FOOD ADVISORY COMMITTEE AND DIETARY
Tuesday, June 8, 2004
5150 Pooks Hill Road
Food Advisory Committee
Sanford A. Miller, Ph.D., Chairman
Linda Reed, Acting Executive Secretary
Douglas L. Archer, Ph.D.
Patrick S. Callery, Ph.D.
Goulda A. Downer, Ph.D.
Johanna Dwyer, D.Sc, RD
Jean M. Halloran
Norman I. Krinsky, Ph.D.
Daryl B. Lund, Ph.D.
Margaret C. McBride, M.D.
Mark F. Nelson, Ph.D.
Robert M. Russell, M.D.
Carolyn I. Waslien, Ph.D., R.D.
Contaminants and Natural Toxicants Subcommittee
Alex D.W. Acholonu, Ph.D.
Marion F. Aller, D.V.M., DABT
George M. Gray, Ph.D.
Ken Lee, Ph.D.
Henry B. Chin, Ph.D.
Temporary Voting Member
P. Joan Chesney, M.D.
Dr. Henry Kim
C O N T E N T S
Welcome and Introductions
Sanford A. Miller, Ph.D., Chair 4
Conflict of Interest Statement
Linda Reed, Acting Executive Secretary, FAC 6
Nega Beru, Ph.D. 10
Scientific Overview of Furan in Foods
Dr. Kim Morehouse 22
Jeremy Mihalov 36
Dr. Don Forsyth 49
Questions of Clarification 58
Scientific Overview of Furan in Foods
Dr. Glenda Moser 69
Questions of Clarification 86
Public Comment 98
Summary and Charge to the Committee
Dr. Terry Troxell 98
Questions of Clarification 105
Committee Discussion and Recommendations 115
P R O C E E D I N G S
Welcome and Introductions
DR. MILLER: I think I would like to get
started to enable us to finish on time and give
people a chance to make their planes, and so on.
First of all, let me welcome the new
members of Food Advisory Committee meeting for this
afternoon's session, which will deal with furans
and the data necessary in order to estimate the
risk of furans in food.
For the record, when I call your name, I
going to introduce the new members of the
committee. This meeting is being held in
conjunction with the Contaminants and Natural
Toxicants Subcommittee of the Food Advisory
Committee, and there several members of that
committee that will be sitting with us in our
When I call your name, will you please
just repeat your name and the institution with
which you are associated.
First, Dr. Acholonu.
DR. ACHOLONU: My name is Alex Acholonu,
Alcorn State University, Mississippi.
DR. MILLER: Dr. Aller.
DR. ALLER: Marion Aller with the Florida
Department of Agriculture and Consumer Services.
DR. MILLER: Dr. Gray.
DR. GRAY: George Gray with the Harvard
School of Public Health.
DR. MILLER: Dr. Lee.
DR. LEE: Ken Lee with Ohio State
DR. MILLER: Dr. Chin.
DR. CHIN: Henry Chin with the National
Food Processors Association.
DR. MILLER: Dr. Chesney.
DR. CHESNEY: I am Joan Chesney. I am
Professor of Pediatrics and Infectious Diseases at
the University of Tennessee and also the title you
see on the roster at St. Jude. I am also here
representing the FDA Pediatric Drug Subcommittee.
DR. MILLER: Thank you.
Since we have some new members, we are
required to repeat the discussion of conflict of
interest for this particular issue on furans.
Linda Reed, who is Acting Executive
Secretary of the Food Advisory Committee, will read
Conflict of Interest Statement
MS. REED: Good afternoon, everyone. As
Chairman Miller indicated, I am Linda Reed, the
Acting Executive Secretary of the Food Advisory
Committee meeting. I would like to welcome
everyone and particularly our member from CDER.
I need to read the conflict of interest
statement into the record again.
The authority to grant permission to
borrow Special Government Employees currently
serving on an advisory committee in a sister
center, in this case, the Center for Drug
Evaluation and Research, is granted to the
Associate Commissioner for External Relations, Mr.
Relying on that authority, Mr. Pitts has
signed a memorandum granting permission for Dr. P.
Joan Chesney to serve as a temporary voting member
for this portion of the meeting concerning furan on
June 8, 2004. Dr. Chesney will represent, as she
just indicated, the Pediatrics Advisory
Subcommittee of the Anti-Infective Drugs Advisory
Because of the breadth of topics to be
discussed at this meeting, all of the members and
temporary voting member have been screened for any
and all financial interests associated with
Based on this review, FDA has determined
in accordance with 18 U.S.C. Section 208(b)(3) to
grant general matters waivers to Dr. Marion Aller,
Dr. Douglas Archer, Dr. Johanna Dwyer, Dr. George
Gray, Dr. Norman Krinsky, Dr. Margaret McBride, Dr.
Sanford Miller, Dr. Robert Russell, and Dr. Carolyn
The granting of these waivers permits
these individuals to participate fully in the
matters before the committee. Copies of the waiver
statements may be obtained by submitting a written
request to the agency's Freedom of Information
Office, Room 12A-30 of the Parklawn Building.
In an effort to enhance consistency within
FDA, the agency has recently adopted a policy
whereby all public commenters will be asked to
report any personal financial interests that could
be affected by the committee's deliberations. A
copy of the policy was provided to any individual
who registered to make comments at this meeting.
Additional copies of the policy may be obtained
from the registration desk.
Similarly, we have asked all of our guest
speakers to complete a financial interest and
professional relationship certification for guests
and guest speakers to identify any potential
conflicts of interest.
Dr. Don Forsyth and Dr. Glenda Moser will
be the guest speakers at this portion of the
meeting. Both have indicated they have no
financial interests in the food industry.
I would like to thank for your attention
and I will turn the meeting back over to Dr.
DR. MILLER: Thank you, Linda.
As a matter of procedure, each of the
speakers have been assigned a time for their
presentation, and in order for us to make certain
we get through the presentations, and most
important of all, the discussion, I intend to be as
ruthless as I can in keeping the time.
We have several limitations on our time.
For one thing, we have to be out of here by 6
o'clock at the very latest. Otherwise, as I
indicated this morning, we may be involved in
somebody else's wedding.
Also, there are some of you who have
planes to catch, and in order for the committee to
complete its business, which will be explained in
just a moment, it is important that we stick to the
The first presenter is Dr. Nega Beru of
the FDA, who will provide the background and
discuss the charge to the committee.
DR. BERU: Thank you, Dr. Miller, and good
afternoon. My name is Nega Beru. I am the
Director of the Division of Plant Product Safety in
CFSAN's Office of Plant and Dairy Foods.
My purpose here today is to provide you
with some of the background on furan in foods to
set the stage for the scientific overviews that
will follow immediately.
I will also lay out what input we are
seeking from the committee.
The structure of furan is depicted on this
slide. It is a 5-member O-ring with two double
bonds. It goes by a number of names as shown on
this slide also, has a molecular weight of 68, a
melting point of -85.6 degrees Celsius, and a
boiling point of 31 degrees Celsius.
This last property, it is fairly volatile,
may be important with respect to how much furan
consumers are exposed to in foods as consumed.
Furan is a colorless liquid that is used
in some segments of the chemical manufacturing
industry. It is used, for example, as a solvent
for resins and in the manufacture of lacquers.
It was the subject of a 2-year bioassay by
the National Toxicology Program in 1993. As a
result, it is listed in the Department of Health
and Human Services report on carcinogens, because
it was found to cause cancer in rodents in the NTP
Furan is formed in food during traditional
heat processing techniques, such as cooking and
canning. Its mechanisms of formation are beginning
to be elucidated, and there appear to be a number
Later in this session, Dr. Don Forsyth
from Health Canada will present to you their
studies on mechanisms of formation of furan in
The discovery of furan in foods is not
new. Furan has been reported in a small number of
foods starting as early as the 1960s, although very
little quantitative data exists in the literature.
Furan was found in coffee, canned meat,
baked bread, cooked chicken, sodium caseinate,
hazel nuts, soy protein isolates, hydrolyzed soy
proteins, rapeseed protein, fish protein
concentrates, and caramel.
What is new here is that FDA has developed
a quantitative method to measure low levels in food
and has found that furan forms in a wider variety
of foods than previously thought including in some
In addition to FDA, Health Canada and
NFPA, together with some of its members, are
investigating furan levels in foods, and, in fact,
FDA, Health Canada, and NFPA are also currently
collaborating In a round robin evaluation of the
method that was developed by FDA.
FDA's finding was made during
investigations aimed at confirming a report in the
scientific literature that furan forms when apple
juice is irradiated. As part of that
investigation, a number of non-irradiated, but
processed foods were also evaluated using a
In the exploratory survey we posted on the
web on May 7, we used a more refined quantitative
method. FDA initially concentrated on foods that
appeared to have high levels during the initial
screen using the semi-quantitative method. FDA
also analyzed foods that didn't necessarily have
high levels in the initial survey, but could
potentially result in high exposures based on
For each type of food, foods were obtained
from two to three manufacturers, and, in addition,
to get at the lot-to-lot variation, two lots were
examined per food.
Foods that were tested include baby foods,
such as apple juice, applesauce, sweet potatoes,
carrots, and green beans, infant formulas, both
liquid and powder, and adult foods, such baked
beans, soups, chilis, spaghetti sauce, tuna,
coffee, and chicken broth.
Over 160 samples were tested in the
exploratory survey including replicas of the same
brand or product, and the results ranged from
nondetectable to approximately 100 parts per
Right after my presentation, Drs. Kim
Morehouse and Jeremy Mihalov will present more
detailed results of the survey, as well as the
exposure assessment that was based on the results.
