IG UNITED STATES DEPARTMENT OF AGRICULTURE
FOOD ADVISORY COMMITTEE
CONTAMINANTS AND NATURAL TOXICANTS SUBCOMMITTEE
Wednesday, December 4, 2002
8:34 a.m.
The Inn and Conference Center
Founders Ballroom
University of Maryland
University College
3501 University Boulevard East
Adelphi, Maryland 20783
P A
R T I C I P A N T
S
MEMBERS
Dr.
Francis Busta, Chairman
Dr.
Henry Kim, Executive Secretary
Dr. Alex
Acholonu
Dr.
Lawrence Fischer
Dr.
Marion Fuller
Dr.
George Gray
Dr. Lawrence
Kuzminski
Dr. Ken
Lee
TEMPORARY
VOTING MEMBERS
Dr.
Goulda Downer
Dr.
Joseph Hotchkiss
Dr.
Thomas Whitaker
C O N T E N T S
AGENDA
ITEM PAGE
Welcome
and Introductions - Dr. Francis Busta,
Chairman,
Contaminants and Natural Toxicants
Subcommittee
(CNTS) 5
Conflict
of Interest Statement - Dr. Henry Kim,
Executive
Secretary, CNTS 8
Opening
Remarks - Joseph A. Levitt, Director,
Center
for Food Safety and Applied Nutrition
(CFSAN) 10
FDA
Action Plan
- Goals and Timetable - Dr. Terry C. Troxell,
CFSAN, Director, Office of Plant and Dairy
Foods and Beverages (OPDFB) 19
- Charge and Questions to the Subcommittee -
Dr. Terry C. Troxell 27
Scientific
Overview of Acrylamide in Foods -
Dr.
Bernard A. Schwetz, Senior Advisor for Science,
FDA 31
FDA
Action Plan
- Major Components of the Action Plan - Dr.
Richard A. Canady, CFSAN, Division of Risk
Assessment, OPDFB 53
FDA
Action Plan
- Toxicology - Dr. Richard A. Canady, CFSAN,
Division of Risk Assessment OPDFB 83
FDA
Action Plan
- Analytical Methods/Occurrence - Dr. Steve
Musser, CFSAN, Division of General
Scientific
Support, Office of Scientific Analysis and
Support 131
C O
N T E N T S (Continued)
AGENDA
ITEM PAGE
FDA
Action Plan
- Formation - Dr. Lauren S. Jackson, CFSAN,
Division of Food Processing and Packaging,
OPDFB 184
FDA
Action Plan
- Consumption/Exposure - Dr. Michael J.
DiNovi,
CFSAN, Division of Biotechnology and GRAS
Notice
Review, Office of Food Additive Safety 222
FDA
Action Plan
- Consumer Risk, Dr. David W. Acheson, CFSAN,
Office of Science 236
Joint
Institute for Food Safety and Applied
Nutrition
(JIFSAN) Workshop, October 28-30,
2002 -
Dr. David R. Lineback, Director, JIFSAN 258
Adjournment 311
P R
O C E E D I N G S
DR. BUSTA: Can we bring this meeting to order,
please? Good morning, everyone, this
morning again. We're pleased that you
are here in full force. According to
the weatherman, I'm glad we didn't start tomorrow because we might not be here
in full force. We have a long agenda,
and we are going to do our best to stay with that agenda.
I would
like to remind each and every one of you--and I'll probably have to do this on
a regular basis--to speak into the microphone, not only to be heard but also
for the recording of your comments.
Again,
welcome to the Subcommittee, and we have a significant challenge that we will
soon hear from Terry Troxell.
I'd like
to have each of the group here introduce themselves, and I'll start off with
Larry Kuzminski and we'll just go around.
DR.
KUZMINSKI: Thank you. Larry Kuzminski from Roxbury,
Massachusetts. I've been retired from
the food-processing industry for three, three and a half years. The postings during that employment tenure
were with Ocean Spray and with the Kellogg Company prior to that.
DR.
WHITAKER: I'm Tom Whitaker. I'm with the USDA, Agricultural Research
Service, in Raleigh, North Carolina.
I'm an agricultural engineer, and my main emphasis of research has to do
with detection of mycotoxins in agricultural products.
DR.
FISCHER: I'm Larry Fischer from
Michigan State University. I direct the
Institute of Environmental Toxicology at Michigan State. I'm an environmental toxicologist.
DR.
FULLER: I'm Marion Fuller. I'm with the Florida Department of Agriculture
and Consumer Services and director of food safety and also a toxicologist.
DR.
LEE: I'm Ken Lee. I chair the Food Science and Technology
Department at the Ohio State University.
DR.
BUSTA: I am Frank Busta. I'm professor emeritus and head of the
Department of Food Science and Nutrition at the University of Minnesota.
DR.
GRAY: I'm George Gray. I'm at the Harvard School of Public Health
and the Harvard Center for Risk Analysis, and my background is in toxicology.
DR.
ACHOLONU: My name is Alex
Acholonu. I'm a professor of biology at
the Alcom State University in Mississippi, president of the Faculty Senate, and
my forte is microbiology and epidemiology.
DR.
HOTCHKISS: I'm Joe Hotchkiss. I'm Chair of the Department of Food Science
at Cornell University and also a food chemist and toxicologist.
DR.
DOWNER: I'm Goulda Downer, president
and CEO of Metroplex Health and Nutrition Services and adjunct professor at
George Washington University.
DR.
BUSTA: We have the FDA representatives
on the back table, and each one of you, we will be seeing you in due order.
If there
is no problem, we'll move on and try and even get a little ahead of the
agenda. Henry Kim will now tell us
about conflict of interest.
DR.
KIM: Thank you, Dr. Busta, and good
morning, everyone. I am Henry Kim, the
Executive Secretary for the Contaminants and Natural Toxicants Subcommittee of
the Food Advisory Committee. First, I
would like to read the appointment of our temporary voting members for the
record. It reads: By the authority granted under the Food
Advisory Committee Charter of July 2002, I appoint Dr. Goulda Downer, Dr.
Joseph Hotchkiss, and Dr. Thomas Whitaker as temporary voting members of the
Contaminants and Natural Toxicants Subcommittee of the Food Advisory Committee
for the December 4-5, 2002, meeting of acrylamide. Signed, Joseph A. Levitt, Director, Center for Food Safety and
Applied Nutrition.
We would
also like to note for the record that Dr. Lawrence Kuzminski is participating
in this meeting as the acting industry representative and a non-voting member
of the Subcommittee.
Second,
the following announcement addresses the issue of conflict of interest with
respect to this meeting and is made a part of the record to preclude even the
appearance of such at this meeting: 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 at issue do not have a unique
impact on any particular product or manufacturer but, rather, may have
widespread implications with respect to foods and their manufacturers.
To
determine if any conflict of interest exists, the committee participants have
been screened for interests in the food industry. As a result of this review, in accordance with 18 U.S.C. Section
208(b)(3), Dr. Francis Busta, Dr. George Gray, and Dr. Joseph Hotchkiss have
been granted a particular matter of general applicability waiver that permits
them to participate fully in the matters at issue. Copies of the waiver statements may be obtained by submitting a
written request to the agency's Freedom of Information Office, Room 12A-30 of
the Parklawn Building.
With
respect to FDA's invited guest speaker, Dr. David Lineback reported that no
conflict of interest exists.
And now I
will turn the meeting back to Dr. Busta.
DR.
BUSTA: Thank you, Henry.
We will
proceed now with opening remarks from Joe Levitt, the director of CFSAN.
MR.
LEVITT: Thank you very much, Mr.
Chairman. It's a pleasure for me to be
here but, more importantly, it's a pleasure for me to welcome each of you, not
just to this meeting but to serving on this Subcommittee, this being the first
meeting of the Subcommittee on Contaminants and Natural Toxicants of our
overall Food Advisory Committee.
As you'll
come to understand better with each meeting, we have restructured our Food
Advisory Committee over the last year so that we have a general, what I think
of as the parent umbrella committee, as well as six subcommittees. The subcommittees tend to be, as permanent
members, small and focused so that we can add and supplement as needed given a
particular issue being raised, and you've already seen some of that today.
We will
be bringing to you a number of important scientific issues for your review, for
your comment and advice, and, as always, we really need your best advice and
will do our best to heed that, and we will strive to make this an integral part
of our workings at CFSAN.
So thank
you for serving and coming to the D.C. area despite the snow warnings, but at
least the transportation from the room to the meeting site is adequate in snow
conditions, so that's good.
Today's
subject, of course, is an important one, the subject of acrylamide. When you think back just a year ago, this
was on nobody's agenda at all. And just
since last spring, think of the number of things that have occurred. There was the announcement and publication
of the Swedish findings last spring.
There was very quickly at WHO expert consultation with experts around
the world, including very strong FDA participation. There have been analytical methods developed. There have been meetings of government
scientists. FDA has drafted an action
plan. We had a public meeting at the
end of September, a JIFSAN research-oriented workshop in October, and this
meeting that we're having today at the beginning of December. So this has been an enormous amount of
activity.
Sometimes,
when you have a lot of activity, I always ask the question: Are we seeing just a lot of motion, or is
there also movement with that motion?
And I think here we've really seen an enormous amount of movement in a
very short period of time when you think of what we know now that we didn't
know six or eight months ago.
I think,
first of all, everybody--there's general agreement that this is an issue that
must be seriously addressed, and I know one person remarked before the meeting
that these kinds of meetings are happening all over the world. Everybody agrees that this is an issue that
we need to address and that it is an important one.
We have
seen good, solid analytical methods developed and utilized that have confirmed
the initial findings. I think when
everybody first heard the first official findings, they were perhaps a little
skeptical. But the methods have been
developed; the findings have been confirmed.
And so that's an important first step.
We know
more about how acrylamide is formed. We
know that it wasn't put in there to begin with. We know that it's formed as a natural part of the cooking
process, and we're trying to understand more about exactly what causes that
formation and what can be done about it.
We've
seen already a number of testing results, some that FDA released at our public
meeting in September, additional results that you'll see released today, as
well as research from other places. We
know and are finding more and more that acrylamide is found in some foods, but
not in others. We know that even where
it is found, there's really enormous variability, even within the same type of
product or the same brand of the product.
So we need a richer database.
Therefore,
we know a lot more testing is needed, and I would just offer one caution. As you look at the data today, you will see
brand names identified with the samples that FDA tested. But we haven't really done enough testing to
know with any measure of precision what to compare with between brands, to know
which brand may be higher or lower than another. That's simply part of the raw data of what we've collected. So it's an area where really a lot more
testing is needed.
We're
finding a lot more research results already.
You'll be hearing--and I'm sure you've already heard--of important
research identifying asparagine as one of the key components of how acrylamide
is formed. You'll hear some important
data today on time of cooking and how the time of cooking may well be related
to how much is formed. These, again,
are important parts of the building blocks.
I think of this as a puzzle to be solved, and each piece of research is
another piece of the puzzle. But we
still have a fair amount of that puzzle yet to be uncovered and
discovered. But when you think back on
a few months, that's an awful lot.
For
consumers, there's still a lot of unknowns.
We know, for example, that acrylamide is an animal carcinogen at high
doses, but we don't know if it's a human carcinogen at the lower doses found in
food. Again, we know there are other
toxicities associated with acrylamide, but its applicability to humans is not
clear. That's why we need more
research.
At this
time, until more is known, we do advise consumers to eat a balanced diet
consisting of a variety of foods that are low in fat and rich in high-fiber
grains, fruits, and vegetables. Today,
what we really want this committee to focus on is the ambitious research agenda
that has been developed. This research
agenda is designed both to assess the risk in people, to understand that much
better, but also to understand how acrylamide is formed and what steps can be
utilized to drive those levels down.
That has got to be our goal.
So as you
listen to the presentations, we would ask you to think of three overriding
questions to see if we really are on the right track:
Number
one, are we addressing the right scientific issues?
Number
two, are there any significant gaps in the research plan that is being
presented to you?
And,
three, have we assigned the right priority to them? Are we doing the right things first so we can put together this
puzzle most effectively and most expeditiously?
I want to
take a moment and thank in advance a large number of FDA staff that you'll be
hearing from today that have put a considerable amount of work in and will
continue in the future, beginning with Dr. Bern Schwetz, the senior science
advisor, who led the U.S. delegation to the WHO consultation and who will
provide an excellent overview; Dr. Terry Troxell, who is director of our Office
of Plant and Dairy Foods and Beverages, what we fondly refer to as "land
food," and this looks like a land-food issue if we saw one; a number of
scientists in Dr. Troxell's division and elsewhere: Dr. Rick Canady, Dr. Lauren Jackson, Dr. Steve Musser, Dr. Mike
DiNovi, as well as our new chief medical officer, Dr. David Acheson, who will
all be making presentations to you today.
I also
want to thank in advance Dr. Dave Lineback, who is director of JIFSAN, for his
leadership in the research workshop that I referenced and for his taking time
later today to share findings from that workshop with the committee.
Finally,
I want to thank Henry Kim, our exec. sec. to the committee, who works hard to
keep everything going.
As a
final note, while the main focus of these meetings is on the scientific
issues--obviously that's why you're here--we also want to be sure that, for
lack of a better phrase, you feel well taken care of in terms of the
facilities, any other logistics. So if
you have issues with that, we welcome feedback. We accept positive feedback, also, should that be suitable. But as we have moved into the College Park
area and we're learning how to have meetings in this area, one of the best
places to stay, one of the best meeting facilities, how do we make these
meetings, we want you to want to come back.
We promise we won't have snow every time. But we do need honest feedback, and we will try to be as
responsive as we can.
With
that, I agree with the Chair. We have a
long agenda. We want to be sure we get
through it. And so I thank you again
for your expertise, for your attention, and your advice on how we can keep this
ball rolling and continue to fill in the pieces of the acrylamide puzzle.
Thank you
very much.
DR.BUSTA: Thank you, Joe.
We will
continue on. The FDA Action Plan, two
sessions, both the goals and timetable and the charge and questions to the
Subcommittee, Dr. Terry Troxell.
DR.
TROXELL: Good morning. I also want to welcome you to the first
meeting of the Subcommittee on Contaminants and Natural Toxicants. I want to thank you for your hard work in
this matter as well as many other issues we will bring to the Subcommittee in
the future.
We are
bringing acrylamide, a very challenging issue, to you as the first issue for
the Subcommittee to consider. The
presence of acrylamide in foods was considered a major concern by the WHO/FAO
consultation in June 2002, and FDA agrees with that conclusion.
Acrylamide
was quite a surprise to food processors, scientists, and public health
officials worldwide when, on April 24th, the Swedish National Food
Administration announced a finding that significant amounts of acrylamide
formed particularly in carbohydrate-rich foods cooked with high-temperature
processes. Formation occurred using
traditional cooking processes, whether prepared commercially or in the home.
What is
surprising is that numerous food scientists who published hundreds of papers
had previously studied the reactions during cooking processes, particularly in
research into chemical-based flavor development, and acrylamide was not
discovered during those investigations.
As you will hear during the presentations today, acrylamide formation is
closely associated with the Maillard reaction that is responsible for flavor in
browning of carbohydrate foods. As
such, acrylamide has likely been present in cooked foods for thousands of
years.
FDA needs
to be able to assess the risk to consumers of acrylamide. Ideally, we need to know the actual risk in
order to make the best decisions to protect the public health. However, there are substantial data gaps
regarding the risk of acrylamide in the food supply. For example, we do not know the bioavailability of acrylamide in
foods versus water where it has been studied.
And we do not know the metabolism of acrylamide in the rat versus
humans, particularly at low levels of exposure. Thus, the uncertainty about risk to human is large.
Ideally,
FDA would want a range of risk management options and would want to understand
the impact of applying various alternatives on acrylamide risk reduction, on
other risks that might be introduced by the alternatives, and the feasibility
of the alternatives. While there has
been a tremendous amount of research in many countries since the Swedish
announcement and there has been some very good progress, particularly on the
mechanism of formation, technological solutions to prevent or minimize
formation of acrylamide are likely to be more difficult than elucidating the
mechanism.
Some risk
management options for acrylamide reduction by telling consumers to not cook
food excessively have the potential to expose consumers to additional risk from
foodborne pathogens. In addition,
because of the wide occurrence or wide variation of acrylamide in foods shown
in the initial results in our exploratory survey, it's clear that more sampling
is needed to describe the distribution of acrylamide in foods.
As a
science-based regulatory agency, the FDA believed it needed to assure that
sufficient science was developed to permit it to make sound risk management
decisions for the public good.
Therefore, FDA developed its action plan for acrylamide in foods. We're bringing it to you today to seek your
expert opinion and comment on the scientific adequacy and completeness. We'll come to the charge more specifically a
little later.
Next
slide, please.
The action
plan is designed around our overall goal, which is through scientific
investigation and risk management decisionmaking to prevent and/or reduce
potential risk of acrylamide in foods to the greatest extent feasible.
The
action plan consists of a number of sub-goals which are intended to ensure that
we have a strong research agenda to provide a sufficient scientific basis to
develop risk management options and public health messages. We'll just briefly run through the sub-goals
as the speakers will address the research goals in depth.
The
sub-goals are: develop rapid screening
methods and validate confirmatory methods of analysis. The second sub-goal is assess the dietary
exposure of U.S. consumers to acrylamide by measuring acrylamide levels in foods. This morning we have provided you with the
results of the levels in foods we have analyzed through November 15th in our
exploratory survey.
Identify
mechanisms responsible for the formation of acrylamide in foods and identify
means to reduce acrylamide exposure.
The primary mechanism is now believed to be known. The major effort in the future will be to
use that knowledge to reduce formation.
The
fourth sub-goal is to assess the potential risks associated at acrylamide by
evaluation of available information and expanding the research into acrylamide
toxicology.
The next
two goals are part of our action plan but are not about the substance of the
research that needs to be done for the most part. The first of these is to develop and foster public-private
partnerships to perform the scientific research. There is intense interest around the world in this issue, and
there is a large amount of work to do.
Therefore, we believe that the quickest and most efficient way to
address this problem is to foster collaboration and coordination of all
research to the extent practical.
As you
will hear this afternoon from Dr. Lineback, the Director of JIFSAN, which is
the Joint Institute for Food Safety and Applied Nutrition, our consortium with
the University of Maryland, JIFSAN has undertaken a major effort to foster that
collaboration and coordination through the WHO/FAO Acrylamide in Food Network
that JIFSAN operates.
The last
sub-goal is to inform and educate consumers and processors about the potential
risks, provide options on how to reduce the risk as knowledge is gained. This is primarily an outreach element, but
we are not going to discuss our consumer message at this meeting. We will be discussing the message with the
Food Advisory Committee at our meeting in late February.
In the
next several slides, I have listed some of the events that have or will occur
to give you a perspective of where we are in the sequence of events and
process.
On April
24th, Sweden announced the finding of acrylamide in foods. At that time, no methods were
available. Therefore, we developed our
own liquid chromatography MS/MS method, which we posted on June 20th on the
website for general use by all researchers.
The
WHO/FAO expert consultation was held only two months after the announcement by
Sweden and provided a sound initial review of the science and the research
needs for acrylamide in food.
On
September 24th, we held a meeting of many federal agencies working on
acrylamide that primarily focused on the toxicology issues.
On
September 30th, we presented this action plan to the public.
October
28th, JIFSAN and our National Center for Food Safety and Technology held a
meeting of scientific experts from around the world to update the status of the
research and then determine the research needs. We have provided you with a copy of the research needs developed
by each work group at the meeting, as well as the Planning Committee's
short-term priority research needs. Dr.
Lineback will address this meeting later today.
We plan
to take this issue, after considering your recommendations, to the full
Advisory Committee in late February.
We're also planning to hold a meeting to determine the status of the
science as of late summer, probably.
Next
slide.
I have
listed here a variety of scientific meetings, clearly not complete, as this
subject will be discussed at many meetings in the next several years. But this Society of Risk Analysis tox forum
and germ cell mutagen risk assessment workshop and so on are just some of those.
In the
next slide, on the international front, in addition to individual country and
EU activities, there are notable international community events. The Codex Committee on Food Additives and
Contaminants is responsible for international food standards for contaminants
and toxicants. We expect acrylamide
will be taken up as new work to develop a position paper which will be used to
determine if the code of practice for maximum levels are appropriate for food
in international trade.
Also, the
WHO/FAO Joint Expert Committee on Food Additives, JECFA, will evaluate
acrylamide. JECFA provides risk
assessment to the CCFAC. JECFA's
determinations are used by many countries in the world as the definitive safety
and risk assessment of food additives and contaminants. Acrylamide has been tentatively scheduled
for the winter-spring of 2004.
Now I
would like to turn to the Subcommittee charge.
You should each have a copy of the charge and questions.
The
Subcommittee is being asked to evaluate whether the research steps outlined in
FDA's Action Plan are scientifically adequate to describe and address the
public health significance of acrylamide in food. In order to support our overall goal, our intention is to build a
strong research agenda that we are asking for your expert advice on. We have the following questions for the
committee:
Based on
what we know about acrylamide toxicology, occurrence, formation, exposure, and
risk, are the research steps appropriate to describe and address the public
health significance of acrylamide in foods?
We have listed three sub-categories of research steps in relation to the
first question relating to occurrence, to exposure, formation, and toxicity.
Our
second question then is: Are there gaps
in the research plan or areas where emphasis should be increased?
The third
question relates to priorities. Besides
gaps and emphasis, we really need to understand if particular items are of
higher priority for research to address.
The next
slide deals with the process. This last
question on priorities is particularly important in order to permit the agency
to make timely decisions informed by sound science. We view the process as an iterative one. We have done the initial hazard assessment
and determined that there is not enough information to develop risk management
options. We are asking you today to
help us complete the data needs identification.
In the
meantime, as you will see, we have begun data development. We will review the state of the science
periodically and use risk assessment as appropriate to determine if there is
another research component that needs to be added, or if we have enough
information to support development of sound risk management alternatives.
Next
slide.
We do not
have a specific timeline for the periodic reviews, but these are among the time
points when we could review the science for decisionmaking. One of those time points would be when there
is a breakthrough in formation research that leads to substantial reduction of
acrylamide levels in foods; when key toxicology data needs are met; at the
FDA-sponsored scientific symposium in the summer of 2003; at the time of the
JECFA evaluation in the winter-spring of 2004; and also in connection with
CCFAC position paper development and possibly development of code of
practice. That will run between 2004
and 2005 and possibly later.
In
summary, as you will see, much has been done in a very short amount of time,
and there is a need to do a great deal more.
At this point in time, we are asking you, the Subcommittee, to evaluate
the scientific foundation of our overall approach. Also, as you will see, you have a very full day, and thank you
very much for your attention and work on this.
DR.
BUSTA: Thank you, Terry.
Are there
any questions of clarification for Terry from the Subcommittee?
[No
response.]
DR.
BUSTA: Well, we're rolling along, very
good timing.
DR.
LEE: Don't worry.
[Laughter.]
DR.
LEE: Don't be too optimistic.
DR.
BUSTA: Always get a little bit of a
lead.
Our next
item on the agenda is the scientific overview of acrylamide in foods by Dr.
Bernard Schwetz.
x DR. SCHWETZ: Good morning to all of you. I will try not to carve into the lead that
has been created. But I also want to
thank you for your willingness to help us with this important issue.
What I
want to do is provide a little bit more background information. Terry referred to a lot that's happened in
the last few months. I want to go back
to the kind of information that we reviewed at the WHO consultation to give you
an idea of what the stage was like at that time as a basis for developing the
plan and for some of the things that have happened in the last few months.
It was
just in April that the Swedes did report finding acrylamide in a wide range of
food, particularly in carbohydrate-rich foods cooked at high temperatures. The results were published in the Journal of
Agricultural and Food Chemistry in July, and that started a lot of activities.
The
Swedish research was prompted by the observation that people without a known
exposure to acrylamide had measurable levels of acrylamide adducts primarily to
hemoglobin, and that triggered the question, of course: Why would they have these adducts to
hemoglobin when we didn't even know they were exposed to acrylamide?
Well,
subsequently, they did further observations in humans, but they also did a
study in rats where they fried rat chow and were able then to measure
acrylamide in that rat chow and were also able to measure the hemoglobin
adducts in the rats. So that gave
further evidence to the fact that high-temperature treatment of feed or food
could contribute to acrylamide and, therefore, measurable adducts on
hemoglobin.
Well,
they proceeded then to measure acrylamide in a variety of foods and looked at
the process of cooking as a means of contributing to the formation of
acrylamide. They certainly suggested
that acrylamide in food was a significant component of the acrylamide exposure
as we knew it, but there was also that concern that it may not account for all
of the hemoglobin adducts that humans carry.
So there could well be exposures other than food, and the uncertainty of
that, of course, led to the need to look harder at what was contributing to
this load of hemoglobin adduct.
I want to
make the point that the formation of acrylamide in food--we have no reason to
believe that this is something that just started in April. It's very likely that that has been going on
as long--we have no idea why it wouldn't have gone on before then. So we have to assume that while the
discovery occurred in April, and the report of it, this is something that's
been going on for a long time.
What is
new is the observation that acrylamide might be present in food from
traditional methods of cooking food, and that gave us a handle of what we
needed to be looking at.
In
response to the Swedish findings, the WHO and FAO convened the expert
consultation on the public health implications of acrylamide in Geneva,
Standard, June 25-27 of this past summer.
There were three of us from the FDA who participated in this group of
some 30 people who were convened to look at this broader issue, and I was one
of those who represented the FDA. So
what I want to do is present you with some of the information that we looked at
and the conclusions that were drawn from that consultation.
As you
might expect, this is not a simple issue.
The fact that acrylamide is present in food and what to do about it and
how to assess the risk is a complicated issue.
And the consultation members were challenged to review and evaluate the
new and existing data and the research on acrylamide relevant to toxicology, to
epidemiology, to exposure assessment, to analytical methodology, the formation,
and bioavailability of acrylamide from cooked food, but also to identify needs
for further information and further studies to help understand this issue, as
well, though, to develop and suggest possible interim advice for governments
and for industry and for consumers relative to the presence of acrylamide in
food.
In order
to do this, we had access to international documents that have been written,
the published literature. We had all of
these documents in front of us in one form or another so that we could review
in detail the information that various countries were looking at to analyze
this problem.
Some
basic facts about acrylamide as we reviewed it. Acrylamide is also something that has been on commerce for many
decades. It isn't a new use in any
sense. It has approved uses as grouting
materials, and it has been used in water purification procedures. Many of us who worked in laboratories are
familiar with polyacrylamide gels in laboratory uses. So there's been a lot of exposure other than food through the
years, and, in fact, some of the known human neurotoxicant situations were from
its use in grouting materials, the application of them.
There
clearly is a contribution to our body burden from cigarette smoke, and that's
another factor that we have to take into account as we consider what would be
consideration of a level that we would try to achieve of human exposure when
you have another significant source of exposure like smoking.
Another
point is that acrylamide and its major metabolite, glycinamide, are both
chemicals of concern because they adduct to DNA and to protein. Glycinamide appears to be particularly
important in creating adducts to DNA.
Just a
comment about the hemoglobin adducts.
While it's convenient to be able to go out and measure these hemoglobin
adducts in people, we have to be careful that we treat these as measures of
exposure, not necessarily measures of risk.
And we go through this a lot in toxicology because you can measure
it. You tend to draw conclusions and
make decisions based on what you can measure.
But we have to be careful to remember that this is probably a good
biomarker of exposure, but whether or not it's a good measure of risk for
individual people or from certain types of exposure is something that we need
to explore in greater detail.
We talked
in this consultation quite a bit about the formation and occurrence of
acrylamide and the fact that it was found in certain foods that were processed
at high temperatures. Carbohydrates,
proteins, amino acids such as asparagine, as well as lipids, the natural
components of food, are all potential precursors to the formation of
acrylamide. The likelihood that there
would be one mechanism of formation is very small. It is more likely that there would be several mechanisms of
formation, each contributing some amount of acrylamide. Increased cooking time or temperature and
low water content seem to be associated with an increased level of formation in
the foods. The acrylamide levels in
food probably reflect formation as well as disappearance of acrylamide, not
just the level of formation in food.
What
about methods of analysis? It was
important to get this group of people because of the new data that came out
from Sweden and the methods that were being used, to get this group to weigh in
on whether or not the analytical methods that were available that led to this
new information coming out were methods that the group was comfortable
with. So we talked about the GC/MS and
the LC/MS/MS methods that were available.
The consultation expressed considerable confidence in these methods, but
recognized that they had not been fully validated, and that validation process
continues today yet. So while we have
methods that people are using, there is a formal process of validation that
we're still going through. And as was
mentioned by Terry, when the FDA had its LC/MS/MS method we were using
internally, we put it on the Web so that everybody would know what method we
were using.
In
addition, Dr. Musser's group has analyzed hundreds of foods, and that's part of
the information that you will be seeing during this meeting.
Regarding
exposures, the consultation prepared an estimate of exposure to acrylamide from
food, but we also noted that there were some pretty significant limitations in
being able to narrow the confidence limits around what that exposure number
might be. It was based on a limited
number of samples, a limited range of foods, and the observation that there
could be a broad range of acrylamide levels in any given type of food. So what you might find in one chip isn't necessarily
representative of what chips in the next bag might be, the next batch. So a lot of variability.
But if
you consider an estimate of a short-term exposure, it was something in the
range of 0.8 microgram per kilogram per day for the average consumer, just
under a microgram per kilogram per day.
