text:
[Federal Register: August 16, 2005 (Volume 70, Number 157)]
[Rules and Regulations]
[Page 48057-48073]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr16au05-3]
21 CFR Part 179
[Docket No. 1999F-4372]
Irradiation in the Production, Processing, and Handling of Food
AGENCY: Food and Drug Administration, HHS.
ACTION: Final rule.
SUMMARY: The Food and Drug Administration (FDA) is amending the food
additive regulations to provide for the safe use of ionizing radiation
for control of Vibrio species and other foodborne pathogens in fresh or
frozen molluscan shellfish (e.g., oysters, mussels, clams, etc.). This
action is in
[[Page 48058]]
response to a petition filed by the National Fisheries Institute and
the Louisiana Department of Agriculture and Forestry.
DATES: This rule is effective August 16, 2005. Submit written or
electronic objections and requests for a hearing by September 15, 2005.
See section VI of this document for information on the filing of
objections.
ADDRESSES: You may submit written or electronic objections and requests
for a hearing identified by Docket No. 1999F-4372, by any of the
following methods:
<BULLET> Federal eRulemaking Portal: http://www.regulations.gov.
Follow the instructions for submitting comments.
<BULLET> Agency Web site: http://www.fda.gov/dockets/ecomments.
Follow the instructions for submitting comments on the agency Web site.
<BULLET> E-mail: fdadockets@oc.fda.gov. Include Docket No. 1999F-
4372 in the subject line of your e-mail message.
<BULLET> FAX: 301-827-6870.
<BULLET> Mail/Hand delivery/Courier [For paper, disk, or CD-ROM
submissions]: Division of Dockets Management (HFA-305), Food and Drug
Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852.
Instructions: All submissions received must include the agency name
and docket number for this rulemaking. All objections received will be
posted without change to http://www.fda.gov/ohrms/dockets/default.htm,
including any personal information provided. For detailed instructions
on submitting objections, see the ``Objections'' heading of the
SUPPLEMENTARY INFORMATION section of this document.
Docket: For access to the docket to read background documents or
comments received, go to http://www.fda.gov/ohrms/dockets/default.htm
and insert the docket number, found in brackets in the heading of this
document, into the ``Search'' box and follow the prompts and/or go to
the Division of Dockets Management, 5630 Fishers Lane, rm. 1061,
Rockville, MD 20852.
FOR FURTHER INFORMATION CONTACT: Lane A. Highbarger, Center for Food
Safety and Applied Nutrition (HFS-255), Food and Drug Administration,
5100 Paint Branch Pkwy., College Park, MD 20740, 301-436-1204.
II. Safety Evaluation
A. Analyses of Data by the World Health Organization
B. Radiation Chemistry
C. Assessment of Potential Toxicity
D. Microbiological Profile of Molluscan Shellfish
E. Nutritional Considerations
III. Comments
A. Studies Reviewed in the 1999 FAO/IAEA/WHO Report on High-Dose
B. Review Article
C. Irradiated Strawberry
D. Reproduction Performance
E. Mutagenicity Studies
F. International Opinions
G. Alkylcyclobutanones
H. Promotion of Colon Cancer
I. Indian National Institute of Nutrition Studies
J. Toxicity Data
K. Failure to Meet Statutory Requirements
L. Trans Fatty Acids
M. Elevated Hemoglobin
N. Dangers of Radiation
O. Nutritional Deficiency
IV. Conclusions
V. Environmental Impact
VI. Objections
VII. References
In a notice published in the Federal Register of October 19, 1999
(64 FR 56351), FDA announced that a food additive petition (FAP 9M4682)
had been filed by the National Fisheries Institute, 1901 North Fort
Myer Dr., Arlington, VA 22209, and the Louisiana Department of
Agriculture and Forestry, P.O. Box 3334, Baton Rouge, LA 70821. The
petition proposed that the food additive regulations in part 179,
Irradiation in the Production, Processing, and Handling of Food (21 CFR
part 179), be amended to provide for the safe use of approved sources
of ionizing radiation for control of Vibrio and other foodborne
pathogens in fresh or frozen molluscan shellfish.
Under section 201(s) of the Federal Food, Drug, and Cosmetic Act
(the act) (21 U.S.C. 321(s)), a source of radiation used to treat food
is defined as a food additive. The additive is not added to food
literally, but is rather a source of radiation used to process or treat
food such that, analogous to other food processing technologies, its
use can affect the characteristics of the food. In the subject
petition, the intended technical effect is for control of foodborne
pathogens, including but not limited to Vibrio bacteria, that might be
present in fresh or frozen molluscan shellfish.
In evaluating the safety of a source of radiation to treat food
intended for human consumption, the agency must identify the various
effects that may result from irradiating the food and assess whether
any of these effects pose a public health concern. In this regard, the
following three areas of concern need to be addressed: (1) Potential
toxicity, (2) nutritional adequacy, and (3) potential microbiological
risk from the treated food. Each of these areas is discussed in detail
in this document. FDA has fully considered the data and studies
submitted in the subject petition as well as other data and information
relevant to safety.
Based on a joint FAO/IAEA/WHO\1\ Committee's conclusion on the
toxicological, microbiological safety and nutritional adequacy of
irradiated foods, the Codex Alimentarius Commission (Codex) published
its standard for irradiated foods in 1983 (revised in 2003) for
adoption by Codex member countries (Refs. 1 and 2). This standard was
based on the conclusion that the irradiation of any food commodity at
an overall average dose of up to 10 kiloGray (kGy) presents no
concerns. The newly revised standard (2003) states that the
\1\ FAO is the Food and Agriculture Organization of the United
Nations; IAEA is the International Atomic Energy Agency; and WHO is
the World Health Organization.
[m]inimum absorbed dose should be sufficient to achieve the
technological purpose and the maximum absorbed dose should be less
than that which would compromise consumer safety, wholesomeness [of
the food] or would adversely affect structural integrity, functional
properties, or sensory attributes. The maximum absorbed dose
delivered to a food should not exceed 10 kGy, except when necessary
to achieve a legitimate technological purpose.
(Ref. 2) The original version of the standard explains in a
footnote that ``wholesomeness [in the context of the standard] refers
to safety for consumption of irradiated foods from the toxicological
point of view * * * and that irradiation up to an overall average dose
of 10 kGy introduces no special nutritional or microbiological
problems.''
FDA did not adopt the 1983 Codex recommendations because, at that
time, it had not sufficiently analyzed the issues of nutritional
adequacy and microbiological safety for all foods at all doses, nor had
the agency pursued the analysis of toxicity beyond the examination of
individual studies (62 FR 64107 at 64112, December 3, 1997).
At the request of one of its member states, WHO conducted a
subsequent review and analysis of the safety data on irradiated food
(Ref. 3). WHO
considered the extent to which data on one type of food can be
extrapolated to other foods and the extent to which individual studies
of irradiated foods can be integrated into a single database to be
evaluated as a whole, as opposed to separate evaluations of a series of
individual studies (62 FR 64107 at 64112). This review included all of
the studies in FDA's files considered to be reasonably complete by the
agency, as well as those studies that appeared to be acceptable but had
some deficiencies interfering with interpretation of the data (51 FR
13376 at 13378, April 18, 1986). WHO's review also included data from
the U.S. Department of Agriculture (USDA) and from the Federal Research
Centre for Nutrition at Karlsruhe, Germany (62 FR 64107 at 64112). WHO
concluded that while levels of some vitamins are decreased when food is
irradiated at doses relevant for food irradiation, few vitamins are
severely affected, with the exception of thiamine and vitamin E.
However, these losses are small (on the order of 10 to 20 percent or
less) at or below an overall average absorbed dose of 10 kGy and are
comparable to losses seen with other forms of food processing, such as
thermal processing and drying (Ref. 3).
Scientists have compiled a large body of data regarding the effects
of ionizing radiation on different foods under various conditions of
irradiation. These data indicate that the effects of ionizing radiation
on the characteristics of treated foods are a direct result of the
chemical reactions induced by the absorbed radiation. The types and
amounts of products generated by radiation-induced chemical reactions
(``radiolysis products'') depend on both the chemical constituents of
the food and on the specific conditions of irradiation. The principles
of radiation chemistry also govern the extent of change, if any, in
both the nutrient levels and the microbial load of irradiated foods.
For a detailed discussion and evaluation of radiation chemistry,
nutrition, toxicology, and microbiology related to irradiation of
flesh-based foods under various conditions of use, see the agency's
final rule permitting the irradiation of meat (62 FR 64107). In the
current rulemaking, FDA has reviewed relevant data and information
regarding radiation chemistry as it applies specifically to fresh or
frozen molluscan shellfish irradiated at absorbed doses not to exceed
5.5 kGy.
The major components of fresh or frozen molluscan shellfish are
water, protein, and lipid. Irradiation of water produces reactive
hydroxyl and hydrogen radicals. These radicals can either recombine to
form water, hydrogen gas, or hydrogen peroxide, or react with other
components of molluscan shellfish. While the most significant effect of
radiation-processing on the protein and lipid components of fresh or
frozen molluscan shellfish results from the chemical reactions induced
by hydroxyl radicals generated from the radiolysis of the water,
radiolysis products of protein and lipid may also result from directly
absorbed radiation. These radiolysis products, however, form in very
small amounts and are usually the same as compounds found in foods that
have not been irradiated (Ref. 4).
The amounts of radiolysis products generated in a particular food
are directly proportional to the radiation dose. Therefore, FDA can
draw conclusions about the amounts of radiolysis products expected to
be generated at radiation doses relevant to the subject petition by
extrapolating from data obtained at higher doses for foods of similar
composition irradiated under similar conditions. In general, the types
of products generated by irradiation are similar to those products
produced by other methods of food processing, such as canning, cooking,
etc., because all chemical reactions caused by the addition of energy
must follow the laws of chemistry. The radiation chemistry of food is
also strongly influenced by the physical state of the food (solid,
liquid, dry, or frozen) during irradiation. For example, the extent of
chemical change that occurs in a particular food in the dry or frozen
state will be less than the change that occurs in the same food when
liquid water is present, all other conditions (including dose and
ambient atmosphere) being equal, because indirect reaction products
from water will be minimized (Ref. 5).
