahead and build
it. What we find, as we build the
molecule is that we build it on five carbon units. As we continue to clip these units together, keeping a linearity
in all cases, you can see that we start to bring into perspective the
cholesterol structure. As you see here,
we have six isoprene units that brought that molecule about. This open change isoprene type molecule we
call squalene, which is a precursor of cholesterol.
If we
took the next metabolic steps, that would be to close these rings. So let's close them. When we close them we no longer have
squalene. We now have the molecule that
is getting closer to cholesterol. We
are pretty much there, almost at the point where we want to be.
Let me
call your attention to an article that appeared in this March issue of Journal
of Nutrition. It concerns a
compound which we call lycopene.
Lycopene, I think you know, is the red coloring matter of the
tomato. Here you can see a paper that
is pointing out that lycopene product, tomato product enhances lycopene
concentrations and it activates the capacity of an oxidant. So, it reacts against reactive oxygen
species, a very important role for these type of molecules with that structure.
So, here
is the question I raise to you, is lycopene a metabolite? Let's take a look at the structure. What do we see when we look at the structure
of lycopene? It basically has the same
5-carbon unit we saw previously that we used to build the cholesterol molecule but,
of course, this is not cholesterol. It
is very close in its resemblance to squalene, with the exception that lycopene
contains ten more carbons but it bears a very strong resemblance to the open
chain cholesterol precursor squalene.
Let's
look at this a little more closely. We
see that lycopene in the tomato is actually converted into beta carotene, which
we all know is vitamin A for us. That
brings us to my point which is very important here. We can take beta carotene.
We can break the molecule in half and derive two molecules of vitamin A,
otherwise known as retinol. But we are
unable to take lycopene and converted it into carotene. Wouldn't it be nice if we could do that, but
we can't. Therefore, we cannot
metabolize lycopene.
So, I
would raise the point with you that lycopene should not be considered a
metabolite. Even though it has this
very interesting structural similarity, it should not be considered because no
human enzyme is capable of changing it structurally to be a useful product.
By the
way, in preparing these comments I went into a database to look for anything
that talked about the metabolism of lycopene and I could not find it. This is a compound that we need to study
more carefully to know just exactly how a living system handles this. But, as far as I know, right now there is no
metabolic following compound from this through our pathways.
Let me
point out some other things regarding metabolites. I think I have given you a very good idea of what it is not. I want to give you a little more insight
into the properties of metabolites. I
think this is something else that you have to take into your considerations
here, particularly when we bring up an issue of safety, though that is not the
issue I want to address with you today.
I want to
address this issue in the context of how metabolites work. Here we have a pathway of A going to B going
to C, in that direction. The reason
this pathway goes in this direction--there are a number of reasons why it is
favoring going from left to right.
First of all, we have to think of energy considerations. If we go from A to C are we releasing free
energy? That literally means that this
is the spontaneous reaction or one favorable.
Well, what happens if we suddenly raise the level of C? We have the potential now of driving the
pathway in the reverse direction.
So, this
indicates that a metabolite is generally kept in what we call a steady-state
concentration. Don't mistake that for
equilibrium; it is not. Steady-state
simply means that it is being formed and being used at the same rate so there
is no build-up of that compound. If it
is formed faster than it is being used there will be a build-up and, of course,
if it is used faster than it is formed there will be a diminution. So, steady-state just simply implies that we
reach a point where we keep that level so we can drive that steady-state
reaction back the other way by increasing concentration of C.
Here is a
principle I am going to leave you with, because metabolites tend to exist at a
constant concentration within a pathway, changes in the steady-state levels are
able to control carbon flux. This could
determine whether a movement towards synthesis or degradation take precedence.
The other
principle I want to leave you with, and this is what I alluded to and didn't
expand on but I think you can certainly see the implications here, metabolites
have free existence. Metabolites
turnover. In the parlance in a
metabolic sense, they are constantly being replaced. They are constantly being renewed. So, this is a very important fact because this keeps a cell from
building up any one particular metabolite.
Some of
you might say, wait a minute, what about storage fat? I don't like that word but that is how it is called, like we have
a closet where we stick fats away and forget about it. Actually, if we look at it we would see that
what we call storage fat is really steady-state fat. Fat is being stored and it is being broken down. I should say it is being synthesized and it
is being broken down. When we shove the
direction in the form of lowered synthesis and breakdown, then we start to
accumulate fat. If we have just the
opposite, like in conditions that favor breakdown, then we have less fat being
stored or, favorable to us as we start seeing ourselves lose weight. The principle I would leave you with is this
one, that nothing is permanent in a living system.
Let me
just summarize some of the points that I have made. I have provided some statements here that will perhaps help you
as you consider what we mean. A liberal
definition of a metabolite can include practically any substance that occurs in
a cell. That seems to be fair game but
you can see that there are some restrictions we have to place on that.
There are
six principles that can serve as a guide here.
I have tried to list them in order of priority. I am kind of imposing on you here and
telling you what I think should be the most important consideration but,
certainly, you have to decide that.
I would
say it is important that we recognize that a metabolite has to be something
created by itself. It has to be
something that is a product of a biological event. A substance that is an intermediate in a pathway, this comes to
play when we start talking about it is not alien to a pathway; it is actually
being recognized and being changed within a pathway.
What is
bringing about those changes--item number three--it has to be a recognized and
acted upon by an enzyme. Item number
four, it has to have a limited biological time of existence. As I told you, nothing is permanent. It has to not violate stereospecificity
principles. This will not apply to all
metabolites but, certainly--certainly, it will apply to many molecules that
would appear to be structural like D- and L-glucose, but that have that subtle
difference that would make them alien in the system. Finally, it has to have a useful purpose. I would say that that is something that
tells us metabolites are serving a cell, keeping the cell alive.
This is
the closing thought that I want to leave you with, and it expands on something
that I told you a little bit earlier:
In a living system, chemical changes never occur suddenly. One of the things that we do in our class is
we ask the students how do you know that this piece of bread has this many
calories in it? The student says, well,
you put it in a bomb calorimeter. He is
correct, absolutely. You take that
piece of bread, put it in a bomb calorimeter, turn on the electrical current,
put some oxygen in there and, wham, we get carbon dioxide and water and we can
measure the heat. Imagine if that
happened inside a cell. You take a
piece of bread and, wham, you get carbon dioxide and water.
The point
is that in a living system chemical changes occur gradually and at each step we
are either moving forward, making a more complex molecule or making a molecule
less complex and deriving energy from that transformation. So, metabolism is a series of
well-engineered steps that gradually sap the energy or remodel the features of
the molecule and take it in from the environment as nourishment. It is characteristic of a living system to
make chemical changes gradually and to generate intermediates that meet other
biochemical priorities. It is the
residues of these chemical changes--that is what we call metabolites.
Questions and Discussion on Dr. Harris'
Presentation
DR.
DWYER: Thank you, Dr. Harris. That was great. Before we take a break, we will take some questions. Dr. Brass?
DR.
BRASS: I have a number of questions so
tell me to shut up whenever you want. I
would just like to probe some of the underlying thinking behind some of your
proposals and principles.
First of
all, I listened to the phrase precursor metabolite and that sounds to me like
an oxymoron. To me, X is a metabolite
of Y. Just because X is a metabolite of
Y, why would it not be a metabolite of other molecules? It might be but it might not be. And, why incorporate the precursor
implicitly as a metabolite?
DR.
HARRIS: I didn't bring that up in my
talk but in the paper I did, I would consider a metabolite as something that is
about to undergo chemical change. I
would say that a precursor that is a metabolite would be like blood glucose. You cannot change glucose in blood. You can only change it once penetrates a
cell. There are certain metabolites
that you cannot change unless they can enter the organelle or compartment in a
cell. For instance, you can't oxidize a
fat until it enters the mitochondria and then it becomes a metabolite. But you could, in that same context, say it
is a metabolite in the cytosol.
DR.
BRASS: I agree with your concept that
we are thinking in the context of human metabolites. I think that is a very important point. I agree to that discussion.
For example, is an essential amino acid a human metabolite?
DR.
HARRIS: If I would see an amino acid in
the blood, and there are plenty of course, I don't think I would call those
metabolites.
DR.
BRASS: In the cell?
DR.
HARRIS: In the cell, I would.
DR.
BRASS: I think that generates a
confusion because I think if it is a metabolite it has to be generated, not
only be a precursor. But I understand
now.
DR.
HARRIS: I am just one step ahead of
you, only from the standpoint that what we call a metabolite seems to be a
derived substance. Now, if the answer
to your question is did the cell make that amino acid, yes. But did that amino acid come from the diet
and now is a digested product of a dietary protein, I would say that is not a
metabolite.
DR.
BRASS: I think that is why we focus on
human metabolites--
DR.
HARRIS: Yes.
DR.
BRASS: --and if we don't we get in a
morass quickly. I think if we don't
make that distinction to be able to be generated by a human reaction, we open
up a large morass. That is why with a
precursor I am uncomfortable because of a variety of substances.
The
second question is you explicitly, in your definition, exclude end products of
metabolic reactions as being metabolites.
DR.
HARRIS: Yes.
DR.
BRASS: That is not clear to me either. Why, if it is generated clearly in a
sequence of enzyme reactions that dead ends and is excreted in the urine
without further change, should it not be considered a metabolite of the
precursors that generate it?
DR.
HARRIS: Again, I am looking at the
subsequent step. If something has now
been passed into the blood the subsequent step is excretion or some other
byproduct. No, I would not say that
those are metabolites but I am beginning to see what your point is. As you can see, in my definition I am always
looking at the next step. I am telling
you that a metabolite has to be recognized by an enzyme and if that substance
in the blood, indeed, came from an enzymatic reaction that assembled that
component, that is a metabolite, yes. I
agree with that. But if it came from
the diet--
DR.
BRASS: I agree; I agree. Again, this is semantics but the whole
discussion is semantics. Yyou said
inside of a cell.
DR.
HARRIS: Yes.
DR.
BRASS: If the enzyme is located on the
outside of the extracellular membrane, is that inside the cell?
DR.
HARRIS: Now, that is a grey area. I would say that we could taper that down
with a definition of recognized in the immediate environment of the cell or in
the act of penetrating the cell. But a
lot of times going through a cell is nothing more than a transport process.
DR.
BRASS: I agree. I agree that it has to be enzymatic
transformation but where that enzyme is located appears less critical. I also have a problem with the concept of
proximity in a metabolic pathway for the definition of whether or not it is or
isn't a metabolite. Let's imagine we
have a 26-step pathway where A goes to Z.
Y is clearly far away from A but unquestionably A goes to B and B is a
metabolite. B goes to C, C is clearly a
metabolite. I could extend that logic
until I get all the way to Y and clearly Y is a metabolite. Even though it is really far from A, it has
to be a metabolite simply by deductive reasoning. So, I think we have to think about proximity for the number of
steps as being absolutely intrinsic to this definition.
DR.
HARRIS: No, I disagree in some respects
because ultimately everything goes into carbon dioxide and water. So, if something becomes carbon dioxide in
water, then it is a metabolite, or is it a metabolite of a substance we are
looking at?
DR.
BRASS: Well, to me, this transforms
into utility and application but I think, yes, carbon dioxide is a metabolite
of glucose.
DR.
HARRIS: Or a metabolite of a hundred--
DR.
BRASS: That is correct. This is about defining a metabolite in an
absolute sense, not whether or not a specific molecule is a specific metabolite
of another specific substance.
DR.
HARRIS: Yes, let me back up one
second. You are touching on a very
important point, I realize that. If
compound B or compound C that is formed maintains much of the parent structure
so that we could say that those compounds actually came from the substance that
we looked at as a reference compound, then we are on good grounds. But if that has gone all the way down to a
point where now, as I showed you, it is an explosive process where we cannot
identify its origin--well, technically it is a metabolite--
DR.
BRASS: I think, for reasons you said,
similarity is a trap because there are many molecules that are very subtly
different that are biologically worlds apart and other structures that look
very different and have very similar functions. To me, the important point is whether or not increasing the
precursor results in net synthesis or net increase in flux--
DR.
HARRIS: That is a kinetic argument.
DR.
BRASS: That is why, for example,
glucose can't be considered a metabolite of palmitate even though we label
palmitate or bicarbon in glucose. That
seems to me a more compelling argument than proximity or similarity.
DR.
DWYER: Before you answer, would you
repeat what you pointed out about the precursor?
DR.
BRASS: Yes, it seems to me that if
something has a precursor-metabolite relationship, if I increase the amount of
the precursor I have to increase the amount of metabolite and that has to be a
net result. The counter example is if I
put radioactivity in palmitate I can follow that radioactivity into all kinds
of molecules in metabolism that are really not net metabolism. To me, that is the difference between a
mish-mash of metabolism and a precursor metabolite reaction that I can actually
change.
DR.
HARRIS: I agree with you. I didn't want to approach this from an
experimental perspective but that is exactly the type of experiment so people
could identify potential metabolites.
As you pointed out, there are a great many traps here, mine fields that
you can fall into. The bottom line is
you cannot make glucose from palmitate in a net way but you can still find the
carbons there.
DR.
DWYER: Ed?
DR.
BLONZ: My name is Ed Blonz, and I want
to thank you for your presentation. As
a biochemist, I also would like to make some comments because here we are
talking about dietary supplements and with dietary supplements we have
botanical products and botanical products are not necessarily essential to the
human body. That was one of your
points, for being a metabolite it has to be essential to the human body. As a biochemist dealing with nutritive
substances, obviously this would be an exception to that and I wanted your
comments on that. Then I have one other
question.
DR.
HARRIS: I don't know why you would say
they are not essential. Obviously beta
carotene is a botanical. You can't make
that.
DR.
BLONZ: There may be some botanicals but
would you say that kava-kava is essential to the human body?
DR.
HARRIS: I am not sure what kava-kava
is.
DR.
BLONZ: There will be many dietary
supplements that are botanicals that at the present time we could not define as
essential.
DR.
HARRIS: I suppose that is going to have
to come down to what you mean by essential.
You are a biochemist so you know the nutritional definition. If the body can't make it to maintain the
pace of metabolism, then it becomes essential.
If the body can make it, it still can be a metabolite but not
necessarily, in that context, essential.
Essential means that it can only be supplied by the body.
DR.
BLONZ: Well, I think the definition of
essential would actually delve into the realm of philosophy with some
botanicals. But I personally would tend
to think that that might be an exception for the need for a metabolite to be
essential in terms of nutritional substance of the human body.
DR.
HARRIS: Yes, I almost look at the word
essential as indispensable. Yes, I am
trying to see if we are talking about two different things in that regard.
DR.
BLONZ: The other thing had to do with
recognition by an enzyme.
DR.
HARRIS: Yes.
DR.
BLONZ: There might be many botanicals
which will not be recognized by an enzyme and they might leave through the
kidney or through some other route--
DR.
HARRIS: Those are what I would rule as
not being metabolites. I would exclude
them. Lycopene was the example that I
brought to your attention.
DR.
DWYER: Any other questions? Yes, Dr. Schiff? DR. SCHIFF: I think it gets very difficult when you
start to compare a vitamin or a single product with a botanical which, in
essence, is a mixture of hundreds and hundreds of different compounds. Maybe the structure of all those compounds
are known or maybe they are not known.
Maybe something about their typical kinetic metabolic fates is known and
maybe they are unknown. That is a whole
leap in a whole other direction. The
variables are incredible.
So, you
know, I would thank you for placing perspectives on it but I want to emphasize
single products. I also tend to agree with Dr. Brass and a lot of his comments
as far as some of the concerns he has.
Thank you for asking those.
Those were questions that I had.
I wouldn't want us to refer to a botanical in the same sense as we refer
to a single amino acid or a single vitamin because of the complexity.
DR.
BRASS: If I could just follow-up on
that. It seems to me, to answer both
those questions if it is not further metabolized in the body is not relevant. The metabolite generated from a botanical is
a constituent of a substrate or a metabolic enzyme.
DR.