FDA made the data collected in this
exploratory survey public on May 7 by posting them
on the FDA's web site. At the same time, we posted
on the web a detailed description of the method
used to analyze the food samples, as well as a set
of questions and answers on the issue of furan in
FDA also issued two notices in the Federal
Register on May 7. One was to announce a call for
data on various aspects of furan in foods, which I
will go into a bit later. The other was to
announce this very meeting of the Food Advisory
Committee and the Contaminants and Natural
When we announced the data to the public,
we did so with a number of message points. Of
course, we said that finding furan in foods is a
concern because based on studies in rodents, furan
is a potential carcinogen in humans.
At the same time we made it clear that
furan certainly did not appear suddenly in food,
its occurrence in food has been reported before.
What is new here is the discovery in a broader
variety of foods than previously thought including
some baby foods.
We also said that this discovery is not an
immediate public health concern. This was based on
our preliminary exposure assessment and a National
Academy of Science's review of the toxicology of
furan done for NASA, and this review is in your
briefing books, which concluded that, one, the
weight of the evidence suggests that furan is an
indirect carcinogen, and, two, calculated and no
observable adverse effect level of 80 mcg/kg body
weight per day.
Nonetheless, we said that there are many
questions that must be answered to improve the risk
analysis. Thus, we said that we intend to conduct
an expanded survey including foods as eaten in
order to determine exposure and risk to consumers
We also said that we will look at what
additional studies are needed to determine furan's
potential risk to human health, as well as studies
on mechanisms of formation and reduction methods if
the risk assessment warrants such studies.
Finally, we said that we will seek input
from our Food Advisory Committee and Contaminants
and Natural Toxicants Subcommittee on what data are
needed to fully assess the risk posed to consumers
by furan in foods, hence, this meeting.
We intend to evaluate all the available
data including input from this meeting, and develop
an action plan to address the issue of furan in
food. The action plan will certainly include an
expanded survey of foods, but may also include
mechanisms of formation/reduction in foods, as well
as toxicity studies to address mechanism and dose
In the call for data we issued on May 7,
we asked for data in several areas. With respect
to occurrence of furan in foods, we asked for data
on the particular foods in which furan occurs and
the levels in these foods, the formation and
occurrence of furan in home-prepared foods as
opposed to, say, manufactured foods, and on
environmental sources of furan in which a typical
consumer is likely to be exposed.
With respect to mechanisms of formation,
we asked for data on possible mechanisms of
formation, as I mentioned earlier, we wrote a
letter here about studies that Health Canada
conducted on mechanisms on formation.
We also asked for data on variables that
enhance or mitigate furan formation in foods, on
the stability or dissipation of furan in foods, and
on the effect of post-production practices, such as
consumer heating of canned foods on the furan
levels in foods.
With respect to toxicology of furan, we
requested data on mechanism of furan toxicity,
mutagenicity, and carcinogenesis, on reproductive
and developmental toxicology, and on metabolism of
furan in vivo including characterization of any
reactive metabolites, and the role of such
metabolites in producing furans adverse effects
We also asked for data on the diversity of
furan pharmacokinetics in humans or the alteration
of furan metabolism as a result of dietary,
medical, or environmental interactions, and data on
whether sub-cytotoxic doses of furan produce any
adverse effects, such as a change in enzyme
activities or ATP levels.
Importantly, we asked for data on the
effects of furan at doses lower than those used in
the 1993 NTP study in order to accomplish the
1. To establish a dose-response curve for
the various toxicological endpoints.
2. To determine whether furan toxicity,
including carcinogenesis, is a threshold dependent
3. To determine whether the carcinogenic
activity of furan is secondary to its hepatotoxic
Last, FDA is also asking for data on the
mutagenicity of furan in the TA100 strain in the
Ames test, and the behavior of furan in other in
vivo assays for mutagenicity or toxicity.
In the Federal Register notice call for
data, we asked that data and comments be submitted
to FDA by July 9, 2004. We also said that we would
share with the committee and the subcommittee any
data or comments we received by June 1.
To date, we have not received any data on
any of the areas we specified in the Federal
Register. We did, however, receive one comment.
That comment was from Dr. James Coglin [ph],
president of Coglin & Associates, a consulting firm
on food, chemical, and environmental toxicology and
The comment describes work done on various
heat-induced heterocyclic compounds including furan
as antioxidants and urged the committee and
subcommittee to consider the beneficial health
protective effects of such compounds in evaluating
the safety of furan in foods.
This brings me to the charge and the
question we are posing to the committee. This, by
the way, are found in Tab 2 of your briefing
The Food Advisory Committee and
Contaminants and Natural Toxicants Subcommittee are
being asked to provide input on data that would be
helpful for further evaluation of the potential
risks posed by the presence of furan in foods.
Essentially, this is the question we are
asking the committee. Taking into consideration
the data needs already identified by FDA in the
Federal Register notice requesting data on furan,
and the presentations you are about to hear at this
meeting, are there any additional data that are
needed to fully assess the risk of furan in foods?
With that I will end my presentation. I
trust this will provide an adequate background for
the more detailed presentations that follow, and I
thank you for your attention.
DR. MILLER: Are there any questions for
clarification? Dr. Dwyer.
DR. DWYER: I wasn't clear from the data
needs if you are also considering doing home-cooked
foods, for example, if I made a sweet potato pie at
home, are you planning on doing those, as well?
DR. BERU: I think in the long run, we
want to do that, and perhaps even consider adding
furan to the total diet study. Certainly, we have
done some preliminary work on home cooking in terms
of what dissipation of furan may take place during
normal home preparation of meals of canned or
jarred foods, and Dr. Morehouse will present some
of those data later.
DR. MILLER: Dr. Callery.
DR. CALLERY: Are you planning to also do
the Ames test on metabolites of furan, especially
metabolites that may have some predicted
DR. BERU: Well, at this point we are sort
of in a data collection mode. We want to see what
work has been done out there, and certainly we
intend to do what we can to fill the data gaps
including those studies.
DR. MILLER: Thank you.
We next have three papers dealing with
overview of furan in foods, the first presented by
Dr. Kim Morehouse from FDA. Ten minutes.
Scientific Overview of Furan in Foods
DR. MOREHOUSE: Hello. My name is Kim
Morehouse and I am a research chemist with the
Office of Food Additive Safety, Division of
Chemistry Research and Environmental Review. My
collaborators on this project have been Ms.
Patricia Nyman, Mr. Timothy McNeal, and Dr. Gracia
Today, I am going to present some data
that we have obtained on furan in foods and sort of
explain to you why we got into this in the first
place, even a little bit more than what Dr. Beru
has presented already.
As was noted earlier, during our
investigation of the possible formation of furan by
ionizing radiation, we noted that heating the
sample caused an increase in the amount of furan
that was detected.
This increase was not due in an increase
in the volatility of the furan, but rather was
indeed due to generation of furan.
We also noted the presence of furan in
pasteurized apple juice that we had purchased
locally at a store, but that furan was not present
in apple juice that we prepared fresh in our
This led us to investigate the presence of
furan in heat-processed foods, and we started
looking at various foods. Originally, we were just
looking at it from the standpoint of comparing
radiation treatment to heat treatment of foods, so
we were doing a very random sampling of products.
Basically, I just went through the store, picked up
samples off the shelf that were canned and
pasteurized products, and this was a quick
semi-quantitative determination. We weren't as
determined that we had to have exact numbers, but
rather an order of magnitude because we were just
trying to say was the radiation going to
significantly increase the amount of furan that
would be present in the total diet at that time.
However, as we got further into this
project, we began to realize that there was a large
number of foods for which furan was present and in
substantial amounts, and it became clear that we
needed to look at it further, as well as needed to
know the quantitative numbers that were there, not
just from a qualitative standpoint.
So, we modified our procedure. In order
to do this, we were using static, headspace
sampling with gas chromatograph determination with
mass spec detection. Our quantitation was based on
stable isotope dilution, as well as standard
addition with known amounts of furan to each food
It is important to note that we were doing
it on each food product because each food product
had a different partitioning coefficient of the
furan between the headspace and the sample.
This method has been peer verified within
our lab group itself by three different scientists,
as I mentioned earlier, and we are currently
participating in a round robin study of the method.
Basically, what we did was we took for
what I call liquid samples, we took 10 grams of the
sample from the food container and placed it into a
headspace vial. For solids and semi-solids, we
took 5 grams of the sample, added 5 grams of water
in the headspace vial. The headspace vial was then
sealed and analyzed.
For some products, it was necessary to
homogenize the sample, and for those products they
were homogenized on ice either using a blender or a
tissue homogenizer. After the samples were sealed
upon the addition of either D4 furan or furan if
necessary. They were vortexed to ensure adequate
mixing of the samples.
It was important to make sure that we did
have adequate mixing because we noted that when we
did not, we retained rather spurious results, but
upon proper control of our samples with proper
mixing and everything, we were able to obtain
extremely good quantitation.
For our studies, we listed limits of
quantitation on the data tables that were presented
on the web. We used rather conservative estimates
of those limits, and for liquid samples, we
determined that was about 2 ng/g, and for solids,
it was about 5 ng/g.
Like I said, these values are fairly
conservative, however, we know that our limits of
detection are much lower than that. For liquid
samples, we estimate those to be about 0.7 parts
per billion, and for the solid matrices, about 1.5
parts per billion.
As Dr. Beru mentioned earlier, we selected
foods based on that initial survey that we were
doing during our radiation studies, as well as from
the literature reports of foods that were known to
contain furan, and using the FDA database to
determine which ones were higher consumption foods.
