October 30, 2002

Dockets Management Branch (HFA-305),

Food and Drug Administration

5630 Fishers Lane,

Room 1061

Rockville, MD 20852

**RE: Docket No. 02N-0393 Acrylamide in the Food Supply**

**67 Fed. Reg. 57827 (September 12, 2002)**

The Center for Food and Nutrition Policy (CFNP, or the "center") of
Virginia Tech---Alexandria is an independent, non-profit research and
education organization that is dedicated to advancing rational,
science-based food and nutrition policy. It is recognized as a Center of
Excellence on such matters by the Food and Agriculture Organization of
the United Nations (FAO). The center uniquely operates like an
independent "think-tank," while maintaining its academic affiliation
with a major land-grant university. The research, education, outreach,
and communications activities of the faculty are conducted in a
relevant, time-sensitive manner that helps inform the public policy
process on food and nutrition policy issues.

Encompassed in the center's activities on food and nutrition policy are
its interests in regulatory issues involving risk analysis including
risk assessment, management, and communication. As such, the Center
respectfully submits the following comments in response to the Food and
Drug Administration's (FDA) request for comment on acrylamide in the
food supply, docket no. 02N-0393 as published in the Federal
Register.[^1]

[Overview of the Comments]{.underline}

The Center recognizes the critical importance of FDA's role in
protecting the public health and commends the agency's aggressive action
plan to address the issues of acrylamide in the food supply. The sudden
"discovery" of acrylamide in foods raised many important public health
questions. Yet finding potential carcinogens in foods is not unique to
acrylamide. The comments contained herein will:

1.  Summarize the Ceres^®^ Roundtable *Acrylamide: Lessons Learned,
    Plans Ahead* convened by the Center for Food and Nutrition Policy on
    September 9, 2002;

2.  Recommend implementation of a comprehensive risk analysis that more
    fully addresses risk management and risk communication.

**[Ceres^®^ Roundtable Focuses on Acrylamide]{.underline}**

The center is active in the international scientific response to the
discovery of acrylamide in commonly consumed foods. In addition to
convening a Ceres^®^ Roundtable on the topic, faculty from the center
have also made presentations on its risk assessment at the Joint
Institute for Food Safety and Applied Nutrition (JIFSAN)---Center for
Food Safety and Applied Nutrition (CFSAN) seminar series; participated
in the Acrylamide in Food workshop hosted by the National Center for
Food Safety and Technology (NCFST) and JIFSAN in Chicago, IL; and
provided verbal comments at the FDA public meeting on September 30,
2002.

On September 9, 2002, CFNP hosted a Ceres Roundtable entitled
*Acrylamide: Lessons Learned, Plans Ahead*. The roundtable addressed
several key questions. First, Dr. Steve Tannenbaum from Massachusetts
Institute of Technology addressed the questions: Why now? Why did it
take so long to "discover" this substance in our foods? Second, what we
know and what *should* we know about the toxicology of acrylamide was
addressed by Dr. Ian Munro from CANTOX. Third, Dr. Richard Forshee from
the Center for Food and Nutrition Policy presented his preliminary risk
assessment study on how much acrylamide consumers are exposed to from
food. Fourth, Dr. Rick Canady from FDA discussed the agency's experience
with acrylamide. And finally, Dr. Sanford Miller from CFNP and former
director of the Center for Food Safety and Applied Nutrition, FDA,
offered some insights from past experiences, such as nitrosamines found
in some alcoholic beverages.

[Acrylamide Forms Naturally during Food Cooking and
Processing.]{.underline} Naturally-occurring carcinogens and other
environmental toxicants, like mycotoxins, are present in our foods
without a doubt. Acrylamide, however, is not known to occur naturally in
the environment, and it is not unique with regard to the formation of
potential carcinogens during the cooking process.