Also recognizing that children probably have on a body weight basis a
higher level of exposure than adults, and that becomes a point of consideration
as we worry about what are the things that we should really be concerned about.
Let's
talk about the toxicity and the toxicology just for a minute. Acrylamide is associated with neurotoxicity,
with genotoxicity, carcinogenicity, and fertility effects in laboratory
animals. Regarding the neurotoxic and
fertility effects, the consultation concluded that the amount of acrylamide in
food was not expected to have neurotoxic and reproductive effects, and that was
an important consideration, but obviously it isn't a conclusion that won't be
challenged. And as we develop more
data, we will be looking to see whether or not, in fact, that holds up to be
true.
Remember
that the estimate of human exposure is a microgram per kilogram per day. The NOAEL for the neurotoxic effects in
animals is about 500 micrograms per kilogram per day, a 500-fold margin. The NOAEL for fertility effects is about
2,000 micrograms per kilogram per day.
So those are the comparisons that we were looking at.
But I
should remind you also that the one known human toxic effect of acrylamide is
its neurotoxicity, and that's primarily from occupational exposures.
The group
talked quite a bit about adduct formation.
Both acrylamide and its metabolite, glycinamide, form adducts on
proteins, and I talked about the hemoglobin adducts as a marker of
bioexposure. But acrylamide and
glycinamide also form adducts on DNA, and it's in that context that we worry
about its genotoxic potential and its carcinogenic potential.
Acrylamide
is genotoxic. It induces heritable
damage in germ cells and somatic cells, and high doses of acrylamide induce
tumors at multiple sites in rats and mice.
IARC, the
International Agency for Research on Cancer, has classified acrylamide as a
probable carcinogen to humans.
Epidemiologic studies are limited, but people exposed to acrylamide in
the workplace have not shown evidence of a carcinogenic effect. But the studies are limited because of the
typical problems that you have with epidemiology studies: limited number of people, limited number of
replications of these kinds of observations.
So at
this point, we're faced with the knowledge that it is a rodent carcinogen, and
no evidence of carcinogenicity in humans from the limited epidemiology studies
that have been done.
To put
this in the context of other food carcinogens, food contains a number of other
chemicals that are carcinogenic or mutagenic in laboratory systems. Polycyclic aromatic hydrocarbons,
heterocyclic aromatic amines, natural components of foods, also are known to be
carcinogenic in laboratory models.
One
concern about acrylamide is that the level of human exposure of acrylamide in
food might be higher, probably is higher than some of these other natural
carcinogens that we find in food, and that's one of the reasons we're concerned
about it.
The
consultation reached a conclusion that I think is shared by all of us that the
exposure for such chemicals as a carcinogen in food should generally be as low
as reasonably achievable. So it isn't a
matter of recognizing that it's there and not doing something about it. We all share the goal of trying to reduce
this. But there was pressure during
this meeting to come up with some quantitative estimate of risk, and we
resisted that. And as a group, we did
not come up with any risk number because we all felt that the data did not
support that at that time, and that, in fact, is something that will be
attempted in the future as we have more data about exposure and the toxicity.
Some
specific recommendations that came out of the consultation. In the area of toxicological research,
recommendations that we need to know more about the metabolism of
acrylamide. We need to know more about
acrylamide and glycinamide binding to DNA and proteins in relationship to the
toxicologic profile. We need to know
more about the bioavailability of acrylamide from food. We also need to know more about the non-food
sources of exposure to acrylamide. And
also if there are opportunities for doing cancer epidemiology studies in
humans, we need to be going there. We
need to do the best we can to find these populations. There are populations that have measurable levels of hemoglobin
adducts occupationally in the world.
The possibility that we might do some cancer epidemiology on those
people.
Further
studies to define the carcinogenic and genotoxic potential of glycinamide. There is information on acrylamide,
primarily given in drinking water, but no studies on glycinamide by itself.
Also,
this issue of germ cell damage, the fact that there's a germ cell mutagen in
food is of considerable concern to us, and that's one of the reasons Rick
Canady and others have been exploring a workshop to get the best minds that we
have together to look at that issue and try to decide what risks might be
associated from that standpoint.
From the
question of acrylamide formation, the consultation recommended that there would
be a systematic examination of processing conditions so that we would have a
better handle on what conditions are associated with the formation and then to
optimize the processing conditions to minimize the formation of acrylamide in
the industrial processes, but as well as home.
We can't overlook the fact that we can add acrylamide to our food based
on how we cook it in the kitchen at home.
It isn't just a matter of what the major manufacturers do out in the
plant.
The
recommendation also was that we examine foods from different regions of the
country, of the world, and different diets to find out how exposures to
acrylamide might vary based on different types of diets that people have from
the standpoint of the methods of analysis, the need for inter-laboratory
validation of the analytical methods, and the need to have data from a broad
range of food types. The need to
develop reference materials so that laboratories across the world could all be
working with the same methods operating under the same conditions. And also eventually to develop low-cost and
simple and reproducible methods for routine monitoring of acrylamide in food.
From the
standpoint of exposure, again, to focus on--develop knowledge of food from
different regions of the country and different diets, different regions of the
world, and also continue to look at the use of biomarkers as an index of
exposure and correlate that with what we know about its presence in food.
Another
recommendation was that there would be an international network for sharing
data on acrylamide in food, and Terry made reference to the fact that Dr.
Lineback volunteered that JIFSAN would be a place where that could happen, and
that has moved forward so that the development of that database to collect
information from industry, from academicians, from government agencies, that
all that information would be made available in one database. That is now happening at JIFSAN.
As you
hear about the FDA Action Plan the rest of this meeting, you will see that what
is in the plan is consistent with a number of these recommendations.
Regarding
the last recommendation that the consultation looked at, what do we tell the
public, what do we tell consumers, the recommendation was that food should not
be cooked excessively but should be cooked thoroughly to destroy
pathogens. And the second piece was
that general advice on healthy eating should be followed, to eat a balanced and
varied diet with plenty of fruits and vegetables and moderate consumption of
fried and fatty foods. So this is not
an acrylamide-unique message. It's the
kind of message that people have been giving for some time, but it is good that
if we are going to try to minimize people's exposure to acrylamide, that is
consistent with a healthy diet, as we have been talking about it in other
contexts.
Just a
couple of points to leave you with, to remind you again of the fact that
acrylamide in food is not new. Our
knowledge of its awareness is new, but it's not a new issue in terms of it
being in food. Acrylamide is a
potential human carcinogen based on the laboratory data, but we don't know yet
what risk it poses to humans regarding the carcinogenic risk.
We
certainly are doing a lot of planning.
There are a lot of meetings, as Terry showed. The world has organized to look at this issue, and that was one
of the good things about the consultation.
It brought all of us together very early on to identify how different
groups might look at the data differently and to begin to talk about common
methods of analysis and common interpretations of the data.
So that's
all I will say. I'll be happy to answer
any questions that you might have.
DR.
BUSTA: Are there any questions for Dr.
Schwetz?
DR.
HOTCHKISS: Yes, Joe Hotchkiss. You briefly touched on this, and it's a
consideration that had come up in my own mind, and I wondered if particularly
the consultation explored--to what depth the consultation explored the
relationship between the known tumorigenic and genotoxic pyrolysis products in
foods, the heterocyclic amines and the series you mentioned. And acrylamide, I think you mentioned that
acrylamide is likely to be higher exposure for food, and I think there probably
is sufficient data to agree with that.
On the
other hand, the toxicology would suggest that many of these pyrolysis products
are considerably more toxic, particularly more genotoxic and carcinogenic. And I wonder to what depth that comparison
was explored.
DR.
SCHWETZ: There was minimal discussion
about that whole topic. I provided this
information on the other chemicals just to provide the context, that we do have
a number of foodborne carcinogens, food carcinogens, but that was not a topic
of discussion to talk about the relative risk or the relative toxicity of these
various carcinogens in food at the consultation.
DR.
BUSTA: Are there any other questions
for clarification? Dr. Fischer?
DR.
FISCHER: Larry Fischer. Bern, you mentioned that the estimate was
mentioned of exposure around 0.8 micrograms per kilogram per day. I'm wondering how that was done. Why were you reluctant, in fact, to think
about a risk but you were willing to make a huge guess at what a typical
exposure might be? Can you tell us
about that number?
DR.
SCHWETZ: Well, it was based on the
known food consumption patterns in various populations and an estimate of what
the Swedes and other groups had already analyzed of acrylamide in food. So it clearly was an estimate, and I don't
even known the confidence range around that estimate. But it was based on known patterns of food consumption and what
limited data we had on its presence in certain food types. So it is an extrapolation to really come up
with a number and say that it's 0.8.
DR. FISCHER: This was for our type of diet, right? A Western diet or whatever you want to--
DR.
SCHWETZ: Well, no, it would be in those
parts of the world where there's good information about what people eat. It took those various food patterns into
account. But we did resist going
through a quantitative risk assessment to predict how many people would die
from cancer. So it's a different thing
to take what data you have on what people eat and a limited number of data
points on what's in the food. But to
extrapolate and try to predict how many people would die from their diets, we
didn't want to go there. And we still
don't. That's why we have a research
plan.
DR.
FISCHER: Yes, I understand.
DR.
BUSTA: Alex?
DR.
ACHOLONU: Please, did I hear you say
that children have higher level of exposure to acrylamide than adults? If you said that, why and how does that
occur?
DR.
SCHWETZ: The reality is that on a per
kilogram body weight basis, food intake by a youngster is higher than it is in
an adult. So that by itself contributes
to a higher--if the children are eating foods that have acrylamide in it, just
based on the fact that they eat more food per unit of body weight means that
they would have a higher level of exposure.
The
offsetting question is: Do children eat
food that has acrylamide in it? And
they probably don't as infants. For the
most part, they don't eat potato chips and French fries and some other things
that might have a higher level of acrylamide.
But at some point as youngsters they begin to at a time when they still
have a high level of food consumption per unit of body weight.
DR.
BUSTA: Any other questions?
[No
response.]
DR.
BUSTA: Thank you very much, Dr.
Schwetz.
We'll
move on to the FDA Action Plan, major components of the action plan, Dr.
Richard Canady.
x DR. CANADY: Good morning. I'm a toxicologist with the Center for Food Safety and Applied
Nutrition, and it's my pleasure to walk you through the major components of
FDA's Action Plan for acrylamide in food.
My basic
goal in this presentation is to give you an overall framework for the
presentation that I'm going to follow.
Most of what I'm going to talk about is going to be covered in detail
within individual presentations later today.
But the purpose here right now is to give you an overall idea of the
framework, the overall action plan that FDA has put forward.
Next
slide, please.
This
slide is to help orient you to my particular talk. I'm going to focus on five subject areas, five of the major
components of the action plan. I'll
talk first about testing foods, then move into mechanisms of formation for
acrylamide, our action plan with regard to that; talk then about the toxicology
part of the action plan; move into education; and then finally wrap up with how
the action plan works through meetings and collaborations.
Next
slide, please.
The first
major component I'd like to talk about is testing foods, and within this
component, the first hurdle that FDA needed to cross was developing a method to
test for acrylamide in foods.
Can you
hear me okay now? Is this working? No?
Okay.
[Pause.]
DR.
CANADY: Methods development is usually
a need-specific undertaking. For
example, we need specific methods to answer a specific decision need. With regard to acrylamide in foods, our
current testing need is to establish the scope of occurrence of acrylamide
across foods, and then also to estimate exposure. So within that particular need for a method for analysis, we need
to have, for example, a good level of detection or an adequate level of
detection, and also sufficient throughput to work through the various food
samples that we need to address in order to understand scope of occurrence and
then to understand exposure.
As we
move into other decision needs, the method of analysis may change. For example, as we move into monitoring
needs or into enforcement needs, we may need to develop additional
methods. But the main point here is that
we've developed a method that is designed to address our current needs, and as
we move forward with the action plan, we may need to move into additional
methods development.
Next
slide, please.
So the
second aspect I want to talk about with regard to testing is testing for
occurrence. In a minute, I'll talk about exposure, testing for exposure, but
the point about talking about occurrence first is that we need basic
information about the scope of occurrence before we can move into testing for
design to understand exposure.
Another
way of thinking about is that we need to test for occurrence to understand if
we're, for example, missing the big picture.
We need to understand all of the foods or at least have a fairly good
idea of the range of foods in which acrylamide occurs before we can move to the
next step of understanding how to estimate exposure.
Another
aspect of testing for occurrence is we need to also understand, for example,
how many samples we would require in order to understand an estimate--or get an
estimate of average for a given food or a given brand, a given exposure group,
a given demographic group, for example.
So we need to have an understanding of occurrence and an understanding
of variability of occurrence before we can move on to estimating exposure.
There are
three stages to determining scope.
First is that we need to confirm occurrence in U.S. foods, and this is
something we've already accomplished, obviously. Second is, again, we need to map occurrence across foods to
inform both formation research. Knowing
that it occurs in one food and not in another food helps you understand
something about the formation mechanisms, or at least the processes that lead
to formation.
Then
after we've described the range of occurrence across foods and understand
something about where it occurs and where it doesn't occur, we would then move
into describing the variation within a food, for example, or within a class of
foods.
Next
slide, please.
As we
develop sufficient understanding of the occurrence, the scope of occurrence,
including its variability, the next stage again is that we move to exposure
evaluation. So the next stage of
testing would be used to determine what we need to know in order to understand
exposure. There's two aspects that we
would use this. First is in risk
characterization--this exposure information.
First is in risk characterization so that we can understand the decision
context we're in with regard to regulatory options or doing something about
acrylamide in food. And the second is
to monitor changes over time. We want
to be able to see, for example, if our actions or any circumstance, actually,
is leading to a decrease in the exposure to acrylamide through food. So we have an intention to look periodically
or look continuously at acrylamide levels in food to understand exposure over
time.
Next
slide, please.
We'll
essentially use all available data that we can to understand exposure, but
there's going to be primarily several breakdowns of that exposure or that
occurrence information. We're going to
use our exploratory survey data, obviously.
We're also going to use information from FDA's Total Diet Study. And, again, I want to emphasize there's
going to be more detailed presentations of this information later.
So we'll
use exploratory survey data. We'll use
Total Diet Study information. We'll use
other information as appropriate to understand the variability and the
occurrence of acrylamide in foods.
Given
some of the information you've heard already this morning, we're also quite
interested in understanding other sources of exposure or just generally
understanding exposure to acrylamide from all sources of exposure.
To
accomplish that, one of the things that we're working towards is collaboration
with the Centers for Disease Control, the National Center for Environmental
Health down in Atlanta, and through that what we intend to do are two basic
things: one is look at NHANES, which is
the National Human--I always forget this acronym because it's not exactly what
the letters are, but it's Human Health and Nutrition Exposure Survey. You all know it so I don't need to actually
say it.
We'll be
working through NHANES, but then we'll also be working through specific focused
population studies prior to NHANES because, as most of you know, if you know
how to spell out the acronym, you also know that it takes a long time to get
the information out of NHANES because it is a large population-based survey and
requires a lot of front work.
Next
slide, please.
I wanted
to give you an idea of the level of sampling that we are currently undertaking
and that we're considering for the future.
Within our initial exploratory survey, we originally thought of looking
at around 600 samples, and we're in the middle of that exploratory survey. We're going to, as needed, develop more
sampling or plan to look at different foods, extend our sampling for specific
foods and so on.
We also
heard recently that around 4,000 or so results are soon to become
available. Now, these results come from
a variety of sources. They may consider
pre-processing results as well as post-processing results, pre-cooking and
post-cooking results. But that
information should be useful, again, in helping us understand exposure.
Again, we
also will be looking at Total Diet Study samples over the next year, and then
continuously after that as needed. We
plan on a basic level of sampling of around a thousand samples a year from the
Total Diet Study. And these are samples
that come from across the country in a rather regimented way.
Next
slide, please.
I want to
stress that FDA's approach to sampling is necessarily an iterative
process. It's iterative in the sense
that what we know today influences what we need to sample, and our decisions
needs today also influence what we need to sample. Again, seven months ago, we didn't even understand that
acrylamide occurred in foods. We had an
initial understanding of some of the foods it occurred in after the Swedes
published their results. We used that
information to decide how to sample for the first iteration. That's our exploratory survey. We also considered information like food
chemistry, food processing techniques and so on, in order to understand where
to sample. And we considered
information with regard to consumption rates, again, to understand where to
sample.
That first
iterative process we're still in the middle of, but once we've collected that
information, we will then understand how to go to the next step. I just want to stress that this is, again, a
process of understanding where we are, figuring out where we need to go. It's an iterative process.
Next
slide, please.
When you
think of iterative processes, you need to have a little bit of an understanding
of where you're going to stop the current iteration, and we have obviously some
understanding of where we would like to stop.
Putting it into specific terms is a little bit hard to do. It is, again, a point of understanding where
you are and then figuring out where you need to go.
With
regard to the scope of occurrence across foods, one of the scope definition
points is really just a sampling to a point of diminishing returns. As we get to a point of understanding that
we've looked across the different food categories adequately and we're not
seeing any more new samples where we see detectable acrylamide, we'll have an
understanding that we're coming to a definition endpoint.
With
regard to variability, the key issue here is being able to confidently estimate
differences between foods or differences between brands or differences between
sources and so on. So that definition
is going to have a little bit more of a statistical basis in the sense that we
need to be able to confidently estimate the need.
Next
slide, please. I don't want to get too
far out of my notes here.
With
regard to formation, this is the second major component of FDA's plan that I'd
like to talk about. What we're
attempting to accomplish here, again, is an understanding of how acrylamide is
formed and then through that understanding hopefully develop methods to prevent
or reduce formation of acrylamide. One
thing to keep in mind, though, is we want to have a reasonable assurance that
our actions result in an overall reduction of potential risk, an overall
reduction of net risk, so that we through our actions don't engender new risk,
don't create new risk through changes to how foods are cooked, for example,
through changes to nutritional content and so on. This is something that Dr. Acheson is going to speak to in a
little more detail later in today's presentations.
Formation
research has two sort of natural divisions or components to it. One is process evaluation, how the foods are
cooked, how they're prepared. And the
second is chemistry evaluation. What
are the actual chemical mechanisms through which acrylamide might be formed?
Next
slide, please.
FDA's
Action Plan with regard to formation uses leveraging to a fair degree in order
to take advantage of the substantial interest and the substantial research
that's out there right now with regard to acrylamide formation. We're working through our National Center
for Food Safety and Technology in Chicago, investigating mechanisms of
formation, primarily through processing evaluation. And Dr. Lauren Jackson will be talking about that later today.
FDA is
also working through the Joint Institute for Food Safety and Applied Nutrition
as a way of leveraging out to a lot of the food chemistry knowledge and also
food processing knowledge with regard to the formation of acrylamide in
foods. Both consortia provide conduits
to and participation with academic institutions, other government bodies, and
industry research.
Next
slide, please.
The third
major component of FDA's Action Plan is evaluation of toxicology, and I have
the pleasure of helping you understand that particular component later on this
morning--actually, the next talk.
Within this component, the overall goal is to examine the likelihood
that adverse events or adverse health effects are caused by exposure to
acrylamide through food. There's three
major sub-components here. First is
identifying the gaps in our understanding.
We need to understand what we don't know before we move forward with
determining the overall risk. We need
to ask basic questions: Do we have
enough information? Do we know all of
the endpoints that we need to consider and so on?
The
second is prioritization of these data needs and these data gaps according to
our decision needs, in this case in terms of our risk characterization
needs. We don't want to do research
just for research's sake. We want to do
research that allows us to understand the risks better.
And the
third component is that FDA will sponsor, coordinate, and in other ways
encourage research in order to accomplish these goals for toxicology.
Next
slide, please.
The
fourth major component of FDA's Action Plan is the very important aspect of
education. FDA intends to develop
educational material to inform and educate both consumers and industry with
regard to the initial risks, and as knowledge is gained, we would like to be
able to provide options as to how to reduce the risk. In providing this information and working with stakeholders--in
providing this information, rather, we intend to work with stakeholders in
developing the messages. So it's not
just going to be solely an FDA-directed enterprise. We will work with stakeholders in developing these messages.
Next
slide, please.
The fifth
major component I'd like to focus on--and this is a component that will not be
focused on in detail through other presentations, although you've already heard
about this through a couple of the presentations, and there will be individual
mentions of collaborations and so on in subsequent presentations. But that's meetings and collaborations. There's intense interest out there and
intense participation at this point with regard to research for acrylamide in
foods. This intense interest has
obvious positive aspects in the sense that there's a lot of new information
coming out. But it has a challenge in
it as well, and that is that we have the potential of what in computing is
called a massively parallel computing situation where what we have is a lot of
information that could be coming from a lot of different sources. The challenge to us is to try to channel
that information and coordinate that information so we can get the most
progress within the shortest amount of time.
And so
meetings and collaborations come to be a quite important component of FDA's
overall plan, and there's four general categories that I would place before
us. First is data needs meetings. We've had a fair number of those
already. We had four or five of those
already, and where we try to understand what we know and what we need to know.
The
second quite important one that WHO/FAO came up with or had as one of the
outputs of the meeting back in June was that we need a centralized location for
understanding--or for sharing research projects and understanding about
acrylamide in foods. The WHO/FAO has
developed the food--or, rather, JIFSAN working for WHO/FAO has developed a food
acrylamide information network, and the intention of this is to allow sharing
of information across organizations, again, to help encourage a massively
parallel computing approach that we get the most done in the least amount of
time.
We also
have interagency working groups, and this is within the U.S., obviously, where
we are trying to coordinate--first of all, understand what research is going on
among the different agencies, and then coordinate that research to the best
advantage. And, again, we have
consortia that we're working through to leverage both through academic,
industry, and other stakeholders with regard to research needs.
Next
slide, please.
This is a
long, detailed slide. The message
really is the amount of text on here, not each individual text. You've seen this list already with Dr.
Troxell's presentation. The intention
here is to show that there's a lot of meetings and collaborations going on where
we are attempting to and making progress at coordinating and encouraging research.
Next
slide, please.
So, to
sum up, for food testing FDA has initiated an exploratory survey and is moving
into exposure assessment as scope and variation become better understood. For formation research, FDA, JIFSAN, and
NCSFT are working with industry, academia, other national governments, of
course, to look into how acrylamide is formed and try to develop an
understanding of how it is that we can prevent or reduce, as feasible,
formation of acrylamide in foods.
In
toxicology, we're seeking an improved understanding of the potential risks for
acrylamide exposures through food, starting with an understanding of the data
gaps, and then moving into sponsoring and coordinating research. Again, the goal there is to help understand
the risk, not to just do research for research's sake.
For
education, we will pass knowledge on to stakeholders as it's gained and
determine messages with their input, with stakeholders' input. And, again, given the worldwide scope of
interest for this food acrylamide issue, I think Joe Levitt mentioned earlier
that there's meetings like this going on all over the world right now. That's been noted several times. We have an opportunity to try to
collaborate, try to coordinate that research to our best advantage.
Thanks
very much.
DR.
BUSTA: Thank you.
Are there
questions for clarification for Dr. Canady?
Dr. Downer?
DR.
DOWNER: Goulda Downer. You talked about the FDA Total Diet Study,
and I suspect I'll hear more about it from other presenters. And you also mentioned the variability
across foods and within food types. Are
you also looking at combination of foods since we tend to eat a combination of
foods and not just one food or food group?
DR.
CANADY: Yes, that's an important part
of the exposure assessment, and it's one of the reasons why the estimates that
were developed by WHO/FAO were a preliminary range of magnitude, order of
magnitude estimates and so on. Because
you're right, for different subpopulations particularly, and even within the
general population, the combination of foods, when you eat particular foods,
what combination you eat them in, will have an important effect on the
variability of intake, at least the daily and the temporary variability of
intakes. So, yes, that's a quite
important part of the exposure assessment.
DR.
BUSTA: Dr. Hotchkiss?
DR.
HOTCHKISS: Yes, Joe Hotchkiss. You've quite appropriately recognized the
importance early on of exposure. I
wonder if you could just clarify something for me. You mentioned NHANES and a couple other databases you said you've
used, and maybe this is included in it, but the most powerful dietary
assessment or exposure data that I know of is used, for example, by EPA for
pesticide exposure. It's available commercially
in the private sector through TAS and other organizations, basically the same
database, which is in part based on NHANES as well as the USDA surveys.
As a
matter of fact, I think that database is, at least in my personal experience,
the most commonly used database on petitions submitted to FDA for food
additives and stuff.
DR.
CANADY: Right.
DR.
HOTCHKISS: You didn't mention that one
specifically, and I wondered if there was a reason for that.
DR.
CANADY: No, there isn't a reason for
that--well, the reason is that I didn't get into that detail. The reason for bringing up the NHANES survey
and working with CDC is to capture the total exposure or, rather, to use this
advantage we have in a biomarker of exposure through adducts to hemoglobin to
our advantage. We will, of course, use
the USDA's database and software packages that combine various consumption data
in order to provide the exposure estimate.
And, you
know, Dr. DiNovi is going to talk about that in some detail. And, again, I didn't mention it simply
because I didn't get into the detail of the exposure assessment. It's not something that we're not going to
use this time for some reason or another.
DR.
BUSTA: Are there other questions for
clarification?
[No
response.]
DR.
BUSTA: I have one on an iterative
approach to testing. What activity will
be utilized to keep the consistencies of value of the earlier data as you
develop new and different types of methods?
DR.
CANADY: That's an important question
because, as you first cast about, not knowing where all it's occurring, you may
not design your sampling to match what you need to sample later on. So the utility of the earlier data and the
degree to which you could mix it in with later data is an important part of the
overall sampling. And that's one reason
that for our initial approach we chose to try to survey across foods and try to
understand where it occurred and not try to initially, for example, develop an
exhaustive and statistically based sampling for each food, because we really
didn't know enough about the variability to design that kind of sampling.
But
you're absolutely right. Some of the
information we have collected initially may turn out to be not as useful for
the exposure assessment as data collected later where we have a better
understanding of what is needed in terms of statistical design.
DR.
BUSTA: Yes, George?
DR.
GRAY: George Gray. I'd actually like to follow up on that
question a little bit. It's thinking
about the huge potential task that is out there to identify and to characterize
the variation in the levels of acrylamide that might be in foods. And one of the things that struck me in your
presentation is one of the things I think FDA wants to think about is matching
the data that are available on consumption to the sampling data.
For
example, you mentioned something about taking the time to characterize the
distribution, the variability of acrylamide across brands. It seems to me that doesn't make much sense
given that our data are on consumption of foods, not brands of foods. So sort of thinking backwards from the
information you have to get to a place where you can design your sampling
strategy--this is probably going to be talked about in the exposure assessment
section. But think backwards from what
you have so that you don't get more detailed information in one area than you
have to match up within another.
DR.
CANADY: Yes, and this relates obviously
to the earlier question as well. It
speaks to the need within our current exploratory survey to address two goals. One is to inform the formation research, and
the other is to help us understand where to sample for exposure.
So, for
example, sampling across brands was important in the sense that it could have
provided information with regard to processing or ingredients and so on with
regard to formation research. But
you're absolutely right. When we go to
exposure assessment, that cross-producer or cross-food type information will
need to be generated as it applies to the exposure assessment, not as it
applies to differences between foods.
DR.
GRAY: And you probably need fewer
samples to characterize that variability.
DR.
CANADY: Yes. So, for example, you would focus on getting a weighted average
based on consumption to some degree, or you would use information in a way that
informed you on that aspect, right.
But, again, we had a dual need initially with our exploratory
survey. One was to try to scope out
what we needed to understand for exposure, but then we also at the same time
needed to understand where it occurred to understand formation--to help inform
formation, rather.
DR.
BUSTA: Other questions for
clarification? Dr. Fischer?
DR.
FISCHER: Larry Fischer. I had this thought, and I'm not sure you can
answer the question. But I imagine the
food industry will shortly, if they're not already, be working very hard to
learn how to produce food that is low in acrylamide, and certainly there are
going to be products advertised with the acrylamide content.
I'm
wondering whether the Food and Drug Administration has any way to get
information from the industry on how they are lowering the acrylamide levels in
their products, which would give very good clues as to how we can solve the
problem. So, in other words, I think we
ought to work--we said we're going to work on how we can lower the levels in
food, but is there a way when industry is working on this that this information
can be made public so that it can be used at home? Because there are two ways to produce acrylamide: either buy it or produce it at home.
DR.
BUSTA: Can you answer that one?
DR.
CANADY: Well, probably not, but I'll
make an attempt.
[Laughter.]
DR.
CANADY: This is why when we talk about
education, we talk about both consumers and processors, processing
industry. We recognize the need to
share information across both groups, and we recognize also that this is a
traditional--a product of traditional cooking, so that education across
consumers is important. And I notice
somebody is walking up behind me.
DR.
TROXELL: I would just add that the
International Acrylamide Food Network, Information Network, is designed to
provide, to facilitate the sharing of information from all stakeholders,
including industry. And, you know, from
my discussions with the food processors, they're extremely interested in
working very hard to find ways to reduce levels, and they're committed to
releasing that information as soon as they have something that's concrete so
that everybody can share in that achievement.
DR.
BUSTA: That was Dr. Troxell.
Dr.
Kuzminski?
DR.
KUZMINSKI: Thank you. Larry Kuzminski. I would like to come at the same question that Dr. Fischer asked,
but from a different angle, perhaps. I
think it was partially answered by Dr. Troxell's comments, but the question
that I had in the same direction was:
Can you give us some more detail about the nature of the consortia that
you are establishing with your various partners in the research on the
formation of acrylamide?