During the course of reviewing chemical effects of irradiation as
part of the evaluation of this and other petitions, FDA became aware of
a reference that suggested that irradiating apple juice may produce
furan (Ref. 6). Because furan has been shown to cause cancer in
laboratory animals, FDA initiated research on whether the referenced
report was accurate and whether furan was a common radiolysis product
in food. FDA has confirmed that certain foods form furan in low
quantities when irradiated and also that some foods form furan when
heated. Studies on the irradiation of molluscan shellfish show that if
furan is formed when molluscan shellfish are irradiated, it is formed
at levels that are undetectable, or below the background levels of
natural furan formation (Ref. 7). Therefore, the consumption of
irradiated molluscan shellfish will not increase the amount of furan in
the diet and is not an issue with this petition.
In the Federal Registers of May 2, 1990 (55 FR 18538), and December
3, 1997 (62 FR 64107), FDA issued final rules permitting the use of
ionizing radiation for the control of foodborne pathogens in poultry
and meat, respectively (referred to henceforth as the poultry and meat
final rules). In the poultry final rule, the agency concluded that
poultry irradiated at a dose not to exceed 3 kGy was safe. In the meat
final rule, the agency concluded that refrigerated uncooked meat, meat
byproducts, and meat food products, as defined in Title 9 of the Code
of Federal Regulations (CFR), irradiated at doses up to 4.5 kGy are
safe, and that frozen meat, meat by-products, and meat food products
irradiated at doses up to 7.0 kGy are safe. Because meat is high in
protein, lipid, and water, the radiation chemistry of proteins, lipids,
and water (in both the liquid and frozen state) was extensively
discussed in the meat final rule. The radiation chemistry of proteins
and lipids discussed in the meat final rule is also relevant to other
flesh foods, including foods such as poultry and fish, that may be
referred to as ``meat'' in common usage, but that do not conform to the
definition of meat in Title 9 of the CFR. Molluscan shellfish,
depending on the species, differ from other flesh foods in that they
contain between 2 and 6 percent carbohydrate, up to 20 percent protein,
and up to 10 percent fat; the remainder is primarily water. While the
carbohydrate level is higher than in other flesh foods, the level is
still low.
1. Protein
With respect to proteins, several types of reactions can occur as a
result of irradiation. One type of reaction is the breaking of a small
number of peptide bonds to form polypeptides of shorter length than the
original protein. Radiation-induced aggregation or cross-linking of
individual polypeptide chains can also occur; these processes result in
protein denaturation. In irradiated flesh foods, most of the radiolytic
products derived from proteins have the same chemical composition
regardless of the protein sources, but are altered in their secondary
and tertiary structures. These changes are similar to those that occur
as a result of heating, but in the case of irradiation, such changes
are far less pronounced and the amounts of reaction products generated
are far lower (Refs. 4 and 8). Studies have established that
there is little change in the amino acid composition of fish irradiated
at doses below 50 kGy (Ref. 9), which is well above the petitioned
maximum absorbed dose for molluscan shellfish. Therefore, no
significant change in the amino acid composition of fresh or frozen
molluscan shellfish is expected to occur under the conditions set forth
in this regulation.
2. Carbohydrate
The main effects of ionizing radiation on carbohydrates in foods
have been reviewed previously in the literature and by WHO (Refs. 5,
10, and 11). One of the main effects of ionizing radiation is the
abstraction of hydrogen from the carbon-hydrogen bonds of the
carbohydrate, resulting in directly ionizing and exciting the
carbohydrate molecule. Carbohydrate radicals may result from ionization
of monosaccharides such as glucose or polysaccharides such as starch.
Radiolysis products formed from starches of different origin are
reported to be qualitatively similar (Refs. 5 and 11). In
polysaccharides, the glycosidic linkages between constituent
monosaccharide units may be broken, resulting in the shortening of
polysaccharide chains and reduction in the viscosity of polysaccharides
in solution. Starch may be degraded into dextrins, maltose, and
glucose. Sugar acids, ketones, and other sugar monosaccharides may also
be formed as a result of ionizing radiation. Irradiation of
carbohydrates at doses up to 10 kGy has minimal effect on the
carbohydrate functionality. The overall effects of ionizing radiation
are the same as those caused by cooking and other food processing
treatments. Carbohydrates that are present as a component of food are
less sensitive to the effects of irradiation than pure carbohydrates
(Ref. 5). No significant change in the carbohydrate composition of
fresh or frozen molluscan shellfish is expected to occur under the
conditions set forth in this regulation, i.e., a maximum absorbed dose
of 5.5 kGy.
3. Lipid
The meat final rule also discussed the radiation chemistry of
lipids (predominantly triglycerides in meat). A variety of radiolysis
products derived from lipids have been identified, including fatty
acids, esters, aldehydes, ketones, alkanes, alkenes, and other
hydrocarbons (Refs. 12 and 13). Identical or analogous compounds,
however, are also found in foods that have not been irradiated. In
particular, heating food produces the same types of compounds, but in
amounts far greater than the trace amounts produced from irradiating
food (Refs. 4 and 14). In addition, alkylcyclobutanones (ACBs), which
are formed in small quantities when fats are exposed to ionizing
radiation, have been identified in meat and poultry. The specific ACBs
formed will depend on the fatty acid composition of the food. For
example, 2-dodecylcyclobutanone (2-DCB) has been reported to be formed
from palmitic acid in amounts from 0.3 to 0.6 microgram per gram lipid
per kGy (microg/g lipid/kGy) from irradiated chicken (Ref. 15). Other
researchers have found that (2--DCB) is formed at significantly lower
rates, 0.04 microg/g lipid/kGy from ground beef (Ref. 16). For
comparison, ground beef tallow contains approximately 25 percent
palmitic acid and chicken fat contains approximately 22 percent
palmitic acid.
One major difference between fish (including shellfish and finfish)
and other flesh foods is the predominance of polyunsaturated fatty
acids (PUFAs) in the lipid phase of fish. PUFAs are a subclass of
lipids that have a higher degree of unsaturation in the hydrocarbon
chain than the saturated (e.g., stearic acid) or monounsaturated (e.g.,
oleic acid) fatty acids. Due to the higher level of unsaturation, PUFAs
are generally more readily oxidized than saturated fatty acids.
Therefore, PUFAs could be more radiation-sensitive than other lipid
components, as observed in some studies of irradiated oil. However,
evidence from meat studies suggests that the protein component of meat
may protect lipids from oxidative damage (Ref. 5). Because the lipid
fraction of meat consists primarily of saturated and monounsaturated
fatty acids with negligible quantities of PUFAs, FDA did not explicitly
address the radiation chemistry of PUFAs in its previous reviews.
The effects of irradiation on PUFAs in fish have been described in
several studies reviewed by FDA. Adams et al. studied the effects of
radiation on the concentration of PUFAs in herring and showed that
irradiation of herring fillets at sterilizing doses (50 kGy), well
above the petitioned maximum dose for molluscan shellfish, had no
effect on the concentration of PUFAs (Ref. 17). Similarly, Armstrong et
al. conducted research on the effects of radiation on fatty acid
composition in fish and concluded that no significant changes occurred
in the fatty acid profiles upon irradiation at 1, 2, or 6 kGy (Ref.
18). The authors also concluded that variations in fatty acid
composition between individual samples were greater than any radiation-
induced changes.
Sant'ana and Mancini-Filho studied the effects of radiation on the
distribution of fatty acids in fish (Ref. 19). They studied two
monounsaturated fatty acids and seven PUFAs (including three different
omega-3 fatty acids) before and after irradiation at doses up to 3 kGy.
The authors observed insignificant changes in the concentration of
total monounsaturated fatty acids and an approximately 13 percent
decrease in total PUFAs at the highest dose, largely attributable to a
loss of the long chain PUFAs, including docosahexaenoic acid. The
overall change for essential fatty acids (e.g., linoleic and linolenic
acids) was minimal (less than 3 percent). The authors also observed an
increase in lipid oxidation based on levels of thiobarbituric acid
reactive substances, but noted that antioxidants such as tocopherol
protect against lipid oxidation (Ref. 4).
In addition, a study summarized in an International Consultative
Group on Food Irradiation monograph compared the fatty acid composition
of unirradiated and irradiated herring oil (Ref. 20). The profile for
12 fatty acids was compared to controls 1 day and 28 days after
irradiation. Only two fatty acids appeared to have decreased by day 28
following irradiation at 50 kGy (Ref. 4).
Research conducted by FDA on various species of seafood also
demonstrated that the concentrations of PUFAs are not significantly
affected by irradiation (Refs. 21 and 22). Therefore, based on the
totality of evidence, the agency concludes that no significant loss of
PUFAs is expected to occur in the diet under the conditions of
irradiation set forth in this regulation. In summary, FDA's review of
the radiation chemistry of proteins and lipids in the subject petition
raises no issues that have not been considered previously in the meat
and poultry final rules (Ref. 4).
In the safety evaluation of irradiated meat and poultry, the agency
examined all of the available data from toxicological studies relevant
to the safety of irradiated flesh-based foods, including studies on
fish high in PUFAs. These included 24 long-term feeding studies, 10
reproduction/teratology studies, and 15 genotoxicity studies with
flesh-based foods irradiated at doses from 6 to 74 kGy. No
toxicologically significant adverse effects attributable to irradiated
flesh foods were observed in any of the studies (62 FR 64107 at 64112
and 64114).
The proposed maximum absorbed dose of 5.5 kGy for fresh and frozen
molluscan shellfish in the subject petition is somewhat higher than the
currently permitted maximum dose for the irradiation of non-frozen
meat. However, FDA previously evaluated the long-term toxicological
studies of flesh foods fed at a range that includes absorbed doses that
are either similar to or considerably higher than the absorbed dose
requested in this petition. In addition, the absorbed dose exceeded 50
kGy in many studies with no adverse effects reported. Therefore, these
data demonstrate that molluscan shellfish irradiated at levels up to
the dose proposed in this petition will not present a toxicological
hazard (Ref. 8).