For each food analyzed, we analyzed from
either two or three brands, and usually from two
different lots per brand. Using this data, we
undertook a systematic manner to obtain
I am going to go through classes of some
of the foods that we looked at. From the infant
formulas, we looked at powders, concentrates, and
what are called ready to feed foods. The
concentrates and powders were prepared according to
label directions, placed in the vials and analyzed.
The ready to feed, of course, are already ready to
feed, so they were just simply transferred into the
You can see that we have a range for the
powders of non-detected to 2 parts per billion, for
concentrates of non-detected to 15, and for the
ready to feed, non-detected to 13.
For the powder and concentrate, they are
based on what would have been consumed.
The ranges I am listing here is because
you still see in the next presentation on the
exposure estimates, the range is what is used for
doing that calculation.
For some of the baby foods that we have
analyzed, you can see the apple juice range from 2
to 8, and you can go on down the list up to the
sweet potatoes and garden vegetables, which were up
to 100 part per billion. Again, you can see that
we do have a fairly large range. Again, the garden
vegetables, we are talking about three
manufacturers and two lots per sample.
For some of the adult foods, we have done
a lot more work. You can see that we range from
bread, where it is non-detected to below our
quantitation level. When we have less than 2
there, that means we can detect it, but it was
below our quantitation level, and in the cases of
the tuna and the canned meats, we listed as less
than 5. That means it was within our detection
limits, but below our quantitation level again.
Again, you can see the spread of the
numbers that we are seeing and the various
different types of products that we have been able
to analyze so far. Just so you don't think it is
all so bad, from our original survey, we do know
that many foods do not contain furan, some of those
listed here, and you will notice that man of these
foods are fairly high consumption products, such as
milk and margarine and yogurt nowadays type of
thing. We also included pasteurized eggs and
potato chips in our original survey, as well.
I was asked the question about the heating
the products. We haven't gotten to the point yet
where we are actually cooking unprocessed foods to
look at that, but it is something we do intend to
do eventually, but what we did look at was what
about the foods from the can and if you heat them.
For the foods we looked at here, a very
limited preliminary study, we did chicken broth,
two different pastas, and the infant food sweet
potatoes. The pasta No. 2 and the sweet potatoes
were only treated one way, that is why there is no
second bar there, but you can see from the pasta
sauces and the sweet potatoes, there is not what I
call a significant change upon heating, whereas,
with chicken broth where you basically have water,
and not much lipids or proteins to be holding back
the furan, it does substantially decrease.
So, depending upon what the food would be,
you would either lose the furan or not, and this
gives us a little bit of idea that we may have less
furan actually in the consumption than what would
actually be in the food as we are opening up the
For the heated samples, they were heated
basically on a hot plate in an open environment
until they boiled for about 10 minutes. In the
microwave, they were heated to boiling, usually for
about a minute for the chicken and pasta. The
sweet potatoes, they were heated what I call until
they were tepid, similar to what a consumer would
What is ongoing? We are obviously
analyzing more foods. This was set as just a
preliminary survey so far, we are doing a lot more.
We are now looking at foods based on using the USDA
consumption database to say what are some of the
other high use foods that we should go ahead and
analyze that we haven't already done before.
Again, still looking at foods that have
been reported in the literature that contain furan
for which no quantitation is available in the
literature. It should be noted that in most
literature they would state that they found furan,
but would not state what the amount was, they
didn't quantitate the amount there.
Of course, we are going to continue to
investigate the effects of heating on the
concentrations of furan.
For those who would like to see the full
tables, of course, the entire method that we used
is available on the web site as was stated earlier,
as well as all the foods that have been analyzed.
DR. MILLER: Questions?
DR. ARCHER: A question, just curiosity.
What do you make of the potato chip data?
DR. MOREHOUSE: There was no furan in
DR. ARCHER: Any hypotheses?
DR. MOREHOUSE: Nope. Again, you are hear
later on some of the mechanisms, and some foods
that we saw high amounts of furan in, we look at
some of the mechanisms that have been proposed for
where furan is coming from, and they don't
correlate with the products, so obviously, there is
multiple mechanisms, multiple pathways, and potato
chips was one of the things that we thought would
contain furan, and did not.
DR. DOWNER: Thank you very much.
It seems to me that the higher fat foods
tended not to have furan detected. I want to ask a
little bit about the milk, though. Were you able
to look at fat-free milk, 1 percent, 2 percent,
regular milk to see if there were any detectable
differences in those grades of fat content in the
milk with respect to furan?
DR. MOREHOUSE: That was back from the
survey work, and I believe all we did was whole
milk, and we didn't see any furan in the whole
milk, so we didn't bother with looking at any of
the others. We figured if it wasn't in whole milk,
why would it be in the others.
DR. MILLER: Dr. Waslien.
DR. WASLIEN: I was particularly concerned
with the furan content of formula, maybe
non-detectable, the 13 sounds low when you are
looking at a gram quantity, but if an infant
consumes a liter a day, you are up there in the
I went and looked at the l.d., the least
dose for mice or rats, and the calculated based on
that, of course, we don't have any data for doses
for humans, would indicate that the amount of furan
taken in is 13, and the dose that is least
detectable or least risk is something like 12, so
you are getting close for some of those infant
Now, my calculation might be wrong, I just
sat and did it right now, and we are encouraging
infants to drink less than a liter of milk a day,
but it is a concern, and that was my major worry.
DR. MILLER: That's true, but the issue
that we are concerned with here is what work would
we suggest to the agency in order to get enough
data in order to be able to come to that
DR. WASLIEN: Well, partly I would think
one of the things you might want to look at is
age-related differences in metabolism since a
newborn infant has all kinds of other metabolic
DR. MILLER: Hold that thought.
DR. WASLIEN: Okay.
DR. MILLER: Dr. Chesney.
DR. CHESNEY: I also have many, many
thoughts as you do, but for the moment, I wondered
if you could clarify the infant formula slide for
me. I didn't quite understand
non-detectable-2-15-13, and you also said based on
consumed, and I may have heard wrong. I wanted to
be sure I understood the slide.
DR. MOREHOUSE: The slide, that is the
range that we found for the products that we have
analyzed. From non-detectable to 2 for the powers,
from non-detectable to 13 for the concentrates, I
think it was, and the powders and concentrates are
based on as it would have been prepared by the
consumer for consumption.
In other words, we took the powder and
made up the solution was it was by label, so it is
based on the prepared formula, not the powder
DR. CHESNEY: I understand. Thank you.
DR. MILLER: Dr. Chin.
DR. CHIN: Going back to your table or
figure that showed the effect of cooking on furan
levels in various foods, there were I guess a
couple of bars where either the value was zero or
there were no values.
DR. MOREHOUSE: Those were because for the
second pasta sauce and for the baby food, we did
not do the second treatment, so the pasta sauce No.
2 was only heated, and the baby food was only
DR. CHIN: Thank you.
DR. MILLER: Dr. Aller.
DR. ALLER: A question again on the infant
formula. I know you mixed that. Was it heated
DR. MOREHOUSE: No, just mixed.
DR. DWYER: Just a question. Could you
explain the difference between limit of
quantitation and limit of detection? It is just
that you can't above the limit of detection, you
can't quantify until you get to 2 parts per
billion, is that right?
DR. MOREHOUSE: Right. Because of the
mass spectroscopy's sensitivity, we can detect it
or we put very stringent requirements on
quantitation right now because the method has not
been totally peer verified, we felt that we didn't
want to say that we could do 1 part per billion,
even though we can see it, but we don't want to
take the quantitation level there yet.
DR. MILLER: Thank you.
The next speaker is Mr. Jeremy Mihalov,
FDA, will talk about exposures.
MR. MIHALOV: My name is Jeremy Mihalov,
Office of Food Additive Safety. This also was done
with Dr. Michael DiNovi. I am going to give you an
overview of our exposure assessment for furan from
the consumption of adult and baby foods.
I will start off, give you an idea for the
model that we used to estimate exposure, and this
is fairly similar to most exposure assessments,
simply that the total exposure for a person to
furan is the sum of the exposures from each food,
overall foods that contain furan, and exposure from
each of those foods is simply the product of the
intake of that food modified by the concentration
of furan modified by the concentration of furan in
We looked at adult foods, baby foods and
also the infant formula, and they were considered
The sources of our data. For intake data,
we used the USDA 1994 to 1996 and 1998 USDA
Continuing Survey of Food Intake by individuals.
This was a two-day survey, two nonconsecutive days.
For each of the years, there was about 5,000
people, so we have data for basically 15,000
individuals, and we know what they ate and how much
for each of those days.
We then looked at the furan concentration
data which you just heard about, and we looked at
those lists of foods, and looked at the survey
data, how much of those foods did those people eat
multiplied by the concentrations, and you can get
an exposure for each individual.
This may be somewhat of an iteration of
what you have already heard. By looking at the
infant foods, we group them into juices, fruit
purees, vegetables, mixed chicken meals, had a
separate for infant formula.
For the adult foods, we grouped them into
brewed coffee, instant coffee, broths, soups that
contain meats, spaghetti sauces, chili, pasta,
ravioli--they were both canned--juices, pork and
beans, canned string beans, canned tuna, canned
Just to go over some of the levels again,
within each food type, the ones I just listed,
within the food types, there wasn't a lot of
variability. Overall, the range, looking at all
the food types, went from limited detection up to
about 125 mcg/kg.
Specifically, looking at the infant food
groups, the highest were the sweet potatoes and the
garden vegetables, juices were generally low, below
10 mcg/kg. The fruits and mixed meals were below
30. Other vegetables ranged between 30 and 60.
With the formula samples, about half were below
limit of detection, and we used the mean, which was
about 7 mcg/kg.