DR.
CANADY: There's two speakers that are
going to speak to that in a little more detail. One is Dr. Lauren Jackson, who is at the National Center--at FDA
within the National Center for Food Safety and Toxicology in Chicago. The other is Dr. Dave Lineback who's going
to speak later on today. So a specific
discussion of how the consortia work I think is maybe better served through
those detailed discussions.
DR.
BUSTA: Dr. Acholonu?
DR.
ACHOLONU: Yes. You spoke about the need for the FDA to
develop education material on acrylamide.
What do you think is the appropriate time for doing this? At this stage or later on when we get more
information on it?
Then the
next question is: Under the rubric of
education, you seem to be advising that people eat balanced diets. Will eating a balanced diet reduce the
intake of acrylamide? Why did you give
that as an advice, to eat a balance diet?
DR.
CANADY: Does anybody else want to
handle this?
[No
response.]
DR.
CANADY: Well, with regard to the
question of when we provide educational information, we provide it when--we
would provide it when we have enough information to help consumers understand
the risk. One of the things we've
discovered recently, for example, is that there's a tremendous amount of
variation across products, within the product class. This is something that Dr. Musser is going to talk about in some
detail.
That
helps us understand that processing--or cooking, traditional cooking, is quite
important in the formation of acrylamide.
There may be other factors involved.
The point is we don't want to go out too soon with information that
provides partial or perhaps misleading information in response to the
situation. So it's important to go out
with information that has an intended effect of reducing the exposure to acrylamide,
and prior to providing that education, we need to feel fairly confident that we
have an understanding of the process.
We need
to provide educational information as we understand it enough to understand the
effects of the information, and Terry is going to give a little more in
response to that. Maybe you can answer
the second one, too.
DR.
TROXELL: I was just going to say Dr.
Acheson is going to talk about the multiple factors involved to be considered
on this issue later on. So we'll be
getting more of that kind of information then.
DR.
BUSTA: Joe, if this is urgent?
DR.
HOTCHKISS: A response.
DR.
BUSTA: Okay. Go ahead.
DR.
HOTCHKISS: Yes, Joe Hotchkiss. I just want to recommend, being a veteran of
mycotoxins and nitrosamines and a whole variety of things, and the IQs and all
of this, that my recommendation, this is the time to go to the consumer. I think the consumer is less concerned that
you know all the information but, rather, the consumer's concern that you're
concerned and you're taking action. And
that's what I think the consumer would like to know posthaste.
DR.
CANADY: Thank you very much.
DR.
BUSTA: That sounds like he's starting
his comments for tomorrow.
DR.
CANADY: Right.
[Laughter.]
DR.
BUSTA: With that, thank you very
much. We will take a 15-minute break,
and we used up our time already. We
will start promptly at 10:20.
[Recess.]
DR.
BUSTA: Let us reconvene, please. We now have the opportunity to hear from Dr.
Canady again. Am I pronouncing your
name correctly?
x DR. CANADY: Yes, you are.
DR.
BUSTA: The FDA Action Plan toxicology.
DR.
CANADY: First I want to make sure
everyone can hear me. Lauren, Dr.
Jackson, can you hear me? You can hear
me. Could I have somebody running the
slides?
[Pause.]
DR.
BUSTA: The technology event should
really have occurred under analytical methods rather than toxicology.
DR.
GRAY: Nothing ever goes wrong under
toxicology.
DR.
BUSTA: Right.
DR.
CANADY: Although we're bringing a lot
of advanced technology to bear on toxicology.
DR.
CANADY: Well, you know me already. Let's got to the next slide.
My goal
in this talk is to go through the toxicology component of FDA's Action
Plan. The overall goal of the
toxicology component is to examine the likelihood that adverse health effects
are caused by acrylamide-containing food, by exposure through
acrylamide-containing foods. I guess I
don't need this in my face. Next slide.
Before I
get into the details of the toxicology component of FDA's plan, I'd like to
provide a little context. And the
context, as Dr. Schwetz and Joe Levitt referred to earlier this morning, is
that this is not a new contaminant; this is not a new chemical under
consideration. There has been nearly 30
years, or perhaps more, of toxicology research with regard to acrylamide, and there
have been a number of individual safety risk assessments that have been done
over the years for different routes of exposure, different kinds of exposure to
acrylamide. And some of those are
listed up here with regard to past assessments.
What has
changed--and you've heard this already, but I'll say it again. What has changed is how we're exposed to
acrylamide. We're exposed through food. We thought we were exposed through
occupational exposures and, you know, to some degree through water exposure
previously. But we know we're exposed
through food now.
The
second thing is that the duration of exposure and the length--or, rather, the
length of exposure and the consistency of exposure is different than we thought
it was before. So we get exposure through
a wide variety of foods, and we get exposure probably most of our life, if not
all of our life, to acrylamide. This is
a new understanding that we have that influences our need for toxicology
information and how we develop that information.
Next slide,
please.
I'm going
to talk a little bit about data gap evaluations. Again, you've seen some of this information before. The point I want to make is that data gap
evaluations have gone on. I'm going to
talk about some of the data gaps and some of the data needs that we've
identified. The data needs that I will
talk about should not be construed as the essential data needs, rather, as
critical to progress with regard to describing risk characterization. However, I'm giving them as a way of helping
you understand where the major areas of uncertainty are with regard to risk
characterization through toxicology research.
Next
slide, please.
Here's
the outline of what I'm going to present.
I'm going to start off with a discussion of toxicokinetics. Then I'm going to go into three areas of
toxicology: first, carcinogenicity;
second, neurotoxicology; and then, third, reproductive and developmental
effects.
Information
that's not on this slide is that for each of the three in the middle, there
should be a phrase "at high dose" injected. Our understanding with regard to these three endpoints or these
three areas of toxicology--as is fairly often the case for risk assessment, but
certainly true for acrylamide--comes from information from high-dose exposures,
and it's more so with some of the endpoints than others.
Then the
last point I want to talk about, the last aspect that I want to cover under the
rubric of toxicology, is safety risk assessment, what's been done, where we are
within the risk assessment paradigm at this point for acrylamide.
Next
slide, please.
One very
important aspect of the toxicology for acrylamide, as is the case for every
time we look at toxicology, is the toxicokinetics. Easy for me to say. What
we do know is that it's absorbed orally.
We don't know the degree of absorption from food, and the reason we
don't know the degree of absorption from food is that most of our understanding
for toxicokinetics and for toxicology comes from exposures through drinking
water. We do know that acrylamide is
distributed widely throughout the body, and it's a fairly uniform
distribution. There are some areas that
have higher levels than others at different developmental stages, for example,
and also within organs in the body.
But, generally, it has a fairly uniform distribution.
Metabolism
has been studied and is to some degree fairly well understood for doses above
1,000 micrograms per kilogram a day.
And throughout this presentation, I'm going to keep the units equivalent
so that whenever I give you a number with regard to a risk value, it's going to
be in this unit of micrograms per kilogram of body weight per day.
We know
that acrylamide undergoes a saturable metabolism to glycinamide through a
specific cytochrome P450, CYP2E1. That conversion
to glycinamide, again, is saturable, and it's something we have some fair
amount of understanding about. It's
also conjugated through glutathione. So
right away, for those of you who understand susceptibility and so on,
understanding polymorphisms for 2E1 and understanding polymorphisms for
glutathione S transferase are fairly important things in understanding
susceptibility variation across populations.
We do
know that acrylamide elimination occurs rather rapidly. Acrylamide elimination occurs rather rapidly
on the order of hours to days. The
thing to keep in mind with regard to this, though, is that it also forms stable
adducts, with protein particularly and with DNA. Those adducts can stay around for the life of the protein;
hemoglobin, for example, through the life of the red blood cells. So adducts remain in the body following
exposure to acrylamide.
Another
important aspect--now, I'll get into this more with regard to neurotoxicity--is
that the duration of exposure affects the level that's effective for
neurotoxicity. A fairly well-studied
phenomenon, and we have a fair amount of understanding with regard to it.
Next
slide, please.
Toxicokinetics
data needs are really some of the most critical since this kind of information
is going to allow us to bridge the gap between high-dose exposures that occur
in animals and the much lower doses that occur through food exposures. So it's one thing that we really want to
have an understanding of as it applies to all the other areas of toxicology.
Some of
the data needs, as Dr. Schwetz mentioned this morning, include bioavailability
of acrylamide through food. We need to
understand just generally dose response with regard to toxicity, disposition in
the body, binding to various macromolecules.
In DNA and in hemoglobin, adduct relationships we understand, in other
words, some more detail about the mechanisms of some of the toxicities and how
that relates to external measures of exposure or to biomarkers of
exposure. And then we need to understand
obviously toxicokinetics within humans to the degree that we can and relate
that to toxicokinetics and animal data that we have some abundance of.
Next
slide, please.
Our plans
for toxicokinetic research include these three major--or, rather, plans for
toxicokinetic research, and again, I want to stress that there's a lot of
interest out there with regard to making progress in understanding the toxicity
of acrylamide through foods so that we're drawing from a lot of different areas
for the information.
The FDA's
National Center for Toxicology Research, as I'll talk about in some detail
later, has nominated acrylamide and its metabolite glycinamide to a National
Toxicology Program. As part of the
studies that are being developed for that long-term study, NCTR is looking into
protein adduct relationships and DNA adduct relationships as they inform both
exposure and toxicity. NCTR is also
going to be looking at bioavailability.
Again, it's a key component of our understanding of--or, rather, our
bridging of the animal data to the food data.
Again, the animal data come largely from drinking water exposures, and,
of course, we're exposed through food.
CDC's
National Center for Environmental Health is also, as I mentioned earlier,
getting involved in terms of understanding the relationship between biomarkers
of exposure and then potentially biomarkers of effect.
Again,
within the context of ongoing research, the acrylamide monomer industry has
been interested in the toxicology of acrylamide, you know, as you might expect,
for quite a long time. So there's
information, ongoing research with regard to toxicokinetics for acrylamide
through that large body of research.
Next
slide, please.
I want to
talk about cancer, what we know about cancer with regard to exposures to
acrylamide. It's pretty clear that
acrylamide causes cancer in animals.
There's two bioassays that provide information, two long-term bioassays
that provide information, and a number of individual mechanistic studies that
provide information. What we don't know
is whether acrylamide causes cancer in humans at the very low doses we see
through foods. The information with
regard to animal bioassays is pretty clear.
It shows that it does occur.
Information with regard to epidemiology doesn't give us information one
way or the other, doesn't give us stronger weight of evidence or weaker weight
of evidence for carcinogenicity in humans.
And this is largely due to the power issues with regard to those studies. There's really only a couple of studies that
have looked for this endpoint, and they did not have enough power.
Can you
hear me with the competing noise?
Okay. What do I need to do? I should close the door. Actually, it doesn't close. I'll just try to get this closer to my--is
that better? I feel like I'm blowing
away the front audience and not reaching the back.
So,
again, with regard to carcinogenicity, we have information from animals, but
the information from epidemiology doesn't help us out at this point. However, I do want to stress that every
health body and government organization that has looked at the weight of
evidence for cancer for acrylamide comes to the conclusion that it's a major
concern.
Next
slide, please.
I want to
point out two areas of data needs for carcinogenicity research. The first has to do with new studies. As I mentioned, FDA has nominated acrylamide
and its metabolite glycinamide to the National Toxicology Program. That nomination is being decided. We expect it to go forward.
We also
need, in addition to that, animal bioassay information which would bring to
bear advances in our understanding of biomarkers and potentially bring to bear
techniques that could allow us to understand low-dose extrapolations better,
biomarkers of effect, biomarkers of exposure, and so on.
In
addition to that, if possible, epidemiology information would, of course, be
very useful. It's not likely we're
going to find populations that are occupationally highly exposed to acrylamide
at this point, at least within the U.S.
So it's not clear whether we can move forward with regard to
epidemiology at this point. But if
those populations could be identified in some way, that information would obviously
be useful.
There's
two areas of research with regard to existing information that may help us make
progress in the shorter term. As I
mentioned, there are existing bioassays out there, animal bioassays out
there. Looking back over that information
using more recent diagnostic criteria may help us understand a little bit more
about the dose response. And, also,
because in those bioassays thyroid tumors were identified and we have a fairly
well-developed process for understanding thyroid tumors, evaluation of that
endpoint through IARC protocols or through recent EPA protocols would be a way
of understanding that endpoint a little better and applying that information to
the human situation.
Next
slide, please.
Our study
plans, again, include nomination to the NTP.
I mentioned this a few times. I
won't go into it in any detail. FDA,
Center for Food Safety and Applied Nutrition, is going to participate fully
within the development of those plans.
Next
slide, please.
The
mechanistic studies, again, are an important part of that study because they
allow us, again, to extrapolate down to the low doses we expect through
food. As with all bioassays, we're
going to have to use fairly high doses, obviously, within the shorter lifetime
of the animals to understand the tumor response. Understanding the toxicokinetics running from the milligram per
kilogram dose range to the microgram per kilogram dose range is obviously
essential to making decisions for food exposures. And we have tools through the biomarkers--we've already made
progress with regard to DNA adducts, for example. We have tools that could allow us to bridge that gap and may help
us make less uncertain determinations of the risk at low dose.
Next
slide, please.
Neurotoxicity. As Dr. Schwetz mentioned earlier today,
neurotoxicity is a known effect of acrylamide exposures. It's known for exposures through
occupational settings. Dr. Schwetz
mentioned grout applications. There's
also been other industrial applications where this endpoint has been
studied. We don't know whether
acrylamide neurotoxicity happens through food exposures.
The
exposures that caused it in humans were quite a bit higher than those that we
see through food. This is one of the
reasons that the WHO/FAO consultation came to the conclusion that focusing on
carcinogenicity and germ cell toxicity was an appropriate conclusion at that
time.
Neurotoxicity
has been studied widely, not just in humans.
It's been studied across various animal models. So we have a fair amount of information. Again, at very high doses with regard to the
toxicity, neurotoxicity in animals.
We know
that cumulative dose is important. We
know that if you are exposed for a longer period of time, the amount of
acrylamide needed is less. It's not a
strictly additive relationship. In
fact, there's been a fairly detailed study that's looked at this relationship,
this Haber's Law relationship.
One thing
we also have a developing understanding of is that there are effects to younger
animals versus older animals. We do not
have information that allows us to say that neuro-developmental effects can be
ruled out for acrylamide. And we have
information that suggests that younger animals are more susceptible than older
animals.
Next
slide, please.
So based
on that information--and I'm going to go into the safety assessment and talk
about what studies are available to understand neurotoxicity for
acrylamide. And when we talk about
that, I'll show you that the study that we used for safety assessments is a
90-day study, not a chronic study.
Because of that availability of information, one important piece of data
that we need to uncover is further understanding of the relationship between
dose and duration. And, again, because
we don't have a clear understanding of neuro-developmental effects for
acrylamide, and given our newer understanding of the continuous exposure to
acrylamide, we need to have an improved weight of evidence for
neuro-developmental effects.
Next
slide, please.
Plans for
neurotoxicity within FDA are still at the early developmental stages, the early
planning stages. We're considering
including neurotoxicity endpoints in the NTP study. We're also considering other ways of developing neurotoxicity,
and particularly neuro-developmental information.
There is
quite a lot of ongoing academic research with regard to neurotoxicity, and
that's something we'll obviously draw from.
And, hopefully, given this new interest in exposures through food, we'll
get more information with regard to low-dose effects and developmental effects
through academics.
Next
slide, please.
A
somewhat less certain but still concerning area for acrylamide toxicity is the
developmental reproductive effects. Dr.
Schwetz alluded to or talked about, rather, in his presentation germ cell
toxicity. This is a rather unusual
finding for chemicals. It's not
something that we run across every day.
So finding that acrylamide has germ cell toxicity is something that we
need to consider carefully.
The
evidence that leads us to the conclusion that acrylamide can cause germ cell
toxicity comes from very, very high-dose exposures, and this is higher than the
neurotoxicity doses that were used, and clearly higher than the studies in the
bioassay that showed carcinogenicity.
We're talking about 40 milligrams per kilogram exposures and through
intraperitoneal injection for that matter, too. So this information, while it is concerning in its unusual
nature, still needs to be taken within the context of very, very high doses
that have been used to show this relationship.
Other
developmental effects are that there are clear reduced litter sizes, probably
related to dominant lethal effects, but those have been shown. But I do want to point out that there have
been no structural malformations that have been shown in the developmental
studies that have been done. This is
not something that would come across as a teratogen through those studies.
Next
slide, please.
Reproductive
and developmental data needs, again, this is to try to give you a context for
what general data needs or general areas of uncertainty or areas of information
need are, not to provide specific crucial data needs for development of
decisions. But we need epidemiology for
germ cell toxicity. This information
could be derived through existing cohorts, perhaps, and it's something we're exploring
through NIOSH and other opportunities.
Bringing
advanced techniques with regard to genotoxic effects is something that was
mentioned at the WHO/FAO consultation and at the JIFSAN consultation or JIFSAN
workshop.
We need
particularly a better understanding of the mutations generated and the dose
response for mutations that are caused in germ cells. Again, because they're very high-dose exposures and typical
routes are not routes that are directly related to food exposures, we need
information with regard to low-dose exposures, with regard to adducts, with
regard to dose-response relationships, obviously. So mechanistic studies are quite important for this because of
the conversion of acrylamide to glycinamide through P450. We don't have a clear mechanistic
understanding of whether it's glycinamide or acrylamide that causes the germ
cell mutations. Having that
understanding would help us obviously understand better how to do low-dose
extrapolation.
Next
slide, please.
Plans for
reproductive developmental effects study.
Again, FDA, we're in the early stages of determining how we might work
this into, for example, the NTP study or in terms of developing other research
programs for this endpoint. One of the
data needs that I didn't go into in the previous slide was that because the
finding of germ cell toxicity is a relatively unusual event, we don't have
straightforward--we don't have methods for evaluating the risks or making
decisions for risks that are routinely used.
So one key aspect of understanding this endpoint is trying to figure out
how we would understand the risk to low-dose exposures, how we would
extrapolate risks, how we would make decisions using risk characterization for
this endpoint.
So for
that reason, we have planned to develop a workshop for germ cell mutagenicity,
risk assessment, where we can help push that area of science forward a little
better and help us understand how we might make decisions for this endpoint.
NIOSH has
a protocol that they put together already for worker studies. They're collaborating with NIEHS to try to
incorporate some reproductive endpoints within that study. NIEHS is also looking at some mechanistic
things. They're looking at these
knockout mice that don't have the enzyme that allows the conversion from
acrylamide to glycinamide. Looking at
the effects in those mice will help us understand the mechanism, obviously, and
help us understand low-dose extrapolation a little better.
Finally,
NTP's Center for Evaluation of Risks to Human Reproduction is considering doing
a detailed review of the reproductive effects of acrylamide.
Next
slide, please.
Safety
risk assessment. I'm going to talk
about safety risk assessment in several slides, several following slides, and
the idea is to give you an understanding of where we are in the process and
also give you an understanding of the data that underlies that evaluation.
Both FDA
and EPA have used the same study, Burek et al., 1980., to develop safety risk
comparison values. Safety risk
comparison values are used as an initial part of the overall risk assessment
process. If you do a safety risk
evaluation and you find that the doses that you're exposed to are lower than
the safety risk evaluation number, you have an early understanding that there's
not a need for further evaluation, that you've done enough evaluation. If, on the other hand, the value is higher,
the exposure value is higher than your safety risk comparison number, then you
have an indication that you need to do further analysis. We're at that stage with regard to
acrylamide.
For the
EPA and FDA safety risk comparison values, we both use the Burek, et al., 1980
study, which is a 90-day study in rats, again.
The lowest effect level was 1,000 micrograms per kilogram, and the
no-observed-effect level was 200. Only
three animals were used to develop that dose response per dose value, and they
saw recovery at 144 days within that group of animals that showed the effects
of the lowest effective dose.
Both EPA
and FDA in this initial determination of safety risk evaluation numbers used
thousand-fold uncertainty factors, and I should mention that EPA is currently
in the process of re-evaluating their IRIS (?) file for acrylamide.
Next
slide, please.
As Dr.
Schwetz mentioned, WHO/FAO did do safety risk evaluation to some degree, or at
least they considered the evidence for toxicity and the evidence for exposure
and made initial evaluations. Their
judgment at that time was that non-cancer effects were unlikely at doses from
food. Dr. Schwetz mentioned a NOAEL of
500 microgram per kilogram per day. The
Burek, et al. study has a NOAEL of 200 micrograms per kilogram a day. Different data sets were used in the evaluations,
and I can go into that in some more detail if you'd like to in questions, but
the point is that the effective dose remains at around 1,000 micrograms per
kilogram a day, and the no-effective dose is something that is driven largely
by the dose studies in various studies--the dose choices in various studies.
DR.
KUZMINSKI: Excuse me. I just want to clarify your first bullet
that's a double negative, non-cancer effects judged unlikely, so does that mean
cancer effects are judged likely?
DR.
CANADY: No. This is a peculiarity of our way of dividing the toxicology
world. We divide into cancer and
non-cancer.
DR.
KUZMINSKI: Okay.
DR.
CANADY: So another way of saying this
is that effects other than cancer were judged unlikely, and then the next part
of the slide talks about what the WHO/FAO came to with their other conclusions
for cancer.
As Dr.
Schwetz mentioned, again, there was no consensus on quantification of cancer
risk within that consultation. But they
did come to a qualitative determination.
We compared carcinogenic potency of acrylamide using sort of a two-step
process. We talked about relative
potency with regard to benzopyrene and heterocyclic aromatic amines, for
example. There's already been some
discussion about this, and we can go into that in some more detail if you'd
like.
Then they
also used the aspect of intake level to give a relative sense of the
cancer--the level of concern with regard to cancer for acrylamide.
Next
slide.
And then
their conclusions were--rather, our conclusions were that there's a major
concern for acrylamide based on relative cancer potency and uncertainty
regarding the germ cell mutagenicity finding.
So they focused on both of the endpoints of cancer and germ cell
mutagenicity.
Next
slide, please.
I want to
go through the safety risk assessment values in a little more detail. There's three groups of information
here. The first group of information is
the dose response information, which I've already gone through in some detail. The second is the exposure, the order of
magnitude exposure estimate that WHO/FAO came up with, and that is something
around a microgram per kilogram of body weight per day. And then the derivation of FDA's acceptable
daily intake, which used a thousand-fold uncertainty factor based on the 200
microgram per kilogram per day no-effect level to come up with a value of 0.2
micrograms per kilogram per day.
I'm
giving you this information really just to try to orient you to where we are,
again, in the process of risk assessment.
If you do the comparison of dose to the comparison of safety risk
evaluation number, you come to the conclusion that risk analysis is needed to
make decisions.
I think
I'll leave further discussion of this to questions, which I'm anticipating
there may be some questions.
Can I go
to the last slide, please?
In
summary, acrylamide causes effects in animals, and those effects are seen at
quite a lot higher doses than we see through food. It also causes effects in humans, and, again, those have been
seen at quite a lot higher doses than we see in humans. However, even though exposures that have
been shown to cause effect are quite a lot higher than those we see in food
exposures, safety risk assessment leads us to the conclusion that we need to do
further risk analysis.
There are
substantial gaps in our knowledge about the toxicology and even at this point
the exposures to acrylamide. So we need
to make further progress on that.
Data gap
analyses by a variety of expert panels have led us to the conclusions that I've
gone through in some detail earlier.
But they basically give us an understanding that we need more
information, and there are specific kinds of information that would be more
helpful than others.
Finally,
FDA has initiated a program to try to develop some of this information, and I'd
be happy to talk about that in more detail.
Thanks
very much.
DR.
BUSTA: Thank you very much.
Questions
of clarification? Dr. Fischer?
DR.
FISCHER: I have a question about the
use of the cancer bioassay and regulation of acrylamide in drinking water. Does the EPA regulate the drinking water
level of acrylamide based upon the cancer bioassay or do they use non-cancer
effects?
DR.
CANADY: I feel a little uncomfortable
talking about EPA programs. My
understanding of it is that it's a technology-based guidance level for water. It's based on the available technology and
the demonstration of its ability to keep acrylamide out of the water. Maybe--I don't know. Henry, do you want to respond to this?
DR.
KIM: I don't have that information
offhand.
DR.
CANADY: Yes, and, again, responding to
EPA programs I think--I don't feel comfortable actually responding to that at
this point.
DR.
FISCHER: Well, I went to IRIS, you
know, and tried to decide from IRIS what they were doing, whether they were
regulating on a non-cancer or cancer effect, and couldn't really spend enough
time to get it out of there. I wasn't
clear from looking at the IRIS thing.
So I guess from your answer it sounds to me like that the FDA doesn't
want to start at that point, that is, using the drinking water standard
procedure for calculating risks to acrylamide exposure.
DR.
CANADY: Well, one of the initial data
needs before using that information is an understanding of the bioavailability
through food. We have an understanding
of the bioavailability through water.
Before we would move to using information like that, one of the first
steps, obviously, is understanding that there is a difference. Also the pervasiveness of exposure and the
continuousness of exposure through food is a different aspect with regard to
those exposures compared to the drinking water exposure, and that information
would need to be taken into account, too.
DR.
BUSTA: Dr. Hotchkiss?
DR.
HOTCHKISS: I had almost exactly the
same question as Dr. Fischer, but with a different acronym. Acrylamide, as we've discussed the range of
carcinogens that occur in foods, some through a result of processing,
acrylamide is quite unusual in that there is also a significant occupational
exposure and a history of that exposure.
I would presume that OSHA, like EPA, regulates acrylamide exposure in
the environment of the workplace. I
think you briefly mentioned something about NIOSH in there, but I wonder what
history is to be learned, at least as a starting point, similar to EPA in
water, from OSHA's regulations and on the basis for which they've made those
regulations. And I understand your
answer is going to be that that's inhalation compared to foods.
DR.
CANADY: Right.
DR.
HOTCHKISS: And we don't know about
foods.
On the
other hand, I heard earlier that we made this kind of thumbnail sketch about
exposure from foods, and you were comfortable with the working group, I believe
it was 0.8 from foods, thumbnail sketch kind of thing. It seems to me that--I would presume that
OSHA has put some effort into their regulatory limits as has EPA, and I wonder
if those have been taken into consideration.
DR.
CANADY: Well, the easiest answer to
that is that we intend to take all information into account as we develop our
risk assessment. OSHA does have a value
for workplace exposures to acrylamide; I believe it's a TLV and I believe it's
0.3 milligrams per meter cubed. If
there's anybody that--what is it?
DR.
FRIEDMAN: 0.3.
DR.
CANADY: It's 0.3. And that's the TLV?
DR.
FRIEDMAN: That's BEL.
DR. CANADY: BEL.
[Inaudible
comments of microphone.]
DR.
CANADY: Sorry, Mr. Chairman.
DR.
BUSTA: Yes, if you could--
DR.
FRIEDMAN: I'm Marvin Friedman.
DR.
BUSTA: Could you give us the answer/
DR.
FRIEDMAN: For the issue of--
DR.
BUSTA: Would the speaker--
DR.
FRIEDMAN: I'm Marvin Friedman. I'm from the chemical--
DR.
CANADY: I'm sorry, Mr. Chairman. I've opened this meeting up, and I didn't
intend to.
DR.
BUSTA: Yes, Dr. Friedman, would you go
to the--if it's all right with the speaker, come to a microphone so we can
record your comments, please?
DR.
FRIEDMAN: First, I want to
apologize. I just sort of answered the
question and didn't mean to use your time.
With
reference to OSHA, OSHA's permissible exposure limit is 0.3 milligrams per cubic
meter, five days a week over eight-hour shifts. You can calculate what that means in terms of individuals'
exposure.
We've run
the math on that, and at 2.3 years of working at that, it's equivalent to a
lifetime's worth of eating whatever the--what is it?--18 micrograms per every
day? That's the way it works out.
With
reference to EPA, EPA's regulation of drinking water, EPA has two levels of
regulation, what they call an MCLG and an MCL, the contaminant level and the
contaminant level goal. All carcinogens
have a contaminant level goal of zero.
So, you know, it doesn't--risk assessment doesn't play in.
As far as
the non-risk number, acrylamide gets into drinking water from polymers, and the
EPA regulates the amount of acrylamide in the polymer. And, therefore, that will turn around
and--because the amount of polymer added to drinking water is regulated, it
will regulate what's added to drinking water.
And that's done virtually on feasibility. The number comes out to be vanishingly small because polymer is
used at a ppm level. But that's how EPA
does it.
My
apologies. I really didn't mean to get
into this.
DR.
CANADY: No, that's fine. Thanks.
DR.
BUSTA: It's for information, and we've
got the numbers down so we can be sure that you're correct by checking them
later.
DR.
CANADY: Yes. But, again, what we intend to do is use all available
information, and prior analyses will, of course, be important in helping us
understanding the approach that we might take.
DR.
BUSTA: Dr. Gray, please?
DR.
GRAY: I'd like to clarify something
that just wasn't clear to me when we talked about all the studies that are
ongoing, and it's frankly because I share Dr. Schwetz's concern about the use
of biomarkers and also know that biomarker information is going to be coming
out for public consumption in the not too distant future. That is, are we being careful to get our
dose-response information in with the biomarkers? For example, in the NTP bioassay, I could imagine that we could
do biomarker measurements both in--we could do blood measurements, we could do
DNA measurements, we could do target tumor measurements, in order to somehow be
able to put in context, even if it's only in the animal studies, the
dose-response information back to biomarkers so that we actually have dose
response for the endpoints we're looking at with biomarkers.