SCHIFF: My issue would be is that if
there would be a product that would be one step away from an existing
botanical, that would be metabolized outside of the human milieu but might be
marketed as a supplement under the metabolite definition. If this would be a substance that would not
be recognized by an enzyme inside a biochemical system, would it then not be
subject to that inclusion?
DR. BRASS: That is why I emphasized the human
metabolite because clearly one could find bacteria or other cellular species
that can generate all kinds of metabolites that are formed in human metabolism. That is not in any of the regulatory
documents but it seems to me that we have to be talking about human generated
metabolites in this conversation.
DR.
HARRIS: Let me comment on that
too. I think that is a very important
point. When you talk about a substance
being recognized by an enzyme that is not necessarily a natural substrate
within that cell, let's say a xenobiotic comes in, we have many instances where
that happens, like cytochrome p450.
This enzyme is designed to rid the body of substances that it is not naturally
producing in its metabolic ways but simply taken in by accident, benzothyrines
and things like that from cigarette smoke.
These are enzymes that will act on the substance and they will recognize
it and cause some kind of a change.
That is why I emphasized that the next step, after you make that change,
is important. Let's say an enzyme
changes a compound to another, if that compound now stops at endpoint, that
first compound is not a metabolite.
DR.
BLONZ: But the second--
DR.
HARRIS: But the second compound would
be.
DR.
BLONZ: Yes.
DR.
DWYER: Dr. Shannon?
DR.
SHANNON: I am struggling with the
definition that the substance be recognized and acted upon--
DR.
HARRIS: Can you say that again?
DR.
SHANNON: If you have a definition that
a substance must be recognized and acted upon by an enzyme, and it seems to me
if my recollection isn't in error, at least some reactions that occur in the
body don't require an enzyme and they produce a product. I remember the term non-enzymatic hydrolysis
for example. So, I wonder why an enzyme
has to be absolute in order to talk about a product as a metabolite of
something else.
DR.
HARRIS: I think I could probably name
the number of non-enzymatic events. I
am talking now about chemical change. I
am not talking about changing the state of a molecule or maintaining its
structure pretty much intact. That
would be something like folding a protein.
Those could be spontaneous events.
But even those, we find, require certain outside agents that affect
their properties.
The only
non-enzymatic event that I am aware of is cross-linking collagen. Once you form those residues that allow
cross-linking to occur, then it becomes a spontaneous event. I am not aware of too many biochemical
processes that do not require enzymes.
The ones I could name I could put on my first two or three fingers.
DR.
SHANNON: But there are some.
DR.
HARRIS: I am waiting to hear them.
DR.
SHANNON: No, no, that is what you just
said. Right?
DR.
HARRIS: I am illustrating the points
where spontaneity occurs mainly from the standpoint of finished molecules, not
molecules that are going to be changed.
All right, let me be a bit more specific. When I take the elements of collagen I have two groups that I am
going to use to form the Schiff base to link them together. Those groups are there. All I need to do is put those two together
and the chemical reaction occurs. But
the enzymes prepared me for that step, and the proximity of the molecules lying
next to one another rolled the reaction in that direction. So, I have to say that is a non-enzymatic
reaction at that last step, but to say collagen cross-linked is non-enzymatic
is wrong. Enzymes are involved in all
the steps to that point where they actually performed the condensation product.
DR.
SHANNON: Explain to me again why
non-enzymatic hydrolysis wouldn't be included.
DR.
HARRIS: I am trying to think of
illustrations or instances where there is non-enzymatic hydrolysis.
DR.
DWYER: Glycosylation--
DR.
HARRIS: Johanna, I am sorry?
DR.
DWYER: Glycosylation of hemoglobin in
the blood.
DR.
HARRIS: That I really can't comment
on. I am not sure. I would have to project that there are
glycosyl transferases that put those carbohydrate units on that
hemoglobin. Wait a minute, if the
hemoglobin is unmodified and you are forming glycosidic bonds, I am sorry, that
is not a spontaneous reaction; that is energy dependent. Is that wrong? Okay, I will step aside on that then. Some of you may be much more aware of that particular reaction.
DR.
DWYER: Dr. Mehendale?
DR.
MEHENDALE: Substances are
biotransformed in the gut by bacteria.
This is a well-known phenomenon, as you are aware. I didn't hear anything in your presentation
that addressed the issues where botanicals might be metabolized by bacterial
flora in the gut.
DR.
HARRIS: We are talking about microflora
here.
DR.
MEHENDALE: I don't think there are many
individuals in this room who do not carry bacteria in their stomachs.
DR.
DWYER: You need to use the mike.
DR.
HARRIS: I have to stay at the podium, I
am afraid. I understand your question
about microflora and definitely they are in the human gut, yes. So, should we consider anything that is
metabolized by microflora, which are really bacteria? Should we feel that is fair game? I am going to have to let you decide that.
DR.
MEHENDALE: I can also think of
endogenous or exogenous compounds that get into what is known as enterohepatic
cycle, the enterohepatic recirculation.
DR.
HARRIS: Like cholesterol.
DR.
MEHENDALE: Like cholesterol.
DR. HARRIS: Bile salts.
DR.
MEHENDALE: Therefore, they are very
much part of the definition because they will go out of bacterial metabolism in
the gut and then in and out of the human cell metabolism.
DR.
HARRIS: Yes, but there again those
reactions are well defined. What are
the bacteria providing other than enzymes to carry out those reactions?
DR.
MEHENDALE: One further question I have
is, you know, the requirement of enzymatic action--there are compounds that, to
me, undergo metabolism and interact with the substance and, therefore, evoke a
response. Where would we put this, this
kind of substance? Generally we
consider protein as enzymes but the substrates may not undergo a change and,
therefore, I suspect--
DR.
BRASS: If that would be a metabolite of
catecholamines, I would say no.
DR.
BLONZ: What about final estrogen that
would bind to an estrogen receptor?
DR.
BRASS: What is the question?
DR.
BLONZ: Well, it is not acted upon--
DR.
BRASS: But it is not a metabolite. Its chemical structure isn't changed. The example that was posed is, does binding
a receptor lead to a chemical reaction where a molecule is changed, whether or
not you have a product precursor relationship, that was implicit in my
thinking.
DR.
DWYER: Dr. Dickinson?
DR.
DICKINSON: I would like to go back to
your example about lycopene and vitamin A.
As I understood it, you said that the reason it wouldn't be a metabolite
is that although it may be broken down to beta carotene, it doesn't eventually
goes to vitamin A and, therefore, it isn't a metabolite. But there are hundreds of carotenoids that
are broken down into various other compounds in the body, and I am troubled by
the conclusion that simply because it doesn't go to vitamin A, all those
metabolites wouldn't necessarily count as metabolites although they might have
functions.
DR.
HARRIS: What I was trying to point out
when I brought the lycopene up is simply the first step in the metabolism of
lycopene is something that we can't do.
But a tomato can convert it into beta carotene. I said we could take beta carotene which we
would then consider a metabolite because we have enzymes to conduct further
metabolism with that compound. What I
tried to indicate is that we have no enzymes for lycopene.
DR.
DICKINSON: In the case of other
carotenoids that might break down into component parts, would those component
parts then be metabolites of those carotenoids?
DR.
HARRIS: If they themselves could
undergo further chemical change through enzyme-catalyzed reactions, yes.
DR.
BRASS: But what if they are end
products? What if they go through a
couple of steps and you get an end product?
I think has to be considered a metabolite, the original dietary
ingredient. Just like I think that
something that is a botanical and is metabolized into p450 and gets
hydroxylated, that hydroxylated product is a metabolite of what you gave. I think linking function to the metabolite
is fallacious. I mean, the
precursor-metabolite relationship is a biological chemistry one, not a functional
one. In fact, the metabolite could be a
detoxification. Just like your concept
in the written document that says it must not represent a threat to homeostatic
mechanisms. That is a concentration
argument. So, I think trying to evoke
all these non-chemical, non-biochemical definitions into what a metabolite is
cloud the water rather than clarify it for what is a much more straightforward
precursor-product relationship that occurs in the body.
DR.
HARRIS: My strongest point that I want
to make to you is that we are talking about defined biochemical pathways and if
we are talking about intermediates in those pathways, we would be perfectly
legitimate.
DR.
BRASS: Okay, p450, a non-metabolic
pathway. It hydroxylates a botanical
precursor to a hydroxylated product that has no function in man.
DR.
HARRIS: That is why I emphasized the
next step as being important.
DR.
BRASS: That is why I emphasized not to
count end products because end products are generated by metabolism. Just because B doesn't go any further
doesn't mean it didn't come from A.
DR.
HARRIS: You are saying that a chemical
reaction is a pathway.
DR.
BRASS: An enzymatic pathway can occur
in one step, a natural product exposed to p450 gets hydroxylated and excreted
in the urine. Because a hydroxylated
compound was generated by the body from a precursor I don't know how to avoid
concluding it is a metabolite. I don't
know any theological reason--
[Laughter]
--that
says it has to be greater than one step. Obviously I am biased because as a
pharmacologist this is what we do all the time. We give a foreign substance to the body, most of which are
derived from natural products, metabolized by reactions to the body to
metabolites. Some of those are active
and some of those are inactive but they are clearly metabolites. Again, the implication of that definition,
that is somebody else's problem but it seems to me that trying to put arbitrary
boundaries on what is or isn't just makes it more confusing.
DR.
HARRIS: Well, I can see your argument
and I can also see the danger in the argument because if I can take any
compound, stick it inside p450 and hit it, it is a metabolite, I don't like
that.
DR.
BRASS: Well, many of us have problems
with parts of the law but that is not our charge. I mean, it is to come up with a working definition of what a
metabolite is. Under the law, if that
precursor turns out to meet any of the precursor definitions that are in the
law and a metabolite may be p450 I feel trapped. I don't like being trapped.
I don't understand the negative potential consequences of it but I feel
trapped in trying to come up with a definition of a metabolite trying to avoid
these traps just leads me into semantic traps.
DR.
DWYER: I think it is time for
coffee. I just wanted to mention that
Dr. Yetley came in while we were in the midst of this. Why don't we take a break and give Dr.
Harris a rest and be back here in 15 minutes?
[Brief
recess]
DR.
DWYER: Could everybody sit down,
please? We are going to start again. There are a couple of issues that emerged as
we were metabolizing coffee. The first
is, I hate to keep getting you up to the mike but I wondered if you could go
back and just give us a little bit perspective on the kava-kava question that
came up, the whole issue of dietary ingredients and where metabolite fits in
that whole thing?
DR.
MOORE: Do you want to wait for a couple
of your AWOL committee members? Do you
want me to wait until they all get back?
DR.
DWYER: Well, while you are waiting could
you please tell us where you come from in your terms of your background? What are you? A lawyer?
DR.
MOORE: Oh, no.
DR.
DWYER: A doctor.
DR.
BRASS: That wasn't very nice; what did
he do to you!?
DR.
MOORE: Before I say no to that, I
should ask the lawyers to raise their hands so I will know how to answer
that! No, my undergraduate and doctoral
training was in nutritional sciences.
Then I spent six years and did my postdoc. at Grand Forks, USDA lab, and
then spent six years in the Army's Occupational Medicine Research Program. I came here in '94 and had the misfortune or
good fortune, depending on your perspective--I was hired right when DSHEA was
happening. I have been there ever
since.
DR.
DWYER: Thanks. Are you a metabolite of DSHEA?
[Laughter]
DR.
MOORE: The question that Dr. Dwyer
asked, to sort of walk through again, is the construct for in the statutory
definition for dietary supplement. It
is important to recognize that the dietary ingredient clauses is but one of
many, many requirements that a product would have to meet before it could be
lawfully marketed. The issue of dietary
ingredients is really the gatekeeper clause.
You don't have to worry about whether it is safe, or is approved as a
drug, or it is intended to supplement the diet or anything else because if it
isn't statutorily "a dietary ingredient" it can't be a supplement and
all those other requirements go away.
Once it
becomes a dietary ingredient, then you superimpose on that all of the other
requirements, does it meet the safety standards? Is it excluded? Is it
thrown out of the box by one or more of these exclusion clauses? If it is a dietary ingredient, is it then a
new one that would require a notification or is it eligible for exemption for
notification? So the issue of the
dietary ingredient definitional construct is simply that it possibly gets you
into being a lawful ingredient but it is not the end-all. What that section
says is that dietary ingredients are vitamins, minerals, amino acids, herbs or
other botanicals, the sort of dietary substance for use by man. In a broad sense, things that are articles
of the usual food or drink of man is the way to look at that.
Then, the
last one is that it is a constituent, a metabolite, a concentrate, an extract
or a combination of any of those others.
For example, to use kava which came up earlier, it gets into the dietary
ingredient box because it is an herb or botanical. The things in it may get into the box because they are a
metabolite of it, a constituent in kava, a concentrate or an extract of
it. So, metabolite isn't the only way a
particular substance can get into the dietary ingredient box. It is simply one of a myriad possibilities,
and something that is a metabolite might also be a constituent where it might
fit into some other category but this is simply one of many.
DR.
DWYER: Just to follow-up on that, could
you tell us, lycopene could also be in the box by other ways, couldn't it?
DR.
MOORE: Right. The most straightforward way is it is simply a constituent. You know, herb or other botanical means
plants, if you will. So, tomatoes are
clearly plants, bioengineered or not.
So, lycopene clearly is a constituent of a plant material and that is
the simple, straightforward way to get in.
DR. BRASS: Again, as I read your background summary and
your list of vitamin, mineral, amino acid and herb, in my construct of
precursor-metabolite relationships I view that upper list as the precursor
which might be a substrate to generate a metabolite in the final clause.
DR.
MOORE: Clearly, that is what the
statute envisioned because that is what it says, a metabolite of something
aforementioned.
DR.
BRASS: Right.
DR.
MOORE: So, it can be a metabolite of
some ephemeral substance. If that
ephemeral substance isn't listed above, than that metabolite isn't a dietary
ingredient.
DR.
BRASS: Right, but trying to keep my
syntax consistent, those would be the precursors and I wouldn't have to argue
whether they were metabolites or not.
They are already the precursors and not metabolites.
DR.
DWYER: So, those are amino acids,
vitamins, minerals, herbs, botanicals and what is the last?
DR.
MOORE: Dietary substance for use by man
to increase the dietary intake. That,
like metabolite, is also not explicitly defined or discussed in the statement
of agreement. How we have applied that
or interpreted it is simply that those dietary substances are those substances
that are in the usual food and drink of man.
So, that is a fairly broad category.
DR.
DWYER: Shall we go around the
table? Any questions? Annette?
DR.
DICKINSON: No, I thought your
clarification earlier that many of these substances that we have been talking
about, like lycopene, would be dietary ingredients in and of themselves for
other reasons, regardless of the metabolite clauses, is a point that I am glad
you made.
DR.
MEHENDALE: I have a question.
DR.
DWYER: Identify yourself.
DR.
MEHENDALE: This is Hari Mehendale. I have a question concerning whether we have
some historical perspective. When this
law was introduced somebody framed this metabolite. Surely, somebody had input into this and I wonder if there is any
information on people who might have been involved at that time who introduced
this term metabolite. That might be
helpful, if somebody has that information, what was thought at that time when
whoever did this introduced this term metabolite.
DR.
DWYER: That is a very good question and
I will answer what I know and then the experts can answer from what they
know. There is no legislative history
for this. It was the first thing I
asked when I was told the purpose of this business. So, that means whatever was discussed was expunged from the record. What that leaves you with is the analog of a
hundred people feeling different parts of the elephant and explaining--what is
it?--a hundred blind people trying to explain what the elephant was. So, there doesn't seem to be very much
common agreement on what the dialogue was that led to this particular
thing. Perhaps there are others who
would like comment on it.
DR.
MOORE: No, I think you are correct from
a purely legal perspective for interpreting and applying the law. While I am sure one could mine the
Congressional Record and find what was the Congressional Record, for legal
purposes it is struck and can't inform whatever decision we make or consider.
DR.
DWYER: Anyone else over here have any
comments on that?
DR.