Cooking foods to enhance flavor and provide protection from foodborne
pathogens can lead to formation of acrylamide. Indeed, this is not the
first time that science has discovered a potential carcinogen that is
formed during the cooking or processing of a food. In his presentation
at the Ceres^®^ Roundtable, Professor Steven Tannenbaum of the
Massachusetts Institute of Technology identified several carcinogens
that arise naturally in the environment or as a result of processing or
cooking foods---polycyclic aromatic hydrocarbons, heterocyclic amines,
mycotoxins, nitrosamines, urethane, chloropropanols, and acrylamide. He
also noted that individuals are exposed to acrylamide through sources
other than food. For example, smokers have nearly four times more
internal exposure to acrylamide than non-smokers, as measured by
hemoglobin adduct formation.

Many relevant questions remain about the formation of acrylamide during
food cooking and processing. A few of these questions are:

-   What is the strength of the relationship between formation of
    acrylamide and cooking temperatures?

-   Is this relationship non-linear such that slight reductions in
    maximum temperatures could lead to large reductions in acrylamide
    without affecting the safety or quality of the food?

-   Would changes in cooking processes have unintended negative
    consequences, such as increasing the fat content of the product or
    increasing risk of illness from foodborne pathogens?

-   What effect does the composition of the raw food materials have on
    acrylamide formation in the cooked product?

-   What other components are related to acrylamide concentration?

-   Can acrylamide concentration be significantly reduced by altering
    the composition of foods being prepared?

[The Center's Preliminary Risk Assessment.]{.underline} In its action
plan, FDA recognizes the need for more information on the concentration
of acrylamide in foods. In the FAO/WHO (Food and Agriculture
Organization of the United Nations/World Health Organization) report,
the data on acrylamide consisted of only 248 samples of foods. Most of
the food categories had fewer than 10 samples and many had only one or
two samples. To compound the problem, many of the samples had acrylamide
concentrations that were below the limits of detection and
quantification. In bakery products, for example, there were 19 samples
and the median value was reported as less than the limit of detection
and quantification. Beer provides the most extreme example of these
problems---one sample was tested and acrylamide concentration was found
to be less than the limit of detection and quantification.

Another difficulty with the current data is that the results for most
food categories are highly skewed---a few samples have very high
concentrations of acrylamide compared to the rest of the samples. This
has important implications for risk assessment and, potentially, for
risk management. The samples with high concentrations have a major
impact on the mean and shape of the probability distribution of
acrylamide concentration. Typically, when a probability distribution is
highly skewed, the most probable values are clustered near the central
tendency (the mean or median) and a long tail with low probability
extends out to the extreme values. Our exposure assessments for
acrylamide from food will vary significantly depending on the amount of
skew and the shape of the probability distributions for acrylamide
concentrations.

Two plausible, alternative probability distributions for acrylamide
concentration in bakery products are shown in Figure 1. Both are
consistent with the mean, minimum, and maximum values reported in the
FAO/WHO Annex 3, but the distributions have dramatically different
shapes and would lead to very different conclusions about the levels of
exposure to acrylamide from foods. For example, in the triangle
distribution 90 percent of the values lie between 0.05 and 0.36 μg/g of
food; in the exponential distribution, 90 percent of the values lie
between 0.004 and 0.257 μg/g of food. The current data on acrylamide
concentration in foods are not strong enough to make an informed choice
about which of these is the more accurate distribution.

In addition to affecting the exposure model to acrylamide in foods, the
shape of the distribution may affect how risk management is addressed.
If most food samples have acrylamide concentrations that are near or
below the limits of detection and quantification and only a few have
very high concentrations, the most appropriate strategy may be to focus
on reducing the concentrations in those few foods that have high
concentrations of acrylamide.

Finally, the currently available data on acrylamide concentrations are
"samples of convenience" based on informed hunches about which foods
might contain acrylamide. There has not yet been any systematic sampling
of food groups or foods within the groups. This is not surprising since
the discovery of acrylamide in foods was recent and unexpected, but it
is a problem that FDA appears to be addressing in its action plan.

It is important to note that while the data issues just discussed
present problems for exposure and risk assessment, they also represent
an important research opportunity. Discovering why there is great
variability in the concentration of acrylamide may provide clues about
how to reduce or limit exposure, if indeed it is necessary and feasible.