With the adult foods, the coffee had the
greatest variability, between limit of detection up
to 80. The juices, tuna, broth, sauces were all
generally low, below 15. The soups and the pork
and beans had a fairly wide variation, the soups
being the highest. The chili, beef ravioli, and
spaghetti, the canned pastas were between 30 and
Going back to discussing the model,
generally, when you do an exposure assessment,
there is a certain amount of uncertainty, and we
compensate the uncertainty with making certain
assumptions. Whenever we make an assumption, we
tend to make it conservative, and this is typical
for agency exposure assessments.
The first assumption is that the
concentration of furan and all the furan-containing
foods will be at the mean within the food type, and
as I said there is generally little variability
within the food types, so we use the mean. When we
are looking at chronic exposure, that is generally
how we do it.
Second assumption, for all foods within a
food type that are shown to contain furan, we
assume that it does contain furan. In other words,
they have seen it in canned chili, so when we did
the exposure assessment, we assume anytime anybody
eats chili, it also contains furan, and as there is
more data collected in the future, those
uncertainties could be reduced.
The last assumption is that the two-day
survey intake data that we used reflects a lifetime
So, getting to the final numbers, we used
the published April 20th concentration data that is
on the internet. Using that, for the adult foods
for people ages 2 and older, that ate those foods,
the mean consumption was 0.3 mcg/kg-body
The 90th percentile, which is what we
consider to be the heavy consumer, on the upper end
of the distribution, is at 0.6 mcg/kg/day.
When we looked at the infant foods, and
these are age 1 or less, that ate those foods, the
mean was 0.4 mcg/kg/body weight, and the 90th
percentile was 1 mcg/kg.
We ran the exposure assessment looking at
the individual foods just to get a sort of profile
of how those different food types contribute to
that overall mean, and this is just a table of how
those foods contribute, coffee being the highest
out of the groups that were tested, going down to
broths being negligible.
For the infant formula, we took a slight
different approach, a more simple approach. There
is sort of standard numbers for infant formula. In
order for an infant to thrive, they need to consume
between 100 and 120 kilocalories per kilogram per
day, and infant formula is usually formulated to
contain 0.8 Kcal/gram when it is prepared, and I
used the mean furan concentration of 7 mcg/kg, and
if you do the arithmetic, you can come out at a
mean exposure of 0.9 mcg/kg/day for an infant
consuming infant formula at the level needed to
To sort of sum up overall, the variability
of the furan levels within a food type is generally
small, so we can pretty much assume that additional
measurements within food types won't have much
effect on the overall exposure, however, because
the number of food types that have been tested is
generally limited, additional measurements in other
types of foods could have an overall effect on the
exposure, especially with foods that are consumed
in high quantities or also foods that have high
concentrations could affect the exposure.
DR. MILLER: Dr. Waslien.
DR. WASLIEN: I did a quick recalculation
of my numbers, and I am off by 1,000, so I skipped
nanograms in there. I just wanted to make that
But even so, I think when you look at
infant formula, I hesitate to take the mean of
values, because the likelihood of a person changing
from one formula to another is not that high, so I
think you are looking at the individual risk from
formula, so the child who is consuming a formula
with 13, if it is a ready to consume formula, is
probably going to be consuming that reasonably
DR. NELSON: I guess a similar question.
On the other food products, did you use the mean in
your conservative estimate, or did you use the
MR. MIHALOV: We used the mean of all the
concentrations for all the food types. Generally,
when you are looking at a lifetime exposure, you
can pretty much assume that if there is a
distribution over time as you consume that food,
one day you might consume the minimum, the next day
you may consume the max, but over the course of
time, you are going to consume at the mean.
Of course, if there is additional data to
demonstrate that there is some reason to why there
is a distribution, you know, that could change, but
generally, for now we use the mean.
DR. RUSSELL: Just a question of
information. With so many adult Americans eating
out, particularly in fast food type restaurants, do
you have any data on fast foods that have been
prepared under high heat conditions?
MR. MIHALOV: Well, the survey data
includes restaurants and home cooking. It is
essentially the survey is given out and whatever
was eaten by those individuals on those two days,
that is what they report.
DR. RUSSELL: But in your analysis of
foods that FDA has analyzed, how many foods come
from that type of an environment that were analyzed
actually? I noticed a lot of canned and jarred
things, very important for infants particularly,
but I was just concerned about the adult exposure.
MR. MIHALOV: Just looking at the list, I
would say a few of them are probably restaurant.
Like I had said, if they found it in a food, we
assume that it is in all foods of that type, so,
for instance, the chili was a canned chili, but we
assume that all chili contained furan when we did
the exposure assessment, so if they had chili at a
restaurant or if they made it at home, that was
taken into account. If there is further data to
show that canned is higher than home-cooked or
restaurant, then, we can make that change.
DR. MILLER: Dr. Lee.
DR. LEE: To continue that thread, I
assume that there is a fair amount of looking at
canned and jarred foods because the furan is fairly
volatile, so the packaging method itself keeps the
furan present in the food, is that a fair
MR. MIHALOV: I couldn't say.
DR. MILLER: Dr. Nelson.
DR. NELSON: That would fit with the
infant formula data because the powdered stuff is
typically spray dried where you have a lot of
opportunity for dissipation of furan as opposed to
the canned concentrate or ready to drink formula.
DR. MILLER: Do you want to respond to
DR. LEE: I just want to continue along
that line of thinking. Have you ever considered or
does anyone have any data on animal exposure,
particularly pets consumption, because you
basically have a pretty monotonous diet, and there
are pet foods that do come in cans, so one would
expect that there would be a fairly good exposure
there that you can model, is there any interest in
looking at that?
MR. MIHALOV: That could probably be done
if we had concentration data. I am sure that there
is some information on how much food a typical
animal eats per day, but it would be pretty much as
simple as that, because a pet would consume one can
or two cans, or something along those lines, but
that could be one.
DR. MILLER: Dr. Chin.
DR. CHIN: I just wanted to comment a
little bit on the thought about foods purchased at
restaurants. I think one of the other
considerations in terms of foods that are purchased
at restaurants is that not only do you consumer the
food at the restaurant, but there are situations
where you have takeout food and you take it home.
You might reheat it in the microwave. We
have seen some limited data where you take a food
from a restaurant, put it in the microwave, and
under those circumstances, at home, you would
produce some more furan.
DR. MILLER: Dr. Dwyer.
DR. DWYER: Just a question about the
exposure assessment. I am a nutritionist and so
when we use these kind of data, we use the Iowa
State method for adjusting the nutrients to pull in
the tails of the distribution.
Do you do that in exposure assessments, as
well? In other words, you have two days worth of
data, and so you are able to get an estimate of
usual intake from that, and I wondered if you
adjust for that. The effect would be to change the
exposure, i believe.
MR. MIHALOV: It doesn't sound familiar.
Basically, we take the distribution of all the
consumers and pull a mean in 90th percentile right
from the distribution, but not adjusting it.
DR. MILLER: Dr. McBride.
DR. McBRIDE: In answer to Dr. Nelson's
point, I looked at that data of the prepared
formula and the powdered formula and thought maybe
it was a difference in processing, might be heating
it more when it is packaged in liquid form.
I also did the calculations for the worst
case scenario because that is something I think you
were getting at, and if you have a chubby
8-month-old who consumes a liter of formula and 5
jar of sweet potatoes a day, I assumed it had to be
at least 8 kilos to do that, I got a worst case
scenario of 8 mcg/kg.
DR. MILLER: How much?
DR. McBRIDE: Eight.
DR. MILLER: Dr. Chesney.
DR. CHESNEY: Not why I am here, but the
fast food issue is intriguing. I wonder if the
packaging contains furan. Most fast food, you get
plastic containers to put it in, and most people
reheat it in the container. Just a thought.
DR. MILLER: Any more comments? If not,
The next speaker is Dr. Don Forsyth from
Health Canada, who will take about the formation of
DR. FORSYTH: First of all, I would like
to thank the committee for the invitation to appear
here today on behalf of Health Canada.
My name is Don Forsyth. I am a research
scientist with the Food Research Division of the
Bureau of Chemical Safety with Health Canada in
I would like to take you through the
background as far as Health Canada is concerned on
this issue. In late March 2004, we became aware of
U.S. FDA's investigation of furan in canned and
bottle food commodities. Upon learning that furan
has been shown to be carcinogenic in rodent models
and has been classified as possibly carcinogenic to
humans, we commenced method development as of April
of this year for support of the study of mechanisms
of formation, as well as a preliminary survey of
Canadian food products.
Although furan is used in industrial
processes, as has been discussed this afternoon, we
considered that the likely source would be
formation during food processing during the initial
start-up of our investigations.
One thing we should mention about furans
in foods, however, is that furan derivatives not
only have been reported in a wide variety of foods
previously, but they are also a significant flavor
and odor component in coffee, cocoa, and various
cooked meat products.
So, these are products or compounds, I
should say, which arise naturally during the
processing and cooking of various food commodities.
Furan itself, the parent compound, has
been previously isolated in coffee, canned beef,
sodium caseinate, soy and rapeseed protein, as well
Looking through the literature, you can
find a variety of possibilities or comments from
previous authors working in flavor and odor studies
about how these compounds are formed.
The three that we chose to look are the
thermal degradation of carbohydrates or the
Maillard reaction, thermal oxidation of lipid, and
decomposition of ascorbic acid and its derivatives.
Just to take a look at an older study
conducted by Persson and von Sydow back in 1974,
one of the first studies that you find where they
are able to determine that certain components in a
processed food could increase the levels of furan
produced within that food commodity under typical
Using a beef, water, and sodium chloride
formulation fairly typical of the day for canned
beef products, they found that even with just these
basic components, there was fairly large levels of
furan produced, however, with the addition of the
fat, as you see in the second formulation shown
here, the levels increased dramatically above the
formulation without the fat.