In summary, FDA has reviewed a large body of data relevant to the
assessment of potential toxicity of irradiated foods. While all of the
studies are not of equal quality or rigor, the agency concludes that
the quantity and breadth of testing and the number and significance of
endpoints assessed would have identified any real or meaningful risk.
The overwhelming majority of studies showed no evidence of toxicity. On
those few occasions when adverse effects have been reported, FDA finds
that those effects have not been consistently produced in related
studies conducted at a higher dose or longer duration, as would be
expected if the effects were attributable to irradiation (62 FR 64107
at 64112 and 64114). Therefore, based on the totality of evidence, FDA
concludes that irradiation of fresh and frozen molluscan shellfish
under the conditions proposed in this petition does not present a
toxicological hazard.
Vibrio bacteria predominate in estuarine environments, and
consequently, are naturally present in most finfish and shellfish (Ref.
23). Most cases of reported diseases attributed to Vibrio species are
associated with consumption of raw molluscan shellfish, particularly
raw oysters. Although Vibrio species from shellfish infect relatively
few individuals, they can cause severe illness, including mortality. Of
the 12 Vibrio species known to cause human infections, 8 have been
associated with consumption of food. V. parahaemolyticus and V.
vulnificus are most commonly isolated from oysters. V. vulnificus is
associated with 95 percent of all seafood-related deaths in the United
States (Ref. 24).
In general, the subject petition relies on published or other
publicly available information or material from previous food additive
petitions to address microbiological issues. The petitioner has
documented that Vibrio species in uncooked molluscan shellfish provide
a significant public health risk. Vibrio bacteria are highly sensitive
to ionizing radiation and are usually eliminated by doses as low as 0.5
kGy. Published D<INF>10</INF> values\2\ for V. parahaemolyticus and
other Vibrio species range from 0.02 to 0.4 kGy (Ref. 25).
\2\ D<INF>10</INF> is the absorbed dose of radiation required to
reduce a bacterial population by 90 percent.
Control of contaminating Salmonella or Listeria generally requires
higher doses than for Vibrio species, because the D<INF>10</INF> values
are higher, about 0.5 to 1.0 kGy and 0.4 to 0.6 kGy, respectively (Ref.
26). Several publications referenced in the subject petition state that
these three genera can be eliminated by doses well under 10 kGy.
Numerous studies demonstrate that a dose of 5 kGy will reduce a
population of Salmonella serotypes, Staphylococcus aureus, Shigella,
and Vibrio by at least six log cycles. Other studies report 5-log
reductions for Listeria and Salmonella at 2.3 kGy and 2.8 kGy. In
addition, D<INF>10</INF> values for irradiation cited in published
literature for several Salmonella serotypes in various fresh foods
ranged from 0.2 to 0.9 kGy. Therefore, irradiation at doses up to the
dose limit in the regulation could significantly reduce the populations
of these organisms (Ref. 25).
Clostridium botulinum (C. botulinum) type E can sometimes be found
in seafood. Because this organism is relatively resistant to radiation,
as compared to non-spore forming bacteria, the petitioner provided data
regarding the likelihood that C. botulinum would grow and produce toxin
in irradiated molluscan shellfish. Included in the petition's
references is an in-depth discussion of the likelihood for outgrowth
and toxin production by C. botulinum type E in fish (Ref. 27). The
author cites studies conducted in his laboratory on the effect of
storage temperature and irradiation on toxin production by C. botulinum
type E in fish. In these studies, no toxin was detected after
incubation with fish of up to 10\5\ organisms at 0 degrees Celsius for
8 weeks, well beyond the shelf life of these products. At 5 degrees
Celsius, no toxin was produced for up to 6 weeks of storage in
inoculated fish that had not been irradiated or for up to 7 weeks when
irradiated at 2 kGy. Thus, it took longer for toxin to be produced in
the irradiated fish than in fish that were not irradiated.
Additionally, the time required for toxin production, 7 weeks, is far
beyond the shelf life of fresh seafood. Therefore, irradiation would
not increase the risk from botulinum toxin.
Current Hazard Assessment and Critical Control Point plans in
effect for molluscan shellfish require storage under proper conditions,
including maintenance at controlled temperatures. Therefore,
irradiation can serve as an effective method for the primary intended
use of eliminating populations of Vibrio species and other pathogens in
molluscan shellfish without adding a significant risk from the growth
of and toxin production by C. botulinum type E (Ref. 25).
The subject petition includes data and information that support the
effectiveness of the proposed irradiation of fresh and frozen molluscan
shellfish at a maximum absorbed dose of 5.5 kGy to control Vibrio
species and other foodborne pathogens. While the data show that
irradiation is effective in reducing the levels of Vibrio species and
other bacteria in fresh and frozen molluscan shellfish, the data also
show that irradiation will not increase the risk of toxin production
from germinated spores of C. botulinum type E.
Based on the available data and information, FDA concludes that
irradiation of fresh or frozen molluscan shellfish conducted in
accordance with current good manufacturing practices will reduce or
eliminate bacterial populations with no increased microbial risk from
pathogens that may survive the irradiation process.
Lipids are a component of molluscan shellfish contributing
approximately 20 to 30 percent to the caloric value of molluscan
shellfish. PUFAs are a significant source of omega-3 and omega-6 fatty
acids and are therefore nutritionally important components of the fat
of molluscan shellfish. As noted in section II.A of this document, PUFA
levels were not reduced significantly by ionizing radiation.
Additionally, the amount of omega-3 and omega-6 PUFAs can vary widely
within a single species and between species of molluscan shellfish. The
omega-3 fatty acid content among most species varies within a factor of
2, and the total PUFA content can vary by more than a factor of 10
(omega-3 and omega-6 PUFAs) within an individual species. Furthermore,
molluscan shellfish are only one of several fish sources of long chain
PUFAs. Because of the variety of seafood sources of long chain PUFAs,
the variation of fatty acid content in molluscan shellfish, and the
observed insensitivity of PUFAs to irradiation, FDA concludes that
irradiation of fresh
and frozen molluscan shellfish under the conditions proposed will not
adversely affect the nutritional adequacy of the diet with respect to
PUFAs (Ref. 8).
Molluscan shellfish contain several B-vitamins including thiamine,
niacin, vitamin B6, and vitamin B12.\3\ Individual food intake data is
available from nationwide surveys conducted by the USDA. These surveys
were designed to monitor the types and amounts of foods eaten by
Americans and food consumption patterns in the U.S. population. FDA
routinely uses these data to estimate exposure to various foods, food
ingredients, and food contaminants. The relative contribution of the
food category ``shellfish and fish (excluding canned tuna)'' is less
than 3 percent of the dietary intake for thiamine, niacin, and vitamin
B6 (Ref. 28). Fish and shellfish are, however, significant contributors
to vitamin B12 intake among U.S. adults, contributing to approximately
20 percent of the total vitamin B12 intake.
\3\ Dietary sources of nutrients have been evaluated using the
1994/1996 Continuing Survey of Food Intakes by Individuals database.
Irradiation of any food, regardless of the dose, has no effect on
the levels of minerals that are present in trace amounts (Ref. 5).
Levels of certain vitamins, on the other hand, may be reduced as a
result of irradiation. The extent to which this reduction occurs
depends on the specific vitamin, the type of food, and the conditions
of irradiation. Not all vitamin loss is nutritionally significant,
however, and the extent to which a reduction in a specific vitamin
level is significant depends on the relative contribution of the food
in question to the total dietary intake of the vitamin. While thiamine
is among the most radiation sensitive, the more nutritionally
significant vitamin in fish and shellfish, vitamin B12, is extremely
resistant to radiation.
irradiation of fresh or frozen molluscan shellfish under the conditions
set forth in the regulation in this document will have no adverse
impact on the nutritional adequacy of the diet.
FDA has received numerous letters, primarily form letters, from
individuals that state their opinions regarding the potential dangers
and unacceptability of irradiating food. None of these letters contain
any substantive information that can be used in a safety evaluation of
irradiated molluscan shellfish.
Additionally, FDA received several comments from Public Citizen
(PC) and the Center for Food Safety (CFS) requesting the denial of this
and other food irradiation petitions. The comments were largely of a
general nature and not necessarily specific to the petitioned requests.
Some of the comments specifically questioned a report of a Joint FAO/
IAEA/WHO Study Group on the wholesomeness of foods irradiated with
doses above 10 kGy. Because the comments were addressed to the Docket
for this rulemaking, the comments and FDA's response are discussed as
(1) One comment states that the petition should be denied because
there are four positive studies mentioned but mischaracterized in the
1999 FAO/IAEA/WHO report on high-dose irradiation. The comment states:
The 1999 FAO/IAEA/WHO report is the most detailed recent review
of food irradiation safety. CFS [Center for Food Safety] anticipates
that FDA will seek to rely on it. It is critical that FDA understand
the defects in that report before making a determination on the
above-referenced additive petition...the four studies were
incorrectly classified as ``negative for high-dose irradiation
effect, possible effect of nutrition or diet.''* * *
The 1999 FAO/IAEA/WHO report acknowledged the Anderson et al.
study (on laboratory animal diets) showed ``evidence of weakly
mutagenic effect'' with one diet that was irradiated, yet it
classified the study as ``negative for high-dose irradiation effect,
possible effect of nutrition or diet'' (p. 117). However, no
indication exists that the irradiated standard PRD laboratory diet
that produced the mutagenic effect was otherwise deficient. Further,
the unirradiated control PRD diet did not produce the mutagenic
effect. Anderson et al. found irradiation of the diet produced the
effect. The 1999 FAO/IAEA/WHO report's classification of the study
as ``negative'' was unfounded. (Emphasis in original.)
In the study performed by Anderson et al. (1981) mice were fed four
laboratory diets irradiated at 10 kGy, 25 kGy, and 50 kGy (Ref. 29).