DR.
CANADY: Yes, thanks for that
question. There was some text that I
skipped over in my talk that went directly to that, and the point is that NCTR
in their nomination to the NTP intended to and will include mechanistic studies
that will help do that extrapolation from external dose to hopefully markers of
effect. So there's a range of
understanding of dose and effect that extends through our action plan, from
CDC's evaluation of external exposure and biomarkers of exposure, through to
NCTR's understanding of DNA adducts, biomarkers of exposures that inform us
with regard to toxicokinetics, and then hopefully the relation of one of those
markers in some quantitative, to the degree possible, way to the effects that
are seen, as you say through tumor incidence or markers in tumors.
So the
intention is to bring to bear this very powerful set of tools of understanding
dose through external, through biomarkers of exposure to hemoglobin, biomarkers
of exposure/effect, if you would, to DNA, adducts to DNA, adducts to other
significant nuclear proteins, for example.
So, yes, the understanding of mechanism and how that informs low-dose
extrapolation is one of the main reasons for going forward with a
bioassay. You can bring to bear all
that information.
DR.
GRAY: Right, because I'm just concerned
that right at the level of as we do these tests we get that information if we
can. For example, I could imagine--it
may not be true, but I could imagine, for example, that these biomarkers we're
measuring are actually sinks. They're
taking some out. And if we look at
target tissues or something, there may not be anything there.
DR.
CANADY: Absolutely.
DR.
GRAY: We need to understand the way in
which these work.
DR.
CANADY: So a key component--
DR.
GRAY: And get that by linking it very
tightly to the endpoints that we think we care about.
DR.
CANADY: Right. So another way of phrasing that is we need
to understand the dose response of the relationship between hemoglobin
biomarkers and biomarkers of effect or measures of effects.
DR.
GRAY: Measures of effect.
DR.
CANADY: Right. Either one.
One may be a good correlate of the other.
DR.
BUSTA: Dr. Downer?
DR.
DOWNER: With respect to safety risk
assessment, given the fact that research is ongoing and that we still lack
concrete knowledge of bioavailability, metabolism, for example, of acrylamide,
how did the FDA quantify this marker of 0.2 micrograms per kilogram body weight
for the daily acceptable intake?
DR.
CANADY: These are fairly--
DR.
DOWNER: This is going back to Dr.
Fischer's question of the 0.8.
DR.
CANADY: These are fairly standardized
approaches for safety assessment. And,
again, they're ways of understanding--of gaining an early understanding of the
toxicology information that allows you to compare it at an early stage in risk
assessment to what you understand about exposure. And we fully understand that our estimates of exposure are early
and just that, they're estimates.
In the
same sense, we understand that our estimates of toxicology or the dose response
are at an early stage. And so comparing
them at this point in the risk assessment gives us a sense of sort of order of
magnitude comparisons. It's not an
exact comparison that allows us to say that this effect will occur. All the regulatory agencies that use these
technologies--or use these techniques, rather, to estimate safety risk agree
that the excedence of these safety risk values does not mean that effects would
occur. So the derivation--to get to
your question a little more directly--of these safety risk values, the ADI in
the case of FDA, is a relatively routine process that allows us to take an early
look across a lot of different compounds at what the relative risk is, and also
allows us, again, at an early stage to compare that to what we think may be
occurring through whatever exposure route it's occurring.
But I
just want to stress that it's an early look.
DR.
DOWNER: It's essentially a proxy
indicator, then.
DR.
CANADY: I'm not sure what you mean by
proxy.
DR.
DOWNER: If the levels are this, then
possibly this is what we're looking at.
DR.
CANADY: Yeah, but it's--I understand
what you're saying. It's an early
decision point.
DR.
DOWNER: Right.
DR.
CANADY: And it's a permissive decision
point. If you find that the exposures
are much less than your toxicity value at that early stage, then you, depending
on your uncertainty, have the option of saying there is no need to go further
with analysis.
DR.
BUSTA: Dr. Lee?
DR.
LEE: Dr. Canady, I appreciate your two
very comprehensive presentations, but speaking of estimates, I want to kind of
get your perspective. Certainly there's
a bit of guesswork in food risk. We've
got a guesstimate from CDC of about 5,000 deaths per year from foodborne
illness. We've got a guesstimate of
about 540,000 deaths per year from cancer from NCI. In your perspective, can you guess as to how many cancers, if
any, we might see per year in the United States as a result of acrylamide
exposure?
DR.
CANADY: No.
DR.
LEE: Do you think that is something
that we can eventually work towards? Is
that something is immeasurable?
DR.
CANADY: Maybe other members of the
committee would like to respond to this as well, but within this risk
assessment paradigm, what we're talking about for risks from a chemical are
relative risks. They are not actuarial
risks. We are not talking about
estimating the number of people that will die.
We're talking about comparing, for example, the relative risk of one
chemical that causes cancer to another chemical that--one chemical that may
cause cancer to another chemical that may cause cancer. There's a way of prioritizing our efforts
and making decisions about what to do.
It should in no way be taken to mean that we know how many cancers will
be caught.
DR.
LEE: Well, maybe there's a different
way I can put this. If you think we
could like magically, say within a year's time, eliminate all acrylamide in
food, would that have an effect on cancer incidence?
DR.
CANADY: I think this is an opportunity
to take advantage of understanding of potential risk and potential health
effects to see whether we can remove this potential risk from the food supply. And that's really the best way to approach
that question.
DR.
LEE: Thank you.
DR.
BUSTA: Dr. Hotchkiss?
DR.
HOTCHKISS: I was a little
surprised. We were provided--and I know
something exists which I believe is in-house at FDA--the Quantitative Risk
Assessment Committee reviewed the then current knowledge of acrylamide in 1998,
and then calculated some specific unit risks in that document, and--which I was
surprised you didn't mention. Then let
me refresh everybody's memory. I'm sure
you all stayed up last night reading this document.
The
conclusion was that the Risk Assessment Committee found the dose-response
curves plotted for the statistically significant tumors to be quite flat, which
could indicate that acrylamide is not a particularly potent carcinogen under the
conditions of the assay in the Fisher rat.
And I'm just wondering--my impression is that your impression is that
this risk assessment done by FDA four or five years ago was not addressed by
you, and I just wonder whether there was a particular reason. Did you feel that the information was not
sufficient given what we now are beginning to learn about acrylamide or what?
DR.
CANADY: I did not go into that
detail. As Dr. Troxell mentioned
earlier, we agree with the conclusions of WHO/FAO that this is a major concern,
at least partly on the basis of the cancer response. But providing a quantitative estimate of the relative risk at
this point, we have not gone to that level of analysis, partly because we need
a better understanding of the exposures, but also because we see an opportunity
to understand the dose response better.
We're
talking about a contaminant that's fairly widely distributed in the food
supply. We need to make decisions in a
careful way. The dose response
assessment that you're talking about was very useful for making the food
contact material decisions that were made at that time. In that case, using that slope or using that
dose-response information, we were able to come to the conclusion that the food
contact uses that were proposed were fine.
They would not provide a risk that was above our criteria, de minimis
criteria.
The
question becomes: Can that
dose-response information, which was adequate for that use, be considered
adequate for the current situation? And
that's a question we're addressing right now.
So I'm sorry if I didn't get into it in detail, but, you know, I don't
mean to--what I mean to do is say that we are considering all dose-response
information and considering, again, opportunities to improve our understanding
of low-dose extrapolation using biomarkers of exposure and using biomarkers
of--using actually effect measures to get to a better understanding of the
low-dose risk.
DR.
HOTCHKISS: Let me understand. It wasn't a matter of detail. I didn't hear you mention it anywhere.
DR.
CANADY: Right.
DR.
HOTCHKISS: So that's a little bit--
DR.
CANADY: I didn't.
DR.
HOTCHKISS: We're interpreting that a
little bit different. Let me also try
to clarify my understanding that this has nothing to do with exposure, whether
it's from food contact or anything.
This is a risk assessment, a unit of risk calculated based on the then
available toxicology data that will not change given that the exposure changes. It's really unrelated to exposure. Am I right?
DR. CANADY: That's right. The dose-response analysis we could do using the existing
information.
DR.
HOTCHKISS: We might generate better
dose-response data that will change this, but we're not going to--that's not
going to be related to dose. And so I
just wonder, this is--
DR.
CANADY: Right. No, I' sorry.
DR.
HOTCHKISS: --the most current thinking
on risk assessment from the agency, and I just wondered whether you found
inadequacies in this or you're just not considering it or moving forward from
it or dismissing it.
DR.
CANADY: No, we're moving forward and
using that information as well as other information we've collected since then,
sure.
DR.
BUSTA: Dr. Gray?
DR.
GRAY: Just quickly, I think
toxicokinetic data could make a big difference, because the absorption, of
course, the amount of material that gets in the body can be important to dose
response. So there are things that
could change, but that was a very thorough evaluation that I'm glad you brought
to our attention.
The
second thing is just a very quick question on this same dose-response
issue. Has anyone calculated under
different potential dose-response models the upper-bound risk that would be
consistent with the epidemiologic studies at this point that find nothing so
that we can even know if this is--how sharp a line to the epi studies draw for
us in knowing--
DR.
CANADY: Are you talking about power
calculations and so on?
DR.
GRAY: Not just power calculations, but
then what is the--yeah, it's based on power calculations. What's the sort of maximum relative risk
that could be there and could not have been detected under certain assumptions
about the shape of the dose response?
DR.
CANADY: During several of the data
needs meetings that we've had, this question has come up, and our understanding
is or my understanding from those discussions was that the power of the studies
is not informative as to what an upper-bound risk might be.
So if I
can understand your question a little better, what I think you're saying
is: Can we derive an upper-bound risk
using the epidemiology data?
DR.
GRAY: No. What I'm saying is the epi studies that find nothing--they find
nothing, and it may be that they're zero, or it may be that they were not
powerful enough to detect a very small increase. And you can calculate what that very small increase could be,
which would just say is that something that's even in the ballpark of where we
are now. Is it helping us understand
that these risks could be lower than the animal data might be telling us?
DR.
CANADY: And the epi studies were on the
order of several thousand people and the exposed were quite a bit fewer than
that. So I guess the way to approach
this is the slopes that have been discussed, both FDA's and EPA's, are not
ruled out by the epi data. That's about
as direct as I can be.
DR.
BUSTA: Unless there is an urgent,
burning question for clarification, we will move on. Thank you very much.
DR.
CANADY: Sure.
DR.
BUSTA: The next presentation of the FDA
Action Plan is on analytical methods/occurrence by Dr. Steve Musser.
x DR. MUSSER: Good morning. It's my group's responsibility to develop the analytical assay
for analyzing acrylamide in foods as well as conducting our exploratory survey
of acrylamide levels in U.S. foods. It
makes me very happy to present this data.
We've done what I consider to be an enormous amount of work in a very
short period of time. We generated a
lot of data. And we still have a long
way to go. We're probably about halfway
through our goal of 600 different types of foods, but we have done this in a
very, very rapid time frame.
May I
have the next slide?
I'm going
to talk about two topics today. The
first part of the presentation will deal with the analytical methodology
itself, why we chose that particular analytical methodology, how we validated
it, why we believe it's accurate, why we think this particular methodology
gives us good results, and over a broad range of foods. And then the final part of the presentation
will deal with the actual levels that we're finding in our exploratory survey
in various food groups.
In a
recent meeting sponsored by JIFSAN in Chicago, there was an analytical working
group, and at that time we went through a number of methods that were used for
detecting acrylamide in foods. Of them,
there were four methods that came out kind of as most often used or most
frequently used by people measuring acrylamide in foods. They are gas chromatography/mass
spectrometry, GC/MS, either derivatizing the acrylamide or looking at it directly
as an underivatized compound; liquid chromatography/mass spectrometry; and
liquid chromatography/tandem mass spectrometry.
In all
cases, the specificity was fairly high, and the limit of quantitation was well
within the lower levels of acrylamide that we're finding in foods. I'll also talk a little bit more about these
methods because I think it's important when we compare data from different
groups that we have some confidence that independence of the method that was
used, we are still getting reliable results from other laboratories.
We chose
to use the liquid chromatography/tandem mass spectrometry method,
LC/MS/MS. The reason we did this when
the Swedish administration first announced their findings, we knew their
methodology was based on this particular type of methodology, and we wanted to
confirm their results as accurately and introduce as few variables as possible
in confirming those initial results.
Subsequently, we developed our own methodology in the absence of having
any other thing to work with, and that method that we're consistently using now
is LC/MS/MS.
Just a
couple of method highlights, and these highlights are issues that have been
brought to me either through some of the meetings, public meetings that we've
had or personal phone calls, questions about the method, or interest in why we
chose a particular way of doing the analysis.
First of
all, sample size, we used a 1-gram sample size. We homogenized a serving, so, for example, a single bag of chips
is about an ounce or 28 grams of material, so we would homogenize that
serving. Or if we were looking at
cereal, again, we'd have a box of cereal and the serving size is an ounce. So we'd take about 28 grams, grind it up,
homogenize it, and then take a 1-gram subsample of that material and do the
analysis.
Stable
isotope. We used a stable
isotope-labeled internal standard, carbon 13.
We have three carbon 13s replaced the natural carbon 12s that would be
found in acrylamide. This is a stable
isotope dilution method. We use this because
our internal standard is identical to native acrylamide with the exception that
it differs in mass by 3 atomic mass units.
So if we're getting quantitative recovery from the matrix, then the
internal standard such as this controls for all other recovery and losses that
might occur through processing, because we're simply looking at a ratio of the
internal standard to the native acrylamide.
We
extract with water. A number of groups
look at hot water, various organic solvents.
We found that there is no difference using hot water, cold water, and
that our recoveries are just as good by shaking it a few minutes with cold
water, though there is a volume effect, and you have to have a sufficient
volume, about a 10:1 ratio, between the particular matrix you're looking at and
the amount of water you use for the extraction.
We use a
two-step solid base clean-up. When we
initially came out with our methodology and published it on the Web in June, we
had a single-step clean-up. We found
that there were a number of particular food matrices where we had to look at
much lower levels, and we needed an additional clean-up step to get rid of some
interferences in some matrix to look at approximately the 10 ppb level.
Chromatography,
we control the column temperature. That
gives us very reproducible retention times, so, for example, we're in kind of a
cold room today. If it were in the
summertime, that temperature might vary by five degrees and retention time
would shift. All of this goes to we
want very precise, reproducible, accurate results that we can rely on from day
to day to day to day. It's all part of
the validation.
We've
looked at about three dozen different kinds of HPLC columns, evaluated them all
for their performance. We found three
that give us acceptable results. We're
currently using one of them, and I'll talk to you a little bit about that next.
Our
method of detection, as I said, is liquid chromatograph/tandem mass
spectrometry. We use Electrospray as
the ionization method. Other groups use
atmospheric pressure chemical ionization as their ionization method. It depends on the instrument
manufacturer. Our particularly
manufacturer gives us better results with Electrospray. Other groups get better results, lower
limits of detection with APCI. It's
really not a dependent variable that makes a significant amount of difference
in the actual analysis.
Next
slide.
We were
interested in using a smaller subsample, 1 gram of subsample, primarily to
reduce our waste stream. We knew that
we were going to be running many, many hundreds of samples, and if we were
looking at using a 10-gram sample size, that meant 100 mLs of waste, larger
sample vials, larger containers. Right
now we've done about 700 individual analyses, probably a little more. That equates to almost 700 liters of waste
that we would have been generating. We
wanted to try and minimize that while still maintaining accurate levels and
accurate measurements.
What I'm
showing here are some results where we've looked at four different
matrices--bread crumbs, cereal, coffee, and potato chips--where we've taken
1-gram subsamples, and this is of a giant homogenate where we've taken kilogram
amounts, homogenized it, done a number of analyses on that, and then taken
1-gram and 4-gram subsamples of those particular matrices. And what we find is that quantitatively the
results are identical whether we use 1-gram or 4-gram subsamples.
We're
also going to expand this to 10 grams just to make sure that we're not missing
anything obvious, but the preliminary results indicate that there is really no
difference as long as the sample is well homogenized between taking a 1-gram
subsample and a 4-gram subsample.
I
mentioned about the two-step solid phase extraction. This particular slide--in the top slide where we have only one
solid phase extraction step, this is for a food that has about a 20 ppb level
of acrylamide down closing in our own quantitation limit. This is the acrylamide peak right here, and actually,
it's a bit obscured by this giant contaminant that's in the matrix. Using the second SPE step, we've been able
to completely eliminate that, and we get a much cleaner, tighter, well-defined
chromatographic peak that gives us better precision in our measurements.
Next
slide, please.
This is
just an example of the kind of--what the peaks look like on the different types
of columns that we found acceptable.
Currently we're using this Phenomenex-Hydro RP. It's a high-carbon-loaded C-18 column. It gives us very nice peak shape, and for the
analytical chemists in the group, sensitivity, of course, is related to how
much--how fast and narrow the peak you can get into the detector. The top one gives us that best peak shape,
and we've just replaced this particular column after doing about 600 analyses,
individual analyses. So we know that it
performs well over a wide variety of matrices and a large number of samples.
Quality
control, of course, is an important factor in doing these types of analyses
where we're looking at a broad range of food products. The most important issue for us is recovery
of the internal standard. So if we put
the internal standard in, because we're basically putting acrylamide into our
sample, if we don't get acrylamide back or we have very small peaks for the stable
isotope-labeled internal standard, we know we've got a problem with that
particular matrix or that we made a mistake during the extraction of the
clean-up. And so recovery of the
internal standard and the peak shape for the internal standard is a critical
factor for one of our quality control points.
We do a
duplicate analysis of every food sample.
That means not just a re-analysis of the extract, but we actually take
another sample of that food and take it through the entire sample process. And what that does for us is allow us to
compare--if we had some odd problem that happened to occur where one of the
samples was particularly high, we like to see them both very close together.
Re-analysis. We also do periodically re-analysis of
samples that have been analyzed previously to see whether they fall close to
those samples that we've already looked at.
We look at the performance of standards every day before doing
analyses. And we also look at the
signal-to-noise and ion abundance ratios.
So in the tandem mass spectrometry, we're producing not only the parent
molecular ion species but fragments, and we look at the relative ratios to each
other to make sure that they are within the expected values, and that gives us
just another way of determining the specificity and accuracy of the
measurement.
Next
slide.
Some more
on method performance. Linearity, of
course, is important. We use a range
from eight parts per billion to 3,200 parts per billion. That's the limits of our standard curve that
we've developed. More importantly, the
response factor is very close to unity across from the very low levels to the
very high levels. And that's a very
good indication of the performance of the method, at least with standards.
Recovery. This is actually a fairly difficult point to
get at. We used the method of standard
additions to calculate recovery. We
feel that that's the most accurate means of determining recovery percentages. We've done it for a large number--about ten
different matrices, as well as proficiency testing samples. And in all cases, it's generally greater
than 90 percent recovery, and usually a little better than that, around 95
percent recovery, for the matrices where we've actually done the standard
additions experiments.
We've
done some preliminary experiments with spiking the matrix with known amounts
and get very similar recoveries, although we feel the method of standard
additions gives us a better estimate of recovery.
Precision. These are well-defined means of determining
precision. Again, if we look at our
four different matrices, we find that our RSDs are all less than 5 percent for
all of those analyses, and that continues to be consistent throughout the range
of samples that we've looked at.
Next
slide.
But I
think the most important aspect of any analytical method is its accuracy, and
accuracy is one of those things that's very difficult to get at with food
matrices. And the way that we've
approached this is to look at proficiency testing where we've had enough
laboratories participating with a well-defined sample and how close we come to
the mean of those determinations.
And so
we've participated in two rounds of testing--one sponsored by the National Food
Processors Association, in which five laboratories used LC/MS/MS; and another
by the Food Analysis Performance Assessment Scheme, FAPAS, which is an
internationally known proficiency testing organization under the CSL of the
U.K., Chemical Science Laboratories in the United Kingdom, and they do
proficiency testing throughout the world.
What's
interesting about the FAPAS results are that there were 37 people who actually
returned results, and of them, 32 of them received satisfactory scores, which
means they were within what would be expected to be the correct range of the
correct result. That means there's a
lot of labs out there doing analyses and a lot of them are getting at least
very consistent results.
Also of
interest was that there were about an equal number of laboratories using GC/MS
versus LC/MS, and that those--there was no statistical bias in terms of
reporting numbers for GC/MS or LC/MS methodology. I think that's important as we develop these databases of people
looking at different products that we have some assurance that we can compare
those results and know that they're relatively in the correct ballpark.
In our
case, the assigned value from this particular proficiency testing scheme was
1,213 micrograms per kilogram, and we reported 1,264. That's within our 5 percent standard deviation expected results.
The next
slide?
That
brings me to conclude the discussion of the method portion of the talk. We're in the process of preparing a final
report for a single lab method validation.
We've been a little slow in doing this, and it's been complicated by a
number of factors. This is a
fairly--typically, when we would do a method validation, it would be for a
single component in a single matrix.
What we're doing now is a single component in multiple matrices. So we're working at do we have enough validation
data to cover the range of samples where we might expect a problem, and then
within those individual samples, do we have enough information on those
particular samples to complete our validation study? And we're really at the point where we believe we've done that,
and we're compiling that information.
It's voluminous now. But I think
that that work will be done. We do have
a valid method for analysis of foods.
We're
also in the process of preparing proficiency testing samples. They're going to be four to six different
types of matrices that we can send out to laboratories who are interested in
doing these analyses, either for us as a contract service or other FDA field
laboratories that might be doing analyses where we want to have some confidence
in their analytical results and everyone is doing the same--reporting numbers
on the same particular matrix. Those
materials have been prepared and are now ready to be sent out.
The next
process for this method will be a three-lab peer verification of the method
where we use another two laboratories, including our own, to verify the range
of results that we get. This is a
fairly standard procedure and, if necessary--and we haven't reached a
conclusion on this--doing a full collaborative study of the method. There's good and bad points to doing a full
collaborative study, but we still haven't decided to proceed that way yet.
Another
item that we're exploring and we're hoping we can get other people interested
in exploring are alternative testing methodologies. LC/MS is good, it's fast, it's rugged. It gives extremely accurate results. But it's very expensive.
Contract laboratories are charging anywhere from $200 to $250 per sample
analysis. So if you get one sample run
in duplicate, you could be looking at a $500 bill. So we're looking at, you know, are there other methods that can
be used that are not as expensive but give results which could be used for
process control or just analysis of--a broader range of analysis--getting more
analyses done by more people and yet still getting accurate results without
having to do LC/MS or GC/MS.
Interestingly,
GC/MS contract laboratories are charging about the same amount for LC/MS, so
there doesn't seem to be a breakdown there.
And,
finally, we're using this method to look at foods. We're looking at foods pretty much every day. We've got a continual shopping basket coming
into the laboratory for analysis.
The next
slide?
Okay. I'd like to move now into what our actual
results are and concentrate a little bit on exactly what it is that we found,
or didn't find in some cases. I'd like
to point out that this is an exploratory survey, that this is by no means a
representative sampling. And I think
what you're going to see from some of the data that I present later that there
is a considerable amount of variation in the foods, and that even though we've
looked at perhaps 300 different food samples, there is so much variation that
this cannot be considered representative in any case.
We chose
the foods based on a number of different parameters. Basically we started out looking at, okay, people in Europe,
different laboratories reported finding this in fried foods. So we picked a number of fried foods,
potato-based foods. We also then
expanded it to crackers and other foods where other laboratories had initially
reported finding acrylamide.
Also,
unpublished findings, contract laboratories and other academic laboratories
would called us and say, hey, we found it in food matrix X, did you find it in
food matrix X? And so we would add that
to our list of foods--much like Dr. Canady said, a very iterative process to
food sampling.
Then we
also did try and take a more concerted effort to choosing some samples by
group. For example, we looked at infant
formula to see if there were significant levels of acrylamide in infant
formula; or by total, so, for example, in cereals we looked at cereals with
very high sales that accounted for large market shares. Again, the sampling is not representative,
and many foods only have one sample.
We'd also
like to constantly expand our number of foods analyzed, so if there are things
which we have--you have our survey results now. If there are food commodities that you think we should be looking
at, we would like to know about that so we can include them in our survey.
Next
slide.
So where
are we and what are we doing? Since we
first published or talked about some of our results in September, we've about
doubled the number of analyses that we've done. So far, about 300 different food samples analyzed, nearly 700
separate analyses, and these analyses don't include any of the analyses we do
for standard curves, proficiency testing, method validation. These are just analyses for foods in the
survey. More than 35 different food
types, and by food types I mean baby foods, coffees, breads, vegetables,
seasonings, those types of food categories.
Next
slide, please.
The data
is not all bad. We don't find
acrylamide in everything. For example,
potatoes, one of those sources for acrylamide in French fries, if you look at
uncooked potatoes, we don't find any acrylamide in them. The same thing for frozen vegetables or
vegetable protein. Uncooked, we find no
levels of acrylamide. Also with meat,
fish, and chicken, raw or cooked, we don't find any significant levels of
acrylamide in those particular samples, and infant formula, no significant
level of acrylamide found in any of the 12 samples of infant formula we
surveyed.
Next
slide.
This next
chart--and there's a lot of data in some of these charts, so if I'm going too
fast or you have questions, please slow me down because there's a lot of
information here.
This is
an example of some of the variability that we found to occur within certain
food types, and one of the more interesting aspects of this is if you were to
look at cocoa, for example, and you only sampled a couple of cocoas, you might
think that, oh, well, there's not much acrylamide in any of them. But what we're finding is we'll go along and
analyze some samples, and as we add more to our data set, we'll find some of
them that have very high levels.
I should
also point out that coffee in this case, the coffee samples are not for brewed
coffee. That's for the raw
coffees. So that would be we take the
ground coffee out of the container, look at that. This is not going out to a coffee vendor and taking the already
brewed coffee and analyzing it. This is
the raw, unbrewed variety.
If I can
have the next slide?
DR.
FISCHER: You haven't looked at any
brewed coffee?
DR.
MUSSER: We have not looked at any
brewed coffee.
DR.
FISCHER: Or cocoa?
DR.
MUSSER: Or cocoa.
DR.
GRAY: But you know water extraction's a
pretty good way to get it out.
DR.
MUSSER: But we--yeah, I mean, we
have--I've talked with a number of laboratories who have done these analyses,
and if you simply multiplied, you know, a six-ounce cup of coffee plus what we
find, you'd find that those results are--it's almost 100 percent
extraction. And it's also an acidic
environment, so it would be expected to be fairly stable.
This is
just some more example data. I couldn't
fit it all in one slide. This is just
some more examples.
The fish
and the chicken, if you remember from the previous slide when we said there's
very low levels in there, we looked at things like chicken nuggets that were
fried and fish sticks that were baked.
And we did find levels in those particular products, detectable levels
of acrylamide. And so we took it one
step further, and we peeled off the breading and we looked at the individual
meat that was in there and we looked at the breading coating. And all of the acrylamide could be accounted
for in the coating that was on these products.
And so when we say fish or fish sticks or chicken nuggets or chicken
tenders, those are--the acrylamide is really in the outside of those products
and not in the meat. We don't find
significant levels in meat.
A couple
of points about this particular slide.
Soups--these are dried instant soups.
We go along and we analyze six or seven different instant soups, find
very low levels. Then we find one that
consistently gives us very high levels of acrylamide.
Likewise,
in French fries that are baked by the consumer and French fries that are
obtained from fast-food restaurants, we find tremendous variability in the
amount of acrylamide that's in product.
Not only do we find variability within individual manufacturers, but
within different locations and the way they're prepared. And this really--this data, as we've been
developing it, prompted us to do a number of different experiments and look at
a number of different food products, because it was starting to become clear to
me and to a lot of the other people looking at this data that we really had an
incomplete snapshot of what was happening in foods in the U.S., in particular
with acrylamide levels in those foods.
Can I
have the next slide?
The first
thing we did was we said let's go out one weekend, and we all kind of live
around the Washington, D.C., metro area, and, you know, go to your favorite
fast-food place or go to some fast-food places, pick up some French fries. So what we ended up with was a large number
of French fries from several different fast-food restaurants, where we looked
at the individual levels in those particular French fries from those particular
locations.
What we
found was that, yes, there's a lot of variation. If you look just here where we have five samples from McDonald's,
they span from about 200 to almost 600, the amount of acrylamide that we found
in those particular--parts per billion of acrylamide in those particular French
fries.
But if
you look at the--what's beginning to develop here is that independent of
restaurant, the median levels are about the same. So if you had only sampled, for example, one low sample from
Wendy's and one higher sample from, say, Fuddruckers, you might be led to
believe that one particular company was giving you higher levels of acrylamide
than another company. But what you find
when you do the sampling is that, at least with French fries and fast food,
those median amounts are all about the same no matter where you would end up,
that there is a detectable amount but that the mean levels are all
approximately going to be right in a central area between 200 and 600 ppb.
Can I
have the next slide?
This was
a very interesting experiment and one where we have a lot of information and
don't exactly know how to interpret it.