**Figure 1.\
Alternative Probability Distributions for Acrylamide Concentration in
Bakery Products\
\
** "Triangle" Distribution Exponential Distribution\
(Min. 0, Mean 0.112, Max. 0.450) (Min. 0, Mean 0.112, Max. 0.450)

![](media/image1.wmf){width="2.2909722222222224in"
height="3.001388888888889in"}![](media/image2.wmf){width="3.001388888888889in"
height="3.157638888888889in"}

*Research Questions*

The Center is conducting an exposure assessment of acrylamide from
foods. The goal of this project is to determine more precise estimates
of acrylamide exposure from food intake in the U.S. by relevant
age/gender groups. The exposure assessment addresses three key
questions:

-   What is the [average]{.underline} exposure to acrylamide?

-   What is the high range or [upper limit]{.underline} of exposure to
    acrylamide?

-   Do certain subpopulations receive higher exposures than others?

*Methods*

Our analysis focuses on the foods identified in the FAO/WHO Summary
Report, Annex 3 as containing acrylamide. These are: potato chips,
French fries, bakery products, crackers, breakfast cereals, corn chips,
bread, batter/breaded chicken, beef, pork, game, organs, fish
(combined), coffee powder, and beer. Using the food codes and individual
food records from the Continuing Survey of Food Intake by Individuals

1994-96, 1998 (CSFII), we identified all foods in the categories listed
in the FAO/WHO Annex 3.

To calculate point estimates (means and 95^th^ percentiles for each
age/gender group) and probability distributions of food intake, these
food categories were aggregated up to the individual level and a 2-day
average was calculated. Whenever possible, the pre-existing CSFII
categories were used.

The data from the FAO/WHO Annex 3 were used to calculate probability
distributions of acrylamide concentration in each identified food group.
Conservative assumptions were made to calculate the probability
distributions of acrylamide concentration. Typically, a triangle
distribution was used to determine the probability distribution for
acrylamide concentration in a food category.

A triangle distribution is defined by only three parameters: the
minimum, the maximum, and the most likely value. The "peak" (the outcome
with the highest probability of occurrence) of a triangle distribution
is the most likely value. From that point, the probability of each
concentration value of acrylamide falls in two straight lines to the
minimum value and the maximum value (see Figure 1). Our use of the
triangle distribution was conservative in several ways. Since the
acrylamide concentrations were typically positively skewed, the mean was
usually equal to or larger than the median. Also, in a triangle
distribution, the probability of high concentration falls at a slow,
linear rate. By contrast, in most skewed distributions, the probability
of high values falls rapidly and becomes a long, skinny "tail" in the
distribution (see Figure 1). By choosing the triangle distribution, it
is unlikely that we have underestimated the probability of high
concentration values. More than likely, we have overestimated the
probability of high concentration value, perhaps by a large amount.

Using these data, we calculated exposure to acrylamide using two
methods. First, we calculated exposure based on point estimates of food
intake and acrylamide concentration. Average exposure for various
age/gender categories was based on [average]{.underline} food intake and
[average]{.underline} acrylamide concentration in each category. An
[upper limit]{.underline} of exposure was based on the 95^th^ percentile
of food intake and the 90^th^ percentile of acrylamide concentration. In
the second method, we used the LifeLine™ model to calculate average
lifetime exposure based on 100 simulated "lives." For technical reasons,
the LifeLine model did not include acrylamide concentration
distributions for crumbed or battered meat products, coffee powders, or
beer. The results of the two approaches were consistent with one another
and with the exposure assessments reported in the FAO/WHO report.

*Two Approaches Used to Assess Exposure to Acrylamide*

*Point Estimates Approach.* The point estimate approach showed that
average exposure to acrylamide from foods was between 0.66 µg/kg body
weight (BW)/day and 0.49 µg/kg BW/day for adults in the various
age/gender categories. For children and teens, average exposure was
between 1.62 µg/kg BW/day for and 0.60 µg/kg BW/day. The upper limits of
exposure were 6.23 µg/kg BW/day for adults (women 20-29) and 17.95 µg/kg
BW/day for children (boys 1-2). The full results are shown in Figures
2a-b.