Then, when they looked at the formulation
with a small amount of carbohydrate added, they
found essentially no increase over the basic
formulation of beef, water, and sodium chloride,
and then finally with the fourth different
formulation shown here, with the fat and the
carbohydrate added in addition to the other
constituents, you get levels similar to the beef,
fat, water, and sodium chloride formulation.
So, in this particular study, the authors
determined that the fat was a precursor for the
formation of the furan.
Briefly looking at our own analytical
methods that we developed to support these studies,
one was a headspace analysis which we used for the
mechanisms of formation and for the food survey,
and also the microextraction technique, which is a
SPME related method developed at Health Canada
which we applied to the food survey results, which
we will be showing later on in this presentation.
Both methods are based on isotope dilution
using a d4 furan surrogate, measurement by gas
Formation studies. We took some of the
test compound or precursor to a small vial
containing 0.5 ml of water. The vials were then
heated for 30 minutes at 118 degrees, conditions
not too dissimilar to commercial canning
procedures, allowed to cool, and then force cooled
to 4 degrees when the D4 furan surrogate was added,
so that we could analyze the resulting anilides
which may have formed during this study.
The first table is on the level of furan
which were formed with the addition of ascorbic
acid and ascorbic acid derivatives. Virtually all
of these compounds are commercial antioxidants
which are used in foods, and you can see that the
ascorbic acid with or without the iron present,
iron is a known promotor of oxidation and
therefore, would be expected to, at least in some
cases, increase the amount of furan which would be
The sodium ascorbate, again relatively low
levels. The dehydroascorbic acid, however, with
either the iron present or absent gave higher
levels, almost 10 times higher than the ascorbic
Isoascorbic acid, again similar in this
case to the dehydroascorbic acid, and the sodium
isoascorbate in the presence of the ferric iron
produced almost again 10 times as much as the
sodium isoascorbate by itself, but again, both half
the levels that we found with the addition of
Finally, the ascorbyl palmitate compound
produced fairly low levels of furan as well.
Then, when we looked at fatty acids and
oils, we found that the degree of unsaturation in
the compound had an effect with an increase in the
levels of furan formed increasing as you go from
linoleic up to the linolenic with an increase of
about 4 times in this case.
Now, in these two fatty acid series, we
did see an increase in the production of furan with
the addition of the ferric iron, and in the case of
the oils, what you see in the last four rows of the
table, again, a similar increase as you go from the
trilinoleate up to the trilinolenate, approximately
again roughly 4 times.
In this particular case, with the oils,
the ferric iron had an increase in the production
of the furan for the trilinoleate, but not for the
Comparisons were made between the reaction
products and the furan standard, and as you can see
in this particular case, the comparison between the
linolenic acid reaction mixture and the furan
standard, you get a very similar pattern both for
the total iron chromatogram as well as the
fragmentation pattern for these two.
So, what we have determined so far is that
at least in the model systems that we have tested
so far, we found that the polyunsaturated fatty
acids, such as the linoleic and the linolenic, did
produce furans likely through a free radical
formation mechanism with ring closure resulting in
the formation of the furan, and also decomposition
of ascorbic acid derivatives particularly the
dehydroascorbic acid and the isoascorbic acid also
led to the formation of furan.
Some of our survey results in baby foods.
Here, we have a comparison between our two
methodologies, the microextraction technique in the
first column, and the static headspace in the
Levels varied as low as 6 parts per
billion, and went as high as approximately 154
parts per billion in the mixed vegetable. Each one
of these values that you see is the average of two
individual analytical determination for each
When you look at adult foods, we found
that the chili products had the highest levels
amongst those that we analyzed with levels ranging
up to as high 227, 236 depending upon the method
value, as well as 152, soups there was a broader
range ranging from as low as 35 ppb up to
approximately 115, 117 ppb.
We have looked at one stew product so far
with a value of approximately 80 parts per billion,
one bean product with relatively low value, 14
parts per billion.
The luncheon meats that we looked, I
believe were both beef or pork based, and they were
all relatively low with levels down to 4 parts per
billion, and no higher than approximately 30 parts
Fresh brewed coffee, as would be typically
served, would range between 14 to approximately 50
parts per billion.
Next steps for our work at Health Canada
include further studies on the mechanisms of
formation using additional model systems, as well
as precursor fortified food matrices.
Examining losses of furan during food
processing and cooking operations, as well as
further examinations of canned and bottled
products. We also have a round robin method
validation study to complete, and that is ongoing
as we speak, and we should be reporting back on
that in just a few weeks.
Then, finally, to continue updating our
health risk assessment as new data becomes
With that, I would just like to thank
everyone for their kind attention.
DR. MILLER: Thank you.
Any comments or questions?
Questions of Clarification
DR. ACHOLONU: I was wondering, is it
advisable to check the concentration of furan in
mixed vegetables? Could you justify using that?
Mixed vegetables, which has different kinds of
vegetables put together, what do you do?
DR. FORSYTH: The premise of that, of
course, is for health risk assessment, in which
case we are interested in consumption of food
commodities that are related to a typical diet, so
this is one particular food product that we
happened to analyze, and that is essentially the
extent of our interest in it at that point.
DR. ACHOLONU: But does it have any
DR. FORSYTH: It has a scientific basis in
the sense that with that particular food matrix,
those are the levels that you are reaching. It
also brings to mind what is causing that formation,
which is something that we are certainly interested
in, because it doesn't fit into the existing models
that we have pursued so far. So, yes, I think it
has a lot of scientific interest.
DR. MILLER: Dr. Krinsky.
DR. KRINSKY: Could you just describe the
conditions for generating the furan from the
linolenic acid? Was this heated, cooked, baked, or
was it just linolenic acid out of a jar?
DR. FORSYTH: I didn't actually conduct
this study myself. My understanding is that the
compound, which I believe was 10 mg of the
precursor would have been added to the vial
containing 0.5 ml of water, and then that would
have been heated to the 118 degrees for 30 minutes.
DR. KRINSKY: Thank you.
DR. MILLER: Dr. Lund.
DR. LUND: Looking at the Persson and von
Sydow data, I wondered if you have had any comments
with regard to the degradation of furan upon
prolonged heating. Some of their data, at least on
the surface, would suggest that upon prolonged
heating, you probably get formation rates equal to
degradation rates because the concentration is not
DR. FORSYTH: First of all, I am not sure
if that is what they were alluding to or not. I
thought that data was to look at probably losses of
furan due to revolatilization during heating and
processing in the kitchen.
I know that there is some concern that you
may actually be creating more furan with
post-processing sample manipulation, but I don't
know if anybody has actually really looked at that
DR. MILLER: Dr. Callery.
DR. CALLERY: We addressed part of this
already, but it's an impressive amount of work that
you have done since March. I have been looking at
this, and I admire you for being able to get so
much data so rapidly. I have a couple of little
The ascorbic acid one in particular, from
what I remember the structure of ascorbic acid,
it's a highly oxidized species and it gets even
more oxidized readily, and that you are actually
asking iron to participate in this reaction to
facilitate an oxidation.
I think the point I am trying to make is
that the furan is more like a reduction or
elimination of water, a couple water molecules, and
more a reduction. If you looked at the oxidation
states of the various carbons, they are not at a
higher oxidation state than ascorbic acid.
So, it may be something very different
going on here that is involving the metal in the
process of making furan, if that is what you are
actually doing. I think the question was also the
yield that you are addressing here, maybe there is
10 mg of ascorbic acid or I am sure 10 mg of fat,
but that nanograms per gram is incredibly small
yield in the process of cooking, so I am wondering
a little about that, too, if you aren't just making
some furan this way out of this particular
DR. FORSYTH: I have no doubt that the
yields, particularly with the ascorbic acid tend to
be quite low, but typically, levels used in food
are reasonably high, and this wouldn't necessarily
be the only way that furan would be formed, and it,
of course, had been alluded to earlier by one of
the other speakers, that we undoubtedly will find
that there is multiple pathways contributing to the
overall levels of furan present in the food.
These are, I can't stress strongly enough,
preliminary investigations into possible means that
furan could be formed. There had been previous
work with some of the ascorbic acid related
derivatives that had indicated that a variety of
furans were formed during thermal degradation, and
this is what we were attempting to follow up on
with this study.
DR. MILLER: Dr. Chin.
DR. CHIN: I would also like to compliment
you on doing such an impressive amount of work in
such a short period of time.
Just a question in terms of your thoughts
on other possible precursors. Are you planning to
look at the possibility that perhaps carotenoids
and similar types of materials might be a precursor
DR. FORSYTH: Our immediate plans, and we
are doing this as we speak, looking at Meyer type
reactions at present.
DR. CHIN: Just a follow-up, and the
reason I am asking is because in products like the
sweet potatoes where there are amount of furan have
been detected, I mean those materials are high in
carotenoids, whereas, they are generally low in
fat, and I don't think the ascorbic acid levels are
particularly high, so just a possibility in terms
of another possible precursor.
DR. FORSYTH: It sounds like we will be
following up with you shortly.
DR. MILLER: Dr. Dwyer.
DR. DWYER: Just a question more from
ignorance than anything else. Are the methods that
you are using in Health Canada and the Food and
Drug Administration's methods the same? I just
looked at chili, and it looked like the Canadian
chili was much more potent than the American chili,
and just wondered if there were some way if they
are not the same method, if there is some way to
get some comparable methods in both countries or to
divide up the work and do some round robin studies,
so that we are not overduplicating things that are
basically the same trading area.