We went out and got four samples of big bags of potato chips with six
different dates codes on them. Now, the
manufacturer was kind enough to provide us with the lots of potatoes that were
used, where they were manufactured, and at what time. And so in this case, the potatoes were all harvested and then
immediately processed, so there was no storage time. They were all run in the same facility and actually all run on
the same line.
So what
we're looking at are not the--in most cases, we're displaying the mean values,
but these are the actual individual analyses, so it looks like there's a lot
more than there really was.
So on
November 5th, this is what we saw grinding up the entire bag of potato chips
and then looking at individual amounts within those potato chips. So we saw some variability bag to bag, and a
lot of variability, you know, lot to lot. And the different colors are not different colors to help you see,
but the color codes are the codes for the variety of potato that was used.
And so
here all of the purple ones are a particular different variety that came from a
different farm, but in one case, we find fairly high levels, and in another
cases, you know, half of that value. So
the same variety produced on the same line producing levels that are of great
variation.
Also,
because these are fresh potatoes, it doesn't take into account any of the
storage factors. You know, potatoes are
really kind of living organisms, and they are constantly using starch in their
storage process. So we don't know what
effect taking the potatoes and storing them for a while prior to the actually
cooking of them, whether that will increase or decrease levels of acrylamide.
Next
slide, please.
We did
some more stuff. When we got French
fries, we didn't just get them frozen, you know, you go into the supermarket
and you get a bag of frozen French fries.
Well, analyzing them as frozen material and looking at the acrylamide
levels in there is probably not representative of really what you see in the
final product, which would be baked.
And we baked them according to the manufacturer's instructions, so if
they said--most of them were 450 degrees for anywhere from 8 to 20
minutes. So we would take whatever the
manufacturer said and cook them in the same oven, and what we found was if you
just look at them--and some of them are precooked a little bit, so they're
fried, maybe pre-fried before they're frozen.
So there are some significant levels of acrylamide that are present in
the frozen product before it even gets baked.
But when
you bake it, the acrylamide levels start to change dramatically and cover a
very wide range. You know, these are
fairly nicely grouped below 200 parts per billion, but we go all the way from
200 to almost 1,300 parts per billion when we bake them in an oven. Of course, this prompted us to do more
experiments.
Next
slide, please.
In this
experiment, we said: Well, what do
consumers really prefer? Because the
analysts, when they were cooking these frozen French fries, said, well, you
know, this isn't how we would eat them.
In other words, we cook them, they're hot. You know, we've cooked them for 10 minutes, they're hot, but
that's not really how we would eat them.
So I thought about this for a little bit, and I thought, well, maybe
what we ought to be doing is looking at how people like to have their French
fries cooked or baked. And so we took
about 12 pounds of French fries from one particular manufacturer, frozen French
fries, and in this case, the starting amount of acrylamide was very low. So I should note that, unlike in the
previous slide where we had a fairly high initial level--or higher levels of
initial acrylamide in the French fries, in this case we have very low levels.
So when
we cooked them for the recommended time, which was 15 minutes at 450 degrees,
we didn't see very much acrylamide. But
no one in the group of the six people we had cook them really wanted to eat the
French fries in that particular condition.
They wanted them to be cooked a little longer, maybe a little
browner. And so what you see is that
when people cook them the way they had a preference--and this is, of course, by
no means a representative sampling. Six
people in my laboratory doesn't constitute a representative sampling. But you do see that those levels do go up
greater than what might be found just cooking them according to the instructions.
So that
adds another variable and dynamic to our analyses. In other words, if we're taking measurements just by cooking them
according to what the instructions say, is that really giving us a
representative level for what might be encountered in consumers' kitchens?
If I can
have the next slide?
This
slide really, I think, is very demonstrative for what we see and why acrylamide
levels tend to correlate with the amount of browning that occurs. If you take a French fry that hasn't been
cooked at all, we don't find any acrylamide in it. We've looked at it. I
should also point out that we've microwaved them and we don't find any
acrylamide.
If you
cook it for 15 minutes at 450 degrees, it's a nice color but it's kind of limpy
and doesn't have any browning effect, and you get a very small amount of
acrylamide. If, however, you cook them
until it starts to brown a little bit, 30 minutes--and I should also point out
that when we cooked them according to the people in my laboratory's preference,
it was about 25 minutes. So the median
was about 22 minutes of cooking, so about 7 to 10 minutes longer than what was
recommended by the manufacturer. And so
we saw levels, you know, approaching this amount at 30 minutes, and this brown
French fry kind of represents what people like to see, a slightly harder
coating, it wasn't a real soft coating, it wasn't real limp. And even after 45 minutes of cooking, where
we have kind of astronomical levels compared to what we had found in typical
products, these French fries were considered just as tasty and desirable even
though they had very, very high levels of acrylamide in them.
So if I
could have the final slide?
What we
have here is lots and lots and lots of data.
But certain trends are starting to develop, and there is a lot of
information to be gained from this initial survey. But, first of all, the analytical method that we've developed we
believe is reliable and comparable to other--gives us data that's comparable to
other laboratories and other agencies producing information on acrylamide
levels in foods.
Also, the
results clearly indicate that there is considerable variability in acrylamide
levels both in commercially produced and in consumer-produced products; that
there are a number of factors which contribute to the variability, and small
numbers of sampling. So if we were to
have gone out and just gotten one sample, and maybe even five or ten, it's not
probably representative of what the median level is going to be for that
particular product.
So that
can be very misleading, and the amount of variability observed in certain food
types and what we've seen with the consumer preparation indicates that there
may be a way of dramatically reducing acrylamide levels.
Those are
the conclusions that I'd like to make from this presentation. Thank you.
DR.
BUSTA: Thank you very much.
Are there
questions for clarification? Dr. Gray?
DR.
GRAY: Thank you. A quick question. Can you just confirm for me that it looks--I just want to make
sure that I get it through my thick skull.
The acrylamide that you're measuring is acrylamide monomer.
DR.
MUSSER: Yes.
DR.
GRAY: It's not bound and you're
bringing it out with water, so you're probably not taking it off of
things. This is acrylamide that's
floating around--
DR.
MUSSER: This is free acrylamide,
yes. And it would be very unlikely that
if you had polymeric acrylamide that you would go back the other way.
DR.
GRAY: Right.
DR.
MUSSER: It's pretty much a one-way
street for the polymerization. You bind
it or you form a polymer. You don't go
back the other way.
DR.
GRAY: And the same with binding to
proteins?
DR.
MUSSER: Yes. If it was bound covalently to proteins, it probably wouldn't come
off.
DR.
BUSTA: Dr. Hotchkiss?
DR.
HOTCHKISS: First a comment. I've always considered analytical chemistry
to be the strength of FDA, and you've done nothing to dispel that belief.
Just a
quick question. Are the data, the
numbers that you present for individual samples corrected for either your
overall recovery or individual heavy isotope recoveries? Or are they as found?
DR.
MUSSER: They are as found. It would be--if we had to do a
standardization for every single one of these 300 samples, we would never be
done.
DR.
HOTCHKISS: Well, let me say, as I
understand it, each sample was spiked with the internal standard.
DR.
MUSSER: That's correct.
DR.
HOTCHKISS: So you know what the
recovery is of that internal standard for each individual sample, right?
DR.
MUSSER: Yeah, really, we're taking
advantage of the stable isotopes because as long as we can assure that we are
extracting most of the acrylamide out of the sample into the solution and that
that's representative of what's in the sample, the stable isotope will correct
for all the other problems that may occur during the work-up and clean-up. I mean, that's just the fundamental basis of
stable isotope label standards. And
we're fairly certain--we've got only one matrix where we know we don't have
good--we're not recovering internal standard from in all the ones we've looked
at. And we kind of use that as our
basis for is it working or isn't it working.
And so we
can get a signal for the internal standard.
You can pretty much be assured that you can quantitate the level of
acrylamide that was in the particular product.
DR.
HOTCHKISS: I understand that, but now
I'm a little more confused. For
example, on a given sample, you get 95 percent recovery of the internal
standard, which I think was the number you--
DR.
MUSSER: Yes.
DR.
HOTCHKISS: And you find the level of
acrylamide in that product that is not labeled. There are two numbers you could report: what you found, or you could take what you found and divide it by
.95, assuming that the--
DR.
MUSSER: Yes.
DR.
HOTCHKISS: --found level was recovered
at the same level as the internal standard.
Now, which way did you go?
DR.
MUSSER: We do not calculate a recovery
into that. We calculate everything
based on a unity of recovery.
DR.
BUSTA: Could I pursue that a little
farther? Where do you put the spike in
the French fries that are baked in your hands?
DR.
MUSSER: Okay. We take the French fries that are baked in our hands, and this is
typical for every sample that we would do.
We homogenize the sample.
DR.
BUSTA: This is after--
DR.
MUSSER: After baking.
DR.
BUSTA: You have at no time put them in
the raw sample--
DR.
MUSSER: No.
DR.
BUSTA: --and then baked them?
DR.
MUSSER: No. No. I don't know how I
would do that, but we could try.
DR.
BUSTA: Dr. Fischer?
DR. FISCHER: Let me get back to this a little bit,
because I had the same question. So
acrylamide, in fact, is two things:
chemically reactive, and it's somewhat volatile, or is volatile.
DR.
MUSSER: Yes.
DR.
FISCHER: So there's a chance of it
being lost from the product while being cooked as well, right?
DR.
MUSSER: That's correct.
DR.
FISCHER: And I understand from your
answer just now that you don't know how much is really lost.
DR.
MUSSER: We don't know how much is lost.
DR.
FISCHER: Now, for the chemically
reactive part, is it possible that acrylamide in a product is bound to protein
or other substances in the product and, as such, is not extracted in that form;
but, in fact, if you were to eat the product, it's possible, I suppose, that it
might be released?
DR.
MUSSER: Yes.
DR.
FISCHER: So do you have any idea about
the bound acrylamide in the product?
DR.
MUSSER: We're pretty certain from a
number of the matrices we've looked at--and if you look at coffee and potato
chips and French fries and bread crumbs, where we have a fairly representative
range of levels and matrices. If the
acrylamide is available free, we're extracting it pretty much
quantitatively. We can't comment on is
there a reversible reaction that's occurring.
I can't even think of one that might be occurring where you've got some
kind of way of binding it to a protein, as you suggest, or in an oil, which
might be more likely, where it's encapsulated and so you would have a capsule
formed, mycel, for example, where the water couldn't penetrate the mycel and so
you weren't extracting it. I mean,
that's certainly a possibility and one that we don't want to rule out. I can't--I don't know.
DR.
FISCHER: I would suggest that if you
use some isotope, radioisotope-labeled asparagine, maybe, or whatever, to get
bound acrylamide in the samples and see whether you can get it out, it might
be--
DR.
MUSSER: We thought about doing those
experiments, and the problem with doing those experiments is that if the
acrylamide reacts with a protein and forms a covalent modification where it is
then not available, in other words, when you make an acrylamide adduct with a
protein, it's a one-way street for acrylamide.
It doesn't come off, unless you chop it up in acid, and then you still
have acrylamide plus whatever amino acid it's bound to. So--
DR.
FISCHER: That happens in your stomach.
DR.
MUSSER: Well, it could, yes. And so you have this radioactive label now
that's bound to acrylamide. It's not
available. It's not really even acrylamide
anymore. It's just an adduct. And so if you did that radioactive
experiment, you're not going to come up with really the free available
acrylamide. You might come up with how
much is bound, but you don't know whether it's actually bioavailable as
acrylamide.
Now, you
could also do some other experiments where you hydrolyze the protein and look
at the bound acrylamide. But it's
probably not reactive at that point.
DR.
ACHOLONU: Alex Acholonu. You said that--
DR.
MUSSER: Wait a minute. Dr. Canady--excuse me. I think Dr. Canady--
DR.
CANADY: One of the reasons we're doing
bioavailability measurements is to look at this exact question. We would look at the incurred amount at
the--naturally incurred amount through cooking, and measure what's found in the
blood so we could measure--we can see how much we extract using the analysis
procedure, see how much we get in the bioavailability measures, and get to the
question you're asking. That's another
way to get to it in addition to what Steve's talking about.
DR.
ACHOLONU: You said that the acrylamide
level tends to correlate with the amount of browning. Is the factor here the color, the browning, or the intensity of
heat applied in the preparation of the food?
DR.
MUSSER: Could you repeat that again?
DR.
ACHOLONU: Yes. You talked about the fact that acrylamide
level tends to correlate with the amount of browning in the cooking, and you
showed that in one of your slides. Now,
what I'm trying to find out is: Is it
the color of the food when it is fried or the amount of heat applied that
determines the level of acrylamide in the food or in, for instance, the French
fries? Browning--and if it is that,
supposing it gets charred, gets black, what would be the amount of the
acrylamide in the French fries?
DR.
MUSSER: I would imagine pretty
substantial as it got black. But to get
to your specific question, Dr. Jackson in the next presentation is going to
talk about those manufacturing processes which might lead to differences in the
acrylamide level, and she'll be able to tell you about temperatures and the
length of time and talk to you a little bit more specifically. Her presentation will deal with your
question pretty much exclusively.
DR.
ACHOLONU: Okay.
DR.
BUSTA: Dr. Lee?
DR. LEE: I was just wondering, there certainly is a
need for inexpensive and accurate screening methods, and there are several
laboratories working on it. Do you have
any predictions as to when these might come online? Say a year from now will we have a less than $250 per sample
analysis?
DR.
MUSSER: I don't know that it will ever
get really cheap. The expense here is
primarily labor. It's fairly
labor-intensive just to get the sample to the point that you can inject it and
analyze it. But it should be much less,
you know, per sample. And one of the
results we saw from the FAPAS test was that one of the participants had used an
electronic capture detector, GC/ECD, and that gave results which were as good
as the GC/MS results for the FAPAS sample.
So, I mean, that's certainly a possibility of one of the tests. We're looking at some UV derivatization
methods that might work as well. But I
don't--there's not enough data on the LC side to predict that. Certainly it looks like ECD is already to
the point that it could be used.
DR.
BUSTA: Dr. Downer?
DR.
DOWNER: Thanks for a very informative
presentation. I noticed that all the
foods from the food guide pyramid were represented in your research with the
exception of fruits. Is there any
reason why that's been excluded?
DR.
MUSSER: No. We did look at some fruits, and they were baby food fruits, like
applesauce, and we didn't find any, any significant levels of acrylamide in
fruits.
DR.
DOWNER: So it's your thinking that
perhaps foods for the general public's consumption--you remember now that we're
recommending that we eat a wide variety of foods, including fruits and
vegetables. Are you going to be doing
just regular fruit that adults consume?
DR.
MUSSER: Well, keep in mind that raw
fruits and raw vegetables in our study didn't show any acrylamide levels.
DR.
DOWNER: Are you going to include cooked
fruits?
DR.
MUSSER: I can't--we don't have enough
data to comment on that.
DR.
BUSTA: Dr. Whitaker--oh, just a second.
DR.
CANADY: One of the ways to address that
particular question is through the Total Diet Study which looks at a
representative sample of foods across a lot of different categories.
DR.
DOWNER: Thank you.
DR.
CANADY: And we intend to do that.
DR.
BUSTA: Dr. Whitaker?
DR. WHITAKER: Steve, there's a lot of good data there, and
it's hard to comprehend it all. But I
noticed in one of your slides on method performance precision, it seemed
to--the variability seemed to increase with concentration that you were
measuring. Have you looked at that?
DR.
MUSSER: Yes. The variability--well, actually, the variability stays about the
same. It's about a 10 percent standard
deviation. What you're seeing is the
amount that's varying. So, for example,
if you had a sample that has 1,000 ppb in it and you added 10 percent, then you
would be plus or minus 100 ppb. If you
have a 100 ppb sample and you're plus or minus 10 percent, it's going to be,
you know, 110 versus 90. So it's an
apparent change, but the actual standard deviation that's observed for the
analysis is the same.
DR.
WHITAKER: The coefficient of variation
stays about the same.
DR.
MUSSER: Stays about the same, yes.
DR.
WHITAKER: But the standard deviation
actually increases with concentration.
Have you looked at that?
DR.
MUSSER: I'll have to look at that more
carefully. There's too much data there.
DR.
WHITAKER: Yes, there is. And we see that in mycotoxin work, that the
variability as a function of the standard deviation does increase while the CB
tends to stay constant. So--
DR.
MUSSER: I'll go back and plot that.
DR.
WHITAKER: You may have information here to go back and describe that.
DR.
MUSSER: I'm sure we have enough. It's just a matter of going back and
massaging it.
DR.
WHITAKER: Yes. One more question. Have you had the time to look at sample-to-sample variability
within a lot or a consignment? I mean,
if you have a lot, you have a thousand bags of potato chips, have you had a
chance to look at the variability from bag to bag or from sample to sample?
DR.
MUSSER: Only minimally. In that study I described on the different
varieties of potato chips that came from the same facility, they were four bags
from the same date code or same lot, produced on the same manufacturing
line. So we took those four different
bags and ground up each one individually and then analyzed them, and there is,
you know, a substantial amount of variability in those bags of potato chips.
DR.
WHITAKER: Yeah, I would think that
understanding that variability would be crucial in trying to get an accurate
estimate of the acrylamide in that lot.
DR.
MUSSER: I think that's very important
yes.
DR.
BUSTA: Dr. Kuzminski?
DR.
KUZMINSKI: A couple of questions
here. Is it the agency's intent--or
maybe this is not a practical suggestion--to recommend a standard method for
the analysis of acrylamide?
DR.
MUSSER: I don't know that we've ever
done that, and I don't think that that would be appropriate in this particular
case, especially given the fact that so many other laboratories have produced
equivalent results with vastly different methods.
DR.
KUZMINSKI: Another question. Just on--a couple of the slides that you
show had data which represented phenomena that you indicated you might to know
what it meant, like the variability of levels given various code dates on
potato chips, I believe, as an example.
I recognize that it's early in the process. This phenomenon or this occurrence has bubbled up in the last
several months very, very quickly. But
is it the intention of the agency to establish at least a procedure or a
mechanism whereby when you--and I'm sure there will be other data which will
reveal phenomena you will not understand also, in addition to this one.
My
question is: Will the agency set up a
procedure or mechanism whereby you consult with other experts in the field, be
it in academia or in industry, that could help explain these phenomena to you?
DR.
MUSSER: I can't speak for what the
agency intends to do. Perhaps, Dr.
Troxell, you'd like to address that.
DR.
TROXELL: Well, we have two consortia
we're working through, for one, and the National Center for Food Safety and
Technology is looking at the formation of the mechanism kind of questions and
will be interacting with a lot of different stakeholders, and we certainly are
going to collaborate not only through them but through JIFSAN, with people all
over the world, to identify, you know, the reasons for the variables that are
involved, and to try to go beyond just the levels but to also correlate particular
levels to, you know, pH and temperature and water conditions and other chemical
factors in foods that may affect levels, as people develop the knowledge to
understand what causes the formation.
I think
Dr. Jackson's talk will be very informative to that this afternoon on what
we've already learned about the mechanism and what factors are important and
what needs to be explored in the future.
DR.
BUSTA: Thank you.
DR.
ACHOLONU: Last question. Will roasting of food or baking affect the
level of acrylamide in the food, baking or maybe grilling or barbecuing, any of
those? Are they out of danger?
DR.
MUSSER: There's some limited
availability of that data. At the AOAC
meeting in September, Procter & Gamble presented some data where they
roasted asparagus, which is very high in asparagine, and they found in that
particular sample it was the highest of all the acrylamide-containing samples
they looked at. So, yes, you can
produce acrylamide levels by roasting or grilling.
DR.
ACHOLONU: And baking?
DR.
MUSSER: And baking. Yeah, in fact, in the French fry data where
we've done that as a consumer baking them, that was all baked. That wasn't fried. All that data is from baked French fries, baked frozen French
fries.
DR.
ACHOLONU: If that is the case, why did
we--why do you emphasize the question of frying and not including baking and
roasting in the write-ups? Why is the
frying of food so identified with acrylamide?
DR.
MUSSER: Oh, that's--
DR.
ACHOLONU: Why are all the readings we
have not talking so much about roasted food, baked food, barbecued food,
grilled food?
DR.
MUSSER: That's probably related to how
the initial results came out of Sweden where they only looked at primarily
fried foods, and so there was a real interest in just looking at fried
foods. But recent data--and probably
why you're not seeing it is that only recently have people expanded the kind of
way they looked at foods to include--plus understanding the mechanism--into
foods that are baked and roasted and not just fried foods. So it's probably just a matter of this
happened very recently and so it's taking a little bit of time for people to
catch up with the initial results and expand their surveys to include other
samples.
DR.
BUSTA: I would like to sincerely thank
all the FDA presenters for the morning, the very succinct presentations,
comprehensive, on time, and the panel for their thoughtful questions.
We will
recess for lunch and reconvene at 1:15.
[Luncheon
recess.]
A F T E
R N O O N S E S S I O N
DR. BUSTA: I'd like to reconvene the Subcommittee. Our first individual on this afternoon on
FDA Action Plan on Formation is Dr. Lauren Jackson.
* DR.
JACKSON: I'd like to welcome you back,
and unlike the previous speakers, I'm from the FDA National Center for Food
Safety & Technology, which is located in a suburb of Chicago. For those of you who don't know what the
NCFST is, it's a consortium between the FDA, the food industry and academic
members, and the main focus of the research that we do at the NCFST is to look
at the effects of food processing and packaging on the chemical and microbial
safety of foods.
The
objectives of this presentation are to summarize what's known about acrylamide
formation, the mechanisms, the precursors and factors that affect acrylamide
formation, identify the research gaps, and then, finally, and most importantly,
discuss the FDA Action Plan on acrylamide, with respect to formation, and
which, to summarize, is to understand the conditions that lead to acrylamide
formation in food for the purpose of developing methods to reduce or prevent
acrylamide formation.
What is
known about acrylamide formation. How
is it formed in food, what are the precursors, the mechanisms, and what factors
affect acrylamide formation, including food processing and food composition.
Almost
immediately after the Swedish group announced the presence of acrylamide in
thermally processed high-carbohydrate foods, there was speculation as to where
acrylamide was coming from. What I'm
going to talk about here in the next several slides are the precursors and
pathways that have been discussed as potential ways of forming acrylamide.
Listed
here are four different pathways or mechanisms. The first three that I have listed here are the acrolein, the
acrylic acids, the amino acid alone have been pretty much disproved as the
major pathway for acrylamide formation.
And the
fourth that I've listed there, the amino acid reducing sugar, Maillard
browning, Strecker degradation has been, pretty much there's been a consensus
that this is the major pathway in food.
Fairly
early on the acrolein pathway was speculated to be the major pathway in
food. Mainly, if you look at the
structure of acrolein, it's very similar to acrylamide, and it's thermal
degradation product of oil, so it's formed in frying oils if they've been
heated excessively. So there was a
reason to believe that the reason why we find acrylamide in fried foods may be
because of acrolein as a precursor.
Acrolein
is not only formed in thermally abused oils, it's also formed in thermally
degraded starch, sugars, amino acids and proteins. As I mentioned, this pathway has been pretty much disproved by
several research studies--well, one major one by the one group at HealthCanada,
Becalski and his group out there, where they heated acrolein in combination
with ammonium carbonate, which is a source of ammonia, and they didn't form
acrylamide.
There
have also been isotope-labeling studies that's pretty much disproved that this
is a viable pathway.
Similarly,
the acrylic acid pathway was speculated to be a pathway as well. Again, it's because acrylic acid is very
similar structurally to acrylamide.
Again, it's a thermal degradation product of alpha and beta alanine,
different diacids in foods and amino acids, and again it's pretty much been
disproved as a major acrylamide mechanism or precursor.
Amino
acids alone, when heated, can form acrylamide.
Dr. Richard Stadler and his colleagues at Nestle Research in Switzerland
did some work pyrolyzing individual amino acids and found that acrylamide does,
indeed, form when heating Asparagine and Methionine. However, the yields from these two amino acids are fairly low,
and the relevance in most foods, such as potatoes and grains, this pathway is
not believed to be a viable pathway in high-moisture foods such as potatoes and
grains.
However,
the relevance in other foods such as coffee, which is roasted at a high
temperature under pyrolysis conditions,
this might be a viable pathway and this needs to be verified.
In September/October,
there were four individual reports that linked acrylamide formation to amino
acids and reducing sugars precursors, and Maillard and are Strecker degradation
pathways. There are two major mechanisms
that this can occur. What I'm going to
do is, in the next couple of slides, summarize what has been presented at the
acrylamide workshop in Chicago that occurred last month, two months ago.
What are
the Maillard and Strecker degradation reactions? They are a reaction between amino acids and reducing sugars or
other sources of carbonyls, and they are key reactions in the formation of
color and flavor in food. They are key
to the flavor and color of french fries, baked products, coffee, cocoa.
The
reasons why people suspected that this mechanism or these mechanisms might
occur is that potatoes and grain products are fairly high, they have fairly
high amounts of free amino acids and are fairly rich sources of carbohydrates,
and some anecdotal evidence was supplied by some of the work done by the
Swedes, where they found a higher amount of acrylamides in foods, as the foods
tended to brown.
So which
of the amino acids are acrylamide precursors?
The identity of the amino acid precursors was determined in model
systems consisting of amino acids and glucose in an aqueous environment. This table that I show here was taken from
Mottram's paper in Nature. He's from
the University of Reading, I believe, in the U.K., and what he did was he
heated up different amino acids, asparagine glycine, cysteine and methionine,
glutamine, aspartic acid, glucose in an aqueous buffer at 185 degrees for 20
minutes. This was in a closed system.
And he
found that asparagine was the major precursor as you can see from the numbers
you have here. You can see here, glycine,
cysteine, methionine didn't form any acrylamide. Small amounts of acrylamide were formed from glutamine and
aspartic acid, and I'll talk about what the implications of those data are in
the next couple of slides.
In a
similar study, Sanders, Zyzak and their group at Procter & Gamble did a
similar type of study, where they looked at acrylamide formation, instead of in
aqueous model system, they looked at a model potato chip. So what they did was they formed potato
chips from potato starch, glucose and a variety of different amino acids, and
they've pretty much confirmed what Mottram found, is that asparagine is the
major amino acid precursor, and again they found small amounts of acrylamide
formed from glutamine.
The
conclusive proof that asparagine is, in fact, the amino acid precursor was,
again, from Procter & Gamble's group.
They did some really nice work looking at isotope labeling of
asparagine. The left part of the slide
here shows asparagine that was labeled at different parts of the molecule with
different stable isotopes, nitrogen 15 or carbon 13, and what they did was they
reacted these labeled asparagine with glucose, heated it up, and then measured
the master charge ratio of the resulting acrylamide.
What they
found was all of the nitrogen and the carbon from acrylamide was derived from
asparagine, and the amid part of the asparagine was actually incorporated as
the nitrogen that's in the acrylamide.
Now that
we know about the precursors, how are they formed? There are two mechanisms that have been proposed. They're slightly different. They both involve Maillard and/or Strecker
degradation reactions.
The first
one is a combination of Maillard and Strecker degradation reactions, and
basically what it is is asparagine undergoes Strecker degradation in the
presence of dicarbonyls, which are formed as a consequence of Maillard
browning.
Mottram
did some nice work looking at or verifying that this mechanism actually does
occur by heating up dicarbonyl, butanedione he used, and he heated it up with
asparagine, the top two. This is where
he introduced there, he did those two up, need then actually measured and found
acrylamide formation which showed that this pathway is actually viable.
There's a
different mechanism that was proposed by Stadler and his group at Nestle, and
this was a little bit different.
Basically, he found that acrylamide could form from the N-glycosides,
which are early Maillard browning products.
What he did was he took N-glycosides of asparagine. The first two are N-glycosides of
asparagine, glucose and fructose and glycosides of asparagine.
He took
he an N-glycoside of glutamine and an N-glycoside of methionine as well, and he
heated those N-glycosides up. I believe
he did it at 180 degrees for 30 minutes in the dry state, and then he measured
acrylamide formation from those N-glycosides.
What he found was the asparagine N-glycosides formed substantial amounts
of acrylamide. Whereas, the glutamine,
and methionine and glycosides form very small amounts, trace amounts, small
amounts.
As I
alluded to, there are, other than asparagine, there are other amino acids that
potentially could form acrylamide. The
formation of acrylamide from glutamine and aspartic acid has been disputed
mainly because the model system work that was done with these pure amino acids,
they actually were not pure. The
glutamine that was used in these experiments had trade amounts of asparagine,
so that might account for the formation of acrylamide from the glutamine.
Aspartic
acid actually is contaminated with trace amounts of cysteine, which again might
contribute to acrylamide formation.
Cysteine has been suspected to be--I didn't show any data on this--but
it might be another possible amino acid.
It's not believed to be a major precursor.
Methionine,
there is a consensus that methionine actually is a precursor, although as I
showed from the data before earlier, that the yield of acrylamide from
methionine is far less than from asparagine.
Then, again, this might for acrylamide via N-glycoside formation by the
two mechanisms that I've shown before--Maillard, Strecker or the N-glycoside
formation.
We know
that these pathways occur in model systems.
We know they've been verified.
How do we know these actually do occur in food? Some of the work, one of the pieces of
information that the asparagine sugar reaction is valid in food comes from data
we have on the free asparagine levels in some of the foods that we analyze for
acrylamide.
In this
table, I've listed types of food:
potatoes, wheat flour, rye flour, asparagus, almonds, coffee and
meat. I've also listed the percent of
asparagine as a percent of the total free amino acids, as well as the amount of
this should be free asparagine on a wet weight basis of the food.