BLONZ: This is Ed Blonz. I don't know the exact pathway but let us
say we are dealing with a substance such as garlic. Garlic, when it is in its full state has a set of compounds, but
when you crush garlic you activate an enzyme system which then breaks down one
compound into another compound that would be a metabolite of the naturally
occurring compounds in garlic. Now, if
we were to take those metabolites of garlic and use those as a supplement, see,
we have an enzyme system outside the human body acting on a naturally occurring
compound. How would that fit into our
definition of a dietary supplement?
DR. MOORE: Probably simply as constituents again
because the limited statement of agreement says that physical acts, if you
will, on things that are dietary ingredients don't change anything. So, to the extent that garlic, at least in
some normal way of use is squashed, that is still the plant or botanical and
the substances that are in that are constituents of it. Regardless of how they got there, they are
still constituents.
DR.
DWYER: Dr. Schiff?
DR.
SCHIFF: Paul Schiff. I think the point is well taken but it goes
back to the big picture versus many small pictures. So, if a plant has its own set of metabolites that it has
produced, you grind it up, the constituents mix, there is some water, there are
enzymes present. A glycoside in one
cell becomes an A-glycan and a human being ingests ultimately both the
glycoside and the A-glycan--they are all metabolites I think.
DR.
BRASS: Except I think it is important
to think about the separation. In the
context of this they are constituents and not metabolites because, to me, if
you open the metabolite to non-human fates--
DR.
SCHIFF: No, no, pardon me, they are
phytometabolites, I agree with you.
DR.
DWYER: We will get back to that
definition again. There are a couple of
other questions, Dr. Moore--you are not off yet. One was Dr. Mehendale's question but maybe you can phrase it
better. It is this whole business of
the human rumen. Again, it is sort of
like the crushed garlic question, but the issue of some of the isoflavonoids, I
can't remember which one it is that is converted in the gut by the bacteria and
the question is whether the bacteria in the gut are in or out. What is the FDA's official view of that?
DR.
MOORE: I don't think we have an
official view.
[Laughter]
DR.
DWYER: This is a first, isn't it?
DR.
MOORE: That is one of those areas of
ambiguity that aren't readily clear from the plain language of the statute or
the statement of agreement. I think
that discussion as to where those types of metabolites or transformed
substances fit may be part of your discussion that will inform our
consideration of that, but we have not outlined a policy about that.
DR.
DWYER: Probionics?
DR.
MOORE: As to where they fit in the
dietary ingredient mode? Probably,
again, to the extent that some microorganisms are typical parts of fermented
foods, some of their constituents, some of them have a long history of use
simply as food maybe not in the U.S. but in other cultures. So, arguably, depending on the bug, they
would be either dietary substances for use by man or constituents of other
foods.
DR.
DWYER: One other thing, are metabolites
organic?
DR.
MOORE: The statute is silent on
that. I don't think it limits it to
inorganic or organic or any other.
DR.
DWYER: I guess it is time to get Dr.
Harris back up.
DR.
MOORE: Okay.
DR.
DWYER: We are giving him training as an
expert witness for a murder trial. You
make big money when you do murder trials; here it is nothing!
[Laughter]
Could you
tell me if you think metabolites are organics?
DR.
HARRIS: No, I would not limit it to
that, no.
DR.
DWYER: What is an example of one that
is?
DR.
HARRIS: Well, up until probably the
last fifty years or so a lot of attention has been placed on inorganic elements
in living systems. I don't have to tell
you Tufts is very famous for work on calcium and iron and my work on
copper. We now know that these elements
are clearly metabolized, not in the usual sense that they are being broken down
to other things; obviously not, but they are able to engage in compounds that
assist in their transport around the cell and ultimately determine their
positioning into enzyme structures, and so forth. So, these are well-defined pathways that are now coming into more
common understanding and, hopefully, more in the literature so you won't have
to ask that question again.
DR.
DWYER: Thank you. Let's start back with some questions for
you.
DR.
HARRIS: Can I raise one question?
DR.
DWYER: Of course.
DR.
HARRIS: Regarding the comment about
microflora again and returning to that, by a physiologist, quite some time ago,
I was told that anything in the gut is outside the body, waiting until until we
enter the system. The case in point
here could easily be seen, you don't produce antibodies to bacteria even though
the bacteria are in the gut. They don't
form any type--it is more of a symbiotic relationship. So, I raise that question with you. When you talk about the gut are you talking
about in the body or out of the body?
DR.
BRASS: I was with you until you got
into the immunity part. There is
mucosal native immunity. I think this
is a grey area, but I think to incorporate both Dr. Shannon's comment and the
comment about the gut flora, if you take that definition, then for example the
stomach acid is outside the body and, clearly, the stomach acid may be a
mediator of a chemical modification of a dietary substance. So, it seems to me that one is trapped into
some kind of precursor-metabolite relationship following oral ingestion, or
some other kind of exposure to the body that incorporates all the body
functions and that includes natural flora to the degree that that is a natural
constituent. It seems to me that,
again, there is a little bit of a trap here, that you are talking about oral
ingestion and the fate of the precursors after oral ingestion and another
molecule that is generated is a metabolite.
DR.
DWYER: Thank you. Dr. Childs, you had a very interesting thing
that we were just sort of chatting about in the break in terms of your thinking
about toxicity and the whole issue of where these things all fit.
DR.
CHILDS: I think we have already covered
that with Dr. Moore. I had been
concerned about going back to the language in the original statute in the sense
that there were multiple pathways to be considered a dietary supplement or
dietary ingredient. I believe, Johanna,
that is what we had talked about.
DR.
DWYER: Did Dr. Moore's explanation
clarify what you were thinking?
DR.
CHILDS: Yes, it did, although I am
still in a grey area over the bacteria issue.
I am not as certain how that will shake out. Then, I am also just wondering, just trying to leap ahead for how
this language might be applied in the future, thinking about GMO organisms and
thinking about other methods of ingestion that might not be dietary,
particularly if you think of aroma and if we see that emerging as a channel for
dietary supplements. I am just trying
to be very far out there in what ways this might move forward.
DR.
DWYER: I think there are already B12
inhalers.
DR.
DICKINSON: Right, but the Act defines
dietary supplement as something that is ingested.
DR.
BLONZ: You have to swallow.
DR.
DICKINSON: Yes.
DR.
CHILDS: All right, so that takes care
of that.
DR.
MEHENDALE: I know the examples to
illustrate a metabolite and metabolism--the examples that you used generally
dealt with intermediate metabolism and production of energy, important areas
and you did a very, very good job. But
if you think about benefits, obviously we can have many, many benefits outside
of those areas as well, not just production of energy. You could also have interventional benefits
in people who might have other metabolic disorders or may not have what we
would like to prevent, disorders, and there are many other areas of benefit even
coming from intervention in toxicities, pharmacological interventions; there
are many of those.
So, I
don't know if benefit with regard to definition of metabolite can be extended
in those areas as well. You may not
have limited that but your presentation was primarily using those examples, and
I wanted your comments on that.
DR.
HARRIS: As I understand it, you want me
to justify why the word benefit was put into my perspective of what it should
be.
DR.
MEHENDALE: Right.
DR.
HARRIS: I suppose looking at how cells
function, obviously cells have all kinds of different mechanisms that are
really geared toward cell survival and basically that is to sustain life. So, I am looking at certain events here, and
they could be protective measures but actually let's look at it from the
standpoint of keeping alive, stepping aside from anything that might harm
us. That is where I put metabolism, in
that perspective.
I see
metabolism as basically two processes.
Typically biochemistry talks about anabolism, which is building new
structures from smaller molecules, or catabolism, which is breaking down for
the purpose of either yielding energy or other purposes. I see all of these as well-designed steps
that keep a cell alive. I also see
where mutations in any enzyme systems can lead to diseases and these diseases
ultimately feed back into some malfunctioning pathway. So, I am looking at maybe more of a divine
nature of a living system rather than a practical nature.
DR.
DWYER: Your definition implies that there
is sort of--
DR.
HARRIS: Ultimate purpose.
DR.
DWYER: --a purpose.
DR.
HARRIS: Yes.
DR.
DWYER: One doesn't have to assume if
one doesn't want to.
DR.
HARRIS: That is correct.
DR.
BRASS: I agree with everything you said
but I don't think it is relevant to the definition of what a metabolite is or
isn't. A metabolite relationship,
again, is a chemical, biochemical, precursor-product relationship. Even for the natural intermediates there are
concentration considerations so let's take a molecule like propionate. Propionate is a natural product of odd-chain
fatty acid breakdown, branched amino acid production. It is important for generating Krebs cycle intermediates. But in high concentrations it is clearly
toxic to cells, unambiguously toxic to cells.
Carbon monoxide is a metabolite of heme breakdown in man. Carbon monoxide is pretty toxic but it is
generated in endogenous metabolism and it is clearly a metabolite, in my mind.
So, I
think trying to prejudge or demand some kind of benevolence or malevolence in
the definition of what a metabolite is really clouding the issue. I think for relevant dietary supplements
those issues are taken care of, to the degree they are, in other aspects of the
law.
DR.
HARRIS: Eric, pardon me for saying this
but I think some of those comments are a cloudy issue. Water.
Water is a metabolism product.
Obviously, water is a dangerous substance. I mean, if you want to sit here and drink a barrel of water, be
my guest but you will not survive. You
will upset all your homeostatic mechanisms.
I guess
what I am saying really is looking in the context of normal--if you want to
call it normal--
DR.
BRASS: Again, we are talking about
exposure to compounds that are not endogenous to man. We are talking about xenobiotics. We are talking about other molecules that are not endogenous when
we talk about plants that contain a number of molecules that are not endogenous
to man. Therefore, their metabolism and
generated metabolites don't mimic human metabolism, and trying to force the
square peg into the round hole doesn't work if I am trying to simply define
whether or not an individual molecule is a metabolite of another molecule.
DR.
DWYER: Let me make sure, your point is
that dietary supplements include xenobiotics in some cases.
DR.
HARRIS: Let's make sure we understand
the meaning of xenobiotic.
DR.
DWYER: Sorry?
DR.
HARRIS: I said let's make sure we
understand the meaning of xenobiotic.
DR.
DWYER: Fair enough. Do you want to comment on that?
DR. HARRIS: I think Eric brought it up.
DR.
BRASS: Well, I included it in molecules
that are contained in other organic matter that are not endogenous to human
metabolism. Fair?
DR.
HARRIS: Yes.
DR.
BRASS: Without being judgmental about
them.
DR.
DICKINSON: But by that definition a
vitamin would be a xenobiotic.
DR.
BRASS: That is a good point.
DR.
DICKINSON: One thinks of a xenobiotic
as things other than naturally occurring materials. One thinks of xenobiotics as being a synthesized--
DR.
BRASS: No.
DR.
DICKINSON: Well, in nutrition we do.
DR.
BRASS: But, again, I think a substance
that is present in a plant that is not used in normal metabolism but can be
metabolized by p450 is going to be a xenobiotic.
DR.
DICKINSON: But it is not a xenobiotic
to the natural biological system--
DR.
BRASS: When you ingest it.
DR.
DICKINSON: --to a biological system
generally though.
DR.
HARRIS: There is an important point
here that has to be made and that is, is it a xenobiotic before the fact or
after the fact? If you are talking
about after the fact, then a vitamin is not a xenobiotic because it is acted
upon by a series of enzymes that converts it into a profactor so it cannot be
foreign to the body.
DR.
BRASS: I don't want to get distracted
into an argument about what xenobiotics are.
Everyone will grant me there are molecules in organic matter that you
can put in your mouth that are not part of endogenous human metabolism. Those molecules can get metabolized and
generate metabolites. That is my point,
and without deciding whether those metabolites are benevolent or malevolent.
DR.
CHILDS: I was just wondering if
phytoestrogens are an example.
DR.
HARRIS: I think Ed brought up the
point--I think it was your point that phytoestrogens will interact with
estrogen receptors.
DR.
BLONZ: They will, but they are also
naturally occurring constituents of a number of--
DR.
BRASS: And undergo metabolism in man.
DR.
HARRIS: Yes.
DR.
BRASS: And those metabolic products are
metabolites of phytoestrogens.
DR.
HARRIS: Yes.
DR.
BLONZ: Clearly, one of the things that
we are dealing with here is once we get past many of the ingredients that are
entailed or are included in the definition of a dietary supplement, the one
category which is problematic is the botanicals because we are not dealing with
essential nutrients per se, although there can be essential nutrients in
botanicals. So, this is where we
introduce a lot of the compounds which might be foreign to the human body but
they are still within our definition and we need to understand how the
definition of metabolites applies to them.
DR.
HARRIS: I think I would argue with you
that mere interception with a receptor type mechanism is not sufficient to say
that chemical changes have taken place.
DR.
BRASS: I agree with that.
DR.
DWYER: Could everybody turn to these
questions because I don't know how long you get to stay, Dr. Harris--
DR.
HARRIS: I will be here all day.
DR.
DWYER: You will be here all day? But I would still like to focus on those and
we do want to go back to these out of body experiences.
[Laughter]
Miss
Hardy just asked whether we want two public comments before the questions. What I want first though is to get Dr.
Harris right now, while it is fresh in our minds, to make sure there are no
questions we want to ask him right now.
So,
question one, is it possible to identify particular scientific criteria,
principles, or conventions that enable a determination to be made about when a
substance is or is not a metabolite of another dietary ingredient?
First of
all, do you have any additional comments you want to make having listened to
our questions so far? You will have
other chances but we want to focus on the issue because these are the questions
the agency wants us to answer.
DR.
HARRIS: One of the comments I would
make, first of all, is I really enjoy the intercourse that is taking place
between us. When I bring you a strictly
biochemical perspective, I realize there are exceptions. For example, the exception of non-enzyme-catalyzed
reactions, and other exceptions could be brought to the fold.
I found
it rather difficult trying to give you numbers. So, if I said a metabolite has to be within a certain distance
number-wise, reaction-wise from a reference compound, I found that
difficult. I think you don't want to do
that but, at the same time, we want to observe the principle.
I think
for everything we are going to be saying there is going to be an exception and
what I am really concerned about is that we don't do a carte blanche here. Let me return to the p450. We have been talking about that enzyme quite
a bit. That enzyme is called a mixed function
oxidase. That means we haven't really
nailed it down as to what molecules it actually acts upon because there is such
a wide spectrum of molecules. I think
Eric would agree with me on that.
Just
because that enzyme is acting on anything we throw at it, is that enough to say
that we have seen metabolism taking place and that we have generated a
metabolite? So, that is why I really
wanted to bring up the idea that, in a metabolic sense, we are dealing with
both a substrate and a product. In
other words, we are going to make something but that something we made has to
be converted into something by an enzyme reaction. To me, I would be relaxed when I think of that being a metabolic
event.
DR.
DWYER: Thank you. Are there any other questions on question
one now?
DR.
MEHENDALE: I just wanted to
comment. Before we realized that the
mixed function oxygenases consist of individual members of a family, I think
the mixed function probably applied to the time when we realized this group of
enzymes carries out many, many functions.
After the advent of the individual isozymes being separated, now cloned
and so on and so forth, I think we are using those terminologies less and less
even though we realize that individual members have some overlapping
activities. I just wanted to clarify
that.
DR.
DWYER: Very good. For question two, are there any things that
immediately come to mind?
DR.
BLONZ: Let me ask you a procedural
question. I have looked through the
materials and I have comments to make on all of them, but I also would like to
make sure that I have listened to all the public comment before I come to any
conclusions. So, how do we handle the
conduct of the meeting as regards that?
DR.
DWYER: We are going right to the public
comments as soon as you ask any questions of Dr. Harris you want to ask.
DR.
BLONZ: So, this is only as regards
addressing Dr. Harris?
DR.
DWYER: That is correct. We are just trying to make sure that any
immediate type of questions are raised but public comments are coming right
along. Then we will go back to the
issues again. Anything on question
two? Anything on question three that
you want to ask now that you have jotted down?
If not, I think we are ready.
The public comment can proceed.
I don't know if the people are here.
If they are, we would love to hear their views. Thank you, Dr. Harris.
MS.