DR. FORSYTH: Round robin testing is
underway. In our own case, it was set aside
because we were concerned with what levels were
present in the Canadian food supply, so that was
our first priority. Now that that is completed, we
do have the two methods which we wish to compare,
not only against FDA's method, but also any
industry methods which are out there, and we will
be doing that through the round robin study.
DR. MILLER: Dr. Russell.
DR. RUSSELL: Yes. Following up to Dr.
Chin, I also had wondered about the sweet potato,
but I was wondering if the soup, it says soups in
both the FDA data and your data, I was wondering if
there was any clues that could be gotten with the
types of soups.
There was a three- or four-fold variation.
What types of soups were looked at?
DR. FORSYTH: I believe there was--I hope
there was a listing of the actual products that we
tested included in your information package. In
any case, we have tested 30 products so far. We
hope to be testing more in the near future but for
the time being, we will be participating in the
round robin study first.
DR. MILLER: Dr. Chesney.
DR. CHESNEY: Again, just for
clarification, and this may seem like a very
simplistic question, but is it correct that the
furan is created by oxidation of the ascorbic acid
products and the polyunsaturated fatty acids, it's
a product of oxidation of those entities, am I
DR. FORSYTH: I think with the ascorbic
acid, I would view it more as a thermal degradation
as opposed to an oxidation per se, whereas, with
the lipids, it is a radical-mediated oxidation
DR. MILLER: Dr. Nelson.
DR. NELSON: Following up on Dr. Dwyer's
comment about the equivalence of method or
recognition of each other's method, I guess, would
the food supplies be considered equivalent enough
for us to sort of accelerate the database by again
sharing the activity? I don't know if we need the
same trading area, we have to have a NAFTA
DR. FORSYTH: Is that related to me?
Presumably, in Canada, we find that we have
different branding as opposed to U.S. foods, but in
cases where you have the same manufacturer, I
personally can't see any reason why the data
couldn't be used.
DR. MILLER: Dr. Downer.
DR. DOWNER: I just wanted to respond to
Johanna's question about the chili. I think in
Canada, they may be using Spam from looking at the
database here, so maybe that is where the
Thanks for a good presentation. I am just
wondering about Dr. Morehouse's presentation when
he looked at no furan detected in some of the
different groups of foods, particularly foods from
animal sources. I was thinking that perhaps
because it was a bit lower in fat.
But on one of your slides, when you talked
about the effect of canned beef formation and you
added fats, it was really the opposite. Could you
talk a little bit about perhaps the differences
that were seen there?
DR. FORSYTH: Actually, in retrospect,
when you look at their study versus our own results
on canned luncheon meats, I have concerns. It was
a 1974 survey, well, different analytical
capabilities than we have now, so I believe that
that work does bear out the results that we were
finding in terms of the presence of fat promoting
the increase in furans.
However, I can't reconcile the findings
that they reported in that publication with our own
and also with FDA's current findings on luncheon
meats, which I would have felt should be
DR. MILLER: Dr. Dwyer.
DR. DWYER: Just a question again about
methods. Is there a standard method, or are you
driving toward a standard method instead of
everybody having their own method especially in
North America, it seems like this might be
something to agree about one way or another?
DR. FORSYTH: There has been a few
factors, time being one of the largest.
Essentially, with the time constraints that all of
the organizations have had, you basically begin
with the people that you have who know how to do
these types of analyses, and you ask them to come
up with a working method, and I believe that is
essentially what has happened here.
The next phase will be these organizations
to have, and this is being done as we speak, a
round robin study in which case we all examine the
same food commodities and see if we get, hopefully,
roughly the same answers. Depending upon the
results of that study, there would then be either
adjustments made or discussions amongst the various
organizations to determine why, if there are indeed
any, there are differences in our results on these
particular food commodities.
DR. MILLER: Why don't we move on. Thank
you very much.
The next speaker is Dr. Glenda Moser. You
have got 25 minutes.
Scientific Overview of Furan in Foods
DR. MOSER: Thank you.
Well, I would like to begin by thanking
the committee for inviting me today and say that my
talk is going to be a little different than those
that have been presented up until this point, and,
in particular, I am going to be talking about some
in-life studies that we did to try and determine as
best we could a mechanism for furan-induced liver
tumors in mice.
In a two-year NTP bioassay, there were
both non-neoplastic and neoplastic findings in rats
and mice of both sexes. In particular, there were
neoplasms, cancer, in the liver in the rats, and
cholangiocarcinomas in the rats, as well as
mononuclear cell leukemia.
The important thing here is that at 2
mg/kg, there was approximately a 90 percent
incidence of cholangios. In mice, there was an
increased incidence of benign tumors of the adrenal
gland, as well as hepatocellular tumors at both 8
at 15 mg/kg.
Here, what you see is more of what I am
going to be talking about today, is the incidence
of your hepatocellular adenomas or your benign
tumors, hepatocellular carcinomas, and then the
adenomas and the carcinomas together in female mice
and in male mice, and you see a dose-dependent
increase in both the males and the females.
Another important factor for the study
that I am going to be talking about is the
incidence of spontaneous liver tumors in both male
and female mice. Historically, in your B6C3F1
mice, you will have somewhere between 20 and 60
percent incidence of liver tumors in control
animals. Usually, it's much lower in your female
mice. It is for that reason that we conducted our
two-year study in female mice.
Sometimes it is difficult when you have 40
or 50 percent incidence of spontaneous liver tumors
to find an increase in male mice.
Cancer, as we are well aware, is a highly
complex, multistage process that is operationally
divided into three stages, namely, initiation,
promotion, and progression. Initiators or
genotoxic agents directly damage DNA. They change
the primary sequence of the DNA.
Genotoxic agents can be carcinogenic after
a single exposure, and, in general, it is found
that genotoxic agents are better carcinogens if
they also induce cell proliferation, so they can
fix those mutations.
Metabolism, there are many carcinogens,
not only liver carcinogens, but carcinogens in
other systems, the parent compound is not
carcinogenic, but it is metabolized or intoxicated
to its toxic moiety.
In the case of furan, you have the
cytochrome 2E1 in the liver that metabolizes the
furan to its toxic moiety. There are a variety of
mechanisms of genotoxicity which we are not going
to talk about today.
What we have here is somewhat of a summary
of assays for genotoxicity after furan exposure.
We have those that are negative, those that are
positive, those that are highlighted in mammalian
systems, and those that aren't, are either in your
Salmonella or your Drosophila.
In spite of the fact that there are some
positive tests for genotoxicity, furan is generally
considered to be non-genotoxic. Non-genotoxic or
epigenetic agents, they are generally believed to
clonally expand those initiated cells.
They provide an environment in which those
particular cells opportunistically grow and expand,
that, in general, your non-genotoxic agents require
multiple exposures, sometimes over the course of
the entire life span of the animal, and generally,
with your tumor-promoting agents or your
non-genotoxic agents, it requires high doses.
In the early stages, tumor promotion is
generally reversible, so that in a 13-week study
with furan, the animals were dosed at 8 and 15 mg,
then, they were held for either 6 months, 9 months,
or 15 months, and 18 months, and evaluated.
In these particular studies, furan was not
reversible, particularly the cholangiocarcinomas.
It is important for us that B6C3F1 mouse
is the mouse used by the National Toxicology
Program. Part of the reason that it is used is
that it is sensitive to cancer, and that's both
spontaneous cancers, as well as chemically induced.
In particular, the liver, of the 500
compounds that the NTP has evaluated, approximately
50 percent of them are carcinogenic in the mouse
liver. Really, that was the reason that we
conducted these studies was to try and make some
association of what relevance are these mouse liver
tumors to humans.
There are a whole variety of non-genotoxic
mechanisms, we are not going to talk about them
today. The one I do want to talk about is the
cytotoxicity in cell proliferation, that furan, in
short-term studies, is necrotic to liver cells,
hepatocytes. It kills them.
After this, in order for the liver to try
and maintain its homeostasis, we have regenerative
or compensatory cell proliferation. There are
certain hypotheses that believe that the mutations
that you may find in the H-ras gene or some of the
other genes are secondary to this cytotoxicity and
cell proliferation, that the DNA is believed to be
inordinately sensitive to mutation when it is
dividing. It is kind of spread out there, kind of
opening itself up, if you will.
Liver cytotoxicity, how do we determine if
a chemical is cytotoxic for the hepatocytes?
Commonly, that is done by clinical chemistry, by
evaluating serum ALT, alanine aminotransferase, or
sometimes SDH levels, sorbitol dehydrogenase, and
secondly, by histopathology, that liver sections
are stained with hematoxylin and eosin, your H & E
stained section, you will commonly find pycnotic
nuclei that generally the nuclei of the hepatocytes
are blue, and those cells that have been exposed to
a cytotoxic agent, their chromatin and the nucleus
is sometimes so blue that it is almost black.
You will find an inflammatory response.
You have the recruitment of both your mononuclear
and your polymorphonuclears to kind of clean up the
debris as a result of this cytotoxicity, and
thirdly are the degenerated hepatocytes or the
We conducted a 13-week study in male
B6C3F1 mice. These animals were exposed by gavage
intergastrically 5 times a week. The dose levels
were 0.5, 2, 4, 8, and 15 mg/kg. We quantified
cell proliferation by BrdU. In these particular
studies, we used an osmotic pump, a 7-day. The
advantage of that is that the liver--the life span
of a hepatocyte in a mouse is generally about 200
days, so at any one point in time, you are only
going to have 0.5 percent of your hepatocytes
So, if we go over the course of 7 days,
then, we accumulate all the cells that are divided,
all the cell replication that occurred in those 7
So, this is an H & E stained liver section
of the mouse, and what you see here, you see the
inflammation that is common after exposures to
cytotoxic agents. You have the influx of your
morphonuclear, of your mononuclear and your
After you look at the incidence of liver
cytotoxicity, after 1, 3, 6, and 13 weeks, you will
see that the highest doses, you have a greatly
increased incidence of cytotoxicity, also, at 8
mg/kg you have a significant increase, and at 4,
you have an intermediate response.