The right
is levels of acrylamide in the food after frying, baking or roasting. This is not an absolute amount there. This is a sliding range. You can find zero
to four stars, depending on how you process the food.
Basically,
what this table shows is that foods such as the top six foods there that have
high free asparagine potentially can form moderate to high amounts of
acrylamide. Whereas, meat, which has
very low levels of free asparagine, you can cook it, roast it and form, depending
on the frosting conditions, again, little or no acrylamide formation.
This is
in direct evidence. Direct evidence was
provided by Zyzak and his group at Procter & Gamble on potatoes, where they
treated a mashed potato, and they treated it with asparaginase, which is an
enzyme that cleaves off the amid group of asparagine. It depletes the asparagine levels.
And then
he fried the potato, and then he found that acrylamide levels decreased to
almost, well, 99 percent--by 99 percent.
So this is direct evidence that asparagine participates at least in
potatoes.
In grain
products, nothing really has been done at this point, but evidence points to
the asparagine sugar precursors and the Maillard Strecker degradation products,
but this of course needs to be verified.
Other
foods that do contain acrylamide-- coffee, cocoa, chocolate, almonds--again,
are believed to be an amino sugar pathway, precursor pathway, but this again
needs to be verified.
Meat, as
Dr. Musser mentioned, he didn't find any acrylamide formation in meat during
his survey work. If you look at
Tareke's paper in the Journal of Ag and Food Chem, they've heated up meat, and
they did form acrylamide only in very small amounts, and it depended, again, on
the processing temperature.
What
factors affect acrylamide formation, including the compositional factors and
processing conditions? And the rest of
my talk is going to focus on these factors.
Most
definitely food composition affects acrylamide formation; first, as a source of
precursors, as I talked about before, amino acids are believed to be major
precursors here. Asparagine levels are
believed to have an effect on acrylamide formation. Methionine, glutamine, aspartic acid and cysteine might have an
effect if they pan out to be actual precursors.
Other
amino acids that might be important include lysine, since they have an epsilon
amino group that could participate in the Maillard reaction and potentially
compete with asparagine for entering into the Maillard reaction.
Sugars
might have an effect. Several studies
have been done looking at the different types of sugars on acrylamide
formation, and it depended on how the experiment was done.
Becalski
looked at the different types of sugars on formation in an aqueous model system
and basically found that the reducing sugars formed more acrylamide than
disaccharide sucrose. However, Stadler,
who did his experiments in a dry state, under pyrolysis conditions, found no
difference. The type of sugar had no
effect on acrylamide formation. It
found equal effect.
And pH
most certainly has an effect on acrylamide formation. Becalski did some work at HealthCanada, where he did model system
work looking at different pH effects, and he found that the higher pHs you get
more acrylamide formation. This is not
really anything that would be surprising since the Maillard reaction occurs at
higher pHs.
Moisture. Moisture content might have an effect. The effect is unclear at this point. If you look at the work that was done by
Mottram and Stadler, their work seems to suggest that the presence of water,
some water, facilitates this reaction, and this really needs to be fleshed out
more.
There are
some additives and other food compositional factors that have been studied or
are currently being looked at.
Sulphites are antibrowning agents, and they've been looked at, to some
extent, by Becalski and HealthCanada, and the Procter & Gamble group, and
they found very little or no effects on acrylamide formation.
Antioxidants
have also been studied to a limited extent by Becalski, and I believe the
Swedish group, and they found no affect on acrylamide formation during frying.
Glutathione
cysteine has been thrown out as a potential way to mediate acrylamide
formation, and mainly in flour and baked products. This is currently being studied by the group at the American
Institute of Baking. I don't have any
data to show you here.
Fermentation. Again, this work is being done at the
American Institute of Baking, and what they're trying to do here is use yeasts
or lactic acid bacteria during fermentation.
They use up some of the asparagine in the flour and might potentially
reduce acrylamide formation.
Processing
conditions. Processing most certainly
affects acrylamide formation.
Temperature and time both affect acrylamide formation.
What I'm
going to show you in the next couple of slides is work that has been done by
Mottram and his group and some of the work that we've done at the FDA looking
at time and temperature.
This is a
graph taken from Mottram's paper, and what he did was he looked at the effect
of this is cooking temperature, this is processing temperature, on acrylamide
formation in a model system. This is a
closed system, an aqueous system. And
Becalski also did a similar type of study, and they basically found that
acrylamide formation occurred anywhere between 120 and 145 degrees. Really, Mottram found acrylamide formation a
lower temperature than Becalski. So
there is disputed at what temperature actually acrylamide does form.
Once
acrylamide does form, the concentrations increase fairly rapidly, up to 170
degrees, and after that temperature acrylamide either degrades or the levels
decrease in the model system. This was
not only found by Mottram's group, this was found by Becalski, and I believe
Zyzak's group at Procter & Gamble, but for sure Mottram's group and
Becalski's group, that there is some drop-off in acrylamide formation or
degradation after a certain processing temperature.
In food,
we find a similar type of effect. This
is a graph that was taken from the Swedish publication in Ag and Food
Chem. What they did was they looked at
acrylamide formation in french fries that were oven cooked. This is the oven temperature. This is not the actual temperature in the
french fry itself. They found, as the
oven temperature increased, acrylamide formation increased fairly rapidly after
140 degrees C.
If you
also look at data from survey work that we've done at FDA, as well as
information that was published from other groups, boiling and retorted foods or
uncooked foods, as well, have very little acrylamide formed, but fried, and
baked, and roasted foods, extruded foods, as well, contain modest to high
levels of acrylamide.
I
mentioned that we do a little bit of work, and this is preliminary work, what
we were trying to do here is study the effects of time and temperature on the
formation of acrylamide in a potato chip.
What we did was we varied, this is frying temperature. We kept time constant here, and we found a
very big difference in acrylamide formed, depending on the temperature that the
chips were fried.
We also
looked at frying time as well. This is
something that we really don't see very much in our literature is time and
temperature together, and this is something that I'll discuss later what really
needs to be done.
We also
found, and these chips were fried at 180 degrees, and we varied the amount of
time here. We found that there's a big
change in acrylamide formation. As you
increase the amount of frying, then you get more acrylamide formed. You can tell here also that there's a
difference in the amount of browning in the chips as well. How they're correlated I really can't tell
you at this point.
To
summarize all I presented so far is that asparagine and reducing sugars are
believed to be the most important precursors in forming acrylamide. Other amino acids may be important. The
Maillard, Strecker degradation pathways are believed to be important in most
foods. The acrolein pathway is believed
to be unlikely, and processing conditions, which is time and temperature, are
critical to acrylamide formation in food.
Now, what
are the research gaps? As I mentioned,
and I showed you a table before that listed the free asparagine levels in
food. There were a lot of question
marks in there, mainly because we don't have information on free asparagine
levels in food. This really needs to be
done. There's a real lack of data on
free asparagine and other free amino acids reducing sugars on a dry-way
basis. This really, we need to have a
database on this, and not only in different foods, but also how foods are
stored.
As Steve
mentioned, potatoes, depending on how they're stored, can form different
amounts of acrylamide during frying depending on the length of storage, the
temperature of storage, and this needs to be studied in greater detail, and
there needs to be a correlation of acrylamide levels produced during processing
and cooking and correlated to the amount of free asparagine and reducing sugars
in the foods as well.
Again, we
need to determine the mechanisms of formation in each food category. Like I said, most people are pretty
convinced that asparagine, reducing sugar, and the browning pathways are the
pathways in potatoes. In grain products
and in other foods it's not really well fleshed out, and this needs to be done.
Very
importantly, we need to determine the effects of time, temperature, pH and
moisture on acrylamide formation in different matrices.
Finally,
we need to study the connects of acrylamide formation, inhibition, destruction
in various reactions and processing conditions.
This
comes to the FDA Action Plan with regard to formation.
One of
our major goals is to understand food processing and our cooking conditions
that affect acrylamide formation and destruction or inhibition in foods, and we
really have a two-pronged approach for accomplishing this goal.
The first
is looking at FDA research. A lot of
the information we get on processing in the past couple months we can get from
the CFSAN exploratory survey data. This
was presented by Dr. Steve Musser before.
Basically, he looked at different types of food here, and what he found
was that in the roasted foods, such as almonds, the breads, cereals, the chips,
which are fried, cocoa, coffee, which is roasted, again, and baked, he basically
confirmed what people believed with respect to food processing, that uncooked,
retorted foods tend to have very low levels of acrylamide; whereas, the baked,
roasted, extruded, fried foods contain higher levels of acrylamide.
We plan,
in addition to the data we get from the exploratory survey, we tend to do some
research also at the FDA and NCFST looking at the effects of time and
temperature and pH on acrylamide formation in greater detail, both in food
products, like potato products and grain products, as well as in model systems
and getting a very good handle on how processing affects the--both time and
temperature together are very important, not just time, not just temperature,
they both have to be looked at simultaneously.
You can't
ignore what is being done worldwide.
There is research being done throughout the world at this point, looking
at formation of acrylamide in foods and understanding the mechanisms, and this
information that's being done worldwide is being funneled into the WHO CFSAN
clearinghouse or Infonet, from what I've heard them refer to, and we're going
to get a lot of knowledge and insight into processing from this as well.
The
second goal of our action plan is to determine the precursors and mechanisms
resulting in acrylamide formation.
Again, we're going to be doing a little bit of work at the NCFST,
looking at verifying the precursors and mechanisms in grain products to make
sure that this is actually the asparagine mechanism actually does occur in
grain products.
Again,
worldwide research is being done, and we're going to get knowledge from that
from the research and what's being put on the Infonet.
Another
goal is to understand the role of food composition on acrylamide levels. Again, the exploratory survey gives us a lot
of information there on which foods tend to form acrylamide, and you can look
at that data and figure out, at least eliminate some foods with respect to food
composition. Worldwide research again
is being done on this as well.
I
mentioned worldwide research. This is
just an incomplete list of the people at least that I know of that are working
on acrylamide formation mechanisms and precursors and processing. In the U.S., we're just a small part
again. We have the food industry
working on this, trade organizations.
As I mentioned, the American Institute of Baking is doing a lot of
work. Academia, you have Food Research
Institute at Wisconsin. Again, these
are the only people I know of for sure that are doing research on that. HealthCanada, in Canada, again, food
industry, trade organizations and academia in these different countries are
also working on this problem as well.
This
information that is going to be gleaned from the research is going to be,
hopefully, fed into that Infonet, the CFSAN WHO Infonet.
What we
plan to do next, what we have planned in the next six months, is to really do a
detailed study of processing time and temperature on formation of acrylamide,
both in model systems and food, and this is just starting right now.
I'd be
glad to answer any questions that you might have.
DR.
BUSTA: Are there questions from the
Subcommittee?
Dr. Gray?
DR.
GRAY: George Gray. Just a quick question. Given that these browning reactions are sort
of surface chemistry, is surface area an important variable, do we know?
DR.
JACKSON: No, at this point, we--there
has been some work--yes, there's nothing really known about that.
DR.
BUSTA: This is Frank Busta, and I've
got a question.
When I
looked at--times and temperatures are very important to me because I've been
doing some on activation of bugs for a long time, and time and temperature is
key.
The times
and temperatures that you showed were of the oil temperature or we heard
earlier of the oven temperature. Is
there any effort to measure the temperature of the potato?
DR.
JACKSON: Well, that's key here. That's why a lot of people worked with model
systems because in a closed system you actually do get to the processing
temperature, and that's one of the reasons why we want to do that, but we have
been trying to think of ways that have thermocouple on the surface of the
potato and try to measure it that way.
Baked products it's probably easier.
I've done some work in the
past on this where you can put thermocouples at different points in the baked
product and measure temperature as it is baked in the oven and then measure
acrylamide in those different levels, and that's what we plan to do as well.
DR.
BUSTA: I have another question, while
we're at that, about the concentration of the sugars. I know in potato chips and other items like that, the
concentrations of the sugar is always monitored to determine what kind of
browning reaction they do get. You
mentioned the fermentation reducing the asparagine. Is there any effort to eliminate the free sugars and see if that,
in fact, stops the reaction?
DR.
JACKSON: I have never seen anything on
that, no. Although one of the slides
show that if you do have starch--I think from the Procter & Gamble study,
they friend their chips with just starch and asparagine, and they still did
form acrylamide, lower levels, though, but during frying you get hydrolysis of
the starch as well, and potentially it can be a source of precursor, but
nobody's ever done that.
Dr.
Hotchkiss?
DR.
HOTCHKISS: Joe Hotchkiss, Dr.
Jackson. I was going to make the same
point and the suggestion that Dr. Busta made earlier. I presume that when, at least in the model systems are closed
systems, so even though there's water in the system, you still can get the system
up to 170 C.
DR.
JACKSON: Right.
DR.
HOTCHKISS: As Dr. Busta pointed out,
the critical thing here I think you're going to find is temperature of the,
particularly surface temperature, and actually this issue was addressed in the
nitrosamines in bacon issue by FDA, actually, and there are ways to measure
surface temperatures during cooking.
The other
thing I might suggest is you correlate this to moisture content because you're
going to find out, I think, as soon as you remove the moisture from a cooked
food, the temperature of that food begins to increase, and you're going to then
dramatically increase the content of acrylamide formed.
DR.
BUSTA: Dr. Lee?
DR.
LEE: Hi. Ken Lee.
Dr.
Jackson, you introduced yourself from the National Center for Food Safety,
which of course is a partnership with industry. Are you finding that the industry is working with you on ways to
prevent acrylamide formation? Does the
information flow free and unencumbered?
DR.
JACKSON: That's a good question,
actually, because--actually, a lot of the data that I presented is from
industry. Procter & Gamble has been
very forthcoming with information.
Frito-Lay has also been very forthcoming with information. So far we've had a good back-and-forth
relationship, but we have to test that as time goes on.
But the
CFSAN Infonet is supposed to be where a lot of the information is going to be
coming from industry as well, not just the NCFST consortium.
DR.
BUSTA: Dr. Kuzminski?
DR.
KUZMINSKI: Larry Kuzminski. I think you presented a compilation of some
very neat work, detective food science technology work to come up in model
systems with a mechanism of acrylamide formation. We've learned, through I guess your September workshop, some very
solid input from some representatives of industry, as you've just noted.
But, to
me, there is still some missing categories there of food groups where I do
believe that it's important for FDA to establish a relationship, provide the
mechanism. The September workshop
seemed to be a very good example of how it could work.
And so
there's responsibility I think on both sides here, in terms of FDA providing
the environment, if you will, the procedural environment, for the sharing of
this information. And, secondly, on the other side of the
coin, there's a responsibility by industry to step up and share what
information they do have, especially those industries, those companies that are
in these various food groups of the various data presentations that we've heard
today.
As I've
mentioned, at a Food Advisory Committee meeting back in July on another issue,
I think, and firmly believe, that the responsible food companies out there want
to know what's in their products and need to know what's in their products. And this issue that has arisen the last
half-dozen months, those companies are probably all over this issue, and it's
just a guess--I have no personal knowledge of that--but just based on
experience over the years gone by.
So I
would encourage the Agency to continue those kinds of procedures and
mechanisms, whereby, under a no-fault-kind-of situation, those companies are
encouraged to come forward and share the knowledge that they have.
DR.
BUSTA: Dr. Fischer?
DR.
FISCHER: You mentioned that there were
very few measurements of--
DR.
BUSTA: Would you speak into the
microphone.
DR.
FISCHER: Excuse me. You mentioned that there were very few
measurements of free asparagine in various foods or food groups. Do you know who is working to remedy this
situation?
DR.
JACKSON: Offhand, I know Mottram's
group. The table that I put in there
was from Mottram. It wasn't in his
papers, but it was provided at the acrylamide workshop. So he is looking into this as well. I don't know if he's undertaking a whole
research project on this, but he's looking through the literature and trying to
compile data in a table form where we can look at different food products and
the asparagine or sugar levels.
But from
what he mentioned, there is very little out there. Researchwise, I don't know if anybody is, offhand, doing this
type of work.
DR.
FISCHER: It seems like this is an
important piece of information.
DR.
JACKSON: It is.
DR.
FISCHER: Do you think you could do that
or could the FDA do that?
DR.
JACKSON: I didn't plan on doing it.
[Laughter.]
DR.
JACKSON: But you're right, it is
important. I think what needs to be
done is we go back and talk to Dr. Lineback and find out, just basically the
purpose of this workshop was to identify the research needs and who is going to
be accomplishing these goals, and that was actually one of the goals, to
determine the free asparagine levels in different foods and publish that.
Now there
might be somebody that is looking into that.
I, offhand, don't know. So I
can't answer your question. I did not
have plans to do that type of work where I am, but it's something that we're
going to have to look at in the experiments that we look at, too, is free
asparagine levels in food.
DR.
TROXELL: [Off microphone.] This is
Terry Troxell. Dr. Lineback will be
addressing this kind of issue as part of his short-term research needs that
have been outlined.
DR.
BUSTA: Dr. Troxell informed us that Dr.
Lineback will be covering some of this in the research needs in his
presentation.
DR.
ACHOLONU: Alex Acholonu.
Your
topic is formation of acrylamide, which is chemical. In chemical reactions, for ease of understanding, we have
something like A plus B, is AB, which is a synthetic reaction, synthesis.
Another
is a situation where you have AB, with heat or something breaking it down,
which is a biodegradation or a degradation process, in which case you get A,
B. You get A, B, two products, from
reacting point.
Then we
have exchange reaction, where you have something like AB plus CD will give you
AD plus BC. In this case, I was
expecting you to come up with a chemical equation to let us understand how
acrylamide is formed chemically. I
didn't seem to see any. Could you
please tell us if the formation is by biodegradation or by synthetic reaction
or by exchange reaction? Where are we
now, as far as the chemical formation of acrylamide is--the formation of the
biochemical or the chemical formation.
DR.
JACKSON: As I understand this question,
acrylamide is believed to form from at last two precursors--reducing sugars and
asparagine. Acrylamide doesn't form
unless--the amount of heat is very important there.
If you
have a food that has asparagine and reducing sugars, such as potatoes, and you
boil them, you will not form acrylamide.
So you have to have all three factors there at the same time to form
acrylamide. It's a chemical
reaction. It's not a simple
reaction. It's not A plus B.
There's a
series of reactions--Maillard reaction is a very complicated reaction. Strecker degra--there are people that have been
studying these reactions for roughly 100 years, and we still don't know
everything about the Strecker and Maillard browning reactions.
I can't
tell you that there is an A plus B because the reactions that occur in between
that do lead to acrylamide formation.
There are intermediate steps is what I'm trying to say. So it's not A plus B equals acrylamide. It just doesn't work that way.
DR.
ACHOLONU: Could you explain to me what
you mean by a precursor.
DR.
JACKSON: A precursor, what I mean by
precursor is one of the chemicals that will eventually--precursors are the
chemicals that, in the proper reaction, will form acrylamide. Precursors are the compounds that will, in
the presence of heat, form acrylamide.
DR.
ACHOLONU: Mainly, a forerunner before
something happens.
DR.
JACKSON: A forerunner, exactly.
DR.
ACHOLONU: Yes. You have told us about the forerunner, but
what of the real thing, when the forerunner participates in a chemical
reaction, it prepares the substance to be biodegraded. It helps in the biodegradation of the
chemical substance, a precursor, a forerunner, it needs that. You can call it--for instance, a vitamin or
an enzyme doing that, making it possible for the object to be biodegraded.
But our
interest now is what is the biodegradation, what is the breakdown process that
gives rise to acrylamide, and this is where we should be. What is this plus this gives this substance
we're talking about, the formation of it, how is it formed, biochemically?
DR.
JACKSON: I can't answer your question
there. Like I said, this is--what I've
shown here is information that was brought up in the past couple of
months. We're really in the beginning,
at the tip of the iceberg to understanding acrylamide formation, so I really
can't answer your question there.
DR.
BUSTA: Other questions?
Dr.
Whitaker?
DR.
WHITAKER: Lauren, you had a slide--I'm
an engineer, so that's why I'm asking this question. You said the treatment of potatoes with asparaginase before
frying drastically reduced acrylamide.
Do you know what's going on there or why that was?
DR.
JACKSON: Well, the amid part of the
asparagine gets cleaved off, and it can't participate in the reaction with the
reducing sugar. It just doesn't form
that way because if you saw the isotope-labeling studies, the amid part of
asparagine is actually the amid part of acrylamide. So once you don't have it there, it doesn't form.
DR.
BUSTA: Dr. Lee?
DR.
LEE: Lauren, I was just wondering,
based on what you now know about acrylamide, have you or your family modified
your eating or cooking habits at all?
DR.
JACKSON: No, my kids love french fries,
so that answers your question.
[Laughter.]
DR.
BUSTA: Any other questions?
[No
response.]
DR.
BUSTA: Thank you very much, Dr.
Jackson.
The next
item is FDA Action Plan: Consumption and Exposure. Dr. Michael DiNovi?
* DR.
DiNOVI: I had french fries at lunch.
[Laughter.]
DR.
DiNOVI: I'm Michael DiNovi. My colleague, Dr. Robie, and myself work in
the Office of Food Additive Safety here at FDA's center in Washington. We're working on the exposure estimation,
the exposure analysis for acrylamide.
At this
point in the day, you've actually heard every fact I'm going to mention in my
slides, so hopefully I'll be able to fill in the details when we get to the
question session and give you a little more of the information that you'll need
to proceed.
You have
to have a robust and reliable exposure estimate in order to make informed risk
management decisions. We think that the
exposure estimation, exposure analysis, is the key element of any risk
assessment. The dose makes the poison.
We will
be doing this exposure analysis the way we do all of our exposure
assessments. There will be no
difference here. It goes to the one of
the questions that came up this morning.
We'll be using, aside from the concentration data that you see here,
we'll be using the food-intake data that we've always used at FDA. So as far as that goes, this will be a
fairly routine, although complicated, process.
I've put
up the generalized definition here just to show you the model that we worked
from. This is the EDI for, estimate of
daily intake, for an individual, which of course we build up using the model to
a population estimate.
The
candle is an equal side and the handwriting is the product.
[Laughter.]
DR.
DiNOVI: What you see here, basically,
to put it in English is that you just take all of the foods where you're
finding material and you multiply the concentration in that food by the
portion, size, and the frequency with which you eat the food. So it's a food intake times the
concentration just added up over all the foods.
As you've
heard today, we'll be using the exposure data that Dr. Musser's group has put
together from the exploratory survey.
We'll be using FDA total diet study data when it becomes available. I'll talk a little bit more about the total
diet study in the next few slides.
We'll
also use data that are derived by other government agencies and the U.S. food
industry, and certainly in conjunction with WHO FAO with data derived from
other sources around the world, when appropriate.
A little
bit about the total diet study. It will
actually serve two purposes here for us.
The diet study's general purpose has been to monitor levels of nutrients
and contaminants in the American diet over the years. It's been around for a number of years. It involves using market baskets of a typical diet. The foods are prepared as they would be
consumed and then analyzed.
It
generally gives you an average number so you can monitor over time changes as
you go through the various market baskets.
It's a well-established system.
I'm not exactly sure, but it's been around for at least 20 or 25 years
now.
What it
will do for us here is two effects. We
will use it in the future from here to monitor changes, as everything we've
heard today goes to reduce the levels of acrylamide in food, we will rely on
the total diet study to show that it's working.
Secondly,
we will use it in my group, Dr. Robie and myself, to validate the model numbers
that we come up with. We always assume
that our models will be high because of the assumptions that we use. We would not want to see a dramatic difference
between the total diet study and our own.
We would know there was something wrong with our model, so we will use
it to go back and validate our model.
The total
diet study, this is probably the only information we haven't heard, is
collected from four regions in the U.S. four times a year, and the cities that
are chosen to supply the foods are changed from year-to-year, from
basket-to-basket so that they remain representative of the regions in the areas
of the country where they're taken from.
On the
food consumption side of the equation, back at the beginning, we're interested,
of course, in the foods that actually are known to contain acrylamide, as
you've heard. We'll prioritize our
decisionmaking there based on the highest levels that are currently found in
food, going down to the lower levels.
Secondly,
we're most concerned with foods that are either consumed in large amounts or by
a lot of people because in the kind of model that we've put together, those are
the foods that would tend to have the biggest effect on the overall
exposure. As you've heard, and I will
mention again, we will use our results to iterate back and prepare more refined
results as we go along.
The
second thing we really need to consider are subpopulations. We've heard a little bit of that also
today. Age and gender, eating habits
are different. This morning the
question came up, a body weight question came up, which I certainly anticipated
hearing. Not only are children lower
body weight, thus, they have higher intakes on that basis.
Anyone
who has a teenager knows, and I was involved with the exposure assessment for
olestra. French fries and potato chips
are eaten by 13- to 17-year-old boys way out of proportion to the rest of the
population in general. Fortunately,
we'll be able to take these kind of things into consideration.
Cooking
practices and cultivars based on area differences of the diet will also
matter. Dr. Acholonu's question this
morning, we will be using USDA's continuing survey of food intake by
individuals. Fortunately, these data
are perfectly designed to allow us to look at these kind of things. There are some bits of brand-name data in
there, probably not enough to make a difference. That's a question that
did come up this morning, and I'm not exactly sure how we'll take into
account. Perhaps we'll be able to use
marketing data down the road to see if that matters, but ultimately we won't
know until we finish doing the assessment whether or not it's even an important
consideration.
Certainly,
the exposure from food has to be taken in context, and you've heard that smoking
and occupational exposure are two sources that are probably going to matter a
great deal in the overall context of exposure.
The
biomarker work will help us out on this.
It may well turn out, for example, that smokers are the whole high end
of the distribution when you look at the overall picture we had. At this point, we don't know that. When we finish doing the first runs of the
analyses, we'll have a better idea.
What have
we done so far? You've heard that we've
confirmed the occurrence. Essentially,
everything that has gotten here today lead us to believe that we will not see a
dramatically different answer from what's been discussed already at FAO and
certainly earlier on. I'll give you a
little more information about the Swedish in the FAO data on the next few
slides.
The
Swedish sample, which was done in April and May, was fairly crude from an
exposure-assessment point of view. They
took the samples, the few samples they had, they broke them into eight food
categories. They took the levels that
they had found in those foods, which they knew only accounted for about 60
percent of the diet in Sweden.
They used
an expected value for the remaining 40 percent to come to the
40-microgram-per-day number that you see here--.7 micrograms per kilogram body
weight. That fed into the WHO FAO.
Information
which we again heard this morning. I'll
give you a little more details about this.
These were one-day food consumption data. That's why this is called a short-term exposure estimate. If you know anything about food intakes and
food intake surveys, the more days you survey, the lower the food intakes will
be. It's sort of asymptotically
reducing system, where you get eventually to usual intake. One day is always going to give you the
highest exposure, so that's what was done here. The Swedish residue data were used because at the time those were
the only ones that existed, and you heard the numbers this morning, .8
micrograms per kilogram at the mean and running up to 3 micrograms per kilogram
at the 95th percentile.
We also
did a longer term estimate, which were based on food intake data from a number
of places, which were, at least from the U.S., for example, two-day data,
perhaps longer from the other nations.
I'm not familiar with the exact surveys that were used, but as you see,
the numbers do go down. The means go
down to .3 to .8 micrograms per kilogram body weight per day.
Our
estimate, right now Donna Robie and I are working. We were hoping to have it finished by today. Unfortunately, we weren't able to get
everything together yet, but we'll be done quite soon, maybe as early as next
week, but we're using all of the data that you heard throughout this morning
from Dr. Musser's group.
Since
this is going to be a Monte Carlo analysis, what we will be able to do with
this is take a sensitivity analysis, which will allow us to say which foods
matter the most and which residue data matter the most. That will go back to the, that's our part of
the iterative process. We'll go back
there. Just in case you haven't seen
the iterative process enough, I have it on my slide, also.
The
residue data needs. These models are
data intensive. Consequently, more data
are better. It's easy for us, more
residue samples. That's really the only
function we need to get. We have plenty
of food-intake data from the USDA. We
will be using both the '94 to '96 USDA survey, which is a two-day survey, and
it has additional children's data from 1998.
We're
also going to go back and use the 1989 to '92 data, since that's a three-day
survey. What we hope to see there is
the effect that I mentioned before. As
you go to more days, you'll see slight lower.
Certainly,
in something found in this many foods, in commonly consumed foods, the days
will matter less because the more commonly consumed the food is the less effect
you see on those sort of surveys, so it may not matter, but at least we'll know
after we're done with it whether or not it does make a difference.
So to
conclude, we'll be using our exposure estimate to establish our
priorities. Of course, public health
considerations will drive those decisions.
The modeling process will also allow us to take a look at mitigation
measures. Once we have the model set
up, we'll be able to put in logical loops to see which foods can most affect
the ultimate exposure, and then, as I mentioned, the data will be fed back to
the various research groups that are looking further and further into the
problem.
That's
it. I'll be happy to answer any
questions.
DR. BUSTA: Are there questions from the committee?
Dr. Gray?
DR.
GRAY: George Gray. We were talking at lunch about whether
anyone has any idea of the relative magnitude of smoking exposure versus food
exposure. You mentioned it, so I'm
asking you.
DR. DiNOVI: I probably shouldn't say. I have seen some of the data I think from
Sweden. It looked to me, and I'm not
the expert, so I'll wait till somebody comes up behind me, that for the smokers
those numbers were a lot higher than the food numbers. That was my impression, even higher than
occupational.