![](media/image3.wmf){width="6.786111111111111in"
height="4.6409722222222225in"}

**Figure 2b.**

**Point Estimates of Exposure to Acrylamide from Foods**

![](media/image4.wmf){width="6.492361111111111in"
height="4.433333333333334in"}

**Figure 3.\
LifeLine™ Model of Lifetime Average Exposure to Acrylamide (g/kg/day)\
**![](media/image5.wmf){width="6.270138888888889in"
height="5.723611111111111in"}

*Simulated Lifetime Exposure Approach*

The LifeLine™ model is presented in Figure 3. It shows that lifetime
average exposure for the 100 simulated lives generally ranged between
0.5 µg/kg BW/day and 1.0 µg/kg BW/day. Only three of the simulated
individuals had a lifetime average exposure greater than 1.0 µg/kg/day.
The patterns of individual lifetime exposure were consistent with the
results reported in the point estimate analysis. Specifically, children
had higher exposures as measured in µg/kg BW/day units, which fell into
the range of about 0.5-1.0 µg/kg BW/day as they reached adulthood.

All of these results, together with the FAO/WHO report, estimate
exposure to acrylamide from food well below the No Observable Adverse
Effect Limit (NOAEL) for neuropathy, which is 500 µg/kg BW/day. All of
the estimates of average exposure to acrylamide from food are 25 to 100
times lower than the NOAEL for neuropathy. However, the estimates are
greater than the reference dose of 0.2 µg/kg BW/day established by the
U.S. Environmental Protection Agency (EPA) for acrylamide in drinking
water. Significant research is required to improve these exposure
assessments and the estimates of cancer risks from exposure to
acrylamide in food. This is particularly important because the
bioavailability of acrylamide from food may be significantly different
than it is from water.

[Toxicology and Cancer Risk of Acrylamide in Foods.]{.underline} During
the Ceres Roundtable, Dr. Ian Munro summarized the brief literature on
acrylamide and cancer risk. To date, animal studies show minimal cancer
risk from acrylamide. In cancer studies using very high doses of
acrylamide in drinking water, male rats receiving the highest dose of
acrylamide had significantly more benign tumors of the thyroid and
testes, but no more malignant tumors of the thyroid or central nervous
system and spinal cord than control rats. Female rats receiving the two
highest doses of acrylamide in drinking water developed more benign
tumors of the mammary gland and thyroid, but no greater incidence of
malignant thyroid tumors than control female rats.

There is no epidemiological evidence that acrylamide is a human
carcinogen. Cohort studies conducted in the 1980s showed no increase in
cancer rates among industrial workers exposed to acrylamide through the
skin and by inhalation. Once acrylamide enters the body we know the
biochemical pathways that metabolize and excrete it. But with regard to
exposure through foods, we do not know how much acrylamide is actually
excreted without absorption by the gut.

Several international organizations classify acrylamide either as a
carcinogen or a probable carcinogen, but much more research is needed in
this area.

[Lessons Learned from Nitrosamines.]{.underline} Issues such as the
acrylamide situation occur regularly, so there are historical examples
on which the FDA can draw. At the September 9^th^ roundtable, Dr.
Sanford Miller discussed the lessons that can be drawn from the FDA's
experience with nitrosamines in malted beverages.

The issue of nitrosamines in malted beverages came about because of a
study conducted by the German Max Plank Institute for Food Toxicology
that discovered nitrosamines in beer. German regulators informed FDA of
this discovery, and the agency began a process to determine how much
nitrosamines were present in U.S. malted beverages.

Before that process was completed, the Ontario Department of Public
Health in Canada discovered that there were also nitrosamines in other
malted distilled beverages, such as American bourbon. Canada immediately
blocked the importation of American bourbon into Ontario. In response,
the United States conducted an analysis of a number of distilled malted
beverages including scotch. It was discovered that all whiskey,
including Canadian whiskey, contained some amount of nitrosamines. The
Canadian block of American bourbon quickly ended.