Cell proliferation. One of the markers,
the ways of quantifying cell proliferation is the
labeling index that measures the S phase of the
cell cycle. There are a variety of methodologies.
You can look at mitotic figures, quantify those.
You can look at KI67 gene, you can look at PCNA, a
proliferating cellular nuclear antigen that is part
of a quaternary complex.
For us, we used BrdU, bromodeoxyuridine.
It's a thymidine analogue, so when the DNA is
replicating, in place of the thymidine, a certain
percentage of the BrdU will be incorporated.
Then, we have an antibody to the BrdU, so
we immunohistochemically stain for cells that have
incorporated this BrdU. There are a variety of
routes of administration depending upon what the
endogenous cell proliferative rate is. You can use
a pulse. So, for instance, if you are looking at
cell proliferation in the skin, you may inject IP
an hour later euthanize the animals.
For us, there is the cumulative is the
advantage, as I said earlier, because you can find
out the cell proliferation that has occurred over a
period of time.
Quantifying, how do we quantify this?
Well, by light microscopy, we look at these
immunohistochemically stained sections. [Off
I am sorry, excuse me. At the 4 mg/kg,
these are the cells that have incorporated the
BrdU. Over here, at 8, you will see many more of
them. So, what we do is we evaluate 2,000 hepatic
nuclei and determine the percentage for those
nuclei that have incorporated this stain.
In our 13-week study, you will see that we
have a significant increase at the 15 mg/kg at all
three time points, 1, 3, 6, and 13 weeks. At our 8
mg/kg, which I found to be interesting that your
calculations were 8 mcg/kg, you have a significant
increase at 1, 3, and 6 weeks. At 3 weeks, you
also have an increase in 2 and 4.
We also conducted a study in female mice
in which they were exposed to 00.5, 1, 2, 4, and 8
mg/kg, and you will see that the highest dose of 8
mg/kg produced a significant increase in your ALT
levels with an intermediate response in the 4.
The SDH was elevated in both the 4 and the
8 mg/kg. If you looked at the hepatic labeling
index, again, you saw a significant increase in
female mice at the highest dose of 8 mg/kg, and no
In light of this data, we conducted a
carcinogenicity study, a two-year study. It was in
female B6C3F1 mice. Our dose levels were 0, 0.5,
1, 2, 4, and 8. Eight, you will recall was the
dose that produced both cytotoxicity and an
increase in labeling index, that we had 50 to 100
animals per group, particularly in our lower groups
we wanted to be able to detect the significant
increase if there was one, so we increased the
number of animals.
They were exposed for two years. They
were exposed by gavage, and this was 5 times per
We conducted necropsies on these animals
after two years, and what you will see here, on the
left, is a normal mouse liver. This was an animal
that was exposed to 8 mg/kg, and at gross necropsy,
you will often find these masses.
We quantified the incidence of these
masses at necropsy. There was a significant
increase, 100 percent of the animals had liver
masses at the final necropsy, and there was also a
significant increase at 4 mg/kg.
We evaluated H & E stained liver sections
for inflammation. As before, you will see that at
your 8 mg/kg, that there was an increased incidence
of livers with both moderate and marked subcapsular
inflammation or cytotoxicity, and there was an
intermediate response at 4 mg/kg.
This is an H & E stained liver section,
and what we have here is a hepatocellular tumor.
It is a metastatic one as it ended up being. You
can see how there is loss, there is disruption of
the normal liver architecture. So, we evaluated H
& E stained sections for the presence of
hepatocellular adenomas, carcinomas, and foci.
You will see at 4 mg/kg, there was a
significant increase in foci. Foci are believed to
be pre-neoplastic liver lesions that have the
ability to progress on to become benign or
malignant liver tumors.
At your 8 mg/kg, you had a significant
increase in the incidence of foci, adenomas, and
What we say here is that there is a very
good correlation between cytotoxicity as measured
by ALT or SDH, and labeling index, and the
incidence of liver lesions. So, when those, at 8
mg/kg, where you had an increased incidence of
cytotoxicity, you had an increase in labeling
index, you also had an increase of masses at
necropsy, and adenomas and carcinomas
At 4 mg/kg, you had somewhat ambiguous
intermediate responses in the short-term assays,
and you had an increased incidence of lesions or
masses at necropsy, and an increased incidence of
pre-neoplastic lesions by light microscopy.
So, in conclusion, what we can say is that
this study demonstrated a dose-dependent increase
in furan-induced liver tumors in female B6C3F1
mice, and a relationship between the dose,
cytotoxicity, compensatory cell proliferation, and
An overview. In this particular study, we
have reproduced the results of the NTP bioassay.
In the NTP bioassay, they used 8 and 15 mg/kg.
They had an increased incidence of liver tumors as
What we noticed here is that there is a
threshold that doses below 4 mg/kg did not increase
the incidence of liver tumors or produce the
short-term effects that would suggest that they
would be hepatocarcinogenic.
At 13 weeks, I did not show the data, but
at 13 weeks, we saw that there was an increase in
cytotoxicity, there was an increase in labeling
index. We have a stop group, so they were exposed
for 13 weeks, then, they were held for an
additional 4 weeks. Both the labeling index and
the cytotoxicity returned to normal in that group.
There are other chemicals with the same
proposed mechanisms - chloroform, carbon
tetrachloride, theocitamide [ph], a whole variety,
that the mutations or the other events that we saw
in these genotoxicity assays may be secondary to
hepatocyte cytolethality or increased cell
This is a biologically plausible
mechanism. It makes sense that cells are killed,
that new cells are produced, and that these
particular cells may be more susceptible to DNA or
The furan-induced effects after short term
exposure are inhibited by p450 inhibitors. We said
that furan is metabolized by cytochrome p450-2E1 to
its toxic metabolite, it's a dialdehyde. If you do
studies in which you give the animals the furan and
the p450 inhibitor, you do not get an increase in
labeling index at these doses. You do not get an
increase in cytotoxicity.
There are similar pharmacokinetics in the
mouse and in the human in vitro, and in general,
the rat metabolizes furan slower than does either
the mouse or the human.
Future areas of interest. It would be
interesting to know that if you gave your animals
p450 inhibitors or maybe developed a transgenic
mouse in which that particular gene was knocked
out, would you get mouse liver tumors.
Are liver tumors due to the bolus dose?
So, unlike food where you are taking a little bit
in all the time, we gave them their furan in one
big dose the first thing in the morning.
Are the positive genotoxic results, are
they due to direct damage to the DNA, as some of
the genotoxicity assays indicated, are they due to
the high doses, or are they secondary to cell
proliferation or other phenomenon?
What are the molecular or the gene
expression changes in liver tumors? That is
something that we have been looking at is to try
and find out are there growth factors, are there
other things, surrogate markers that we could find
in the blood that might help us identify those
chemicals that are possibly carcinogenic, in
particular, liver carcinogenesis, and, in
particular, those that do a biocidal toxic
Do these same mechanisms occur for
cholangiocarcinomas? Is there a threshold for--and
I am sorry, these say cholangiosarcomas, they
should be cholangiocarcinomas--is there a threshold
for cholangiosarcomas, similar to what we found
with the mouse liver?
Is the mode of action of the
cholangiocarcinomas similar to that of the mouse?
Do biliary tract epithelial cells have
pharmacokinetic parameters similar to that of
hepatocytes? It is the biliary epithelial cells
that are believed to be the precursors of the
cholangiocarcinomas. What is the relevance of the
mouse liver findings to cholangiocarcinomas and
leukemia in humans?
This particularly has to do with the
pharmacokinetic parameters. What are the
concentrations in the organ systems of interest?
Are there populations of humans that are
susceptible to furan-induced effects and is age a
factor, whether it be the baby food or the elderly?
There is a lot of evidence that indicates that
infants don't have the same intoxification or
detoxification systems as adults, so does that make
them more susceptible or less susceptible?
Finally, I would like to thank my
colleagues, those who actually did the work,
particularly, the--well, anyway, my
colleagues--particularly the toxicology technicians
and the animal care and the laboratory assistants
who certainly did 99 percent of this work, the ILS
Histology Department for the H & E stained liver
sections, Dr. Robert Maronpot at NIEHS, who read
the liver sections, Julie Foley at NIEHS, who
helped with the cell proliferation studies, and Dr.
Questions of Clarification
DR. MILLER: Dr. McBride.
DR. McBRIDE: I have two questions.
Firstly, is there any data in the mice that is age
related? Secondly, if I am remembering right, you
had the only slide that showed any changes at or
below 2 mg/kg dose was the one slide on
cytotoxicity, I forget how that was measured, and
if I am understanding you right, that was
reversible at least in time.
DR. MOSER: That was in the 13-week study,
so let me see if we can find that data. Do you
know, was that in the 13-week?
DR. McBRIDE: Yes, at the 13-week.
Although it was reversible, it might still be of
import because, of course, as we are looking for
any change, we are looking for the lowest dose,
especially in humans where there may be multiple
factors that affect risk.
In other words, was this the only finding
that you found at 2 or lower mg/kg?
DR. MOSER: I think that we had some cell
proliferation at 3 weeks in this 13-week study, so
there was a significant increase at 2 weeks at 2
mg/kg at 3 weeks, and that is the only significant
finding that we had.
DR. McBRIDE: But on your other slide, it
was a 0.5 mg/kg, the one before that.