Mice were also fed unirradiated diets as a negative control.
Additionally, mice were injected intraperitoneally with a known
mutagen, cyclophosphamide, at 200 mg per kg of body weight (mg/kg body
weight) as a positive control. The study report stated that mice
consuming one diet (PRD diet)\4\ irradiated at 50 kGy resulted in a
slight increase in post-implantation deaths over the unirradiated diet
when compared to the positive control. The other three irradiated diets
showed no significant increases in early post-implantation death. The
comment provides no information to explain why the Anderson et al.
study on radiation-sterilized laboratory diets should be considered
relevant to the conditions proposed in this petition for the
irradiation of molluscan shellfish to a maximum absorbed dose that will
not exceed 5.5 kGy. Moreover, the comment provides no analysis of the
study and no information to demonstrate that the ``weakly mutagenic
effect'' associated with the laboratory diet irradiated at 50 kGy is
attributable to irradiation of the diet.
\4\ The PRD diet is a formulation of 5.125 g/100 g Barley, 10.0
g/100 g maize meal, 18.125 g/100 g oats (Sussex Ground), 20.0 g/100
g wheat, 20.0 g/100 g wheat feed, 5.0 g/100 g white fish meal (crude
protein 66 percent), 2.5 g/100 g yeast, 10.0 g/100 g soya extract,
7.5 g/100 g dry skimmed milk (crude protein 33), 0.75 g/100 g salt
(NaCl), and a 1.0 percent vitamin mineral supplement.
(2) The comment states that ``[a] thorough discussion of the
Bugyaki et al. study in a 1970 FAO/IAEA/WHO Expert Committee report
highlighted it as a significant positive finding.'' The comment goes on
to state:
The 1999 FAO/IAEA/WHO report admitted that Bugyaki et al. showed
``chromosomal abnormalities in germ cells due to formation of
peroxides and radicals,'' but - without explanation - classified the
study as ``negative for high-dose irradiation effect, possible
effect of nutrition or diet'' (p. 118). That is plain inconsistency;
the `peroxides and radicals' resulted from the irradiation (see
Bugyaki et al., at p. 118: ``... some of the changes produced by
radiation -- the free radicals for example -- will disappear with
time.'' [translated from French]). Further, the same Expert
Committee agreed 29 years earlier that Bugyaki et al. demonstrated
``certain disturbing effects'' of high dose irradiation. That
Committee did not discount the effects as artifacts of nutrition or
diet, as the 1999 Committee did. The 1999 FAO/IAEA/WHO report's
classification of this study as `negative' again lacks a rational
foundation. (Emphasis in original.)
In Bugyaki et al., a 1968 report on irradiated wheat, mice were fed
a diet containing 50 percent freshly irradiated wheat meal (50 kGy);
the balance was basic food powder (the basic food powder was described
by the author to contain 55 percent vegetable matter, 35 percent animal
matter, and 10 percent complementary nutrients) (Ref. 30). Control
animals were fed a diet containing 50 percent wheat that had not been
irradiated with the balance being the basic food powder. Because the
authors were concerned that compression into pellets may affect the
irradiated foods, the animals were fed the food in powder form. The
authors note that there were readily observable
physical and chemical changes in the wheat meal irradiated at 50 kGy.
The authors state that both the treated and untreated animals
developed tumors. However, the tumors found in the treated animals were
different than the tumors found in the untreated animals. The authors
note that the treated animals had a slight increase in anatomic-
pathological lesions; however, they go on to state that there was no
well defined damage. Additionally, they state that there were
alterations in the meiotic chromosomes of the treated animals. The
authors conclude that animals consuming a large part of their diet
irradiated at doses as high as 50 kGy may deserve special attention.
The comment provides no information to demonstrate why the Bugyaki
et al study on freshly irradiated wheat at 50 kGy is relevant to the
conditions proposed in this petition for the irradiation of molluscan
shellfish to a maximum absorbed dose that will not exceed 5.5 kGy.
Foods irradiated at such a high dose often require careful control of
temperature and atmosphere to prevent compositional changes that would
make them unsuitable for food use. The agency notes that several long
term feeding studies using foods irradiated under appropriate
conditions at doses greater than 50 kGy demonstrated no toxicological
effects that could be attributed to the irradiated foods.
(3) The comment states:
The 1999 FAO/IAEA/WHO report states the study performed by
Moutschen-Dahmen et al. showed ``increased pre-implantation
embryonic deaths; not confirmed by cytological analysis'' and
possible effect of nutrition or diet'' (p. 115). The suggestion of
an effect of nutrition or diet is unsupported. (Emphasis in
original.)
The agency has previously addressed the study by Moutschen-Dahmen
et al. (51 FR 13376 at 13387) and noted:
There was no increase in post-implantation losses. Post-
implantation losses, determined by counting dead embryos, are
believed to be the most reliable and sensitive indicator of dominant
lethality. The authors found only pre-implantation losses, which are
much less sensitive than post-implantation losses and merely a
measure of total implants dead or alive subtracted from the total
number. In addition to the possibility that results of the study
could be spurious, any number of factors other than dominant
lethality may cause pre-implantation losses, such as a decrease in
the number of eggs ovulated.
If these effects were real, one would expect to see some effect
on post implantation losses at a lower dose because post-
implantation losses are a much more sensitive indicator than pre-
implantation losses, as mentioned previously.
The agency concluded:
Although the findings reported may be statistically significant,
the authors were uncertain as to what to attribute these results.
They concluded that the most probable mechanism by which these
effects could be produced would be via chromosomal aberration. The
studies necessary to establish an association between these effects
and chromosomal aberrations were not conducted. Additional treatment
levels below that conducted as mentioned previously to detect post-
implantation losses or examinations of the 24 to 48 hour fertilized
eggs could have proved better evidence of causality, but these
studies were not conducted. Thus, although pre-implantation losses
were observed, FDA concludes that there is no biological
significance to this observation because it was not reproducible.
The comment provides no information to demonstrate why the
Moutschen-Dahmen et al. (Ref. 31) study (1970) in which mice were fed a
laboratory chow diet, of which 50 percent was irradiated at 50 kGy is
not exceed 5.5 kGy. The study was designed to look for mutations that
would be lethal to the animals. Further, the comment provides no
information to demonstrate that the pre-implantation deaths were caused
by dominant lethal mutations that were induced by the consumption of
irradiated food. Finally, the comment provides no evidence to refute
the agency's previous conclusion.
(4) With regard to another study (Ref. 32), the comment states
that:
The 1999 FAO/IAEA/WHO report admits the study showed
``significant increase in the mutation frequency induced by the high
dose irradiated foods,'' but nevertheless classified the study as
``negative for high-dose irradiation effect, possible effect of
nutrition or diet'' (p. 115). This is patently contradictory; the
`negative' classification again lacks explanation. (Emphasis in
In the study performed by Johnston-Arthur et al. (1975), Swiss
albino mice were starved for 36 hours and then fed normal and
irradiated ( 7.5 kGy, 15 kGy, and 30 kGy) laboratory chow for 7 hours
(Ref. 32). The mice were then injected intraperitoneally with
Salmonella typhimurium TA 1530 and the bacteria were incubated in the
mice for 3 hours. The mice were then sacrificed and the bacteria were
harvested and tested using the host-mediated assay test for
mutagenicity. The results indicated a significant increase in the
mutation frequency in the bacteria that were exposed to the 30 kGy-
sterilized food. No significant differences were observed in the
bacteria that were harvested from the mice fed the 7.5 kGy and 15 kGy
diet when compared with the control.
Johnston-Arthur et al. study on the irradiation sterilization of lab
chow at 30 kGy is relevant to the irradiation of molluscan shellfish to
a maximum absorbed dose that will not exceed 5.5 kGy. Moreover,
mutation studies with S. typhimurium are intended to screen for
possible mutations affecting animals that can be tested in long term
animal studies. However, several properly conducted long term feeding
studies performed on animals fed with foods irradiated at higher doses
(up to 56 kGy) have shown no mutagenic effects to the subject animals.
Finally, the agency notes that the subject of this regulation is
the petition (FAP 9M4682) regarding shellfish and not the 1999 FAO/
IAEA/WHO report on high-dose irradiation. In its review of the
published literature on the safety of irradiated foods, the agency
finds that properly conducted animal feeding studies showed no evidence
of toxicity attributable to irradiated food. On the few occasions when
studies reported adverse effects, the effects were not consistently
reproduced in related studies conducted with similar foods irradiated
to doses equal to or higher than those for which the adverse effects
were reported, as would be expected if the reported effect were a toxic
effect caused by a radiolysis product (62 FR 64107 at 64112 and 64114).
One comment submitted a paper (Kevesan and Swaminathan, 1971) that
reviewed studies performed in the 1950s and 1960s on irradiated
substrates and irradiated foods (Ref. 33). The comment states that
numerous studies from the 1950s and 1960s found a variety of toxic
effects in animal feeding and in vitro studies, which on the whole cast
doubt on the safety of the technology. The comment asks FDA to ``take a
closer look at the host of past positive studies cited therein.''
The comment further states:
[A]ttempts to discount all of the past positive findings as
aberrations, products of chance, or artifacts of diet will no longer
suffice. These studies need further FDA review particularly in view
of the 2003 Codex Alimentarius standard revision that allowed for
higher absorbed doses of radiation than previously permitted.
The agency notes that the subject of FAP 9M4682 is the irradiation
of molluscan shellfish to a maximum absorbed does of 5.5 kGy, not the
recently revised Codex standard. Furthermore, the authors of the paper
referenced by the comment do not come to the conclusion that the
comment implies. Rather, the study's authors
(Kevesan and Swaminathan) conclude that ``major deficiencies in the way
some of the experiments have been designed and conducted coupled with
inadequacy of genetic data urgently necessitates further investigations
before concluding that the irradiated food materials `can be consumed
with impunity'.''