HARDY: We have two people that are on
the agenda that are going to speak today, the first one being Dr. Philip
Harvey. Each commentor will be
permitted to talk for ten minutes. The
timer is on the podium while you are up there and then I will be watching it
too and I will give you a signal when you have two minutes left. So, Dr. Harvey?
DR.
DWYER: Dr. Harvey has written a
thoughtful letter.
Open Public Comment
DR.
HARVEY: The letter was written by Scott
Bass and Emily Marden. You have the
letter. I mean, I was just going to
read through that. I don't know if it
is redundant or not.
MS.
HARDY: Many of the people in the
audience do not have the letter.
DR.
HARVEY: Okay, I am just going to go
ahead and read the written comments that were submitted by Sidley and Austin.
There are some introductory points but I will just get to the specifics.
I am
chief science officer for the National Nutritional Foods Association, or
NNFA. NNFA appreciates FDA's
solicitation of comments on the definition of metabolite. NNFA believes that the term has a clear
scientific definition and was explicitly included in the DSHEA definition of
dietary supplement on those terms.
NNFA, therefore, takes the position that there is no need for FDA to
redefine or narrow the category.
One, the
definition of a dietary supplement in DSHEA includes metabolites. I think this was discussed extensively in
terms of the DSHEA definition, defining a metabolite or a vitamin, mineral,
herb or other botanical, amino acid or dietary substance. Specifically, the term dietary supplement
means a product, other than tobacco, intended to supplement the diet that bears
or contains one or more of the following dietary ingredients: (a) a vitamin;
(b) a mineral; (c) an herb or other botanical; (d) an amino acid; (e) a dietary
substance for use by man to supplement the diet by increasing the total dietary
intake; or, (f) a concentrate, metabolite, constituent, extract, or combination
of any ingredient described in clause (a), (b), (c), (d) or (e).
Two, the
definition of a metabolite is not contested.
Metabolite is uniformly defined in scientific and general use
dictionaries as any substance produced by the body's metabolism or by one of
the body's metabolic processes. A
metabolite thus includes any substance that is created by the body as it builds
up, breaks down, or converts the nutrient.
This
inclusion of the term metabolite in the DSHEA definition of dietary supplement
indicates that the drafters of DSHEA contemplated allowing any compound that
results from metabolism of one of the other defined dietary ingredients to be
marketed in dietary supplements.
The range
of metabolites is potentially broad, including what are called intermediary
metabolites, molecules that are not identical to the original
nutrient/supplement but are created to get to another step along a chain of
alterations that leads to the molecule the body is trying to make or excrete.
Three, a
wide array of dietary supplements are already on the market as
metabolites. A wide range of dietary
supplements already on the market as metabolites of dietary ingredients, and
here are a few examples. One would be
MSM, a metabolite of DMSO, a garlic-oyster smelling substance. Glucosamine sulfate, a metabolite of
chondroitin sulfate; pantetheine, a metabolite of pantothenic acid; methionine,
a metabolite of SAMI, or a metabolite of homocysteine. Those are just some examples.
Four,
like other dietary supplements, metabolites must meet the statutory safety
standard. The definition of metabolite
is, therefore, very clear and there is no reason FDA should move to redefine or
narrow this category.
At the
same time, all dietary supplements, including metabolites, are subject to the
statutory safety standard, which NNFA urges FDA to continue diligently
enforce. Under this standard, dietary
supplements must not present a significant or unreasonable risk of illness or
injury under conditions of use recommended or suggested in labeling, or under
ordinary conditions of use. Some products
on the market clearly fail that standard regardless of their definitional
status under Section 21 of the U.S.C.
Five, new
dietary ingredient provisions also apply.
The new dietary ingredient, or NDI, provisions of DSHEA apply to all
dietary supplement ingredients including metabolites. NDI is defined as a dietary ingredient that was not marketed in
the United States before October 15, 1994.
DSHEA requires that manufacturers of dietary supplements containing an
NDI file a notification establishing the safety of the ingredient 75 days before
it is placed on the market.
The
safety of a dietary supplement containing an NDI is established if there is a
history of use or other evidence of safety establishing that the dietary
ingredient when used under the condition recommended or suggested in the
labeling of the dietary supplement will reasonably be expected to be safe.
Thus,
manufacturers of dietary supplements containing NDIs are subject to both the
general safety standard noted above, as well as the NDI standard. NNFA believes that these safety standards,
together with FDA enforcement, are adequate to ensure that metabolites are
adequately regulated.
Based on
these comments, we urge FDA not to modify its interpretation of the term
metabolite. Thank you.
DR.
DWYER: Could we take questions now or
would you be willing to answer some questions?
DR.
HARVEY: Sure.
DR.
DWYER: Yes?
DR.
BRASS: Do you agree that human
metabolite is implicit in the phrase metabolite?
DR.
HARVEY: Yes.
DR.
SHANNON: Do you really think the
definition is not contested?
DR.
HARVEY: You know, that is our position.
DR.
DICKINSON: Could we ask a question of
Dr. Moore related to that? Could we ask
whether there has been a warning letter or other action related to whether
something is or isn't a metabolite?
DR.
MOORE: I don't know that there is a
warning letter. I know that there are
untitled letters where we have asserted that certain analogs of things that
would fit into one of the other categories are not metabolites. For example--I remember the colloquial name
but not the chemical identity--but it is an analog of coenzyme-Q. That was argued to be a metabolite of and we
asserted that it is not a metabolite; it is a chemically prepared substance
derived from that, that fell outside the scope. We haven't really defined or carved out much more than that for
metabolites.
DR.
BLONZ: Dr. Harvey, in your definition
of metabolite, in the first paragraph you say that a metabolite, thus, includes
any substance that is created by the body as it builds upon, breaks down or
converts the nutrient. Now, not all of
the dietary ingredients are nutrients.
DR.
HARVEY: Correct.
DR.
BLONZ: Then you also put in the third
paragraph to get to another step along a chain of alterations that leads to the
molecule the body is trying to make or excrete. Could you expand on what you mean by that?
DR.
HARVEY: You know, listening to the
prior comments, I mean these compounds are precursor substrates and are making
one intermediate constituent or are converted to another. Some of those are excreted based on
metabolism and, you know, it is just that process specifically.
DR.
BLONZ: It was my thought that in many
cases they might be trying to make or excrete something in response to the
presence of that very ingredient. So, it
might not be a physiological process that happens outside the presence of that
ingredient; it could be just a reaction to its presence. Again, coming back to our friend cytochrome
p450, there are many reactions to putting foreign substances in the body.
DR.
DWYER: One issue that is troubling here
is the purposefulness again.
DR.
BLONZ: Yes.
DR.
BRASS: Yes, I don't think you should
try to decipher what the intent of the body is.
DR.
DWYER: Could I ask just probably a very
stupid question? In your section four,
it says all dietary supplements are subject to the statutory safety
standard. Of course, NNFA is urging
diligent enforcement. The question is
there could be a standard after the fact.
Right? If you leave that very
broad and you don't know something is harmful and then it turns out to be
harmful, what is the protection to the consumer? Is this a license to cause trouble?
DR.
HARVEY: I am not going to speak
specifically for FDA but, you know, there is a possibility--you know, these
things are kind of living--that new evidence comes out based on a better
understanding of these substances that could possibly change that. But generally, as we see that as
constituents that the body could use or eliminate, and there are things for
which we still don't one hundred percent know the exact mechanism or what is
going on but unless there is some physiological change or condition of
abnormality, then there is a possibility that that could be addressed. In terms of FDA enforcement, you know, they
would be looking for some type of an illness or injury, some event and a
sequence of that and, you know, they may consider enforcing on that.
DR.
DWYER: Other questions?
DR.
BLONZ: Let me just ask one more thing,
by this definition you would be arguing to say that testosterone or estrogen
would be a metabolite of a fatty acid and could be included as a dietary
supplement, as a metabolite of that substance.
DR.
HARVEY: Correct.
DR.
BLONZ: Thank you.
DR.
DWYER: Dr. Dickinson?
DR.
DICKINSON: It might under the
definition by a metabolite but whether it could legally be included would
depend on other provisions of the law, such as not including ingredients that
are drugs or that are controlled substances that are otherwise excluded.
DR.
BRASS: This is where I think the
concept of net product and not simply tracing carbons through pathways makes a
big difference. Again, you can ingest
any carbon and find it in any other molecule in the body under a wide variety of
circumstances, but if it doesn't result in net structural contribution then I
don't see how it can be viewed as a metabolite.
DR.
DWYER: I am troubled again. The word is used in the standard, as I
understand it, as the last in a paragraph that lists specific things, and it
seems to me a metabolite is a derivative--
DR.
BRASS: No, it is an alternative
way. My interpretation is the things
above it are the precursors--
DR.
DWYER: Yes, right.
DR.
BRASS: --and metabolites of those
things.
DR.
DWYER: Of those things.
DR.
BRASS: So, again, because glucose is a
dietary constituent and just because you can feed somebody glucose and find
glucose and carbons in every molecule in the body doesn't mean all the other
molecules immediately become metabolites of it. There has to be net contribution to synthesis.
DR.
DWYER: Back to our colleague at the
mike, then do you consider substances, other than things where precursors were
amino acids, vitamins, minerals, herbals and botanicals or dietary substances
for use by man, to be metabolites?
DR. HARVEY: They could be, yes.
DR.
DWYER: Would you give an example? Is an example estrogens, metabolites of fat?
DR.
HARVEY: Estrogens metabolites of
fats? I mean, carbon from cholesterol
is a steroid. You know, it just depends
on how far downstream.
DR.
BRASS: No, but if you eat more lipid,
you eat more palmitate you don't get net incorporation of palmitate into
estrogen. You might get carbons traced
through infinite pathways that end up there, but you don't get net production
so it can't be a metabolite.
DR.
HARVEY: I am thinking of another
example of arachidonic acid into cell membranes. I mean, this does occur over a period of time, lipid especially. You know, you can change, especially with
fatty acids, over time net incorporation of those dietary substances from
either foods or dietary supplements into cell membranes.
DR.
BRASS: The specific phospholipids that
are metabolized might be argued as metabolites because, again, there is a
product-precursor relationship. But you
can't say because it is incorporated into the cell the cell is a metabolite of
the lipid.
DR.
DWYER: Any other comments or
questions? Are those all clear? Does anyone at the table over here have any? I was puzzled by this precursor-product
relationship. Is that your
understanding?
DR.
TAYLOR: I think we are here to hear the
discussion you folks would have about that, and we certainly don't have
anything in our record that would be relevant to it.
DR.
DWYER: Thank you. Thank you, Dr. Harvey.
DR.
HARVEY: Thank you.
MS.
HARDY: Dr. Dentali?
DR.
DENTALI: Thanks very much. I am Steven Dentali. I am the Vice President for Scientific and
Technical Affairs at the American Herbal Products Association, a trade group
that represents manufacturers of botanical products. I don't have a written statement. I didn't come prepared with one but I would like to respond to
the interesting discussion from this morning.
I have a
doctorate in pharmaceutical sciences, a minor in pharmacology and
specialization in botanical and natural products chemistry.
From the
natural products chemistry, from botanicals, I just want to say for the record
that flavonoids, terpinoids, alkaloids but not altoids but certainly the
menthol in the peppermint oil that goes in the altoids, all these others fall
into a class of secondary metabolites.
That doesn't really have relevance here for the discussion because we
are talking about metabolites of compounds, and botanicals is already included,
and constituents of botanicals are already included. So, if you are taking menthol, that is already included but it is
well within the definition of the metabolite standard within natural products
chemistry. I know Dr. Schiff can back
me up on that.
In the
same way--I am sorry, I have forgotten your last name--Brass, thank you--I took
a course in pharmacology called drug disposition and metabolism. So, I was uncomfortable with the limitation
of the excellent discussion on metabolism, of intermediate metabolism and human
cellular metabolism to be limited to just that. It is clear the course I took was talking about xenobiotic
metabolites. So, the design of drugs
and metabolism of drugs--this is clearly within the definition of what a
metabolite is and shouldn't be arbitrarily excluded.
I think
we see some of the limitations and try to limit it to within the body and to
limit it within the realms of intermediate metabolism when, clearly, there are
plasma esterases that occur; there are reactions that take place outside cells. You know, we seem to move the discussion
from cells to the body but clearly in plasma metabolites are formed. There are non-enzymatic reactions that
produce metabolites. Neurotransmitter
metabolism, just as an example.
That is
really the point I wanted to make. I
think the point of secondary metabolites is something to recognize. There are metabolites that plants make. In fact, these are pretty much the compounds
of interest for botanical products.
They don't come into play here because of the way the statute is
written.
I do think
that the metabolism as known in pharmacology--certainly there is no reason to
exclude that from the definition. I
don't see that we have any charge to do that.
That is pretty much what I have to say.
DR.
DWYER: Come back to the secondary
metabolism. What is primary metabolism?
How do you define that?
DR.
DENTALI: Well, it would be the
compounds that we know are necessary for the structure of the plant, basically
proteins, carbohydrates, fats. We know
exactly what they are for. We didn't
really know exactly why--I am not sure we still know why coffee beans contain
caffeine. I don't think they are doing
it for our benefit. But alkaloids are
considered a secondary metabolite of a plant metabolic process. They may be doing it for their benefit since
we eat the coffee beans and coffee is still around and is grown quite a bit;
surviving well; there is a lot of coffee around because it contains caffeine.
DR.
DWYER: So a secondary metabolite is
defined primarily by human knowledge?
DR.
DENTALI: Human knowledge--could you
repeat that, please?
DR.
DWYER: If we went back to 150 years
ago, everything would have been a secondary metabolite because we didn't know
about anything--
DR.
DENTALI: Yes, we knew a little bit
about alkaloids but not a lot. Yes, it
is based on our knowledge of plant chemistry; our knowledge of human
metabolites back about the same time.
DR.
DWYER: How about some questions for Dr.
Dentali?
DR.
DICKINSON: You made the point that, as
an intellectual matter, metabolites of xenobiotics should still be considered
metabolites. But would you argue that
those are necessarily dietary supplement ingredients?
DR.
DENTALI: Not necessarily, no. However, for flavonoids in a botanical it
would be a dietary supplement ingredient.
A drug metabolite, if it is already sold as a drug, does not make it a
dietary supplement ingredient.
DR.
DICKINSON: And a secondary metabolite
in botanicals or the botanicals themselves would be dietary ingredients for
reasons other than that they are metabolites.
DR.
DENTALI: They are already constituents.
DR.
DICKINSON: Right.
DR.
DENTALI: Yes, the garlic was a very
good example, made after the fact.
DR.
SCHIFF: I think when Steven was talking
about secondary metabolites, I would want to emphasize that he means secondary
phytometabolites in phytometabolism. He
referred to caffeine and, if I remember correctly, glycine carbon dioxide and
ammonia, assembled correctly, gives you caffeine in the plant. To me, something primary in a plant would be
an amino acid.
DR.
DWYER: Fair enough. Any other questions? Anybody over here have anything? No?
Thank you. It was very
enlightening.
DR.
DENTALI: Thank you.
DR.
DWYER: Let's just go around and make
sure there are no other questions that have come to mind for Dr. Harris or any
of the folks who have been kind enough to share their views with us, or any
questions of clarification that are needed from the scientists representing the
agency. Yes, Dr. Dickinson?
DR.
DICKINSON: At the risk of complicating
this unnecessarily, I have been sitting here, fretting about one thing that Dr.
Harris said and what it means in the context of other ingredients that we know
are used in dietary supplements. That
is, he put a great deal of emphasis on the stereoisomer that is produced
naturally in the metabolic system, and is suggesting that that be one of our
criteria for what is an appropriate metabolite of one of these other
ingredients as we talk about it.
I just
want to separate that concept from the established recognition that there are
many essential nutrients where there are synthetic forms of the naturally
occurring nutrient that are well accepted as equivalent forms of the nutrient,
and that that is a separate issue from this question of whether a metabolite is
the appropriate stereoisomer. I
wondered if somebody from FDA would comment on that.
DR.
BRASS: But you are not quibbling that
stereoisomers have to be considered distinct molecules--
DR.