DR.
GRAY: This was measured by the
biomarkers.
DR.
DiNOVI: By the biomarkers. Done by the biomarker analysis, yes.
DR.
BUSTA: Dr. Canady?
DR.
CANADY: Again, there's very few data
that answer this directly. Maybe
bounding is a way to approach it. It's
not ten times higher, and it's something greater than, so it's two or three
times higher, the smoking input for those smokers. Again, there's a lot of variation in the smoking level, so
getting this sort of measurement is not very easy to do.
But it's
not like it's 100 times higher, and it's probably not greater than 10 times
higher than the food exposure.
DR.
GRAY: Thanks.
DR.
BUSTA: Dr. Lee?
DR.
LEE: Ken Lee. I was wondering what do you have in mind when you say
occupational exposure?
DR.
DiNOVI: People working with acrylamide
gels or working in the acrylamide industry.
DR.
LEE: Would you expect or would you
think this is insignificant, somebody working like frying french fries, would
there be an occupational exposure?
DR.
DiNOVI: That's a good question. I would be surprised, actually. It's a very reactive molecule, and I would
guess, with all of that intense heat, I realize it's forming, but in the food
matrix, you've got a way to sort of protect it. I think once it's out in the air, I would be surprised if there
was much that actually gets up into the inhalation. I doubt you could get a lot, but I could be wrong. I don't think anybody knows.
DR.
BUSTA: Dr. Fischer, do you have--
DR.
FISCHER: No.
DR.
BUSTA: Other questions?
[No
response.]
DR.
BUSTA: You've been exposed. Thank you.
[Laughter.]
DR.
BUSTA: We're running ahead of
time. Consequently, if Dr. Acheson
wants to talk about consumer risk, are you ready?
DR.
ACHESON: Yes.
DR.
BUSTA: All right, Dr. Acheson?
We'll
continue on the FDA Action Plan on Consumer Risk.
x DR. ACHESON: Okay.
The focus of what I'm going to talk to you about is the aspects of
consumer risk, and certainly some of this has been raised earlier in the
discussions this morning.
Next
slide, please.
Basically
the question that I'm going to really discuss around is in relation to
acrylamide in food, what is the risk to the consumer?
Next
slide, please.
But I
want to begin by just reiterating the overall goals of where we're trying to go
with this, and the overall goal of the action plan is through scientific
investigation and risk management decisionmaking to prevent and/or reduce
potential risk of acrylamide in foods to the greatest possible extent. One of the sub-goals of that relates
particularly to consumers, and I've put that on the bottom half of the slide,
where we want to inform and educate consumers and processors about the
potential risks throughout the assessment process and as knowledge is
gained. And I think that's an important
element here that, as we learn new things, our goal is to communicate these to
the relevant individuals, whether they be the consumers or industry or whoever.
Next
slide, please.
We see
this as primarily trying to achieve a balance between a lot of complex issues,
and I've really put here the three items that I see as the most critical part
of this balance. The first is the
importance of a balanced diet, and, again, there's been some discussion of that
and I'm going to come back to that. The
second is a lot of what you've heard about in terms of the risk from exposure
to acrylamide in food and just exactly what those are. And then the third part of this balance that
I think is critical is the dangers of inadequate cooking, which I think we have
to keep in mind.
Next
slide, please.
So in the
context of this whole complexity in risk management, what we don't want to do
is to create one problem by solving another, and that's always a consequence of
risk management strategies. And,
therefore, maintaining this balance is a critical part of where we have to go
with these problems.
Next
slide, please.
You've
heard about a number of potential risks of acrylamide exposure, both through
occupational but obviously the focus here is on food. And, principally, these have involved issues that relate to
neurological consequences, reduction in fertility, effects on germ cells, and
the role as a potential carcinogen.
Next
slide.
So what
do we know now about some of these areas?
The prior speakers have addressed a number of these issues. We've heard a little information about
animal studies. You've heard a lot
about the variability between foods insofar as our exploratory data has gone to
date. And you've heard a little bit
about what's known about human exposure through international studies and what
we're going to do to try to address that.
And, obviously, the key element is to get a better understanding of the
risks related to these various factors.
Next,
please.
This
whole area is generating a bunch of consumer questions, and what I've done here
is just to list some that just came off the top of my head, and I don't really
think these necessarily capture them al, but these, I think, are important
issues. For example, will eating
certain types of food cause cancer?
What is safe to eat? Should I
stop eating certain types of food?
Should I be cooking foods differently?
What should I be doing differently to protect myself and family? And what can I do right now?
Next
slide, please.
Obviously,
one of our goals is to get answers to these types of questions, and the
strategy is to address as many of these issues as possible with the goal of
protecting public health. And you've
heard about some of the mechanisms that we're going to undertake to achieve
those goals, through toxicological studies, studies on the formation of
acrylamide in foods, epidemiological studies, and risk analysis.
So what
about the risks to the consumers? And
in order to develop the most appropriate kind of consumer advice, we have to
understand these risks as best as possible.
And I just listed here some of the questions that relate to that
understanding. How much acrylamide are
consumers exposed to? And you've heard
about the mechanisms where we're going to try to address that. A key question is: Are there toxicological effects from this level of exposure? We may be able to determine a level through
exposure and the amount in the food, but are those toxicological? And what are the factors that lead to the
generation of acrylamide? Clearly, that
is a key element in terms of generating the right consumer advice.
The
action plan is going to address these issues, and the correct consumer advice
will address multiple factors and issues:
the variability that we've heard about, the effect of different types of
cooking on acrylamide levels, and, most importantly, I think, the need to
maintain a balanced diet.
Next
slide.
So to
come back to my three points--the importance of a balanced diet, the risks from
exposure to acrylamide in food, and the potential dangers of inadequate
cooking--what I want to do now is to just go into these three in a little more
detail.
This, I
think, is a key slide of where we are right now, and that is, maintaining a
balanced diet. What you see here is the
food pyramid, which I'm sure you're all very familiar with, and to point out
that there are components in various parts of this pyramid that have been
implicated as sources of acrylamide. In
the bottom part we have breads and cereals, which certainly have been
documented when cooked in certain ways to have acrylamide. I think the other key point, though, to
emphasize here is that some of the food groups that have been emphasized as
having been high in acrylamide, foods that contain lots of fat, are already at
the top of our pyramid, and the recommendation is that they should not be
consumed in excess anyway.
Next
slide, please.
So,
again, to emphasize this point, we mustn't lose sight of the current dietary
guidelines in the context of what the consumer messages are, and it's important
to eat a variety of foods, to balance the food you eat with physical activity,
choose a diet with plenty of grain products, vegetables and fruits, choose a
diet that's low in fat, saturated fat, and cholesterol, moderate sugars,
moderate salt and sodium, and moderate alcoholic beverages.
Next
slide, please.
So coming
back now to the second point of the risks from exposure to acrylamide in food,
and one of the key questions here is whether some consumers are at greater risk
and whether the message needs to be a little different depending on the type of
consumer. And you've certainly heard
some of the issues that are coming in that regard, principally age of the
consumer, and there's already been a little discussion on the fact that
children and teenagers will consumer larger amounts of food in relation to body
weight.
This is
also reflected in the trends of consumption, and, again, different types of
ethnic groups, different age groups, have different consumption patterns. All of this has to be built into the advice
that we try to come up with.
I think
it's also key here to keep in mind the risk from acrylamide in food relative to
other risks from food and, again, not wanting to create one problem by solving
another. And we've already--there's
been a little discussion earlier in relation to other carcinogens in food. How does acrylamide stack up against
that? And how does acrylamide stack up
again other issues in relation to food in regards to foodborne pathogens, which
is what I'm going to come on to in just a moment.
Next
slide, please.
So to
stick on this theme of the risks from exposure, again, we're back to the
variations in level, and we have to determine what that means in terms of the
risk. And, again, I want to emphasize
this point on whether will the levels seen in foods pose a significant risk,
and we really have to try to make that determination to come up with the correct
message.
The third
point of this balance is the cooking.
We've already heard and we know from both the studies that we've done
and studies that have been done in many other parts of the world that cooking
certain types of food did elevate acrylamide levels. But, again, a key point, are these levels harmful? We don't know yet.
Cooking
food properly is certainly a key food safety issue, and using lower
temperatures or shorter cooking times may increase the risk of infection from
foodborne pathogens. So we have to be
very careful in terms of maintaining this balance of what advice, what consumer
recommendations we make in relation to cooking temperatures.
Next
slide.
Sticking
with this theme of cooking, we certainly know from the data that we've obtained
to date that some food items generally contain higher levels of acrylamide than
others. And some of those that Dr.
Musser has already talked about relate to breads and fries and chips. These typically are not foods that one would
associate with being sources of foodborne pathogens. But others are much more likely to be, and we can probably come
up with many different examples. The
one that I've put there on the slide is a combination where you may be roasting
chicken with potatoes, where clearly you want to cook the meat product adequately
to ensure that foodborne pathogens are taken care of, and yet in the context of
potential acrylamide formation in the potato, you may want to limit that.
So the
consumer messages in the context of cooking temperatures may not be that clear
to figure out, and the last thing we want to do is to give a message that
reducing temperatures may be the answer if it increases risk from exposure to
foodborne pathogens.
Next
slide, please.
So, as
I've said, the correct message is critical.
Using lower temperatures or shorter cooking times certainly may increase
the risk of infection from foodborne pathogens. Lowering cooking temperatures may lead to higher residual fat
contents of certain foods, which is probably something else that we may not
want to encourage. And we certainly
need to be very careful not to give the impression that cooking all food at
lower temperatures is a good idea just across the board as a single, straight
message.
Back to
achieving a balance. Only by
understanding the risk can we develop the appropriate risk management advice to
maintain a balance of food intake and food safety, which I believe are two of
the critical elements that we have to keep in mind when we're trying to come up
with the correct consumer messages.
So where
are we now? Our current consumer
message is that consumers are advised to eat a balanced diet, choosing a
variety of foods that are low in fat and rich in high-fiber grains, fruits, and
vegetables. And as I pointed out with
the food pyramid, if the messages are followed, that will certainly limit
exposure to some of the high-fat-content foods which have already been
indicated.
CFSAN is
going to continue to revise the consumer message--and that's an important thing
to get across--as new information is obtained during implementation of the
action plan. And these messages may
related to dietary choices, they may relate to cooking methods, and they may
relate to the risk of this issue as we discover more in relation to health.
Next
slide.
Finally,
clearly this is a complex problem, and as you heard from a number of the
speakers, we know that acrylamide has been in food for many years. But now that we know that, we have to
develop a management strategy in order to deal with it. We have to develop messages, and we've got
to develop messages for industry, for retail, and consumers. And I think this may not be the same message
for all parties, even though the overall goal will be the same. And our plan is to work with stakeholders to
maximize public health safety in the context of the balanced message that I've
tried to get across.
Thank
you. I'd be happy to take any
questions.
DR.
BUSTA: Questions from the
committee? Dr. Acholonu?
DR.
ACHOLONU: I have a general
question. It is believed that
acrylamide is used for treating water, and as long as it's a polymer, there is
no dangers, but some document--still, there are some that are contained in
water that we drink. Has EPA or FDA set
a standard, the minimum limit of the concentration of acrylamide in water that
we drink? If you don't understand my
question--
DR.
ACHESON: Oh, I fully understand your
question, but there may be somebody here who knows what EPA has done. I am not familiar with what the EPA standard
is, if they have even set one.
DR.
BUSTA: Dr. Canady is approaching the
microphone.
DR.
CANADY: This was actually discussed a
little bit earlier today, and there is a treatment technology-based control for
acrylamide levels in drinking water that EPA has set. Again, it's based on the treatment technology, which is to use
the polymer to remove sediment, and the control is on how much of the monomer
can be in the polymer. But that is the
control that's available by EPA.
DR.
BUSTA: Go ahead, Dr. Downer?
DR.
DOWNER: I concur with all you've just
said. My question is simply this: As a clinician, the challenge of John Public
to have a balance, what you call a balanced diet, which we commonly refer to as
healthful eating, has been a challenge.
DR.
ACHESON: Yes.
DR.
DOWNER: How do you see this message
attached to the eating plan that we've developed for John Public making a
difference and improved on, in fact?
You know, the obesity issue is here, the lack of physical activity, and
I don't think the public is not aware of what we recommend for them. I think many subgroups and subpopulations
have not tied into, have not been brought in fully into some of the
recommendations we have made because they're so generic. And one of my big fears is that if we don't
get them on board, and get them on board early, some segments may take away the
message that we should never eat potatoes again, we must never do such a thing
again.
And I'm
just curious. How do you see the
message of acrylamide being integrated into the healthful eating plan that we
have already laid out that's not being followed?
DR.
ACHESON: I think you have just hit on
one of the key complexities of trying to figure this out, because as you so
rightly point out, we have some pretty clear messages already that currently
are falling on a number of deaf ears.
One of
our challenges is to try to get over the correct message in the context of all
the other aspects of diet in relation, as you point out, to obesity, a number
of other critical issues that require attention.
One of
our concerns is not to go out with the wrong message too soon, because as you
point out, what we don't necessarily want is to have the public say we
shouldn't eat potatoes. That's why it's
important to maintain the current message until there is very clear evidence to
switch it.
Now, what
you're asking me perhaps is what's the mechanism that we're going to get that
message over, and maybe we would be looking for some Advisory Committee help on
that.
I think
it's very complicated, and we have to try to get it right.
DR.
FISCHER: I have a question.
DR.
BUSTA: Sure, go ahead, Dr. Fischer.
DR.
FISCHER: You say in one of your slides
achieving a balance, toward the end, that only by understanding the risks can
we develop the appropriate risk management advice to maintain balance of food
and food safety.
I'd like
you to tell us, if you can, what are the criteria that you would use to let you
know that you now understand the risk so that now you can begin addressing the
acrylamide questions that the public have.
Basically I'm asking you to try to find out when this might be coming
about, because understanding the risk, knowing the risk, or having a good idea
of it, even, is going to take quite a while, I would imagine.
I guess
I'll end with saying I don't think you can wait that long to talk about
acrylamide, because what you're going to have to do is change some
behaviors. If, in fact, there is a high
risk, you've got to get people ready for this.
DR.
ACHESON: I certainly don't want to
leave you with the impression that we are going to wait until we fully
understand the total complexity of this before we say anything. And I tried to make that point in the latest
slides to say that, as we learn new things, we are going to go out with new
messages.
What
we've got to do is to make sure that we don't give the wrong message and that
this message is put in the context of the many other aspects related to food,
whether it be due to food safety or eating too much or, as your colleague was
saying, obesity in relation to the food pyramid.
It's
certainly not our intention to wait until all the data has been acquired,
because I come from academia before this position and I know you never can ask
enough questions. There's always one
more experiment. So that's not the
intention that I want to leave you with, that we need to understand this fully.
Coming to
your last comment, if we determine that there are some significant risks or if
somebody else determines that there are significant risks, part of the
clearinghouse situation where hopefully there will be the sharing of
information, then for sure it would be appropriate to come out with the right
messages.
DR.
BUSTA: I have a comment. The term "balanced diet" concerns
me because it's so broadly used. Some
people think of it as a 30-30-40 diet.
Some people think of it as a pyramid.
Maybe some people don't consider that pyramid the right pyramid.
I
frequently don't find people think of a balanced diet being consistent with the
dietary guidelines necessarily, and I think that that appears to be a term that
may or may not indicate variety, although the dietary guidelines lead off with
variety. So in that message, I'm a
little concerned with that.
I was all
the way through here trying to see the role of the research and how the
research is going to keep feeding into this and how it's not going to
contribute to the lament of the consumer that this is the concern of the
month: I'm not supposed to do this, I'm
not supposed to do that, put a label on this, put a label on that.
How are
you going to respond to good research with a message to the consumer without
just getting in line with all the other concerns and, in fact, diffusing the
response of the consumer?
DR.
ACHESON: Those are very critical
questions of how we deal with this. You
raised the issue of what do we mean by a balanced diet, and there are certainly
nutritionists who question the food pyramid.
I think
the critical message is to continue to eat plenty of fruits and vegetables, et
cetera, et cetera, along those lines.
Now, whether you specifically prescribe to the pyramid or not is in some
ways moot. But it's a guide.
What we
want to avoid is confusing the issue, and maybe that's what your--that's
underlying your question, that there's already a lot of complexity out
there. And although the focus of this
meeting is on acrylamide, as your colleague points out, there are many other
aspects in relation to food consumption, whether it be food pathogens, whether
it be simply that people eat too much or too much of the wrong thing.
We have
to figure out a way, the simple messages that take into account the science,
and that was the other part of your question.
How does what I'm talking about relate to the science? Well, lt's take some very specific examples.
Supposing
the science demonstrates that cooking certain types of food for excessive
periods of time is clearly associated with very high levels, and it would
suggest that maybe it's going to go that way.
But you need to determine, well, what's the significance of those
levels. Then you could potentially
develop guidelines along that track or advice along that track to say, well, we
recommend that certain types of foods not be cooked excessively.
And,
again, I think the science, as we understand more about the formation that's
outside of cooking, due to the levels of asparagine and other chemicals, you
know, maybe there is some advice there on the industry side that has nothing to
do with the consumer. So far we have focused
on consumer advice, which is a key part of this, but I am linking, you know,
what industry may be doing as well as part of that in terms of trying to
minimize acrylamide levels. So it
shouldn't be focused solely on what you and I are doing in our kitchen.
DR.
BUSTA: But you bring up the food safety
issue on microorganisms, and, of course, if you boil it, you're in good shape
both ways. But I know of food
microbiologists who find a real problem with the message of eating more fresh
fruits and vegetables, and yet the fresh fruits and vegetables are being
implicated in more foodborne illness situations.
DR.
ACHESON: But, of course, you wash them
first, right?
DR.
BUSTA: As I said--
[Laughter.]
DR.
BUSTA: I love washing raspberries. It's so effective.
[Laughter.]
DR.
BUSTA: And so these balances of
messages are really a concern. Thank
you.
Dr. Lee?
DR.
LEE: Along those lines, has there been
any discussion at all of acrylamide labeling or, for example, where does
acrylamide stand in California Prop. 65?
DR.
ACHESON: I frankly can't speak to
either of those. I'm not aware of any
discussions of acrylamide labeling, and I couldn't speak to the issue of
California. I don't know.
DR.
BUSTA: Are there other questions? Questions?
[No
response.]
DR.
BUSTA: Thank you very much.
The
prerogative of the Chair says we will take a break right now, and we resume in
25 minutes at 10 after 3:00 to hear Dr. Lineback. I will start at 3:10.
[Recess.]
DR.
BUSTA: If we can reconvene the meeting,
please. We'll now hear from the Joint Institute
of Food Safety and Applied Nutrition, JIFSAN.
Dr. David Lineback, the director, will be talking about the Chicago
conference--is that right?
DR.
LINEBACK: Thank you very much. It's good to be here.
The
background that we came from really started the afternoon of the Swedish press
conference release. I have taught a
short course in starch chemistry for about 20 years, and when Reuters made the
mistake of saying that acrylamide was formed by the eating of starch, I thought
that was hilarious. So I called three
of my friends that taught with me and I said, well, now, can you explain
this? Is this transformational
heating? And about two hours later, I
got a call from one of our major food industries. They said, Dave, I think we have a problem developing. I happened to chair the scientific advisory
panel for the AECC, and they said could you take this on and begin to monitor
it? So that afternoon I called two or
three others.
And that
really started the story of how this whole thing started developing and my
involvement. We began discussions with
a group of about six or eight of us looking at mechanisms particularly, and by
the time that we had one of our last phone calls, the planning committee had over
30 on it. And we have a larger group that
has been meeting together by conference call since that time.
It became
apparent that one of the things that was needed was a workshop in which we
could concentrate on the science issues, the sciences behind many of the issues
of the acrylamide situation, and in an environment where we could openly
discuss this. So we had the meeting in
Chicago. It is a workshop. The dates are there.
The next
slide--the focus was on science. And I
come back to this and keep harping on it because at about the same time, Europe
was having their meeting on the 15th and 16th.
In my talk to Martin Slane [ph] in the EC, he was really caught up by
"you're science, you're science."
And I said, yes, that's what we're about. Because they were going to get into some of the policies with the
15 member nations. But ours was the
knowledge gaps and the research priorities.
And this
is the target audiences that were identified in their orders of priority. The prime audience was the American food
industry that was participating, then academia, and then the regulatory
agencies domestic and international.
Next
slide. What we were really looking at
was how can we get the various players--industry, academia, and government--to
work together collaboratively and cooperatively in addressing the issues so
that we can maximize the limited funding that all of us have to devote to this.
In the
next slide, these are the actual goals and objectives. To identify the data gaps--now, one thing I
should point out is that when we did this we were working post-WHO/FAO
consultancy. So that became the
base. The file report from that and its
recommendations became the base from which we operated. We did not try to go back before that.
So,
really, get the data gaps. And
we--there's an international perspective, but we hadn't really thought about it
first, I'll point out in a couple of moments, because we had so many of the
internationals begin to contact us and say can we be part of this.
To look
at some research needs and then, out of this, to identify a select number of
high-priority research needs to be included in a coordinated research agenda,
which we are going to work to develop.
And
finally, the Workshop Planning Committee, a group of about 30 to 35 of us
talking about we're going to identify a list of short-term action items and
actually lead on to the action part of this.
This was
an invitational meeting only because we wanted to concentrate on the science,
so we brought mainly the scientists to the table. We had 171 people accept the invitations and 170 of them attended
the meeting. So I thought that was a
pretty high attendance level.
There
were a number from outside the United States.
And I just had this down--you've heard several of these names
today. We could say that the major
players were here. Karl-Erik Hellenas
from Sweden was involved in the original work of Margareta Tornqvist, who was
also here; and Leutzow from Rome.
Dennis Marroni is with one of the largest--probably the largest
acrylamide manufacturer out of Europe and has an extensive background in the
toxicology of this.
In the
next slide, you'll see some of the names that you've heard today. The ones from Japan--Japan was just starting
to do its work on the analysis of acrylamide in Japanese food. And Dr. Goto [ph] and the National Food
Research Institute was doing it, so he sent two of his people over to be part
of this meeting. And then, of course,
WHO was there, and you've heard -- Stadler.
Varelis was doing the work in Australia.
In the
next slide, we had five working groups.
And each of these working groups prepared the straw man position paper
specific to their area. This was set up
with 20 invited participants and up to 20 observers. The participants were supposed to be the active participants; the
observers could make--every once in a while.
But when we got to the meeting, that broke down rapidly because we had
quite a few of our internationals here and a lot of the other observers, that
they just got involved in the participation right away; the chairs of each of
these groups involved them. So, really,
the mixture of participants and observers soon became a pretty large group of
participants.
Each of
these had a series of seven questions that they were going to address in
general, plus specific questions for their group. And in the next slide, the kinds of questions are what are the
primary areas concerning occurrence--I have these listed so you can go through
them.
We were
doing this to try to pull us together so that when we made the final report in
the last morning we were working from a common set that we could all come back
and address. And if you know, working
with a group like that, when the five groups got together they went all the way
from totally disregarding this and using the approach that they wanted, to
going down question-by-question. So if
you happen to look at the proceedings on our website, you'll see the very--they
get it covered, but not like the way it was planned.
The next
slide has three of them. We were
interested in what missing information is needed to enable the proposed
research. Quite often you see a
research area you need to get started, but some of the information to actually
initiate that is lacking. So we were
trying to identify that. And finally,
we were trying to rank these research areas.
The next slide has one.
And then
a very important point is how did these groups link together? If the tox group was making a
recommendation, was there knowledge needed from one of the other groups to
effectively do that? So we had the
groups trying to identify with each other.
In the
next slide, the proceedings are now posted on our website. Now, the "proceedings" are in
quotes, because they're not true proceedings.
So if you go in and think you're going to see something very
standardized, you're not. You're going
to see what happened at the meeting with the outcomes. And each of the groups--we said a limited
number. Well, a limited number of
scientists is anyplace between 1 and 20, I think. Because some of the groups had two recommendations, up to about
20-something. So at the last morning,
we took those and let each of them give one or two of their top priorities,
which we put together in a larger group.
Then
after the workshop was over, the planning group went over those and identified
a set of what we called "action items." In the next slide, we start those off, and you have them
listed. I'll cover them briefly.
The
analytical methods was to establish proficiency testing program and
materials. One thing I'd like to point
out is we're not unique. If you look at
what's going on around the world, if you look at the Swedish group or you look
at the Nordic countries now, with Norway doing--Sweden coordinating part of--very
similar recommendations are being made in almost all of those areas, including
the EC meeting on the 16th of October.
Toxicology
was to develop data on the absorption, distribution, metabolism, excretion of
acrylamide, to develop and conduct studies on the DNA protein, glycidamide and
acrylamide adducts to determine the metabolic consequences. There's a real question about the
glycidamide and the acrylamide adducts as to measurement and is the adduct
really a measure of exposure, is it a measure of detoxification? How does it play into this?
In the
next slide, the methods of formation.
You've seen part of this extracted today, so I don't think we need to
dwell on that.
In the
next slide, the methods of formation, of course, you've just seen today
two. The second one, looking at some of
the kinetics, needs to be done. I think
this is being done in some of the laboratories now more, in the organic
laboratories, where they're looking at it in the organic models. This not a food model system, but some, like
you saw out of Stadler's and Moltram's lab.
Then the
next slide, exposure. This is one that
is being looked at now in several areas around the world. In fact, on the Infonet we just got
a--coming out of Poland, where Poland is now looking at the measurement in
their foods and the number of foods.
And they're going to look in exposure there, which I thought was very
interesting, to see this come out of that sector of the world this soon.
The next
slide, the risk communication. We
brought that in at the last because I think it's come up today quite well, is
the issues that we face in this communication area--they had several others
besides these action items, which were to conduct some attitudinal
research. We've been asked to formally
document the unique process used to develop and accomplish this. Because I don't--I've been around for
awhile, but don't remember ever seeing an issue that has the extent of
cooperation globally that this is developing in a very short time that we're
seeing today at government level and also at industry level. And I'll point that out in just a moment.
So
they've been asking us how do we make this work, how do we get all these people
together in such a short time and get this participation. I think there are some unique things it
takes to do that, but we'll be looking at that.
In the
next area, an information clearinghouse, which we'll come back to. The Acrylamide Infonet is going to satisfy
part of that.
Now, what
are we going to do with these short-term action items? Actually, day before yesterday, we had a
conference call of the five work groups and two of us that are heading this,
and we began to take these and say, okay, now, how do we reduce these to some
project outlines which are truly high priority, that we can now get action on? So we'll have those with who might be able
to do it--private sector, industry, government; where is it logical to be
done? What will it cost? And what kind of time frame do we need this
information in?
We plan
to have this by about the 15th of January, going back to that larger group of
50 or 60 I was talking about, to share this with them. And then the rubber hits the road, because
we'll talk to them--who's got the money, who wants to invest in this, do you
want to do it as an individual corporation, as a trade organization? Do you want to pool money through an
academic institution or through something like JIFSAN? And we'll try to fit these up and actually
get work started in each of these high-priority areas.
Now, the
Acrylamide Infonet started out to be the WHO/FAO Acrylamide and Food Network,
which was one of the recommendations coming out of the expert consultancy in
June. They came to us because we
already had a risk assessment--this analysis clearinghouse we were operating,
and asked us if we would do it. If
you've worked with WHO or FAO, you know that they have a very endearing way of
doing this. And just at the last, when
you say what kind of resources do you have available, they say, we have our
minds. You know, go ahead and run it
for us.
So we got
it up and running. Now, it will
function as a global resource and inventory of ongoing research,
surveilles. Right now, there are two
sections that are online, and that is what we're calling a research section,
and a literature section is under it.
When you
come in and look at it--and the URL's up there, when you come in, you'll come
into a page that just says what it is, something like what you've got
here. Down at the bottom, it will say
to go on to the research page. When you
get to the research page, it's going to ask you do you want to enter data or do
you want to enter a research project, do you want to search, or do you want to
send us a message? You've got all three
choices in there.
Let's say
that you're going to come in--we'll use FDA's announcement this morning,
because I've been after them already because they're a partner in this. They'll come in and, where it says
"research," they'll hit the research button and want to put in some
data. They're going to have a choice of
several boxes, ranging from analytical methodology to a research project to
neurotoxicity to carcinogenicity, and you may check more on what it's in.
So this
morning, they may come in now and check that they've got acrylamide content in
food--they'll check that box. And when
they do that, then there's--you'll have a lot of information in there that
you're going to furnish us. Only about
half that will ever be made public.
Because when you come in to search the other part, you'll see the
project, you'll see the thesis that's being tested, you'll see the organization
which is doing it. And if they want to
put an address, they will; if not, you'll see maybe a URL. The Japanese came in yesterday and put their
food data in that they had just released this week, and so they have the URL
right into where they're data site is.
We have
a--somebody asked about the asparagine content of foods a while ago. We have a literature search from the
University of Wisconsin--FRI was first put in.
It says "literature search," and when you go to that, it gives
you the website address and takes you right into their website where that
information is. We're not actually
putting the information now into our own site as much as we're linking where it
is. And so you would be able to see that
and go into--find where that data is in all these other areas.