FDA agrees with the conclusions of the review article in the
context of studies performed prior to 1970. However, many properly
conducted studies have been performed after this review was written. As
previously noted in this document, the agency finds that properly
conducted animal feeding studies showed no evidence of toxicity
attributable to irradiated food. On the few occasions when studies
reported adverse effects, the effects were not consistently reproduced
in related studies conducted with similar foods irradiated to doses
equal to or higher than those for which the adverse effects were
reported, as would be expected if the reported effect were a toxic
The comment provides no additional information that would cause the
agency to change its conclusion on the safety of irradiated food.
One comment submitted a paper (Verschuuren, Esch, and Kooy, 1971)
describing the effects of feeding rats irradiated strawberry-powder and
irradiated strawberry-juice (Ref 34). The comment states that rats fed
``irradiated strawberry powder supplement showed a statistically
significant growth deficit compared to the control animals fed the same
diet, including the powder supplement, but which was unirradiated.''
The comment goes on to state:
FDA's internal reviewers in 1981 and 1982 (reviews are attached
to study) twice classified the Verschurren (sic) et al. study as one
the agency should ``accept'' without reservations, only to be later
overridden by a third reviewer who was able to reclassify the study
as ``reject.'' This change was based on the third reviewer's
suggestion that the study was hampered by ``inadequate diet and
restricted food intake,'' a surprising suggestion as nothing in the
study supported that conclusion
The comment misrepresents the conclusion of one of the reviewers
who did the initial review of the study. Initially, the study was
accepted by two reviewers. However, upon further review by one of the
initial reviewers and a third reviewer, this paper was rejected in the
secondary review because of inadequate diet and restricted food intake.
The comment provides no information that would alter the agency's
conclusion that some of the diets were incomplete and restricted.
Moreover, the comment provides no information that explains why the
consumption of irradiated strawberry-powder is relevant to the
consumption of irradiated molluscan shellfish with a maximum absorbed
dose of 5.5 kGy.
One comment states that a study conducted at Columbia University in
1954 ``supports other studies that yielded adverse health effects,
which our organizations have previously submitted to this docket.''
The comment submitted part of a report, ``Termination Report--Part
1, Food Irradiation and Associated Studies, September 15, 1954,'' which
was conducted at Columbia University for the U.S. Atomic Energy
Commission. The report compares the fertility of ``Professor Sherman's
high generation rats'' that were fed either ``Sherman diet 16'' or a
``modified Sherman diet''\5\ (milk powder was replaced by skim milk
powder and irradiated butterfat). The report concluded that there was a
significant decrease in the fertility of the rats fed the irradiated
diet. The report also mentions that there is significant vitamin E
destruction; however, the comment did not include the entire results
and discussion section with the authors' discussion.
\5\ The control diet was ``Sherman diet 16,'' consisting of 1000
g ground whole wheat, 200 g whole milk powder, and 20 g salt. The
``irradiated diet'' consisted of 1000 g ground whole wheat, 147 g
skim milk powder, 53 g irradiated butterfat, and 20 g salt.
FDA reviewers have previously reviewed a subsequent publication of
a report of this study (Ref. 35). At the time of the study, it was not
well recognized that irradiation of fat in the presence of air can
stimulate oxidation leading to rancidity and high levels of peroxides.
Such rancidity can lead to nutritional deficiencies due to the animals
reducing their food consumption and destruction of vitamins. FDA
reviewers concluded that it appears that littermates were mated and
that the females were mated almost continually, allowing little time
for rest between litters. If there was a nutritional or oil
peroxidation and palatability problems with the diet, it would be
exacerbated by the continuous breeding of the females. Considering the
report's mention of considerable vitamin E destruction, the effects
seen appear to be the result of a nutritionally inadequate diet, not
toxicity, and would not be relevant to irradiation of molluscan
shellfish.
One comment states that the petition should be denied because the
number of positive mutagenicity studies (including those discussed
previously that were identified by the comment as mischaracterized or
ignored) compares favorably with the number of negative studies. The
comment states that ``[m]ore than one-third of both in vivo and in
vitro studies are positive'' for mutagenicity, suggesting there is
``bias in the official posture in support of the safety of
irradiation.''
The suggestion of the comment that FDA showed a ``bias in the
official posture'' on the safety of the consumption of irradiated food
is not supported by any substantive information.
The Bureau of Foods Irradiated Foods Committee (BFIFC) recommended
that foods irradiated at a dose above 1 kGy be evaluated using a
battery of mutagenicity tests to assess whether long-term feeding
studies in animals were necessary (Ref. 36). Mutagenicity studies are
primarily used to screen for potential mutagenic effects. Animal
feeding studies are more reliable for determining the true mutagenic
potential of a compound that is consumed in food (Ref 37). Moreover,
one cannot draw valid conclusions from data simply by summing positive
and negative results without fully evaluating the individual studies
and assessing what conclusions such studies support and considering the
totality of evidence. If the occasional report of a mutagenic effect
were valid and significant to health, one should have seen consistent
adverse toxicological effects in the many long term and reproduction
studies with animals. This has not been the case.
The comment states that the petition should be denied because ``[a]
majority of Parliamentary Members voted for a provision that the EU's
list of foods authorised (sic) for irradiation should not be
expanded,'' and ``[a] working group of the Codex Alimentarius
Commission's Contaminants and Food Additives Committee in November,
2002, recommended against approval of a Codex proposal to remove the
present 10 kiloGray radiation dose cap, which would allow any foods to
be irradiated at any dose -- regardless of how high. (Emphasis in
original.)''
The agency notes that the subject of this regulation is the
petition (FAP 9M4682) to permit irradiating shellfish at a dose up to
5.5 kGy, not whether the maximum dose in the Codex General Standard for
Irradiated Foods should be
raised above 10 kGy. The act requires FDA to issue a regulation
authorizing safe use of an additive when safety has been demonstrated
under the proposed conditions of use. FDA notes that the Codex General
Standard for Irradiated Foods has recently been revised (Codex 2003) by
supplanting reference to a maximum overall average dose of 10 kGy with
the statement that ``[t]he maximum absorbed dose delivered to a food
should not exceed 10 kGy, except when necessary to achieve a legitimate
technological purpose.'' (Ref. 2). The comment fails to demonstrate why
the debate within Codex leading up to this change is relevant to the
One comment states that the petition should be denied because of a
report published by the Organisation for Economic Co-Operation and
Development (OECD) which states:
Hitherto available data indicate, however, that increased rates
of mutation and chromosomal aberration will probably be induced in
certain cases. Although experiments indicate that the genetical
(sic) effect, in cases where it is induced, is relatively small
compared to the effect of direct exposure of animals to radiation,
the same experiments indicate that the possible effect will not be
negligible.
The comment goes on to state that ``[r]ather than being refuted by
subsequent evidence, the OECD's statement regarding likely induction of
mutations and chromosomal aberration has been confirmed in many
studies, cited in this and our earlier comments.''
The 1965 OECD report, entitled ``Steering Committee for Nuclear
Energy Study Group on Food Irradiation,'' reflects scientific
understanding at the time it was written (Ref. 38). The document is a
compendium of published and unpublished (at the time) reports on the
effect of irradiated substances on a variety of organisms. The report
concluded that ``it is impossible to arrive at any definite conclusion
as to the presence or absence of genetic effects if irradiated food
were used for human consumption or for animal feeding.'' Furthermore,
the report states that more rigorous studies should be performed and
when contradictory results are found, the reasons should be determined.
Since the report was compiled in 1965 numerous studies have been
performed on the effects of consuming irradiated foods in multiple
animal species and in humans. Starting in the 1980's, FDA has reviewed
these and other studies, and while many of these studies cannot
individually establish safety, they still provided important
information that, when evaluated collectively, supports a conclusion
that there is no reason to believe that irradiation of flesh foods
presents a toxicological hazard. The comment provides no evidence to
refute the agency's conclusion.
One comment states that ``certain chemical by-products formed in
food that has been irradiated, known as cyclobutanones, could be toxic
enough to cause significant DNA damage, potentially leading to
carcinogenic and mutagenic effects.'' In addition, the comment states
that ``[t]wo major international food safety groups -- CCFAC (Codex
Committee on Food Additives and Contaminants), and SCF (The Scientific
Committee on Food of the European Commission) -- deemed the indications
of toxicity strong enough to necessitate considerable additional
study.''
2-ACBs have been reported as radiolysis products of fats (Refs. 39a
and 39b). Studies performed by researchers have reported that certain
alkylcyclobutanones can cause single strand DNA breaks detectable by
the COMET\6\ assay (Ref. 40). Several animal feeding studies have been
conducted with fat-containing foods irradiated at doses far higher than
would be used on molluscan shellfish. If 2-ACBs, at the level present
in irradiated foods, were of sufficient toxicity to cause significant
DNA damage, one would expect to have seen adverse effects in those
studies where animals were fed meat as a substantial part of their
diet. Moreover, the COMET assay has not yet reached the level of
reliability and reproducibility that is needed to be considered a
standard procedure for testing potential genotoxins. At present, the
assay is of value primarily in basic research of cellular response to
DNA damage and repair, in both in vitro and in vivo systems (Ref. 41).
\6\ Single cell gel electrophoresis or `Comet assay' is a rapid
and very sensitive fluorescent microscopic method to examine DNA
damage and repair at individual cell level.
Also, contrary to what is implied by the comment, the Scientific
Committee on Foods of the European Commission concluded, in July 2002,
``[a]s the adverse effects noted refer almost entirely to in vitro
studies, it is not appropriate, on the bases of these results, to make
a risk assessment for human health associated with the consumption of
2-ACBs present in irradiated fat-containing foods.'' The genotoxicity
of 2-ACBs has not been established by the standard genotoxicity assays
nor are there any adequate animal feeding studies in existence to
determine no-observed-adverse-effect levels (NOAELs) for various
alkylcyclobutanones. Reassurance as to the safety of irradiated fat-
containing food can be based on the large number of feeding studies
carried out with irradiated foods which formed the basis for the
wholesomeness assessments of irradiated foods published by FAO/IAEA/
WHO.