DICKINSON: Yes.
DR.
BRASS: --in whatever category one is thinking
about?
DR.
DICKINSON: Yes.
DR.
DWYER: Shall we take an hour for lunch
or do you want to take less? Let's take
sixty minutes which will bring us to about 12:35. We will be back here at 12:35.
So, we are a little ahead of the schedule, which is fine with me.
[Whereupon,
at 11:35 a.m., the proceedings were recessed for lunch, to be resumed at 1:40
p.m.]
- - -
A F T E
R O O N P R O C E E D I N G S
Discussion of Charge and Questions by Subcommittee
DR.
DWYER: Does everybody have these
questions? What is your pleasure? Shall we just go through the questions one
by one? All right?
DR.
BRASS: It might be useful--I have kind
of a conceptualized definition that was useful for me in trying to integrate
various aspects of this. I don't
pretend it is perfect. It is not
worth-smithed but it is conceptually how I thought about this. That might be helpful?
DR.
DWYER: Yes.
DR.
BRASS: It is a functional
definition. What it says, in my mind,
is X is a metabolite of Y if ingestion of Y by humans results in net production
or increased flux of X incorporating structural elements of Y.
So, there
are two parts to it. First of all, it
involves ingestion by man. Two, it
involves a true precursor-product relationship that Y is giving net production
of X and it is a direct structural interaction. In other words, the fact that catecholamine increases cyclic ANP
wouldn't fit the definition because cyclic ANP incorporates no structural
elements of catecholamines.
So, it is
in two parts. It is ingestion by man
which, as we heard, was the key for supplements; yields net production of and
is structurally a precursor of. Those
seem to me to be the elements which I thought were critical in incorporating
the issues we talked about with Dr. Harris' presentation, an attempt to relate
those in a way that made functional sense to me.
DR.
SHANNON: I think that is useful. We would probably need to work on what
structural similarity means--
DR.
BRASS: Incorporating structural
elements of.
DR.
SHANNON: Right. What I mean is if that can be quantitated in
any way because otherwise, again, if it has two carbons--
DR.
BRASS: Well, I was trying to find
exceptions where, if there was a direct net production and incorporation of the
elements--I was just trying to differentiate and gave the cyclic ANP example
that was so well brought up earlier where these other indirect hormonal effects
are some downstream effects when you produce a compound. Again, it is not word-smithing but that was
the concept I was trying to get across.
DR.
DWYER: I have one addition to
that. It has concerned me all
along. It is getting all of this to
something that is useful from the standpoint of the regulators. If you will bear with me while I draw some
circles--
DR.
BRASS: I didn't intend it to be this
formal.
DR.
DWYER: You talk about metabolites and
we are talking about other dietary ingredients, and it seems to me that what
they are talking about here that needs to be defined is this, that intersection
in the van Dyke diagram. Does everybody
agree with that on the committee?
DR.
BRASS: So, this was a clever ploy to
get me away from the microphone! I
think that I do disagree.
DR.
DWYER: All right.
DR.
BRASS: Because I think that from
conceptualization, the other dietary constituents or ingredients are the
precursors of metabolites. Now, a
metabolite might also turn out, by coincidence--
DR.
DWYER: That is what this is supposed to
be.
DR.
BRASS: No, I view that as the same
thing.
DR.
DWYER: How would you draw this diagram?
DR.
BRASS: Well, I personally would draw
them as two non-overlapping circles, acknowledging that it may turn out, by
coincidence--see, this again is an interesting definition--by coincidence it
might turn out that some of the metabolites also are constituents of dietary
supplements, but that is not intrinsic to their definition.
DR.
DICKINSON: These are dietary
ingredients. These are metabolites and
some of those metabolites are dietary ingredients.
DR.
SHANNON: What makes them dietary
ingredients? What makes those fractions
dietary ingredients?
DR.
DICKINSON: You are right, I almost need
two circles over here, don't I? These
are legitimate dietary ingredients as defined elsewhere. These are their metabolites. Actually, all of those metabolites that meet
that definition are dietary ingredients also.
But also--
DR.
BRASS: No, they are not.
DR.
DICKINSON: --there are many other
metabolites.
DR.
BRASS: The way you initially drew it is
dietary ingredients generate metabolites.
It may turn out, purely by coincidence and not by definition--again, I
am trying to focus on the definition which is our charge--it may turn out that
some of those metabolites turn out to be dietary ingredients by
coincidence. For example--
DR.
DICKINSON: No, no, I am saying--
DR.
BRASS: --glucose is a metabolite of
sucrose. Right?
DR.
DICKINSON: Yes, it may also by itself
be a dietary ingredient.
DR.
BRASS: And by coincidence glucose turns
out to be a dietary ingredient but not intrinsic to the definition.
DR.
DICKINSON: No, I meant to show just
that it is only metabolites of ingredients that are already dietary ingredients
that are going to be ingredients because they are metabolites.
DR.
BRASS: What you are doing is defining
X.
DR.
DICKINSON: Y.
DR.
BRASS: Y, I am sorry. You are defining Y by saying Y has to be a
dietary ingredient or one of those precursors that are listed above.
DR.
DICKINSON: Yes.
DR.
BRASS: And I agree with that. Again, I was trying to focus on what a
metabolite was.
DR. DWYER: Come and play with us over here with the
circles.
DR.
BRASS: I like my own game! You don't share!
[Laughter]
DR.
DICKINSON: All right, what fraction of
the second circle is relevant to us?
DR.
BRASS: A hundred percent.
DR.
DICKINSON: All of it.
DR.
BRASS: Because that is the definition
of a metabolite, and that is what our charge is.
DR.
DICKINSON: But all of those may not be
legitimate dietary ingredients.
DR.
BRASS: Well, there may be other parts
of the statute but in terms of defining what a metabolite is, that is the
definition.
DR.
DWYER: Then there is a whole bunch of
other substances that are metabolites but not under the law.
DR.
CHILDS: Doesn't that get you back to
your original drawing?
DR.
DWYER: Yes, I think so.
DR.
CHILDS: Which I thought was a clear
portrayal.
DR.
BRASS: Again, defining whether it is a
metabolite per se doesn't define whether or not it is an appropriate thing to
be marketed under DSHEA.
DR.
DWYER: Right.
DR.
BRASS: And that is what I am trying to
keep absolutely separate as we define what a metabolite is, or at least for me
when I think about what a metabolite.
That is, I have to keep that separate or I get into all kinds of caveats
that I can't incorporate into a definition.
DR.
DWYER: Isn't something you said a lot
earlier, that the upper list, the amino acids, vitamins, minerals, herbals and
botanicals or dietary substances for use by man, are the precursors?
DR.
BRASS: Again, in my definition that is
the list of things that are in Y. Again, I was trying to write a generic definition because I don't
want to be trying to interpret--we are having enough problems interpreting one
word and I am trying to avoid getting us distracted and trying to interpret a
bunch of other words. So, this seemed
to me to be a generic way of saying that, but I would agree with you and my
intent is Y would be that list of precursors.
DR.
DWYER: Could you read the definition
again, Eric, to make sure I understand it?
DR.
BRASS: X is a metabolite of Y if, one,
ingestion by humans of Y results in net production or increased flux of X. The phrase increased flux is to recognize
that there may be a metabolic intermediate which doesn't accumulate, as Dr.
Harris was referring to, but simply increases the flux through it in a way that
affects biologic function. But the
other part is two, that X has to incorporate structural elements of Y. That is, there is a direct
precursor-metabolite structural link.
Again, that is to get rid of the hormonal thing. If Y was a hormone, there are a variety of
Xs that change in response to hormones.
Those would not be metabolites because they don't incorporate structural
elements of the hormone. Again using
Dr. Harris' example, if a molecule was an allosteric regulator of a pathway it
would affect the concentration or flux of a number of substances, but because
it didn't represent a structural precursor those would not be true metabolites
of the precursor. So, those are the
scientific criteria I was trying to incorporate into the syntax.
DR.
DWYER: Dr. Schiff?
DR.
SCHIFF: Eric, if I could ask you a
question because I think this is very good conceptually and I just want to make
sure I am on the right page with you here, let's go back to a tougher example. We will take a botanical. We will pretend it has 200 ingredients in
it. Let's isolate ingredient 144--I
just picked that, being ingested by a human through some process, defined or
undefined; it hydroxylates to hydroxy-144; hydroxy-144 you would consider a
metabolite.?
DR.
BRASS: It would be a metabolite of Y.
DR.
SCHIFF: That is correct.
DR.
BRASS: Absolutely correct. That was my intent.
DR.
DWYER: Any other questions or
comments? Dr. Harris, do you have
comments you wish to make on this? Not
allowed?
DR. DICKINSON: Can I ask for clarification? We have asked questions before at advisory
panel meetings of experts who were in the audience. No?
MS.
HARDY: Well, you know, we had time
allotted for questions earlier in the day.
Now it is supposed to be just you deciding answers to the questions,
having already heard answers to the questions earlier. Technically, he is invited by the FDA so,
you know, it is FDA's perspective.
DR.
BLONZ: I had prepared answering each of
the individual questions, hoping that discussion of each of those points would
lead us up to formulating a definition.
We very well may come back to this but with some different understanding
with more commentary. Are we going to
go thorough these individual charge questions?
DR.
DWYER: Yes, we are in just a
moment. First I need to get what is
wrong with this diagram in terms of circles, and then we will go to the
individual questions. Basically, I am
still having trouble with why this first diagram I drew is not in line with
your thinking.
DR.
BRASS: Well, it very well may be.
DR.
DWYER: I think it is.
DR.
BRASS: Okay.
DR.
DWYER: What I am saying is that a
dietary ingredient, other than amino acids, vitamins, minerals, herbals and
botanicals or dietary substances for use by man, a metabolite of those
substances is what we are talking about.
We are only talking about metabolites in that defined way, that a
substrate or a precursor, as I guess you called it, has to be one of those
things.
DR.
DICKINSON: That is what that shows.
DR. BRASS: Yes, I think that is what that shows. I agree.
I agree with Annette. I think
that shows the relationship of causality and product precursor, and not the
overlap.
DR.
DWYER: Does it imply Y always has to be
before X?
DR.
BRASS: Because you have the arrow.
DR.
DWYER: There is directionality and
there is temporality?
DR.
BLONZ: That is why Y came first.
DR.
CHILDS: I think what is happening is
that we think of this as your starting diagram and your diagram as the
concluding diagram.
DR. BRASS: It will turn out that there is an overlap
between but that area of overlap is not intrinsic to the definition.
DR.
BLONZ: One of the issues that I have
with the definition is what would happen if you were to have an amino group as
part of a reaction? Would the donation
of that amino group then make that amino acid a precursor to the product?
DR.
BRASS: It would depend on the
specific. The answer could be yes. Is an amino acid a precursor of urea?
DR.
BLONZ: Well, urea is a pretty
uncomplicated substance.
DR.
BRASS: But that is the example.
DR.
BLONZ: One of the examples we have is
an amino group from glutamine which then makes it glutamic that shovels that
compound down the road. Are you saying
it is the metabolite of both?
DR.
BRASS: Yes, conceivably that is
true. I don't know for a fact--I
apologize--whether adding glutamine increases the net flux through a set of
reactions. I don't know which way it is
limiting. So, again, both clauses have
to be true under the functional definition I proposed but, yes, one metabolite
might have more than one precursor, i.e., might be a metabolite of more than
one molecule.
DR.
DWYER: One other question that might be
asked is are there other ways, such as a structural definition rather than a
functional definition, that might be thought of? It seems like there are some because they are in the paper. It has to be something that is an
identifiable organic compound.
DR.
BRASS: No.
DR.
DICKINSON: It doesn't have to be
organic.
DR.
DWYER: It doesn't have to be
organic. It has to be an identifiable
compound.
DR.
BRASS: You have to know what X is. X is a specific molecule so, yes, there has
to be a specific molecule.
DR.
DWYER: Does it have to have any
similarity to an amino acid, vitamin, mineral, herbal, botanical?
DR.
BRASS: In my opinion, the answer is no
because we would argue all day whether molecule X and Y were similar, and we
could go through 300,000 individual examples and develop 300,000 individual
answers from the people on this committee but we wouldn't get insight into an
extrapolatable definition.
DR.
CHILDS: But isn't that incorporated in
your definition?
DR.
BRASS: Well, that is why I put
structural element because that is different than similarity. Again, is an L-amino acid similar to a
D-amino acid? It depends on whether or
not you transfer RNA or not; one you recognize and one you don't. Again, I was trying to avoid that kind of
discussion which I think would require individualization of every kind.
DR.
DWYER: Are there any other
criteria? Do you have to know exactly?
DR.
BRASS: In my opinion, you do not. So, again, it terms of scientific
principles, I do not think you need to know the pathway. I don't think you need to know the number of
steps between. I don't think you need
to know whether it is a good or bad molecule.
I don't think any of those things are intrinsic to the definition of
what a metabolite is or isn't. So, I
tried to be reductionist. Again, I
apologize that it is not clear and needs word-smithing but conceptually I have
tried to incorporate what I think are the core concepts of a definition of
metabolite that would apply to the maximum number of situations I can think of.
DR.
MEHENDALE: Would humans include also
microflora in the gut?
DR. BRASS: Well, I avoided that very carefully by
saying ingestion by humans, and I think a reasonable interpretation of that
would be ingestion by humans who have bugs in their gut, and acid in their
stomach, and water in their blood and all the other non-enzymatic mammalian
processes.
DR.
MEHENDALE: So, it is not intended to
mean only by human cells, human tissues.
DR.
BRASS: I was impressed by the
discussion both by you and Dr. Shannon this morning about other non-enzymatic
pathways so I modified what I had originally scribbled on the airplane.
DR.
DWYER: Could I just ask one other
clarifying thing? You called this a
functional definition. I guess last
night I was thinking about relationships and I guess it comes under function
but, to me, they are a little different.
One thing you might want to think about in the definition is what does
it have to do with safety. Anything?
DR.
BRASS: Nothing. Other criteria apply. I mean, X may be safe, may be unsafe or may
be safe at low doses or certain doses and not others. Those are all unrelated.
They are not intrinsic to the definition of what a metabolite is.
DR.
DWYER: Essential function?
DR.
BRASS: Irrelevant.
DR.
DWYER: Bioaccumulation?
DR.
BRASS: Irrelevant.
DR.
DWYER: Stereoisomers; regulatory
function?
DR.
BRASS: Irrelevant.
DR.
DICKINSON: Except that X may only be
one isomer.
DR.
SHANNON: But that is not intrinsic to
the definition.
DR.
BRASS: Yes, X is a molecule. That is why I clarified earlier that we
acknowledge that stereoisomers are different molecules.
DR.
DWYER: Proximity?
DR.
BRASS: Irrelevant.
DR.
SCHIFF: Proximity--you do have
incorporating structural elements.
There is certainly an element of proximity there.
DR.
DWYER: An element of proximity.
DR.
BRASS: Yes, but it is not numeric--
DR.
SCHIFF: No.
DR.
BRASS: It is functional proximity.
DR.
DWYER: And then directionality, you
said yes.
DR.
BRASS: Again, that is because X is a
metabolite of Y.
DR.
SCHIFF: Eric, let me ask you, is not,
to coin a term, the beauty of your definition that it more or less removes all
of the mechanistic functionality involved, and it simply says we have this and
somehow it is getting to this?
DR.
BRASS: Well, that was my intent. That was my intent because every time I tried
to word-smith syntax I was arguing with myself the way I argued with Dr.
Harris, and any time I tried to get specificity I could think of examples and I
could think of no reason to pose those limitations on my functional definition
in the context of what we are trying to do.
DR.
DWYER: Dr. Schiff, would you repeat
what you said?
DR.
SCHIFF: I will try. I think I said that perhaps the beauty of
the definition was that it tended to stress independence of mechanism, or as
many of the other considerations dealt with a lot of functionality and a lot of
mechanism.
DR.
DWYER: Are we about ready to go to
questions?
DR.
BLONZ: Yes, let's go to questions.
DR.