DR. MOSER: Okay, and I think what it was
there, it's a statistical thing, we only had 10
animals per group, and we had 2 animals that did
show some evidence of cytotoxicity. These slides
were read blind. It is not a significant increase,
but there is something.
DR. McBRIDE: And the question of age of
DR. MOSER: Age of mice. All the
short-term studies that we did, the mice were 6 to
8 weeks old when we started, and that is because
the liver continues to divide and is really not
mature until about 10 weeks of age, so we tried to
make sure that all of our studies were done the
same, be they the short term or the long term.
So, that our short-term studies and
long-term studies, they all started exposure at the
same age. It is just that with your 2-year
studies, of course, we went out to the end.
DR. MILLER: Dr. Gray.
DR. GRAY: I think something that we want
to try and learn about here that is really
important for thinking about this food situation is
something you touched on in one of your last
slides, and that is this question of dose rate.
Is there any other data to help us
understand that, because as you mentioned, other
compounds that are thought to act in this way show
a strong dose rate effect. For example, chloroform
gives you very similar mouse liver carcinogenesis
Ninety percent, 100 percent response, you
give the same dose in drinking water over the
course of the day, no tumors at all.
DR. MOSER: Right.
DR. GRAY: And if dose rate is an
important factor here, that is something we need to
know because that is a big difference between our
animal studies here and the way in which people are
likely to be exposed.
So, I mean I don't know if there is
something in the literature you can help us
understand, or if it is something that we need to
think about as a study going forward is
understanding whether there is a strong dose rate
effect for liver tumors and the other tumors that
are out there.
DR. MOSER: Let me say, and that is why I
put it up there, chloroform has a mechanism of
inducing liver tumors that appears to be very
similar to that of furan. If you give chloroform
by gavage, the same way we gave the furan, you will
get liver tumors. You give them the very same dose
in the water, you do not get liver or kidney
So, that indicates that maybe small
amounts over the course of time doesn't have the
same effect as just one huge dose, and particularly
maybe first thing in the morning. They are
nocturnal, you know, they move, they do things at
night. So, who knows? But that is a very, very
DR. GRAY: And at this point, there really
isn't anything in the literature to help us on the
furan front on this?
DR. MOSER: I think that Greg Kadaras [ph]
has done a little bit of work, and I think it has
been inhalation, and I will have to check on that,
but he has done work that I believe has been by a
mechanism other than gavage.
DR. MILLER: Dr. Krinsky.
DR. KRINSKY: Thank you for the nice
cancer cell biology review. You used the term
"threshold" and "dose dependent." Those are not
identical, and I think that is important in terms
of human consumption, because if, in fact, your
data indicates that there is a threshold level
prior to seeing toxicity, that may have very
important implications as far as human consumption
DR. MOSER: I would agree. The idea of
the threshold is that there is, from my definition,
okay, in this study, is there is a dose below which
you really don't see the cytotoxicity, you don't
see the compensatory cell proliferation, and you
don't see the liver tumors, as compared to dose
response, which means, you know, a low dose you get
a low response, medium dose, medium, high dose,
DR. KRINSKY: And the mechanism for the
DR. MOSER: What we would have to say is
that whether it's a matter of intoxication, you
know, that there is just so many mixed oxidase
function enzymes to produce the toxic metabolite,
or there is a detoxification mechanism, you know,
it is believed that glutathione is a way of
detoxifying the metabolite, and there may well be,
and we know that is the case, only so much
glutathione, so there is only so much to help us
cart that toxic metabolite out. Beyond that level,
you may see toxicity.
But the truth of the matter is, when I
look at the literature, glutathione is the only
detoxification mechanism they have looked at.
There may be others.
DR. MILLER: Dr. Russell.
DR. RUSSELL: Again, thank you for that
presentation. In thinking about populations of
humans that might be susceptible to furan-induced
effects, the one that comes to mind right away to
me is alcohol users, because it is such a potent
stimulator of p450-2E1.
DR. MOSER: Exactly.
DR. RUSSELL: I think that that ought to
be looked at in your model, but in epidemiologic
models if this gets carried on to humans, that this
really may be a population that is much more
DR. MOSER: I think there was a study done
at CIIT, and it was a short-term study in which
they induced the cytochrome p450-2E1 by exposing
the animals to acetone, it was. I don't think it
was the alcohol should have done the same thing.
DR. RUSSELL: Yes.
DR. MOSER: So, you have these higher
levels of the enzyme that is producing the toxic
metabolite, and we also know that certainly alcohol
consumption is a prerequisite to certain kinds of
liver damage and ever certain kinds of liver
cancer, so that is a very good point, and I
wholeheartedly agree. Thank you.
DR. MILLER: Dr. Callery.
DR. CALLERY: Let me probe that 2E1 a
little further. I want to know if you know that
the 2E1 in mice is the same as the human 2E1 is one
question, and then another is, I am probing my own
memory here, do you know Carlson's work at Purdue
DR. MOSER: No, I am sorry, I don't.
DR. CALLERY: I believe he has got a null
DR. MOSER: Oh, does he?
DR. CALLERY: Where the styrene was still
converted to styrene oxide and had the same
viability for potential carcinogenicity.
DR. MOSER: I think that's interesting
because it's like everything else, you know, we
have looked at the 2E1. There may well be other
means of intoxication, we just haven't looked at
DR. CALLERY: Or detoxification.
DR. MOSER: Exactly.
DR. CALLERY: The other is I am trying to
relate the mouse to the human, and especially in
the glutathione concentrations and such, and the
redox activity in the glutathione system. I don't
know how that relates to the human.
DR. MOSER: I don't know either. Does
anybody know if the glutathione levels are
comparable in mice and in humans, or in the liver
anyway? I am sorry, I don't know.
DR. CALLERY: Then, I guess the last one
is you had mentioned that you were at 2 mg/kg and
we have an estimation that the human exposure might
be 1,000-fold less. Does that have any meaning to
DR. MOSER: Well, there is species
extrapolation, as we all know, is extremely
difficult. Not only that, we have got a tissue
extrapolation here, you know, that we are not
necessarily talking about, a high incidence of
liver cancer in this country, not to say that it is
not important, and most of the liver cancer that we
see in this country we believe to be more
associated with hepatitis and alcohol consumption.
So, does that mean that I think that those
levels are safer? Not absolutely at all. It does
appear that the mouse is more sensitive to liver
tumors than some of our other models. Actually, a
better question is well, what about the
cholangiocarcinomas. I mean they saw almost a 90
percent incidence at 2 mg/kg in your NTP bioassay.
Is that relevant?
Well, here, we don't know, at what dose do
you continue to get these cholangiocarcinomas. As
I look at the literature, and I am not an expert on
that by any means, it does appear that the rat is
more sensitive to at least cholangiocarcinomas than
are mice or humans, that in all the reading I have
done in the last week or so trying to prepare for
this, there is only one study in which there was an
increased incidence of cholangiocarcinomas in mice,
and that was with PCBs, polychlorinated biphenyls,
and they were on some sort of a restrictive diet,
and the incidence was not as high as what you are
seeing in your rat.
So, again, we go back to the species is
extrapolation, is that data in rats relevant to
humans at that dose. I wish I knew.
DR. MILLER: Dr. Chesney.
DR. CHESNEY: You just mentioned
hepatitis, and I was thinking that another human
population that might be at risk for furan are
patients with hepatitis B and hepatitis C, and
there is an animal model for hepatitis B, and I am
blocking on the species. I think it might be the
prairie dog, but I am probably wrong about that.
DR. MOSER: Is it the woodchuck?
DR. CHESNEY: It's the woodchuck, that's
right. Thank you.
DR. MOSER: Don't ask me how I knew that.
That just came out of some deep recesses.
DR. MILLER: I am going to call for a
break. Can we be back here in 10 minutes.
DR. MILLER: The FDA received only one
request for public comment, that by the National
Food Processors Association. It was to be
delivered by Dr. Richard Jarman.
Dr. Jarman has said that in the interest
of facilitating the discussion, he submitted a
statement which he intended to read and which you
have all received a copy of, and he is prepared to
allow the statement to stand in lieu of having to
make a presentation.
So, the statement will be incorporated in
Summary and Charge to the Committee
DR. MILLER: Now we come to the nitty
gritty. Before we begin our discussions, Dr. Terry
Troxell of the FDA will summarize and re-present
the charge and reading of the questions, and then
we will proceed with our discussions.
DR. TROXELL: Thank you. My name is Terry
Troxell, Director, Office of Plant and Dairy Foods.
I don't want to take much of your time. I
just want to recapitulate a little bit to
facilitate your discussion. The main points here
are the actions we take and what are the data
needs, the charge, and the questions.
As we have said, we have developed the
method. The method was posted on the web site. We
are going to be doing a round robin, so we should
sort out any differences in levels being observed.
We did an exploratory survey, more than
160 foods were in our first round, and with 40 more
since we published a notice in the Federal
Register, and 30 from Canada. We are now at 230
foods, and we will be testing a broader range of
The preliminary exposure assessment was
done. We utilized the first 160 samples,
obviously, because things are moving so fast, we
were not able to incorporate all the data that we
We also obviously did our call for data
and then we have established international
interactions. We provided Canada with our method,
and they very quickly developed additional methods,
similar, so that we could generate a lot of data
together, and we also coordinated, so that we could
minimize duplication of effort, so that we can
maximize the results at this point.
The other thing you should be aware of is
that the EU has a heat tox project, which is to
look at investigating thermally processed induced
toxins in foods, and they are going to incorporate
furan in that process.
So, again, as with acrylamide, we are
trying to maximize our collaborations to try to
zero in on the problem as