Moreover, researchers have recently demonstrated that 2-DCB does
not induce mutations in the Salmonella mutagenicity test or
intrachromosomal recombination in Saccharomyces cerevisiae or the
Escherichia coli tryptophan reverse mutation assay (Refs. 42 and 43). A
further study, published in 2004, has demonstrated that the Ames assay
showed no difference between 5 concentrations of 2-DCB and the
controls, including samples incubated with S9. The results indicate
that 2-DCB does not produce point or frameshift mutations in Salmonella
and is not activated by S9. The study also investigated the toxicity of
2-DCB and concluded ``that the potential risk from 2-DCB, if any, is
very low'' (Ref. 44).
One comment states that 2-DCB is a unique radiolysis byproduct of
palmitic acid, and ``[b]ecause palmitic acid appears in molluscan
shellfish in varying quantities and high percentages, the FDA should
refrain from considering the petition until potential cytotoxicity and
genotoxicity of 2-DCB in each type of shellfish covered by the petition
is thoroughly studied.''
FDA agrees that 2-DCB is a radiation by-product of triglycerides
with esterified palmitic acid and that molluscan shellfish contain
significant amounts of such triglycerides. FDA previously reviewed
studies in which animals were fed diets containing irradiated meat,
poultry, and fish which contain triglycerides with palmitic acid (62 FR
64107 at 64113), and concluded that no adverse effects were associated
with the consumption of these irradiated flesh foods. The comment
provides no evidence to refute the agency's conclusion regarding the
not exceed 5.5 kGy.
One comment states that two studies by Delinc[eacute]e et al. on
the potential genotoxicity of 2-DCB were mischaracterized in the 1999
FAO/IAEA/WHO report. The comment states that while ``[t]he 1999 FAO/
IAEA/WHO report properly labeled Study 5 as demonstrating a `possible
effect of high-dose irradiation.'* * * it rationalized this by saying
the level of the lipid
present in the experiment was three orders of magnitude greater than
the normal lipid level in chicken meat.'' In addition, the comment
states that ``[s]tudy 6 did not, in fact, use an `extremely high level'
of 2-DCB as claimed in the WHO Secretariat's proof note. The level of
2-DCB, according to the researchers, was carefully calibrated and
multiplied by the appropriate toxicological safety factor, to determine
the safety of chicken irradiated for shelf sterilization.'' In summary,
the comment states that ``Delinc[eacute]e et al. conclude that applying
the standard toxicological safety factor of 100 below the `no-effect
level' means that 2-DCB failed the standard safety test'' and should be
denied under Sec.  170.22 (21 CFR 170.22).
In the first study cited, Delinc[eacute]e et al. incubated rat and
human colon cells for 30 minutes in solutions containing 0.3-1.25 mg/ml
2-DCB and determined by the COMET assay that there were single strand
DNA breaks (Ref. 45). The authors also state that they observed a
cytotoxic effect at increased concentration. Cytotoxicity can confound
the results of the COMET assay such that standard protocols attempt to
use concentrations below that producing cytotoxicity (Ref. 46).
Delinc[eacute]e notes that the 2-DCB concentration in the lipid
fraction of chicken irradiated at 58 kGy (Raltech study) is 17 microg/g
lipid (Refs. 45 and 47). Thus, the concentration of 2-DCB used in the
assay was 17 to 73 times higher than that in the lipid fraction of
radiation sterilized chicken. As the average dose in the Raltech study
was 10 times higher than the maximum dose requested in the shellfish
petition, the concentration of 2-DCB and other alkylcyclobutanones
would be far lower in the lipid fraction of shellfish than in the
experiment by Delinc[eacute]e. Moreover, the concentration reported in
the study cited is the concentration in a liquid solvent (solvent not
reported) in direct contact with colon cells. As one would not consume
pure irradiated lipid from shellfish, the concentration of any 2-DCB
from shellfish would be diluted substantially by the major components
in shellfish and further by other components being consumed
simultaneously. Thus, cells in the colon of humans would be in contact
with concentrations more than a thousand times lower than those used in
Delinc[eacute]e's study. In the Raltech study in mice, chicken
constituted 35 percent of the diet by dry weight, and there were no
adverse toxicological effects that could be attributed to the
consumption of irradiated chicken.
In the second paper (Ref. 40), the authors administered 2-DCB to
rats by pharyngeal tube at doses of 1.12 and 14.9 mg/kg body weight.
They reported the higher concentration as equivalent to the amount
found in 800 broiler chickens treated at 60 kGy (equivalent to
approximately 40,000 wild eastern oysters irradiated at the maximum
dose requested by the petition). They harvested colon cells from the
rats 16 hours later and performed the COMET assay. Although the authors
observed single strand DNA breaks at the higher concentration, no
effect was seen at the lower concentration.
In its review of studies in which animals were fed diets containing
beef irradiated at 56 kGy, pork at 56 kGy, poultry at 6 kGy, fish at 6
kGy, horse meat at 6.5 kGy, fish at 56 kGy, and others (62 FR 64107 at
64113), the agency found no evidence of toxicity attributable to the
consumption of various flesh foods, which contain esterified palmitic
acid and other fatty acids, and which should also contain 2-DCB and
other alkylcyclobutanones.
Furthermore, the comment misrepresents the paper's conclusions. The
comment states that the ``failure to pass the 100-fold safety factor''
means that 2-DCB fails the standard set under Sec.  170.22, and
therefore, the petition should be denied. Contrary to what the comment
implies, the authors did not conclude that the ``test failed the 100-
fold safety factor.'' Rather, the dose applied to the animals was set
on the basis of calculations such that the lower dose would be
equivalent to 100 times the amount of all 2-ACBs consumed if all fat in
the diet were irradiated at a pasteurizing dose (3 kGy); and the larger
dose was set to be 100 times the total alkylcyclobutanones from
radiation sterilization (60 kGy) of all dietary fat. The authors noted
that there was no effect at the lower dose and that the higher dose was
equivalent to the amount from 800 radiation-sterilized broiler chickens
and questioned this approach to the use of safety factors.
FDA notes that Sec.  170.22 provides that ``[e]xcept where evidence
is submitted which justifies use of a different safety factor, a safety
factor in applying animal experimentation data to man of 100 to 1 will
be used.'' FDA and food safety scientists worldwide have long agreed
that the evaluation of the safety of irradiated foods requires
consideration of the whole food, not the testing of each component
(although identification of major radiolysis products will aid in the
interpretation of data) (Ref. 5). Applying a 100-fold safety factor to
a processed food is neither feasible nor rational. Similarly, testing
each component of a food separately is impossible. There are too many
components to test them all, and many food components that occur
naturally will cause adverse effects if tested in isolation at an
exaggerated dose. For example, naturally occurring food components,
such as solanine from potatoes, tomatine from tomatoes or various
vitamins and minerals, would cause toxic effects if consumed in amounts
100 times greater than normal. Thus, requiring a 100-fold safety factor
for each component of a food (that occurs naturally or is produced
through processing) is not appropriate.
An affidavit written by Dr. William Au that was submitted by CFS
and PC, states that radiolysis compounds (e.g., 2-DCB) are formed
during the irradiation of food and that ``[t]heir potential health
hazard has not been adequately evaluated. Without conclusive evidence
of the potential health consequences of these products, the safety of
irradiated food cannot be assured.''
The affidavit provides no basis to conclude that the multitude of
studies on irradiated foods (which contain the radiolysis products
referred to) are inappropriate for the evaluation of the safety of
those foods. In FDA's review of the consumption of irradiated flesh
foods for a previous petition on irradiated meat, FDA concluded that
``the results of the available toxicological studies of irradiated
flesh foods also demonstrates that a toxicological hazard is highly
unlikely because no toxicologically significant adverse effects
attributable to consumption of irradiated flesh foods were observed in
any of these studies'' (62 FR 64107 at 64114). As those foods would
have contained the radiolysis products, including 2-DCB, produced by
the irradiation of fats, Dr. Au is incorrect in stating that its
potential hazard to health has not been evaluated.
One comment references a paper published in 2004 that summarizes
the European testing of 2-ACBs. The comment quotes language from the
paper stating that ``the in vitro and in vivo experiments with
laboratory animals demonstrated that 2-ACBs have potential toxicity,''
and the comment states that ``the paper concludes that as far as the
possibility of health hazards from consuming irradiated food, `further
research is highly required''' (Ref. 48). The comment concludes by
asserting that ``unfortunately, no comprehensive research on the
toxicity of 2-ACBs has been undertaken to date, leaving this
uncertainty as a huge obstacle to FDA's making a reliable decision on
the five pending petitions.''
FDA disagrees that the conclusions of this paper would prevent
the safety review of FAP 9M4682. The conclusions submitted by the
comment selectively quote from the authors' conclusions. The authors
Although our results point towards toxic, genotoxic and even
tumor promoting activity of certain highly pure 2-ACBs, it should be
emphasized that these experimental data are inadequate to
characterize a possible risk associated with the consumption of
irradiated fat containing food. Other food components may influence
the reactions of 2-ACBs not evident from our experiments on purified
2-ACBs. More knowledge is also needed about the kinetics and
metabolism of 2-ACBs in the living organism. It would, therefore, at
present be premature to draw the final conclusion that 2-ACBs are a
health hazard on consumption of irradiated food, but further
research is highly required.
(Emphasis added) As previously noted in this document, FDA has
reviewed studies in which animals were fed diets containing irradiated
meat, poultry, and fish which contain triglycerides (62 FR 64107 at
64113). The agency concluded that no adverse effects were associated
provides no additional information that would alter the agency's
conclusion that the consumption of irradiated fat-containing foods does
not present any health hazard.
One comment submitted a paper entitled Foodborne Radiolytic
Compounds (2-Alkylcyclobutanones) May Promote Experimental Colon
Carcinogenesis (Ref. 49) and a commentary by Chinthalapally V. Rao,
Ph.D. (Ref. 50) that states that the petition should not be approved
until additional research is performed on a purported correlation
between the consumption of ACBs and the promotion of colon
carcinogenesis.
