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

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

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

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.

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

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.

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

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.

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.

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

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,

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.

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

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

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

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

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,

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

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

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

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

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.

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

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

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

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.

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

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.

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

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.

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

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

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

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

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

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

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

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

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

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.

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

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.

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

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

assumption?

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

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

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,

thank you.