DWYER: Question one, can we go around
the table and try to answer this one?
Maybe your best answer would be ditto if one person says it. Is there someone who would like to start?
Is it
possible to identify particular scientific criteria, principles, or conventions
that enable a determination to be made about when a substance is or is not a
metabolite of another substance?
DR.
DICKINSON: Yes, and Dr. Brass has
outlined that for us very nicely I think.
DR.
SHANNON: Ditto.
DR.
SCHIFF: Ditto.
MS.
HARDY: Identify yourself.
DR.
SHANNON: Michael Shannon, ditto.
DR.
SCHIFF: Paul Schiff, ditto.
DR.
BLONZ: Ed Blonz. We were given a number of definitions from
various sources, both biochemical and from dictionaries, and they were really
all over the place. It is my opinion
that we need to come up with something as it applies to DSHEA, not necessarily
one that would be an English definition but one that would apply to a dietary
supplement legislation.
I also
think that in the definition we have to have some means of stating that this
reaction should be independent of any exogenous influences. So, the chemical reaction would take place
only when there was a certain chemical agent in the body. That should be independent of the fact that
this would happen when there were no outside influences. So, when an individual is under the
influence, or they have liver problems and so forth and certain metabolites
might be created, would those be metabolites?
So, perhaps we could have under ideal conditions or in normal
situations, some sort of caveat for that.
DR.
DWYER: Let me understand, you said in many
ways you agree but it must apply to DSHEA.
Then the second point was less clear to me. It must be independent of what?
DR.
BLONZ: Of any exogenous affecters.
DR.
BRASS: Otherwise unadulterated human.
DR.
BLONZ: Exactly.
DR.
BRASS: I agree with you about the
exogenous thing. I am less sanguine
about liver disease--
DR.
DWYER: Let's go around the table. Hold your comments until then.
DR.
BLONZ: Well, liver disease might not
have been the most ideal circumstance.
DR.
DWYER: Does everyone understand what is
meant by exogenous affecters? Give one
example.
DR.
BLONZ: Alcohol.
DR.
DWYER: Thank you. We will go around. Dr. Mehendale?
DR.
MEHENDALE: I have similar
comments. Susceptible populations is
another example. Aged populations is an
example. Exposure to alcohol, smoke is
another example. But I don't think we
need to worry about that in this definition because those are safety issues
and, hopefully, the safety issues will cover those aspects.
So, I am
a little ambivalent but I did want to bring my thought process into play at the
table. My thinking is that those
observations will be covered under safety regulations. I don't know that we need to worry about
those in this definition.
DR.
DWYER: But the safety is determined after
the fact rather than before. In one
case you have a license to put something in and then you determine the safety
by body counts, or whatever. In the
other case you don't allow the thing in.
I mean, isn't that the difference?
DR.
DICKINSON: It is a difference but it
isn't a carte blanche. There are
procedures to go through before you put a new ingredient on the market.
DR.
CHILDS: I am comfortable with the
definition, and I agree with the fact that there are safety and other factors
built into the larger Act.
DR.
DWYER: Eric?
DR.
BRASS: In response to question one, I
would say yes, as I think we tried to articulate in our discussion.
In
response to the comments that have been made, I think intrinsic to the
definition--what I proposed is DSHEA specific in that it incorporates human
ingestion and that is the relationship that is unique to DSHEA. This would not be a definition that would
apply in any other context, other than DSHEA, because a metabolite need not
occur after human ingestion in other contexts.
If I give a drug IV it gets metabolized. A plant itself, as we have heard, metabolizes itself. Animals and bacteria have unique metabolic
pathways. So, the DSHEA-ness of my
definition, if you will, is the ingestion by humans because I agree with you,
it is a very important differentiation.
With
respect to whether or not the definition has to incorporate special classes of
endogenous conditions--age, liver disease, renal disease, etc.--I think that is
really hard to try to do and would carry over, I think, to other safety
concerns. If it requires an exogenous
enzyme so you have to take Y and an enzyme that mix in your stomach, then I
think the exogenous affecter clause might come into play.
DR.
DWYER: I think we are getting some
place. My sticking points are, first, I
don't think ingestion by humans is specific enough and, if you want it to be a
definition that is meaningful under DSHEA it has to say specifically amino
acids, vitamins, minerals, herbals, botanicals, or dietary substances produced
by man.
DR.
BRASS: Well, that is what Y is.
DR.
DWYER: That is fine; let's say it in
the definition.
DR.
DICKINSON: Or let's add a second
sentence that says for purposes of this definition X is--
DR.
BRASS: Y is, yes.
DR.
DICKINSON: Right.
DR.
DWYER: Then the second thing is again
about the safety thing. I am not sure
that I am satisfied about that.
DR.
BRASS: Well, believe me, I would love
to put in a clause that says it has to be a safe molecule, but I don't think
anybody would allow me to do that because to the degree safety is an issue, it
is addressed in DSHEA itself, not in the definition of metabolite,
unfortunately from some people's perspective.
DR.
SCHIFF: I agree.
DR.
DWYER: Okay, I still am not satisfied.
DR.
BRASS: Is there a way to deal with it?
DR.
CHILDS: Johanna, is that any different
than the fact that herb or botanical is listed, and we know there are toxic
herbs and botanicals that are automatically excluded by the prior language in
the Act? So, how would this be
different than that kind of generic reference to herbs and botanicals?
DR.
DWYER: I don't know.
DR.
SCHIFF: Johanna, the definition we are
looking at, we seem to be reasonably close to agreeing on. When it comes to the nomenclature that is
involved here, Eric's definition really refers to not a botanical but the
individual constituents of the botanical, which makes it very different from a
vitamin identifiable, a mineral identifiable, an amino acid identifiable, but
for the an herb or other botanical really by direct implication he means the
constituents, the individual constituents present in the herb or other
botanical.
DR.
DWYER: Okay.
DR.
SCHIFF: I know we can't modify the law,
but for the record, I think that is the intent of the definition.
DR.
DWYER: Well, for the record, we are
defining metabolite and we don't intend to expunge the legislative history.
DR.
BRASS: But, again, he was trying to
address your concern about what Y is.
DR.
DWYER: Okay, but I would like to see a
definition of Y, and the definition of Y then also includes constituents of
herbals and botanicals.
DR.
CHILDS: To support Johanna, it is in
that herb and botanical area where we have had the issues in the past with
DSHEA.
DR.
SHANNON: Excuse me, I didn't understand
what you just said about constituents.
DR.
DWYER: That it isn't herbals and
botanicals, as Dr. Schiff said, it is specific compounds in herbals and
botanicals.
DR.
SCHIFF: This definition could not apply
to a whole plant. It would apply to the
individual chemical compounds that are present in the plant.
DR.
SHANNON: I see.
DR.
SCHIFF: As it could apply to a single
vitamin or a single mineral. That is my
point.
DR.
BRASS: And I appreciate that
clarification--
DR.
SHANNON: I am not trying to cloud that.
DR.
BRASS: No, it is critical. It is part of my trying to avoid defining
what an herb or other botanical encompasses.
DR.
SHANNON: That is fine.
DR.
BRASS: And if herb or other botanical
means all the constituents of that herb or botanical, then I agree. If there is some other interpretation of
what those words mean that limit what would be the definition of Y, then I
would accept those limits. But my understanding
is what your understanding is.
DR.
DWYER: Yes, Dr. Dickinson?
DR.
DICKINSON: Herb or other botanical
means whole herb or any of its parts, including the roots, the flowers, the
seeds or whatever. But it isn't logical
that there would be metabolites of the whole fruit. Their constituents are also covered in part d), e) or whatever it
is that refers to the constituents or extracts or so forth. But for metabolites we are still talking
about metabolites of single compounds.
DR.
BRASS: Again, I apologize because what
it says is a concentrate, metabolite, constituent, extract or combination of
any ingredient named above. Constituent
is not above. Constituent is in the
same clause. What is above is herb or
other botanical. So, again, I have
interpreted that to mean the herb, botanical, all its parts down to the molecular
level. If there is some other
interpretation of that that takes precedent, then that would be critical to
know because that is what metabolite applies to. That is the universal Y.
DR.
DICKINSON: Well, an herb or botanical
for purposes of normal products is some large piece of it or some extract of
it, not a single compound of it. But we
could use the word constituent or component as a foregoing word that applies
to--
DR.
BRASS: Again, it doesn't say metabolite
of a constituent because constituent is not above. It says metabolite of an herb or other botanical. So, again, I was trying to avoid that in the
definition of metabolite by saying Y is whatever Y is. If Y is an herb or botanical, I imply Paul's
implication but if that violates some other interpretation I don't want to
impose it.
DR.
DICKINSON: But we could add a sentence
that says, you know, logically or biochemically speaking, a metabolite of an
herb or botanical will be a metabolite of a particular constituent.
DR.
BRASS: I think that is very reasonable
and common sense.
DR.
DWYER: Say that again.
DR.
DICKINSON: For purposes of an herb or
other botanical, a metabolite is understood to be a metabolite of a particular
constituent.
DR.
SCHIFF: Individual constituent.
DR.
DICKINSON: Individual constituent.
DR.
DWYER: Does everybody agree with that?
DR.
BRASS: Yes, as long as it doesn't
violate any legal or regulatory interpretation that has already been made. Again, there may be some history that
excludes constituents from that discussion that would make this re-interpreting
the regulation. I just don't know.
DR.
DICKINSON: Would Dr. Moore be able to
comment?
DR.
DWYER: Dr. Moore, are you able to
comment on that? And would you also
comment on the safety issue?
DR. MOORE: I will do that one because it is
straightforward relatively. The safety
issue is separate because there are separate provisions of the Act to deal with
safety. So, from a definitional point
of view, it wouldn't need to be there.
We
haven't specifically addressed the issue of things that fit into dietary
substances by man, herb or botanical, which may be an entity with lots of other
smaller entities within it. Arguably,
once something is used--and, again, this isn't something in case law or policy,
but arguably, once something is used, like an herb or botanical, it becomes a
dietary substance because now it is part of the usual food or drink of
man. We have interpreted that dietary
substances include those things in it as dietary substances if those substances
are the reason, in part or in whole, that someone would use that thing.
So, I
think while we don't have nice language that is cleared by our attorneys, the
concept that has been articulated, while we haven't tried it in policy, in a
practical sense is consistent with how we view it.
DR.
DWYER: Good.
DR.
BRASS: Paul, let me try another spin on
your concern because I think it is very important. Another way to think about it is, okay, let's say you can't do
it. Let's say you give Y as a complex
plant part and you generate X. X may or
may not be a metabolite of that herb because in order to meet the second
clause, the structural relationship, you are, in fact, going to have to
practically identify the molecular constituent in the herb to show the
product-precursor relationship. So,
whether you know it, when you define Y as an herb or not to show that, in fact,
there is a molecular element that is a precursor for X you are going to have to
identify the constituent and show the product-precursor relationship.
DR.
SCHIFF: I just think inherent in this
is the big difference, when you say herb Y is a mixture, whereas when you say
amino acid Y is a single--
DR.
BRASS: Absolutely correct; absolutely
correct.
DR.
DWYER: Have we settled on that one? We will go on and then at the end maybe we
can play a little bit with this and try some compounds, if we can think of some
compounds.
DR.
SHANNON: Can I just ask what kind of
notes you took in terms of resolving the issue of the role of exogenous substances
being required to produce the metabolite?
I am not sure what kind of resolution we got on that issue.
DR.
DICKINSON: You thought that might be
irrelevant.
DR.
BRASS: Well, I could think of no
example but, again, Dr. Blonz' point was a fair one, that implicit is that this
is metabolism that is occurring by an otherwise unadulterated body. So, if one put an enzyme mix--I can't think
of an example.
DR.
SHANNON: But you could ingest a
substance as well as another substance that is a foreign enzyme and now you
have created a metabolite. The question
is would we be satisfied with that product or not?
DR.
BRASS: No, because that is not a human
metabolite and, again, that is the DSHEA-ness of the definition, in my opinion.
DR.
DWYER: Do you have some language there
that would be helpful, Dr. Shannon?
DR.
SHANNON: Well, I think Dr. Brass kind
of said it. We are talking about the
ability of humans to create that metabolite rather than an exogenous substance
that is creating that metabolite. I think
we have accepted that we would include endogenous normal microflora but we
would not include anything else that might be considered exogenous.
The other
issue I am not sure what kind of resolution we had about was humans and whether
or not this definition would refer to a reference human or does it even have to
be a healthy human. If so, is it age
specific, gender specific, pediatric patients in terms of kind of breadth to
give that term, humans, for the purposes of defining metabolite?
DR.
DWYER: Does anyone have an opinion
around the table?
DR.
BRASS: I think it is a really valid
question. Every time I tried to get
around it I came up with 16 pages worth of, you know, verbiage that ended up
creating more questions than it answered.
So, I think it is a valid question.
I just don't know how to address it, other than to say human. Again, I could imagine a supplement being
differentially metabolized in different people, for better or for worse--
DR.
SHANNON: Based on age, gender, disease.
DR. BRASS: Yes, sure.
DR.
SHANNON: Perhaps we could say in
normal, healthy adults.
DR.
BRASS: But that would exclude a unique
metabolic pathway that existed in somebody who is sick who might generally
benefit from the supplement.
DR.
SHANNON: Or a pediatric patient.
DR.
BRASS: Right, etc. As I say, I thought it hard to get more
specific. From my perspective, if there
were a group of people with a disease, healthy, male, female, you know, the
phytoestrogens are going to be metabolized differently on a gender specific
basis; children--I think that would be okay with me but I see no way around it
being okay.
DR.
DWYER: Weren't we saying that would all
come under the safety? Dr. Moore, do
you have an opinion on this? No?
DR.
BRASS: Again, if a metabolite were
uniquely generated in women, should it be given to adolescent boys? That again becomes a safety issue, not a
definition of metabolite issue, it seems to me.
DR.
DWYER: Is that, in fact, how the agency
looks at that? Is that a safety
issue? Is it an issue inherent in the
definition? Or, are we asking you
something you don't want to answer?
DR.
WALKER: This is Dr. Walker. Just inherently, I think we are interested
really in the broader definition of metabolite. The safety issues generally are taken care of under a different
rubric. So, I think if we can confine
it really to the definition of metabolite it is a very helpful discussion for
us.
DR.
DWYER: Let's go on to question two,
which is very long. There is a shorter
version up there. Consider and discuss
the scientific strengths and weaknesses of the following concepts with respect
to their usefulness in identifying whether a substance is or is not a
metabolite of another dietary ingredient.
So, we
are talking about strengths and weaknesses and the first thing they ask you to
talk about is direct or indirect participation in catabolic and/or anabolic
sequences. Why don't we start here for
a change and go around this way? Dr.
Mehendale, do you have a comment on this one, participation in catabolic or
anabolic sequences?
DR.
MEHENDALE: I have to think about it a
little bit.
DR.
DWYER: Nancy, do you have any comments?
DR.
CHILDS: No comment.
DR.
DWYER: Eric?
DR.
BRASS: Irrelevant. Again, what specific kind of pathway is or isn't
involved is not relevant to the definition.
DR.
DWYER: Annette?
DR.
DICKINSON: It seems to me that we have
already been through these points under question two and have considered them
and incorporated them into the shorter definition, have either considered them
irrelevant to this definition or have included consideration of them, for
example in specifying that structural elements must be incorporated.
DR.
DWYER: So, what is your answer?
DR.
DICKINSON: I that think a), b), c) and
d) are all--
DR.
DWYER: Irrelevant?
DR.
DICKINSON: Well, not necessarily
irrelevant, but if they are relevant they are covered by our short definition.
DR.
DWYER: How about you, Dr. Shannon?
DR.
SHANNON: I agree, not irrelevant but I
think they are encompassed by the short definition. I will say that in terms of a), I was a little confused by both
the term participation and pathway.
When I first read it I was assuming it to say that if the substance
appears anywhere or occurs anywhere along the metabolic pathway, but it seems
that is not really what it is saying.
At any rate, I do think that the issues here are encompassed by this
definition we are heading towards.