Raul et al designed their study to determine if 2-ACBs,
specifically 2-tetradecylcyclobutanone (2-tDCB) and 2-(tetradec-5'-
enyl)-cyclobutanone (2-tDeCB), will promote the carcinogenic effects of
azoxymethane (AOM), which is known to induce colon preneoplastic
lesions, adenomas, and adenocarcinomas in rats (Ref. 49). The paper
states that the ``[p]resent report is the first demonstration that pure
compounds, known to be exclusively produced on irradiation in dietary
fats, may promote colon carcinogenesis in animals.''
Many different chemicals, some of which occur naturally in the
human body, are known to promote carcinogenesis (Ref. 51).
Additionally, Dr. Rao states that colon cancer is largely influenced by
dietary lipids such as animal fat. Moreover, FDA notes that Dr. Rao
states that the precursor lipids (which will be consumed in millions of
times greater amount than the 2-ACBs, 2-tDCB and 2-tDeCB) are
influential in the promotion of colon cancer.
The data showed no significant difference in tumor incidence
between treatment groups. Raul et al reported no apparent difference in
the number of aberrant crypt\7\ foci (ACF)\8\ per centimeter of colon,
except that the 6 month treatment group receiving 2-tDeCB showed an
increase in the total number of aberrant crypts (Refs. 52 and 53).
However, the study has design flaws that make it difficult to
understand the relevance of the data. Both FDA and Dr. Rao note that
these flaws include: (1) Use of a limited number of animals (6 male
Wistar rats per group); (2) use of a poor animal model (Wistar rats);
and (3) alcohol, the vehicle in the study, has been linked to tumor
promotion in many studies. Most importantly, as Raul et al point out in
the discussion in their paper, the exposure of rats to 2-ACBs
(milligrams per kilogram body weight) was three orders of magnitude
higher than human exposure would be (micrograms per kilogram body
weight).
\7\ A crypt is a cell that is used as a pathological marker. A
crypt focus is a grouping of crypts. An aberrant crypt is a crypt
that has altered luminal openings, thickened epithelia and are
larger than adjacent normal crypts.
\8\ Aberrant crypt foci of the colon are possible precursors of
adenoma and cancer, and ACF have been observed in animals exposed to
colon specific carcinogens, e.g. AOM.
Given the limitations of the animal model and study design,
ambiguous data, and the absence of close relationship between the
chemical exposure used in the study and the expected human exposure,
the agency finds that the comment provides no substantial or reliable
scientific information to show that there is reason to believe that the
consumption of 2-ACBs will promote colon cancer. Moreover, the agency
notes that long term feeding studies performed using irradiated foods
that contain 2-ACBs did not show any promotion of colon cancer. The
results of these latter long term feeding studies are more relevant
than results from the Raul paper because the 2-ACBs were fed in the
diet as in human exposure and the levels of exposure would still have
been increased over usual dietary levels.
One comment states that the petition should be denied because six
positive studies conducted by the Indian National Institute of
Nutrition (NIN) were ignored in the 1999 FAO/IAEA/WHO report. The
comment states that FDA should give full consideration to the NIN
studies, most notably the children's study using freshly irradiated
food. The comment also states that the validity of these studies is
supported by expert commentary and two published defenses by the NIN
A commentary by Dr. William Au submitted with the comment states
``[s]ome reports in the peer-reviewed literature on mutagenic
activities of irradiated foods were not considered in the 1999 FAO/
IAEA/WHO report (Bhaskaram and Sadasivan, 1975; Vijayalaxmi, 1975,
1976, 1978; Vijayalaxmi and Sadasivan, 1975; Vijayalaxmi and Rao,
1976).'' ``Although the observations from these studies are not
confirmed by some publications in the literature, the positive findings
have support from other publications (Bugyaki et al., 1968; Moutschen-
Dahmen, et al., 1970; Anderson et al., 1980; Maier et al., 1993).
Furthermore, repeated observations of activities that have significant
public health implications such as polyploidy in somatic cells, genetic
alterations in germ cells and reproductive toxicity should not be
ignored, but should be considered seriously and explicitly by FDA with
respect to the pending food irradiation petitions.''
petition (FAP 9M4682) submitted by NFI regarding shellfish, not the
1999 FAO/IAEA/WHO report on high-dose irradiation. The studies cited by
the comment are not related to irradiated shellfish or other irradiated
flesh foods.
The comment implies that FDA has not considered the cited studies
despite the fact that FDA previously discussed the reason why some of
the study reports could not be used to support a decision on irradiated
foods (51 FR 13376 at 13385 and 13387). In 1986 FDA addressed the
studies performed at the NIN (Ref. 54) and stated:
A committee of Indian scientists critically examined the
techniques, the appropriateness of experimental design, the data
collected, and the interpretations of NIN scientists who claimed
that ingestion of irradiated wheat caused polyploidy in rats, mice,
and malnourished children. After careful deliberation, this
committee concluded that the bulk of these data are not only
mutually contradictory, but are also at variance with well-
established facts of biology. The committee was satisfied that once
these data were corrected for biases that had given rise to these
contradictions, no evidence of increased polyploidy was associated
with ingestion of irradiated wheat.
The agency agreed with the conclusions of the committee of
scientists that the studies
with irradiated foods do not demonstrate that adverse effects would
be caused by ingesting irradiated foods.
(51 FR 13376 at 13385)
Moreover, the agency notes that adverse effects which should have
been seen if the conclusions drawn by the NIN researchers were valid
were not observed in studies performed using similar foods irradiated
at higher doses and consumed for longer periods of time. Finally, we
note that the paper by Maier cited in the comment by Dr. Au concluded
that ``* * * the consumption of irradiated wheat does not, therefore,
pose any health risk to humans.''
One comment states that the petition should be denied because it
does not contain specific data about the potential toxicity of
irradiated molluscan shellfish. The comment concludes that ``FDA cannot
credibly assess the safety and wholesomeness of foods covered by the
petition if no toxicology data were included in the petition.''
The petitioner (FAP 9M4682) did not submit copies of toxicological
data specific to irradiated shellfish. However, as noted earlier, FDA
has reviewed a large body of data relevant to the assessment of the
potential toxicity of irradiated flesh foods. The agency disagrees with
the statement that ``FDA cannot credibly assess the safety and
wholesomeness of foods covered by the petition if no toxicological data
were included in the petition.'' There was no reason to submit
additional copies of studies that have previously been reviewed by FDA.
The comment provides no basis to challenge FDA's reliance on these
studies to assess the safety of irradiated molluscan shellfish.
One comment states that the petition should be denied because ``* *
* in the course of legalizing the irradiation of numerous classes of
food over a 14-year span, the FDA relied on dozens of studies declared
`deficient' by agency toxicologists.''
FDA notes that the animal feeding studies reviewed in support of
this petition (FAP 9M4682) were not considered deficient by agency
scientists. Rather, they were considered acceptable or accepted with
reservation by the agency scientists because even though all studies
may not have met modern standards in all respects, they provided
important information. Those studies categorized by FDA scientists as
deficient were not relied on in the review of this petition. Although
some of the studies accepted with reservation might not have been
reported in full, used fewer animals, or examined fewer tissues than is
common today, they still provide important information that, when
evaluated collectively, supports the conclusion that consumption of
molluscan shellfish irradiated under the conditions proposed in this
petition is safe (Ref. 55).
One comment submitted by CFS and PC states that the petition should
be denied because Delinc[eacute]e et al (Ref. 40). stated that ``* * *
the results urge caution and should provide impetus for further
studies.'' The comment further states that if established irradiation
researchers and numerous medical experts urge caution and further
research on the safety of irradiated food, then ``reasonable
certainty,'' as required by 21 CFR 170.3(i), is missing.
The comment quotes selectively from the conclusions of
Delinc[eacute]e regarding ACBs and omits other portions more relevant
to this petition. For example, the sentence immediately prior to the
sentence quoted states: ``The requisite concentrations are very much
higher than those that can be reached through the consumption of
irradiated foods that contain fat.'' Additionally, the authors note in
the referenced article that ``[i]t should be mentioned once again that
in many animal feeding experiments with irradiated foods in which it is
known that cyclobutanones was also in the feed, no evidence has been
found to indicate an injury from irradiated foods that have been
consumed.'' In a comment to the docket in response to the statement
made by CFS and PC, Dr. Delinc[eacute]e states that ``[u]nfortunately,
the authors Worth and Jenkins did not take my precautions into account
but made a story about the `dangerous' cyclobutanones. In my opinion
they greatly exaggerate the risks of 2-alkylcyclobutanones (2-ACB),
which we still do not know very much about'' (Ref. 56).
One comment requests that the agency remove the food additive
petition from the expedited review process.
FDA has established a process to give priority to petitions for
technologies intended to reduce pathogen levels in foods (64 FR 517,
January 5, 1999). FDA notes that petitions under expedited review are
subject to all controls and requirements regarding safety data
applicable to comparable petitions in the standard review process.
Accordingly, valid scientific evidence, as defined by Sec.  171.1 (21
CFR 171.1), is required to support the approval of an expedited
petition. Likewise, the standards for safety and for data presentation
are identical to the standard review process. The comment provides no
information to support removing the petition from the expedited review
One comment requests that FDA review all of part 179 to determine
if the regulations adequately protect the public health based on the
best available scientific information.
This comment is outside the scope of this petition.
One comment states that the petition should be denied because ``FDA
did not review studies that met the protocols established by the
National Academy of Sciences/National Research Council (NAS/NRC) as
required by 21 CFR 170.20.''
The comment provides no information to demonstrate that the studies
reviewed by the agency in support of this petition (FAP 9M4682) fail to
meet the standards set forth under Sec.  170.20 (21 CFR 170.20).