Now, in
the next, oh, one to two months, we'll expand that so that there'll be a
discussion area, there'll be a Q&A session where there'll be area where
scientists can discuss, we may have actually more--some may want to actually
have some data that has to come in, then we'll make some arrangements for
that. We'll get down into the larger
part, then, where it acts as a discussion forum and a network for active
researchers and others in the field.
Periodically--and
we're still working with FAO and WHO to identify what the timing is on this--we
will actually have little summaries.
We're not going to summarize data, but what we're going to do--let's use
the analysis for example. If we begin
to see departures from what have been the trends, what's been reported, we'll
flag this, that here are some data or here are some reports that are beginning
to move this to higher levels or in another direction that may represent a gap
to us.
Next
slide. I would like to, really, just
close this off by indicating, as I mentioned, the cooperation. When we had put ours together, the EC
decided to have a meeting on the 15th and 16th with a very similar goal to what
we were working with. They actually
were moved to the 16th--they backed it up to the 15th and invited 15 member
nations in. They had little problem,
which anybody does if they've got 15 member nations all doing their own things
and they're trying to get on a coordinated basis so that they can head them in
the same general direction. And you
know what I mean, it's like herding mice when you're trying to get something
together to get them--where they're already in various procedures. In fact, Norway has got a very formal system
of collaboration involving a number of their industries, too.
And
you'll notice that they have the science committee of the EC, the WHO, the
JECFA that is going to work on the toxicology and bioavailability, the CIAA,
which is the confederation of the European food and drink industry, is forming
the bridge between industry and the EC.
Dominic Tyman [ph] was over here last week. We visited. So we're
coordinating with them.
And the
next slide, the last one, it's interesting to see that they took the
organization that we were using in the USA for the five work groups that I
identified before, the organizations that took responsible. One of the unique things about our meeting
was each of the areas and organizations took the responsibility for a white
paper and for putting it together.
You'll notice Europe did the same thing. And in some places, we have the same organizations, like where
ILSI is involved or IFIC is involved, we have a corresponder there. So this is also enabling these groups to
link to each other now, because of the similarities as well as they already had
contacts.
That
pretty well is what we have put together as the meeting and the peripheral
parts that went with it as far as getting the--it's up on the Web, the
proceedings are--getting the Infonet.
They decided they want to go with Acrylamide Infonet, it's shorter,
people can remember it better, and so we've done--
And also,
looking at what Europe--again, you see the group that we're working with now
extends through Europe, Australia, Japan.
We have contacts with all of these now coming in. We're trying to get the Dutch data that came
out last week. I was in contact with
them yesterday, so we're trying to get it linked in and available to us.
So I'd
encourage you, when you want to--we don't have very much on yet, but if you
have projects or anything--and you don't have to feel like you're giving away
secrets, because the descriptor box can be as brief as you want it. If you're an industry or a government organization
and just want to say "we're working on mechanisms" or "we're
working on analytical values in foods," you can do that. The main thing is to find out who's doing
what around the world.
Thank
you, and I'll take an questions.
DR.
BUSTA: Questions, anyone? Dave, let me know how this is going to link
with the research plan of FDA. How is
this--are they just going to--is FDA going to just draw on this, or is there
some kind of formal connection?
DR.
LINEBACK: Well, there is some formal
connection because, you know, JIFSAN is a partnership between FDA and
University of Maryland. So, of course,
as we've put this together, we have weekly meetings of what we call our working
group. And as this develops, we're going
back and forth. You have to realize
that in many ways the FDA plan is very similar to some that we've seen being
developed from the other countries. So
as we monitor these, you know, we're changing this information back and forth.
So we're
hoping--and I hope they're hoping the same thing--that quite a bit of the
information coming in here will be of direct use to them as they look at the
various aspects of their action plan.
That was one of the reasons that we said yes, we would go ahead and do
this working within our current resources.
DR.
BUSTA: Does FDA's action plan get fed
into this directly?
DR.
LINEBACK: Well, I hope it will. We just haven't made a link with it yet,
because there's no reason why it shouldn't.
There's no reason why quite a few of the action plans shouldn't be in
this so everybody can look at them and see the similarities. We just hadn't made the link with them. We sat down and talked a little bit about a
meeting yesterday, but we haven't gotten back to some of these yet as to what
we link.
I think,
as we all know, we think it's very essential and they're planning to do this,
because this is one of the leadership things we'll show the world from here, is
that we're putting our information in there.
The industry has assured me that if we can blind part of their data,
they'll come in too. And so if we can
begin to get this, it will encourage sharing among the other parts of the
world.
DR.
BUSTA: Dr. Lee.
DR.
LEE: Dave, what incentives are there
for handling proprietary information?
DR.
LINEBACK: We're making those
provisions. I think I can give it to
you in outline. This has not become the
problem in some other parts of the world that it has here, yet. It has become very much of a problem in
Germany. By German regulations, even
though their government has made some of the analyses, they cannot release the
analyses unless there's an imminent health problem. So it's a Catch 22. Since
they can't prove there's an imminent health problem, they can't release it. They went to their industries and asked
their industries if they would release the data, and the industries said no,
they would not. So they're having to
take a very different approach to it.
They now are working with the industries to analyze the foods and they're
going to take the 10 percent worst values in each of the food groups and then
say to the industry can you lower the content?
But what
we're doing in this is, I think that as the data--as we can get the data coming
in and look at the research values--we talked with the WHO and I've talked with
our industry extensively--they're not going to be comfortable. And I don't blame them. I've been on record saying we don't want to
do it this way. So we have found out one
or two ways that we can blind data and protect the industry in doing that. One of them would be to go through a trade
organization, and if the trade organization doesn't want to do it, they can go
through their attorney firms. I've
worked with two of the attorney firms and they say, you know, you're getting
into attorney-client relationship. So
that doesn't give them a real problem.
We've done that in other cases, other areas in this.
So we're
looking at the ability to do that. I
cannot do it. So I don't want any data
like that coming to me unblinded, because we're -- like the FDA is. But I've been assured that we're getting
very close to having it work out so that we can have the data blinded.
DR.
LEE: Just a follow-up. To you think there's any danger of biasing
the acrylamide-content-of-food information if there's an incentive to show that
you've got low acrylamide, but there might be a disincentive if you were very
high on the spectrum--of sharing something like that.
DR.
LINEBACK: Well, I think, Ken, you have
to look at it two ways. Here in the
United States, if we can put it in without revealing the industry or the
product, then we don't have to worry about the top 65 in that case, because
this is blinded. You can't do it. There's quite a few people in the world that
I've talked with now, including in the EC and in CIAA, that, again, feel we
have about all the analytical data we need in most foods now. There's just a whole bunch of foods that we
don't have. Those are the ones that we
need to concentrate on. Because right
now, we seem to be refining the extents rather than, you know, doing much-- So
yes, some people would like to come in lower.
If you saw what was released this morning, there's quite a variability
anyway. And so I think what's going to
happen is there is not going to be as much a danger, as much pressure to do
this, particularly if the data is blinded.
Now, when
it goes to JECFA, for their meeting for the risk assessment, it goes in in
what's called the Gems [ph] form and through the WHO site database, and there
it's aggregated much more. Like where
here in the United States we have our different breads, for example, our backed
products, there they have breads and rolls together with only a very limited
number of categories under that. And so
while we would not find it satisfactory in looking at our own food supply, it
gives them the data that they want to use in a risk assessment.
DR.
BUSTA: Other questions? Dr. Kuzminski.
DR.
KUZMINSKI: Dr. Lineback, just to build
on a discussion I had with Dr. Jackson at a break. And the discussion I had with her related to will they validate--will
the center at Argo validate some of their model findings that were initially
driven by the discovery in finished product back to the model findings--will
they validate those findings in pilot process technology? And Dr. Jackson can correct me if I got her
answer wrong, but the answer to that by her was yes.
And the
next question that I asked was do you have access to all of the technologies,
the process technologies that have contributed to this finding of acrylamide in
finished product? And the answer to
that was no.
So I
guess my question to you, sir, is how can JIFSAN be used by the various
partners that you've outlined in your second-to-last slide in terms of
assisting the agency to find those technologies that they perhaps don't have in
their own resource stable, yet need to validate some of their mechanistic
findings?
DR.
LINEBACK: That's an excellent
question. Of course, as you well know
from your own background, a lot of this is going to depend upon the openness of
many of the companies and the technologies, so we can get at them. And that's been one of the concerns. Now, in the Norway approach right now, and
Sweden has also -- but Norway started out with 64 people from all the
areas. They started out: Acrylamide in
food, what do we do?
And they
brought these together. And they got 13
companies in Norway who are actually--they're in the bread area and in the
potato chip area--who are actually working as their laboratories, using many of
the commercial processes. So as they
feed it back into a small panel of scientists, which are going to meet three
more times before next August. They
look at what's come in, they evaluate it, and they shoot it back up to the
companies themselves to use the various technologies. Now, we're hoping that more of that information will become
available as they move along, which we can then look at in our systems.
Another
approach that's being used to some extent by the bakery area is using AIB, with
its standard formulas, and then modeling some of the different technologies
used in the bakery industry to look at the processing effect.
But you
know as well as I do, it's only going to be how well can share getting into
those various technologies and how widely they're used.
DR.
BUSTA: Other comments? Thank you very much.
We now
are in the section on public comment.
Three individuals have registered to make 10-minute public comment
presentations.
The first
one is Dr. Henry B. Chin, vice president, Center for Technical Assistance,
NFPA--National Food Processors Association.
DR.
CHIN: Thank you. Good afternoon. My name is Henry Chin, and as Dr. Busta said, I'm Vice President
of the Center of Technical Assistance for the National Food Processors
Association. I also serve as Chair of
the--excuse me. I also serve as staff
secretary for the NFPA Toxicology Committee, and I was the Chair of the
Analytical Methods Working Group during the recent JIFSAN Analytical Acrylamide
in Foods Workshop. So I'd like to make
a few comments.
Ever
since the news release by Sweden's National Food Administration on the findings
of acrylamide in food, NFPA and the food industry have been actively working to
get a better understanding of this issue.
We recognized early on the need to address questions regarding the
reliability of analytical procedures, and that's why we were involved with the
proficiency testing early on, sources of acrylamide in the diet and the
underlying issues about the relevance to public health.
We
recognize that considerable progress has been made on these issues in a
relatively short time, and efforts and actions to increase our understanding
continue. We believe that the template
as provided by FDA's Action Plan is a valuable aid toward expanding our knowledge
base.
Now, FDA
and WHO and nearly every other recognized authority on this issue have stressed
that consumers should continue to follow established dietary guidelines and eat
a well-balanced diet consisting of a wide variety of foods in moderation. We are in agreement with both expert bodies
that more information is needed to help assess the true public health
significant of acrylamide in food.
During
this time, NFPA has actively sought information from many experts, raised many
questions, and considered many research proposals ourselves. During our comments this afternoon, I'd like
to share some of what we've learned and offer our thoughts on FDA's research
plan.
This
morning we heard the details of FDA's research plan and accomplishments to
date. Based upon what we know
now--well, we believe that while the collection of analytical data is
important, as was mentioned, we also believe that the data needs to be put in
proper context. Based upon what we know
now, any collection of animal data on levels of acrylamide in food can be
nothing more than a snapshot of a moment in time and a place in time. We believe that it is important that FDA
ensure that all interested parties, including consumers, understand that the
analytical data developed by the agency is not a warning to consumers on acrylamide
or a finding of risk associated with any particular food or individual brand.
In the
seven months that have passed since the news release, the amount of knowledge
that we know about acrylamide has increased substantially. We know that it can be found in a variety of
foods, and we have some clues, as was mentioned by Dr. Jackson and others,
about the mechanism of its formation.
We know that the amino acid asparagine is a key component for the
formation of acrylamide, as is the presence of reducing(?) sugar and the
application of heat. While the role of
asparagine may not preclude other mechanisms for the formation of acrylamide,
this is, nonetheless, a very significant finding that deserves further attention.
As was
mentioned, very limited information is available on asparagine content in
foods, and how those levels might vary with factors like season, variety of
crop, storage conditions of the crop, and, of course, the age of the crop in
terms of how long it's been in storage.
If you
look at the analytical data, the connection with asparagine provides some
rationale for the occurrence of acrylamide in the foods and does point out that
this is not an issue that's going to be confined to just specific categories of
foods or forms of cooking.
We are
only aware of two compilations of the asparagine content of foods. I think one was mentioned by Dr. Lineback,
the work at FRI, and there's another one.
But that is very limited, and that doesn't really--those data
compilations don't really go to the variations in levels and they're not very
complete.
Thus, we
recommend that the draft research plan be updated in light of the information
about asparagine and that some resources be directed toward obtaining better
information about the asparagine content of foods.
While the
Human Nutrition Information Service at USDA has collected data on the amino
acid content of--essential amino acid content of foods for years for their
handbook series of eight publications, asparagine was not included in that
compilation because it was not identified as--or is not classified as an
essential amino acid.
We would
suggest that FDA either consider partnering with USDA to collect additional
data or perhaps, as we indicated, modify by their action plan to obtain
asparagine data on their own.
As was
also discussed earlier, FDA has also already analyzed many foods for the
presence of acrylamide and has announced their plans to analyze many more
samples next year. We believe that the
results from those analyses will continue to show that acrylamide will be
present in a wide variety of foods and that it will continue to show the
variability within and between products.
Now,
while the Total Diet Survey will address some foods as consumed at home, it
will not necessarily provide information on home-prepared foods and how those
levels can vary according to typical cooking and food preparation styles.
Some
experts believe that in terms of total dietary exposure, home cooking will
provide to be both the biggest contributors and perhaps the most variable and
difficult to control. Clearly, a
systematic study of home cooking would go a long way toward filling this data
gap. The fact that home cooking and exposure
to home cooking will need to be better known and understood as FDA characterizes
potential risk and examines the merits and implications of any risk management
steps. So we would recommend to the
extent possible that FDA consider home cooking more in their action plan.
Turning
now to the area of toxicology, given the short amount of time that has passed
since the initial reports of acrylamide in food, there really has--no real new
information has emerged that would address the numerous toxicological
uncertainties raised by researchers who have identified, who have studied this
issue. These uncertainties include the
relevance of rodent tests to human, specifically the absorption, distribution,
metabolism, and excretion profiles differences--profiles between different
species and whether acrylamide in food, for example, can be equated with
acrylamide in water or other types of exposure.
The
proposed studies at NCTR will go a long way toward answering some of these
questions, but they will not go all the way.
Since
late summer, we've heard a great deal about the work that's been done by
companies in the chemical industry on acrylamide. Some of those studies include clinical studies with human
volunteers. We urge FDA and NCTR to
take advantage of the expertise in the chemical industry and to collaborate, if
possible, with those efforts, particularly with respect to study protocols that
would be relevant to human exposures to the diet.
We
believe that it is critical that we assess through research whether concerns
identified with acrylamide intake in animal models can be extrapolated to
humans.
DR.
BUSTA: You have two minutes.
DR.
CHIN: Okay. Thank you.
Among the
highest priorities identified by the JIFSAN workshop was the research on the
bioavailability of acrylamide, and we wholeheartedly agree with that
assessment. I think there are some
questions about the relevance of acrylamide in diet and whether bio--and,
again, bioavailability issues, and, again, that should be a high priority for
FDA.
I'd like
to mention just in closing that--well, in summary, I'd like to recommend that
FDA develop more information on asparagine content of foods, study effects of
home cooking, look at the pharmacokinetics in humans and investigate the
possibility of protective mechanisms in humans, and also to look into a risk
analysis when more information becomes available.
NFPA
remains committed to working with the FDA and other regulatory agencies and
other stakeholders on this issue. We
plan to work with JIFSAN to assemble industry data on acrylamide, and as NFPA's
own survey becomes finalized, we intend to share that data and analyses as part
of our cooperative effort.
Again, we
commend FDA for a well-thought-our research plan and the very relevant and
appropriate advice to consumers that there is no evidence to recommend changes
to the currently established dietary guidelines, and that the focus should
remain on eating a well-balanced diet consisting of a wide variety of foods in
moderation.
Thank
you.
DR.
BUSTA: Thank you, Dr. Chin.
The next
presentation is by Dr. Marvin Friedman.
He is with SNF SA. You're going
to have to tell me what SNF SA is.
DR.
FRIEDMAN: SNF SA is in the chemical
industry. Let me make it clear that the
issues of today and tomorrow are not issues of the chemical industry. We didn't do it. We aren't responsible for it.
There's no way we can clear this up.
However,
there is some overlap in the area of toxicology because we've been stewards of
the acrylamide industry. We've done a
considerable amount of toxicology.
I'd like
to quote Katherine Harris. I'm from
Florida. Katherine Harris was the
secretary of state in Florida. Her
attorney said at the end of the presidential election, "I don't have a
horse in that race." SNF SA
doesn't have a horse in this race.
Next
slide.
Who is
SNF? SNF was created in 1978. We're the world's leading manufacturer of
acrylamide and polyacrylamides. We have
the two largest acrylamide plants in the world, and they're getting larger. The plants are located in France and the
U.S. In the U.S. they're in Savannah,
Georgia. The polymer plant in Savannah,
Georgia, is the largest acrylamide polymer plant in the world. We supply over 100 countries worldwide. We have a website, biopolymers.
Why are
we here? The first thing we want to
indicate to you is the program that we currently have ongoing. We commend the FDA for a lot of the research
that they proposed, and it was so obvious that it was similar to our plan. We'll go through the similarities. We want to establish a dialogue, and the
most important thing is we want to avoid duplication--avoid duplication for two
reasons. We want to avoid duplication
of efforts because it's a waste of money, and we want to avoid duplication of
effort because if you come up with three different results, then you have two
out of three, and then four out of seven and nothing goes well. So do it right the first time.
Next
slide.
We have a
broad line of research in neurotoxicology, human metabolism, DNA adducts,
genotoxicity, and cancer. I ought to
tell you that in 1997 I let a contract with RTI. We knew acrylamide was in food.
We couldn't figure out where it was.
We let a contract with RTI to tell us where it was, and they couldn't
figure it out either. So that shows you
our efforts.
Next
slide.
As far as
neurotoxicology is concerned, you've heard a lot about glycinamide. I've heard it used a few times. It's the metabolite of acrylamide. In order to determine how you extrapolate
neurotoxic doses from rats to man, we're going to have to have some sort of
notion whether glycinamide or acrylamide is the active form. We currently have ongoing studies at the
Medical College of Georgia that are designed to do that. So at the end of this series of studies, we
should know whether we're going to look at blood levels of glycinamide or blood
levels of acrylamide at least as far as neurotoxicity is concerned.
By the
way, I don't know whether I mentioned this, I left a copy of these slides with
the lady at the front desk. If she's
going to duplicate them and pass them out, I don't know.
Next
slide.
Perhaps
the most valuable and talked about study, we have just completed exposing
18--24 human volunteers to acrylamide.
The first thing we did is we did a rodent study at the doses that we
exposed to humans; then we exposed humans to three levels of acrylamide orally
and one level dermally. The level
dermally was administered on three consecutive days. We collected urine, red blood cells. We've done hormone levels.
We've done all sorts of--everything we can to assure that these people
are in good health when they leave. And
we are awaiting--a study was done at Covance Clinical Laboratories in Madison,
Wisconsin, and the analyses are coming from Dr. Tim Fennell at RTI. I've seen
the first urines out of these studies, and they're very interesting, different
than rats.
Next
slide.
This is
the critical slide. We have Dr.
Fennell, who's done the DNA adducts on a variety of materials, low molecular
weight like ethylene oxide and acrylonitrile, is now working on whether
acrylamide produces DNA adducts. He's
doing it with LC/MS procedures. Our
goal is to, one, find out if we get any DNA adducts; two, to find out if those
DNA adducts correlate with the organs in which you get the tumors; and, three,
to determine whether there's a significant rate of repair.
If I were
in your position reviewing what the FDA's doing, I would wait until this study
is done before I fund a lot of millions of dollars to do another
carcinogenicity study. If we don't get
DNA adducts, then my personal opinion is our database is okay. If we do get DNA adducts, that's a different
issue.
Next
slide.
DR.
BUSTA: When will that study be done?
DR.
FRIEDMAN: That study will be done--Tim
has promised us March for a final report.
So he gives us--I should be seeing the data in--I know right now he's
making the standards and doing--there's never been a study of acrylamide and
glycinamide reacting with DNA in vitro.
He's doing that study right now.
Genotoxicity
studies. The question we're dealing
with here is that acrylamide has an unusual characteristic that it looks like
its mutagenicity is not caused by a reaction with DNA but caused by a reaction
with proteins associated with DNA. And
there are a variety of candidate proteins that are being looked at. The ones that we find most interesting are
KRP-2. KRP stands for kinesin-related
proteins. I think the "R" is
"related." But the point is
that kinesins are the proteins that acrylamide interacts with to cause
neurotoxicity. And these are real good
candidates. If you don't get DNA
adducts, you have to ask what causes the genotoxicity, and this is a good
candidate. The way I explain it to my
boss is that it's not enough to say he didn't commit the murder. You have to say who did. And we think this is the culprit for the
genotoxicity.
Next
slide--oh, schedule-wise, we expect those to be done at the end of the summer.
Effects
of polyacrylamide cell proliferation.
We find that acrylamide causes cell proliferation in those organs which
are target organs and not organs which are non-target organs. We find cell proliferation on the tunica
vaginalis. We find cell proliferations
in the thyroid. We do not find it on
the liver, for example. Now, we have
completed these studies and are awaiting publication.
Next
slide.
Early
on--this goes back to the 1997, '98 time frame--we did a tumor-by-tumor
analysis and a data gap analysis with the Crump Group. Dr. Shipp, who wrote the straw man document
for the Chicago meeting, did the data gap analysis. And she identified that there were studies on the thyroid gland
and glial cells in cultures that represented data gaps in cancer. She also felt that the data that we had on
mammary fibroadenomas and the tunica vaginalis were enough to explain why we
got those tumors.
Next
slide.
To that
end, we have gone to the world's expert on the biochemistry of the thyroid
gland, Dr. Jacques Dumont, at the Free University of Brussels, and he is taking
apart the thyroid piece by piece to try and figure out what acrylamide does to
the thyroid. We have not been able to
find a direct effect on the thyroid, which is not inconsistent with the way
most chemicals affect the thyroid. Most
affect hormone levels rather than have a direct effect. That's what we're finding with acrylamide.
Last
slide. There is a question as to
whether acrylamide causes glial cell tumors.
We have been looking at direct effects on glial cells and do not find
anything with acrylamide. We've been
having all sorts of trouble getting glycinamide into these cells, and that's the
next study as soon as we can make some glycinamide.
An
important take-home message is that there's a whole other world out there of
people who are doing research. This
represents the research program, and really the two have to meld and come
together and work together. We are
completely prepared to do some. I don't
like--I don't think--I personally don't think my company wants a one-way
street, we'll send the data in and then get no feedback for it.
DR.
BUSTA: Thank you very much.
DR.
FRIEDMAN: Was that under ten minutes?
DR.
BUSTA: Fifteen seconds under ten
minutes, very good. Thank you.
The final
presentation or public comment is from Mr. Jeff Stier, Associate Director of
American Council on Science and Health.
MR.
STIER: Thank you, Mr. Chairman, for
allowing me as the representative of the American Council on Science and Health
to offer comments to the Contaminants and Natural Toxicants Subcommittee.
For the
past 25 years, ACSH as a public health consortium has focused its efforts on
the education of the public and the media about discrimination between real and
hypothetical risks to human health.
We've emphasized, for example, that cigarette smoking poses a real and
continuing health threat to Americans, while minuscule traces of synthetic
pesticides and other chemicals in our food do not.
We're
pleased to continue in this role today by offering our comments on
acrylamide. My comments are based on a
paper by the American Council on Science and Health released this week, written
by Dr. Joseph Rosen, Department of Food Science at Rutgers University, and
peer-reviewed by an all-star panel, people including Michael Dubick, a senior
research pharmacologist at the U.S. Army Institute of Surgical Research; Dr.
Peter Guengerich, professor of biochemistry and director of the Center in
Molecular Toxicology in the Department of Biochemistry at Vanderbilt University
School of Medicine in Tennessee; Dr. David Klurfeld, professor and chairman of
Department of Nutrition and Food Science at Wayne State University; and a range
of other top-level scientists have peer-reviewed our publication. And my comments are based on that
publication.
The
presence of acrylamide in carbohydrate-rich foods cooked at high temperatures
was first noted, as you all know, last spring and engendered a spate of press
releases and articles of international attention and even a lawsuit in
California. But to what extent was all
this attention reflective on the actual level of risk posed by acrylamide in
foods for human health?
At
present, according to our findings that have been peer-reviewed, there is no
credible evidence that acrylamide in food poses a human cancer risk. Indeed, there is only limited evidence that
acrylamide in foods poses a significant animal cancer risk. Studies in rodents have examined the effects
of high doses of acrylamide in water and only a couple of species and have not
found consistent results. To assume
that such evidence can be extrapolated directly to humans is not scientifically
sound.
Epidemiological
studies of human exposure in high-dose occupational settings do not provide a
basis for expecting that acrylamide in foods reasonably could be expected to
cause human cancer. Even though the
route of exposure in these studies was not via ingested foods, the fact that
there was no increased cancer risk should help allay food-related concerns.
It's
important to note that neurotoxicity has been found to result from acrylamide
in such settings, thus substantiating that the substance can indeed be absorbed
from environmental exposure.
As the
American Council on Science and Health has tried to get its point across for
many years, putative toxins or carcinogens typically are examined in high-dose
rodent tests that are conducted over the animal's life span. But such tests are not necessarily close
replicas of human chronic exposure to low or trace levels of these substances.
One
hypothesis suggests that any chemical at high enough dose will kill some cells,
thus causing an animal's body to increase cell proliferation to replace those
killed. In and of itself, this
increased rate of cell division makes the animal more susceptible to any
carcinogen or mutagen. It also skews
test results and artificially inflates the risks calculated from the test
results.
Further,
the fact that a chemical causes cancer in one species does not necessarily mean
that it will be carcinogenic in another closely related species, let alone in
humans. Sometimes only one gender of
one species will be susceptible to the carcinogenic effects. Such was the case with the artificial
sweetener saccharin, which caused bladder cancer in second-generation male
rates, but not in female rats, mice of either sex, and certainly not in humans. And as I'm sure we all know, recently the
National Toxicology Program delisted saccharin from its roster of possible
human carcinogens.
ACSH, the
American Council on Science and Health, encourages the FDA to learn from this
reversal when evaluating any possible carcinogenic risk from acrylamide.
The human
diet is replete with chemicals, both naturally occurring and cooking-induced,
that can cause cancer in high-dose rodent tests. Avoiding them would leave practically nothing for humans to eat.
The
chance that acrylamide or, indeed, that any of the plethora of chemicals in our
foods increased the risk of human cancer is hypothetical at best. Like the World Health Organization and the
Food and Agriculture Organization, ACSH does not advise consumers to alter
their food choices or food preparation methods on the basis of health risks
that at present have only been postulated.
ACSH
suggests that the FDA not pressure industry to adopt processes to reduce
acrylamide before the potential risk to human health posed by this compound
have been more clearly defined.
It is
also premature to advise consumers to adopt different cooking methods to avoid
production of a substance that presently is not known to pose a human health
hazard. For example--this is very
important as we try to put in perspective a variety of risks. Advice to reduce cooking times or
temperature for consumers could result in greater microbiological
contamination, a known and serious and real risk to human health. Such a well-meaning attempt to improve food
safety based merely on a precautionary principle could, if consumers focused
their attention on diminishing acrylamide production and neglected cooking
foods at the proper temperature, diminish human health.
In
summary, ACSH thinks that any emphasis on the human carcinogenic potential of
acrylamide, especially before the collection of substantial amounts of
additional data, is premature and to be avoided.
I thank
you for your time.
DR.
BUSTA: Thank you. Will you leave us a copy of your text?
MR.
STIER: Absolutely. I believe it was e-mailed, it was
submitted. But I will leave a copy of
my testimony and ask that our full report be submitted for the record, and I
will send that along.
DR.
BUSTA: Thank you.
We are at
a point that we've concluded today's agenda.
I could tempt Terry to start tomorrow morning and then he wouldn't have
to show up tomorrow, but no, we won't do that.
DR.
TROXELL: I'd rather (?).
[Laughter.]
DR.
BUSTA: For the Subcommittee, tomorrow
after getting a summary from Dr. Troxell, we will go into open discussion on
the five various items that have been addressed today, discussing it with as
much depth as we feel necessary. I
think we will have an opportunity to expand or ask questions if we have
questions of the FDA that weren't answered today.
If you
have any burning need for data or information that someone could spend the
night getting, we could always generate that.
[Laughter.]
DR.
BUSTA: But I haven't seen anything like
that. A three-inch notebook so far is a
start.
Then
after we go through the discussion, then we will go systematically and respond
to Questions 1, 2, and 3. We'll go
around and each of us will make comments on each of those, if you see fit. That constitutes the kind of balloting that
we will have.
After
that, we will get our skis on and depart.
Any
questions, any needs?
[No
response.]
DR.
BUSTA: What's six inches of snow to a
Minnesotan?
[Laughter.]
DR.
BUSTA: We will recess overnight and
reconvene tomorrow morning at 8:30.
Thank you, all, thank you, FDA and the public speakers.
[Whereupon,
at 4:10 p.m., the meeting was adjourned, to reconvene at 8:30 a.m., Thursday,
December 5, 2002.]
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