DR.
DWYER: So, you would put proximity,
which is b), also in the same category?
DR.
SHANNON: Yes.
DR.
DWYER: Encompassed by the definition?
DR.
SHANNON: Yes.
DR.
DWYER: How about you, Dr. Schiff?
DR.
SCHIFF: I completely agree with
Annette. I think what we have up there
and what we have talked about literally covers most of these variables,
although I have a hunch that probably we are dealing with
"metabolites" as more than being catabolic but we don't need to go
into that.
DR.
DWYER: Could you expand upon that
because I found it difficult in just thinking about how I have always used the
word in my own work.
DR.
SCHIFF: Break down, not build up.
DR.
DWYER: Correct, I have always thought
of it as being catabolic rather than anabolic.
I guess for the output of an anabolic process I have always used a
different word than metabolite. I have
used words like product for example.
Maybe I am the only one but I am a little uncomfortable.
DR.
SCHIFF: I don't think it is relevant to
the definition as we are looking at the definition.
DR.
BRASS: The definition of metabolite
encompasses what you have described as products.
DR.
DWYER: Dr. Blonz?
DR.
BLONZ: The strengths and weaknesses of
these four, I have both a) and b) as yes.
They definitely play a role in the definition or metabolite and they are
very well covered by our definition.
For c), I do not consider a precursor to be a metabolite. So the preceding portion of c) is not
there. Then, d), similarities to other
ingredients, I don't think that analogous substances are metabolites as well.
I had
hoped that somewhere we might talk about biofunctionality but to get into that
might be delving into more specifics than the simple definition that we are
hoping to come out with. I also had
some desire that we talk about metabolism vis-a-vis critical control
points. If you would have a metabolite
that would be past a critical control point and would be treated differently,
it would under this definition be a metabolite but it would be treated
differently in the body.
DR.
DICKINSON: I didn't understand that.
DR.
DWYER: I don't think I understand it.
DR.
BLONZ: There are a number of mechanisms
whereby--
DR.
DWYER: Well, wait, is it relevant to
question two? We can discuss more at
the end but really I would like to get question two nailed down because that is
what we are supposed to be doing.
DR.
BLONZ: Well, let's postpone it until
afterwards.
DR.
DWYER: Fine, bring it up at the end.
DR.
BLONZ: Yes.
DR.
DWYER: And your answer for d) was what?
DR.
BLONZ: I would place that as a weakness
because I do not feel that analogous substances can be considered metabolites.
DR.
DWYER: And c)? Where did you put c)?
DR.
BLONZ: Precursors, a weakness because
precursors are not metabolites unless, of course, there were some sort of loop
as in a Cori cycle type arrangement where a precursor could become a metabolite
and then it cycles around. So, if there
was a cycle a precursor could be a metabolite but that would be that
circumstance. Biochemistry is very
complicated.
DR.
DWYER: I am still not sure we have
answered this question. Am I right that
the group feels that direct or indirect participation in catabolic and/or
anabolic sequences or pathways is not useful in identifying whether a substance
is or is not a metabolite? Is that
correct?
DR.
DICKINSON: No.
DR.
BRASS: No. I do not find it useful, but I want to emphasize that the
indirect clause is outright misleading and dangerous, and that goes to the
allosteric regulation part or the hormone part, that a molecule can indirectly
influence a pathway but have no structural particular precursor
relationship. So, I think the indirect
is absolutely inappropriate and the direct is unnecessary.
DR.
DICKINSON: But the direct is
incorporated.
DR.
DWYER: Okay, that clarifies it a little
bit. Anything else we want to suggest to
the agency about direct or indirect participation? Back to the proximity, what are the strengths of proximity in
terms of number of steps away?
DR.
DICKINSON: The number of steps I think
we have said here are not relevant, but participation in the pathway is
relevant because this definition requires that it result in an increase in the
end product or in the X.
DR.
BRASS: Of the metabolite. It has to be a product-precursor
relationship.
DR.
DWYER: So, the strength is that it is
product-precursor relationship?
DR.
BRASS: Just to go back to some of the
things Dr. Harris talked about, apparently when A goes to B goes to C goes to
D, all those are metabolites of A, no matter how downstream they are, as long
as they continue to be directly affected by the amount of A present.
DR.
DWYER: But is that true within this
context now? We are talking about
trying to provide some guidance to this agency that has to administer a law on
dietary supplements. It is not to
define metabolite for students in pharmacology.
DR.
BRASS: No, it is absolutely
critical. Take a compound like a
phytoestrogen, it may be sequentially metabolized to five different molecules. All of them are metabolites of the original
phytoestrogen.
DR.
DWYER: And what is the weakness of proximity?
DR.
BRASS: Its vagueness. You can't define a number of reactions that
are both necessary and sufficient.
DR.
MEHENDALE: I am trying to understand
why the proximity was put here. So, in
trying to understand the intent I wonder if proximity was thought of because
certain metabolites can interfere with other pathways, and the proximity
becomes an issue where in that pathway the interference might occur. To give an example, with porphyria you can
have interference very early or sometimes later in the synthesis of heme, and
the product preceding the step that is interfered is excessively accumulated,
excessively excreted. In that sequence
then, the later the interference, the lower the adverse effects. I don't know if I am making that clear. Therefore, if there are ten steps, if you
are interfering with the first step the impact is enormous. If you are interfering with step number nine
the impact may not be as enormous. And,
I don't know if that proximity is because of such considerations.
DR.
BRASS: I think that is fair. My guess is that what the proximity was
trying to differentiate is, again, net influence versus carbon tracing or atom
tracing. Again the example I spoke of
earlier, if you put a radiolabel in palmitate you will get a radiolabel in
glucose but there is no net synthesis of glucose from palmitate. It represents just mixing in metabolic
pools. So, in my mind, proximity means
close enough to have a net influence on the "metabolite" not simply
contributing an atom to it some place down the line. As Dr. Harris nicely illustrated, there are certain parts of
metabolism where pathways pool. Acetyl
CoA is a good example. So, anything
that generates acetyl CoA will put carbons into a billion things even though it
doesn't contribute to their net synthesis.
DR.
DWYER: Is the agency able to tell us
why they asked the question? Just as a
person who doesn't work with some of these pathways every day, I would think
that it just would make sense to the common person that something closer to a
thing, absent all of the knowledge around this table, would be more likely to
be the thing, or close to the thing. If
it walks like a duck and talks like a duck, it is a duck.
DR.
WALKER: I think you have done a good
job of discussing issues related to proximity, and I think that those
discussions are helpful for us. I don't
think we need specific number of steps or that type of a discussion. On proximity, I think what might be helpful
in the discussion of proximity relates a little bit to the structural
elements. If you could discuss
structural elements in the context of proximity, whether or not you think that
the proximity is relevant to structural elements, that would be very helpful
for us.
DR.
BLONZ: So, we are really talking about
anabolic versus catabolic processes. If
you are dealing with structural elements where you can get a contribution to
acetyl CoA which would then be a structural element that would lead to steroid
hormones, cholesterol and so forth, you do have a substance that ends up
being--can't physically be in there but it is a building block. So, do we want to say number of steps or are
we talking about some sort of functionality issue as well? Can we separate catabolic from anabolic
processes in this?
DR.
DWYER: Well, the people who administer
the law or the people who write the law aren't necessarily chemists so the
simpler one keeps it, the better.
DR.
BRASS: I agree with all the
comments. This link between both net
production and structural contribution--I mean, originally I had the word
significant in front of structural contribution but didn't want to answer what
significant meant. It is easier to
visualize for catabolic because most of the molecule can be traced through. For anabolic I think this net influence
component is really key. There are a
whole lot of things you can give that contribute carbons to acetyl CoA that
don't affect the rate of cholesterol synthesis; that don't affect the rate of
anything synthesis. They just mix into
that pool because the regulation is different.
I think
your point earlier about are you proximally distal to regulatory steps that you
put in also is intended to implicitly incorporate by this net concept. If you are proximal and you don't change the
regulatory step you are not going to get any change in that flux.
DR.
DWYER: On this business of catabolic
versus anabolic, is everybody satisfied?
I am still uneasy about that.
DR.
SHANNON: I am too.
DR.
DWYER: You are satisfied?
DR.
SHANNON: I am uneasy.
DR.
BRASS: But think about amino acids
contributing to the synthesis of glutathione.
Think of N-acetyl cysteine. Is
glutathione or the acetaminophen conjugate, are those metabolites of N-acetyl
cysteine?
DR.
SHANNON: No, I wouldn't think of them
as metabolites of N-acetyl cysteine.
The analogy that comes to my mind is if you make catecholamine from an
amino acid, is the catecholamine a metabolite?
DR.
BRASS: Yes, I think it is.
DR.
DWYER: Well, we don't.
DR.
BRASS: Because I think you are thinking
narrowly catabolically.
DR.
DWYER: The problem is different
scientific disciplines are looking at this differently, basically
pharmacologists.
DR.
BRASS: Well, that would make it easy
because thinking as a pharmacologist it is only catabolic.
DR.
DWYER: Ah!
DR.
BRASS: But I don't think that is right
in the context of what dietary supplements, vitamins and minerals do. They are both building blocks and broken
down too. I think any interpretation in
the context of what has been posed has to recognize that putting two molecules
together may generate a metabolite as well as breaking one molecule into two
different ones.
DR.
DWYER: Okay, but the problem is that we
are here as scientists so I am concerned that the shoemaker should be true to
his last and, you know, that is how we use the term in our--
DR.
BRASS: But this goes back to the
DSHEA-ness of the definition. If you
want be to put DSHEA aside and simply give a definition metabolite, I would
give you something completely different.
I wouldn't have written what I wrote on the board.
DR.
DWYER: I see your point. I am still uneasy about anabolic. Could we get another opinion from any one of
the three of you in terms of how we can provide assistance to your
quandaries? I am looking at the table
in the back.
DR.
SCHIFF: Johanna, can I ask a
question? If we accept the precepts of
that definition with its provisos, is it mandatory that we open the
catabolic/anabolic box? I don't mean to
push it away or not do my duty, but I don't know that we need to do that. Am I the only one who thinks that from the
definition, not from the duty standpoint?
DR.
MEHENDALE: I also agree. I don't know that we really need to concern
ourselves with whether it is anabolic or catabolic. In the example that Eric was discussing with Dr. Shannon, you
know, it was also referred to as a synthetic reaction and even by that
definition it is a metabolite because structural elements are in the product.
So, I am not sure we need to concern ourselves with anabolic or catabolic so I
am falling in that column as well.
DR.
BRASS: Again, I don't want to pretend
this definition solves all problems because you could take what I have put
literally here and say superficially that every protein is a metabolite of
lysing and, therefore, I can give any protein as a dietary supplement and that
may or may not be a logical thing to say.
DR.
DWYER: You know, as a nutritionist, I
am very uncomfortable with that.
DR.
BRASS: Again, that is why I originally
had "significant" so that if you contribute one amino acid out of
twenty no reasonable person could say that you are contributing to the net
synthesis of.
DR.
DICKINSON: But, Johanna, I don't
understand what you are uncomfortable with because as a nutritionist what you
deal with all the time is nutrients going to build body parts basically.
DR.
SHANNON: Which she doesn't call
metabolites.
DR.
DWYER: I don't call them metabolites; I
call them products.
DR.
DICKINSON: Well, can you learn to call
them metabolites?
[Laughter]
What is
it that you are afraid of? What is it
that you see coming that we don't see?
DR.
DWYER: As I said, you know, it makes
the definition useless.
DR.
BRASS: I think you mis-extrapolated
what I said. What I said is there are
obvious limitations to any scrolled up definition and as part of the
legislative record, I was saying, clearly that just because an amino acid is a
precursor of a protein, that should not be construed as a metabolite by this
definition because there is no way to construe that a single amino acid would
change the rate of synthesis of a given protein, i.e., the net production
clause or, two, that any single amino acid contributes significantly to the
structure of any given protein. So,
what I am saying is that it required common sense interpretation. I think it contains enough specificity that
with the legislative record and the thousands of word-smiths that exist in the
FDA they can turn it into an interpretable clause. I was, in fact, arguing not to get hung up on these points as
long as the concepts are clear to the agency who will turn it, if they want,
into a regulatory context that will resemble nothing I wrote.
DR.
DWYER: Well, that is their right I
guess. What about possessing qualities
or similarities to other dietary ingredients relative to speed/time,
compartmentalization and fate?
Oh, we
skipped semblance. Are there any other
things that would be helpful? I think
we have gone about as far as we can get on the structural business. Is that correct? What about semblance to another dietary ingredient? Do we have any guidance there in terms of
strengths, weaknesses or other comments for function, structure or
combination? Dr. Mehendale?
DR.
MEHENDALE: Just to open it up, I might
share a couple of thoughts. Semblance
is similar but it can mean it actually participates in the pathway of another
ingredient in this case. Or, sometimes
it could also interfere with that pathway, antimetabolite. Metabolites and antimetabolites closely
resemble each other. So, don't know if that was the intent there,
semblance meaning either overload a pathway or interfere with a pathway.
DR.
DWYER: So, you are saying the strength
is that structure sometimes is associated with function?
DR.
MEHENDALE: Yes.
DR.
DWYER: And structure sometimes isn't
associated with function?
DR.
MEHENDALE: Yes, in that context those
points could be relevant.
DR.
DWYER: Anybody else?
DR.
BRASS: No, other than, again,
similarity is a trap. I think it is
impossible to define and it can be misleading, as was just said.
DR.
DWYER: Nancy?
DR.
CHILDS: I have nothing to add.
DR.
DWYER: Annette?
DR.
DICKINSON: I just have a question. We talked a lot about enzymes. I am assuming enzymes might also be
metabolites in that they are synthesized in the body from protein and other
components and certainly an enzyme does not share the functional
characteristics of the amino acids that went into it. So, function may, in fact, change in the metabolite as opposed to
the precursor but I don't see that as a problem. I see that as just how the system works.
DR.
BRASS: There are a lot of examples with
small molecules where the native molecule--the ingested molecule is inactive;
it gets metabolized; it is active, and the ingested molecule is active and the
metabolite is inactive and the structural modifications can be very subtle,
taking away double bond.
DR.
DWYER: I don't see how with that
definition, with the caveats we have here, an enzyme could be regarded as a
metabolite.
DR.
BRASS: That goes to the protein example
that I spoke to earlier, that it would not be a reasonable extrapolation.
DR.
DWYER: Because of the clauses down
there.
DR.
DICKINSON: It would not be what?
DR.
BRASS: A reasonable example because if
you ingested an amino acid you would have a hard time showing the change in net
synthesis of any given enzyme.
DR.
DWYER: Dr. Shannon?
DR.
SHANNON: Nothing to add.
DR.
DWYER: Dr. Schiff?
DR.
SCHIFF: No, nothing to add.
DR.
DWYER: Dr. Blonz?
DR.
BLONZ: I had said on c) that I did
think it was helpful in helping define it because I didn't feel that a
precursor was the equivalent to a metabolite
DR.
DWYER: Very good. Thank you very much.
DR.
DWYER: Let's go to d) and then we will
be done with this one; d), is possessing qualities or similarities to another
dietary ingredient relative to speed/time, and they got into reaction rates and
so forth; compartmentalization; and fate?
Shall we start with Dr. Blonz?
DR.
BLONZ: With this one, I had said I
didn't think this is helpful because I didn't think that analogous substances
would be equivalent to being a metabolite.
DR.
DWYER: Dr. Schiff?
DR.
SCHIFF: I think our definition handles
this well. I wouldn't pick anything in
particular out of here.
DR.
DWYER: Are there any strengths or
weaknesses there?
DR.
SCHIFF: No.
DR.
SHANNON: I would agree with Dr. Blonz
that a weakness would be the issue of analogs.
DR.
DWYER: Dr. Dickinson?
DR.
DICKINSON: No comment.
DR.
DWYER: Dr. Mehendale?
DR.
MEHENDALE: No comment.
DR.
DWYER: Dr. Childs?
DR.
CHILDS: No comment. I am assuming that we have reconciled the in
and outside the body issue.