The end of the trade dispute, however, was not the end of the issue for
the FDA. The agency was now faced with a problem. Nitrosamine was a
known human carcinogen that was present in these distilled beverages.
The issue attracted a great deal of media attention, and some groups
advocated a ban on these beverages, especially since beer and other
distilled beverages are not necessary for a healthy diet.

Obviously, the FDA did not ban all distilled beverages in response to
this finding, but the agency decided it needed to take some kind of
action. The FDA recognized that there was insufficient information to
make an informed policy decision, so it developed an action plan in
collaboration with the malt beverage industry.

By this time the beer brewers had discovered that the origin of the
nitrosamines occurred during the drying of the malted hops. This kilning
was mostly done by direct drying, such as gas-heated forced air. The
agency, together with the industries, agreed that the agency would not
take any regulatory action, but they would monitor the research that was
being done by the industry. This is an important point---the research
was being done by the industry, and monitored by the agency. The end
result was that a kilning process called indirect heating was developed,
and the new indirect heating process solved the nitrosamine problem.

The important issue in the nitrosamine case was twofold. First, the FDA
did not acquiesce to the pressures from Congress and others to take
immediate action on malt beverages before it had developed the necessary
science and evaluated alternative courses of action. Second, the FDA
worked with the industry in supervising the research, making sure that
standards were met and that the resources were being devoted to
nitrosamine research.

[Conclusions from the Roundtable---The Science on Acrylamide is
Lacking.]{.underline} The science shows that acrylamide is a known
neurotoxin and suggests that it may be a carcinogen. The discovery of
acrylamide in commonly consumed foods raises many important public
health questions. Unfortunately, the current science on acrylamide is
not adequate to properly assess the risk it poses to human health or to
formulate appropriate and effective regulatory policies. Critical areas
for research include:

1.  Understanding how acrylamide forms during food cooking and
    processing;

2.  Analyzing the concentration of acrylamide in food products;

3.  Validating the detection methodology among and within laboratories;

4.  Funding research to understand the human health effects from
    exposure to acrylamide through foods; and,

5.  Incorporating the results of these research programs into
    comprehensive risk assessment models to evaluate whether regulatory
    interventions are necessary and, if so, which policy options would
    most effectively protect public health.

**[Crafting Efficient and Appropriate Policies]{.underline}**

The Center applauds FDA's action to conduct research that will shed more
light on a number of aspects related to acrylamide in the food supply.
FDA should take this opportunity to develop a comprehensive plan that
includes [all]{.underline} elements of a risk analysis---risk
assessment, risk management, and risk communication.

Future research will undoubtedly identify other compounds in foods that
may or may not pose a health risk. It is therefore critical that the
agency implement an action plan efficiently and effectively to protect
the public health when the risk is great, as well as protect the public
from scare tactics when there is little or no risk.

The Center urges FDA to:

1.  Assess the risk to public health from foods containing acrylamide
    and use this assessment as a template for other substances that
    surely will be "discovered" in the future. This risk assessment
    should include: *a*) a thorough and critical re-examination of the
    literature on cancer risk and acrylamide and *b*) a critical
    evaluation of research gaps that need to be filled before a
    regulatory policy is put in place;

2.  Manage the public health risk from acrylamide in foods if a hazard
    exists. The center suggests that FDA collaborate with scientists
    from industry and academia to eliminate or minimize the hazard if
    the risk assessment shows that there is a risk to be managed.

3.  Develop a risk communication plan together with communications
    experts from the public relations and/or advertising industry,
    media, and consumer advocacy groups that accurately communicates the
    level of risk to public health from acrylamide in cooked foods and
    from foodborne illness from improperly cooked foods.

![](media/image6.jpeg){width="2.55in" height="0.83125in"}Respectfully
Submitted,

![](media/image7.jpeg){width="2.4791666666666665in"
height="0.5416666666666666in"}

Maureen L. Storey, Ph.D. Richard A. Forshee, Ph.D.

Acting Director Research Assistant Professor

[^1]: Federal Register, Notices: *Assessing Acrylamide in the U.S. Food
    Supply.* September 12, 2002 (Volume 67, Number 177), Pages
    57827-57828.