1
FOOD ADVISORY
COMMITTEE AND DIETARY
SUPPLEMENTS SUBCOMMITTEE
FURAN MEETING
Tuesday,
June 8, 2004
1:55 p.m.
Bethesda Marriott
Grand Ballroom
5150
Pooks Hill Road
Bethesda, Maryland
2
PARTICIPANTS
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.
FDA
Dr. Henry Kim
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C O N
T E N T S
PAGE
Welcome and Introductions
Sanford A. Miller, Ph.D.,
Chair 4
Conflict of Interest
Statement
Linda Reed, Acting Executive
Secretary, FAC 6
Opening Remarks
Nega Beru, Ph.D. 10
Scientific Overview of Furan
in Foods
Analytical
Methods/Occurrence
Dr. Kim Morehouse 22
Exposure
Jeremy Mihalov 36
Formation
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
4
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
deliberations.
When I call your
name, will you please
just repeat your name and
the institution with
which you are associated.
First, Dr.
Acholonu.
5
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
University.
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
6
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
them.
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.
Peter Pitts.
Relying on that authority, Mr. Pitts has
signed a memorandum granting
permission for Dr. P.
7
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
Committee.
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
regulated industry.
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
Waslien.
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
8
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.
9
Miller.
Thank you.
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
time schedule.
The first
presenter is Dr. Nega Beru of
the FDA, who will provide
the background and
discuss the charge to the
committee.
10
Opening Remarks
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
11
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
study.
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
of them.
Later in this
session, Dr. Don Forsyth
from Health Canada will
present to you their
studies on mechanisms of
formation of furan in
foods.
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,
12
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
baby foods.
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
semi-quantitative method.
13
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
consumption data.
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
14
nondetectable to
approximately 100 parts per
billion furan.
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
foods.
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
Toxicants Subcommittee.
When we announced
the data to the public,
we did so with a number of
message points. Of
15
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
16
an expanded survey including
foods as eaten in
order to determine exposure
and risk to consumers
more accurately.
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
response.
In the call for
data we issued on May 7,
17
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
18
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
including carcinogenesis.
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
following objectives:
1.
To establish a dose-response curve for
the various toxicological
endpoints.
2. To determine whether furan toxicity,
including carcinogenesis, is
a threshold dependent
event.
3. To determine whether the carcinogenic
19
activity of furan is
secondary to its hepatotoxic
effects.
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
safety.
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
20
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
packages.
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.
21
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
toxicology?
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
22
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
Analytical
Methods/Occurrence
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
Perfetti.
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
23
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
laboratory.
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
24
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
product.
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.
25
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
26
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
27
different lots per brand. Using this data, we
undertook a systematic
manner to obtain
quantitative data.
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
vials.
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.
28
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
29
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
30
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
jars.
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
have done.
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.
31
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.
Thank you.
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
potato chips.
DR. ARCHER: Any hypotheses?
DR.
MOREHOUSE: Nope. Again, you are hear
32
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.
33
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
levels.
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
formulas.
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
34
data in order to be able to
come to that
conclusion.
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
differences.
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
35
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
itself.
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
microwaved.
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
36
also?
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.
Exposure
MR. MIHALOV: My name is Jeremy Mihalov,
Office of Food Additive
Safety. This also was done
37
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
that food.
We looked at adult
foods, baby foods and
also the infant formula, and
they were considered
separately.
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
38
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
corn.
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
39
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
100.
Going back to
discussing the model,
generally, when you do an exposure assessment,
there is a certain amount of
uncertainty, and we
40
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
exposure.
41
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
weight/day.
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
42
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
grow.
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.
Thank you.
43
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
correction.
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
every day.
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
highest value?
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
44
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
45
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
assumption?
MR. MIHALOV: I couldn't say.
DR. MILLER: Dr. Nelson.
46
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
that?
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
47
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
48
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?
49
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,
thank you.