DR.
BRASS: Nothing further.
DR.
DWYER: No pros, cons, strengths,
weaknesses?
DR.
BRASS: I think they are all a weakness
to the point that they don't help intrinsically define what a metabolite is,
can be misleading and to the degree anybody would think a chemically
synthesized analog would be a metabolite would be very dangerous.
DR.
DWYER: And this goes for speed and
time, compartmentalization and also fate?
We are all agreed that those are not particularly helpful? Is there further guidance for the whole last
issue? Is there further guidance that
you would like with respect to this?
DR.
WALKER: I think you have covered it
very well. I think what you are doing
so far is very helpful to us.
DR.
DWYER: Any other comments? Shall we do question three first round, then
take a break and come back and finish, hopefully?
DR.
BRASS: It depends on how long it is
going to take. If it is quick, we might
just as well finish.
DR.
DWYER: You never know. Okay, discuss the scientific validity and
likely usefulness for identifying when a substance is or is not a metabolite of
another dietary ingredient. If so, what
characteristics associated with the criterion make it valid or useful? Why don't we go around and discuss a little
more or at least jot down--we think we have a definition but then what
characteristics are associated with the criterion that make it valid or
useful? We need some characteristics.
DR.
BRASS: It emphasizes the
product-precursor relationship. It
emphasizes that the formation of the metabolite is the result of human
ingestion. It emphasizes that there has
to be a product-precursor relationship in the form of net production of the
product from the precursor, and that it has to incorporate structural elements,
i.e., it has to follow along the same processing metablic pathway whether it is
enzymatic or non-enzymatic.
DR.
DWYER: Could you give them again?
DR.
BRASS: Could the transcriber read that
back?
[The transcriber read back the record]
DR.
DWYER: Anyone have any other
suggestions? Annette?
DR.
DICKINSON: No, I think it is both valid
from a science point of view and I think it is also very likely to be useful in
terms of putting this human scope around it and limiting it in that fashion.
DR.
DWYER: Dr. Shannon?
DR.
SHANNON: No comment.
DR.
DWYER: Dr. Schiff?
DR.
SCHIFF: I like its functionality, its
flexibility but, yet, with enough scientific rigor to put flesh on it.
DR.
BLONZ: My concerns have to do with the
biofunctionality issue. I would like to
see there be some sort of way of relating the originating substance, the Y, to
the X in terms of biofunctionality.
DR.
DWYER: What do you mean by biofunctionality?
DR.
BLONZ: Well, when you are not dealing
with a substance that all of a sudden is doing something different in the body,
something that was nothing like the original substance--
DR.
DICKINSON: But it is; it will be.
DR.
SHANNON: It doesn't have to be.
DR.
BRASS: Well, it may or may not be. Again, if Y is an inactive molecule and it
is activated metabolically to an active X, would you like to exclude that from
a definition of a metabolite? Their
functionalities are completely different.
One is no function; the other is very functional.
DR.
BLONZ: That is a good point where you
could get activation of a substance. My
concern, of course, is for the darker side of things.
DR.
BRASS: Yes.
DR.
BLONZ: I wouldn't want to see products
on the marketplace that might start out as benign that would fit our definition
of metabolite but would end up being precursors to other substances.
DR.
BRASS: I agree 10,000-fold but I don't
think the definition of metabolite is a way to exclude those products from the
market.
DR.
SCHIFF: If we consider a lot of the
herbals the biofunctionality is, at best, only modestly defined if not
ill-defined, and then the exact molecules responsible are rarely defined. So, that opens the door--and I agree with these
gentlemen that the dark side is a concern--but that opens the door in the
definition that I would rather not open.
DR.
BLONZ: Well, perhaps the important
thing is to get it on the record then.
DR.
DWYER: Dr. Mehendale, do you have a
comment?
DR. MEHENDALE: I think the definition has scientific
merit. I think it is going to be highly
useful, likely to be highly useful. The
agency asked us to provide some boundaries and I think in the definition we
have pretty good boundaries actually.
So, I like it. I think it is a
good product.
DR.
DWYER: Dr. Childs?
DR.
CHILDS: Nothing. I think it is a useful and concise
definition. I still have a little bit
of a concern about it applying to all populations, particularly when it goes
all the way down potentially to young children and to disease states, but I am
not sure the definition is the place to address that. That might be elsewhere in the statute.
DR.
DWYER: Dr. Brass?
DR.
BRASS: No.
DR.
DWYER: If it worked, then we could go
back to the marketplace examples which are in the back of Dr. Moore's
presentation this morning. One was
cholesterol to steroid hormones.
DR.
BLONZ: In each of those the first
substance would have been a precursor, if you will, and the second one would
not be the metabolite.
DR.
DWYER: Let's start with some
vitamins. Anybody think of a
precursor? I think of a provitamin beta
carotene. Does the definition work for
this?
DR.
SHANNON: I am sorry, what are you
looking for?
DR.
DWYER: I am trying to see if we can go through
these examples that he gave us and whether it works.
DR.
BRASS: You can eat a lot of cholesterol
but you will not change your testosterone level.
DR.
DWYER: So, the steroid hormone would
not be a metabolite of cholesterol.
DR.
BRASS: That is correct. That would be my interpretation. It falters at the second step because you
don't get net production.
DR.
DWYER: No net production.
DR.
BRASS: I am sorry, you don't increase
the amount of steroid hormone, that I know of.
DR.
DWYER: What about prostaglandins and
arachidonic acid?
DR.
BRASS: That is a complicated one. I think the answer is probably
prostaglandins are a metabolite of arachidonic acid. I don't know that much about the oral fate of arachidonic acid,
whether it survives in the stomach, but even if it got into the mucosal cells
of the stomach if you dump arachidonic acid on a mammalian cell it will make
more prostaglandins.
DR.
SHANNON: Yes, it will.
DR.
BRASS: Now, whether that is the result
of oral ingestion or not--I have never given oral arachidonic acid and followed
its fate, but in concept it very well might be, yes.
DR.
DWYER: Dr. Moore, did you give me your
arachidonic to prostaglandin sequence?
Thanks, Dr. Moore. Does everyone
see this? Let's just look at this. Arachidonic is where?
DR.
BRASS: Right in the middle.
DR.
DWYER: So, we are right here and we are
saying that prostaglandins are where?
Down here.
DR.
BRASS: No, to the right; they are all
over the place.
DR.
DWYER: And we are saying it is--
DR.
BRASS: It may or may not be.
DR.
DWYER: PG2 is a metabolite.
DR.
BRASS: Here are the data I know, if you
take a mammalian cell or a mammalian organ and provide it additional
arachidonic acid it increases its prostaglandin production. Okay?
So, that leads me to think the answer is yes. However, after oral ingestion of arachidonic acid, I don't know
if it reaches enough cellular cyclooxygenase to change net prostaglandin
production after oral ingestion. So, my
answer is I don't know. I wouldn't be surprised
if the answer was yes but I don't know that the answer is yes.
DR.
DWYER: Does anyone know around the
table here?
DR.
DICKINSON: Yes.
DR.
DWYER: Yes, you do know and it will
increase it?
DR.
DICKINSON: I know someone on the
audience who I believe understands this pathway and he says it does. He says oral ingestion will increase it.
DR.
BLONZ: I think one of the connections
is with heavy meat consumption too which requires arachidonic acid. It has been shown to increase, yes.
DR. DWYER: Anything more on that particular one? What about catecholamines?
DR.
BRASS: Let me point out again this is
an issue where the time factor and the proximity might be of interest to some
people because if the mechanism is that arachidonic acid gets incorporated into
cellular phospholipids and only later comes out and does it, or something like
that but, again, I think it is conceivably a yes.
DR.
DWYER: What about catecholamines and
amino acids?
DR.
BRASS: I assume you mean a specific
amino acid.
[Laughter]
DR.
DWYER: Yes, I will give you a specific
amino acid, glycine.
DR.
BRASS: No.
DR.
DWYER: What about methionine?
DR.
BRASS: How about the precursor amino
acid for catecholamines? Tyrosine?
DR.
DWYER: What about that?
DR.
BRASS: Yes.
DR.
DWYER: So, the answer is like the rabbi
said, yes and no?
DR.
BRASS: Well, it depends. See, for tyrosine, I don't know the answer
after oral tyrosine ingestion. I only
know it for in vitro and organ perfusion. I don't know if oral tyrosine changes catecholamine levels or
not.
DR.
SHANNON: I don't think it does.
DR.
BRASS: I don't know. If it fails, it fails because of the oral
ingestion clause.
DR.
DICKINSON: And because there are other
regulatory steps.
DR.
BRASS: Yes, there are other regulatory
steps but in some cases you can overwhelm those by giving enough, but I don't
know; I don't know.
DR.
BLONZ: Let me add in here. I don't know what would happen with tyrosine
as a supplement, but this is part of the rationale for having high protein
breakfasts and having hefty levels of neurotransmitters during the day, it is
primarily because of the tyrosine composition.
I don't know what the effect would be if you were to take tyrosine on an
empty stomach and whether that would affect neurotransmitters.
DR.
BRASS: As I said, I don't know either.
DR.
BLONZ: It would make a difference as to
what we would decide as to how it fits our definition.
DR.
BRASS: I think the point is the
definition would work because if it didn't, it wouldn't be and if it did, it
would be.
DR.
DWYER: Any other comments on amino
acids? Yes, Dr. Mehendale?
DR.
MEHENDALE: I think there are also
examples with tryptophan. Everyone
knows about the cheese and wine combination, and so on. So, I guess the answer would be yes.
DR.
BRASS: But also for serotonin.
DR.
DWYER: How about substrates, inosine-5
monophosphate?
DR.
BRASS: I just don't know what the
regulation of that pathway is and whether ingesting would change it or
not. I know the pathway, I don't know
the regulation.
DR.
DWYER: Let's get some vitamin
examples. I have been trying to think
of some and I can't. Well, vitamin D,
what do you think, hydroxy--
DR.
BRASS: 125 is a metabolite.
DR.
DICKINSON: But it is also a
prescription drug and so out of balance for this purpose.
DR.
BRASS: Yes, so are catecholamines.
DR.
DWYER: The metabolite would be
what? Vitamin A, retinal?
DR.
DICKINSON: We don't make retinal but
you could go from retinal to some of the vision compounds, rhodopsin.
DR. DWYER: So, rhodopsin would be a metabolite? How about a mineral example just so that we
work through all of them?
DR.
DICKINSON: We have all of a sudden
become ignorant!
DR.
SHANNON: Calcium gluconate. I guess that is organic, isn't it?
DR.
DICKINSON: I mean, I can think of
examples where deficiencies of minerals inhibit things, but I don't know to
what degree extra minerals increase, say, some of the antioxidant enzymes.
DR.
BRASS: I don't know if, you know,
superoxide dismutase is sensitive to copper exposure or magnesium
exposure. I don't know. I can't think of any immediately. Iron and ferritin, ferritin as a metabolite
of iron. There is not a lot of
structural contribution there so it would be hard-pressed to do it. That is, again, where the oral ingestion in
humans came in so that, for example plutonium is not a metabolite of uranium
because you just can't do it.
DR.
DICKINSON: But if you give extra folic
acid and B12 you change red cell synthesis.
I don't know what all the intermediates are there but there are some
metabolites that get created.
DR.
BRASS: It is not a product-precursor
relationship.
DR.
DWYER: Any mineral example? How about herbal, botanical examples or
constituents of those?
DR.
SCHIFF: Let's see, saw palmetto is loaded
with long-chain fatty acids, straight-chain fatty acids and those get chopped
down and metabolized. That would be an
example, I suspect.
DR.
DWYER: I think we are pretty much
toward the end of the end-game. Shall
we just go around the table once more and try to conclude? I know, Dr. Blonz, you had a question.
DR.
BLONZ: Well, I think we have covered
it. That had to do with the
biofunctionality and also with the idea that a metabolite would end up past a
critical control point and might have an undue influence on metabolism whereby
the originating product would not. This
is something that, hopefully, we would deal on the safety side of things, but
it is still a possibility from a biochemical standpoint.
DR.
BRASS: An example of that, again, if
you give methenolone you can increase cholesterol synthesis, unlike if you give
the acetyl CoA precursor.
DR.
BLONZ: Right.
DR.
DWYER: Anyone have any comments on this
for Dr. Blonz, a clarification? If not,
I would just like to go around the table one last time to make sure we have any
other additions or insights on all of this clarified for the record. I would also like to ask the agency to email
us the final disposition of this, rather than just posting it on the web, if it
is okay.
DR.
BRASS: You will see in the
Congressional Record of the proposed rule.
DR.
DWYER: I doubt that, but if it is
possible we would like to see it. Are
there any other issues you wish to have us answer, Dr. Moore?
DR.
MOORE: No.
DR.
DWYER: Fine. Do you have other--
DR.
BRASS: No, I don't. I think the discussion has been good. My final thought would be just to emphasize
the concepts that have been discussed, not the specifics, because I think the
concepts here are what is important, not any errors in word-smithing or
mis-articulation.
DR.
CHILDS: I simply want to mention, as we
had the agency reinforce for us earlier, that safety is outside of the context
of this definition.
DR.
DICKINSON: But safety needs to be
addressed.
DR.
DWYER: It may be outside the context of
the definition but is truly very critical.
DR.
CHILDS: Yes, I agree completely. I was just simply trying to say we have
addressed that. We have focused on it,
and what has been brought to our attention is that that is elsewhere in the definition--not
in the definition, elsewhere in the language.
DR.
DWYER: Dr. Mehendale?
DR.
MEHENDALE: Yes, I also want to
emphasize that the definition, as we have evolved it, is really in addition to
other regulatory areas.
DR.
DWYER: Dr. Blonz?
DR. BLONZ: I think that the definition is very silent
but, again, we are talking about DSHEA and it opens the door and it really puts
the onus on the agency in a post-regulatory environment to be able to police
and check for those substances that may fit the definition of a metabolite but
really might have a dubious place in the marketplace.
DR.
DWYER: Do you have suggestions for how
best to protect the public?
DR.
BLONZ: Well, to my way of thinking the
best way is improved surveillance. I
think they are doing as good a job as their budget will allow them but, given
the surveillance with MedWatch, and so forth, you really do need to keep in
consult with biochemists, toxicologists and so forth, and find out what is
going on and what people are taking. It
is really do the best you can. That is
all I can urge.
DR.
DWYER: Dr. Schiff?
DR.
SCHIFF: I am pleased with the
definition. It is more than I thought
we could do, to be honest with you. It
is functional; it is broad-based; it is moderately cohesive. I think it gives the agency a good base from
which to build.
DR.
DWYER: Dr. Shannon?
DR.
SHANNON: As others have said, I hope
that today was useful to the agency in terms of finding ways to make these
products safer.
DR.
DICKINSON: I share Dr. Schiff's
feeling. I came into this meeting
thinking we might stir around for quite a while and not come up with much, but
I think we have come up with something that is useful and I think it has been a
very productive discussion.
DR.
DWYER: Thank you for a very useful
meeting. I too am concerned about the
issue of surveillance being necessary and the safety issue. I think the resources that are being devoted
to the Middle East rather then the East Coast, and I work on the East Coast and
live on the East Coast--I am a little concerned about the resources available
to the agency to do the safety mandate.
Nevertheless, we have made a lot more progress than I was afraid we were
going to make with a green chairman.
Can I
urge you to fill out the questionnaires that the folks at the University of
Maryland gave us? If you could do it
today and drop it in the box, that would be great. If not, drop it in the box when you get back to your airport.
We will
look forward to getting together probably shortly for yet another session on
these esoteric issues that are of such importance to the country. Dr. Walker, will you end the session?
DR.
WALKER: Yes, I would like to thank you
very much on behalf of our office and the agency. I would like to thank Dr. Dwyer for leading a very interesting
session. I think what has been said
today will be very, very useful for us, and I would like to thank you all for
the time and the interest that you have shown by coming here and joining us in
this discussion. So, thank you all very
much.
[Whereupon,
at 2:25 p.m., the proceedings were adjourned.]
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