Section 170.20 states:
The Commissioner will be guided by the principles and procedures
for establishing the safety of food additives stated in current
publications of the National Academy of Sciences-National Research
Council. A petition will not be denied, however, by reason of the
petitioner's having followed procedures other than those outlined in
the publications of the National Academy of Sciences-National
Research Council if, from available evidence, the Commissioner finds
that the procedures used give results as reliable as, or more
reliable than, those reasonably to be expected from the use of the
outlined procedures.
FDA has consistently taken the position that many scientifically
valid types of data may properly support a finding that the proposed
use of a food additive will cause ``no harm'' to consumers. For
example, Sec.  170.20 which sets forth the general scientific criteria
that FDA uses in evaluating a food additive petition, cites the
``principles and procedures * * * stated in `current' publications of
the National Academy of Sciences, National Research Council'' as a
guide that the agency uses in its safety evaluation of food additives.
NAS has written testing standards for both public and agency use, but
these testing requirements have been stated in relatively general
terms. In practice, FDA has applied toxicological criteria and exposure
information that were current for the time in assessing the safety each
food additive. The agency has continuously adjusted food additive
testing recommendation as necessary to reflect both the steady progress
of science and the most current information about population exposure
to additives (Ref. 57).
FDA concludes that the data considered for this regulation, when
evaluated in its entirety, are sufficient to support the safety of
consumption of irradiated molluscan shellfish at a maximum absorbed
dose that will not exceed 5.5 kGy.
battery of experiments prescribed by the BFIFC to assess the potential
toxicity and mutagenicity of irradiated food was based on the
assumption that only 10 percent of the food supply would likely be
irradiated and fell ``[f]ar short of those battery prescribed by the
FDA's Red Book, but the FDA [did] not comply with the abbreviated
battery of experiments before legalizing the irradiation of pork, fruit
and vegetables, poultry, red meat, eggs, sprouting seeds and juice.''
petition (FAP 9M4682) on shellfish, not the BFIFC report (Ref. 36) nor
the FDA Red Book (Ref. 37).
The BFIFC report is an internal document prepared by FDA scientists
that provides recommendations for evaluating the safety of irradiated
foods based on the known effects of radiation on food and on the
capabilities of toxicological testing. While the report and the
commentary on it have aided FDA's thinking regarding the testing of
irradiated foods, the report established no definitive requirements.
BFIFC recognized that it may not be necessary to perform reproduction
and chronic toxicity studies in cases where there was evidence that
irradiated foods provided no mutagenic or other toxic effects that
could be seen in shorter studies. Therefore, BFIFC recommended that in
the absence of chronic and reproductive feeding studies, foods
irradiated at a dose above 1 kGy be evaluated using a battery of
mutagenicity tests, as well as 90-day feeding studies in two species
(one rodent and one non-rodent). BFIFC also recommended that chronic
studies would only be indicated when two of the four mutagenicity tests
showed mutagenic effects, and that the reproductive toxicity tests
would only be indicated when the 90-day studies showed a potential for
effects on the reproductive system. Furthermore, BFIFC also recommended
that foods should be considered generically as a class, based on their
composition i.e., proteins, lipids, and carbohydrates. Consistent with
these recommendations, FDA has considered several relevant chronic
feeding studies, as well as the macronutrient composition of molluscan
shellfish in the safety determination for this regulation. Therefore,
there is no need to conduct additional mutagenicity studies to
determine whether chronic studies are needed.
Finally, FDA's Red Book represents the agency's current thinking on
the information needed for the safety assessment of food ingredients,
not processed foods, such as irradiated molluscan shellfish, and it
does not bind the petitioner to follow specific procedures that are
recommended in the Red Book. Furthermore, even if the Red Book applied
to processed foods, alternative approaches would be permissible if such
approaches satisfy the requirement of the applicable statute and
regulations. The comment contains no evidence to demonstrate that the
studies considered for this regulation, when evaluated in totality, are
insufficient to support the safety of consumption of irradiated
molluscan shellfish at an absorbed dose no to exceed 5.5 kGy.
One comment states that the petition should be denied because there
is evidence that the consumption of trans fatty acids increases the
risk of coronary heart disease and recent research shows that
irradiation increases the amount of trans fatty acids present in ground
beef (Ref. 58).
The paper submitted by the comment purports to show a 3.4 percent
increase in the amount of trans fatty acids when ground beef is
irradiated at 1 kGy at 25 degrees Celsius, and a greater increase in
trans fatty acids at higher doses. For example, the paper states that
unirradiated beef contains 4.60 <PLUS-MINUS> 0.31 percent trans fatty
acid, 4.40 <PLUS-MINUS> 0.31 percent trans fatty acid when stored for
60 days, and 5.00 <PLUS-MINUS> 0.31 percent trans fatty acid when
stored for 90 days. When beef was irradiated at 3 kGy, they report 8.00
<PLUS-MINUS> 0.00 percent trans fatty acid for all three storage times.
When beef was irradiated at 8 kGy, they report 11.00 <PLUS-MINUS> 0.50
percent trans fatty acid at day zero, 10.50 <PLUS-MINUS> 0.50 percent
trans fatty acid when stored for 60 days, and 10.00 <PLUS-MINUS> 0.31
percent trans fatty acid when stored for 90 days.
The fat in beef has a natural background of trans fat that ranges
from 3 percent to 10 percent and research performed by the agency shows
no change in the amount of trans fatty acids present when ground beef
is irradiated at 25 degrees Celsius (Ref. 59). Additionally, Consumer
Reports (August 2003) found no trans fats were produced when ground
beef was irradiated. The agency has reviewed the paper submitted by the
comment and concludes that the researchers did not demonstrate that
there was an increase in the amount of trans fatty acid present in
irradiated ground beef, or that irradiation showed a dose dependent
response. In fact, the paper fails to demonstrate that the researchers
were measuring the quantity of trans fatty acids (Ref. 60). Therefore,
the agency concludes that there is no basis to deny the petition based
on increased amount of trans fatty acids in irradiated ground beef.
consumption of irradiated food may contribute to an increase in the
number of still-born children. The comment provides three studies to
substantiate this comment: (1) An unpublished report states that the
consumption of irradiated potatoes increased the hemoglobin
concentrations in healthy human volunteers; (2) a published study that
shows that elevated hemoglobin levels were found in pigs consuming
irradiated potatoes; and (3) a published study appearing to show that
``high hemoglobin concentration at first measurement during antenatal
care appears to be associated with increased risk of stillbirth,
especially preterm and small-for-gestational age antepartum
stillbirths.''
The comment suggests that the consumption of a high carbohydrate
diet may increase hemoglobin levels and this may lead to an increase in
the frequency of still born children among pregnant women who consume
irradiated carbohydrates. FDA notes that consumption of shellfish would
not contribute significant carbohydrates to the diet because the
maximum proximate carbohydrate composition of shellfish is 10 percent
The first study (1967) compares the hemoglobin and hematocrit
levels of 7 human volunteers who, for 14 weeks, consumed potatoes that
had been irradiated at 14 kGy (Ref. 61). The study does not include a
baseline prior to feeding; it provides a single measurement. The
hemoglobin values reported show a slight increase during the period of
consumption of irradiated potato, but they are still within the normal
range of hemoglobin values (Ref. 62). Additionally, there is no
concurrent control group to demonstrate that the irradiated potatoes
were the cause of the increase in hemoglobin values.
The second study (1966) submitted by the comment compares piglets
fed both irradiated and non-irradiated potatoes (Ref. 63). The authors
conclude that the pigs fed irradiated potatoes did not differ
significantly from the control animals in the parameters measured,
except that the pigs fed irradiated potatoes grew slightly faster, had
a more rapid increase in hemoglobin levels, and had a higher hemoglobin
concentration at the end of the experiment. The authors state that
``[t]he second generation pigs provided no indication that the
irradiated potatoes might give rise to deleterious effects'' (Ref. 64).
The third study entitled ``Maternal Hemoglobin Concentration During
Pregnancy and Risk of Stillbirth'' (2000) compares the hemoglobin
concentration during antenatal care, the change in hemoglobin
concentration during pregnancy and the risk of still birth (Ref. 64).
The study compares the hemoglobin concentrations at first measurement
of 702 primiparous (bearing first child) women with stillbirths
occurring at 28 weeks or later to 702 primiparous women with live
births. The authors concluded that high hemoglobin concentrations at
first measurement appeared to be associated with an increased risk of
stillbirth, especially preterm and small-for-gestational-age antepartum
stillbirths. The authors note that the study was limited to primiparous
women with singleton (first) pregnancies and that the conclusions can
only be interpreted within that small sub-population. FDA also notes
that the study did not investigate other potential confounding
variables such as nutrition or physical activity.
FDA acknowledges that hemoglobin concentrations were not reported
in studies such as the Bugyaki et al. study that reported gestational
effects. However, FDA notes that none of the long term reproductive
studies performed with irradiated foods that were found to be
acceptable or acceptable with reservation in 1982 showed effects on
reproduction. This is substantiated in the second study identified by
the comment. Therefore, given the limitations in design of the
additional two studies, the agency finds no basis to conclude that the
consumption of irradiated shellfish will increase hemoglobin levels.
Similarly, FDA finds no basis to the purported association between
increased hemoglobin levels and an increase in stillbirth rates.
In an affidavit written by Dr. William Au that was submitted by CFS
and PC, he states that ``[i]onizing radiation is a teratogen, mutagen,
and carcinogen whereas some other procedures for food decontamination/
sterilization such as heat and steam are not. Whenever other processing
methods or combination of methods are equally effective in reducing the
risk of foodborne disease are available, the use of radiation procedure
should be avoided.''
While methods other than treatment with ionizing radiation are
available to eliminate or reduce microbial contamination of food, the
existence of such methods is not a reason to prohibit safe
alternatives. Additionally, the act does not authorize FDA to
arbitrarily limit other safe alternatives. The fact that radiation can
be teratogenic, carcinogenic, or mutagenic when applied directly to
living organisms is not relevant to the safety of irradiated shellfish.
Most food processing techniques (such as grinding, slicing, boiling,
roasting) would be harmful to living mammals but that is unrelated to
the safety of the food. Irradiating the shellfish will not expose
consumers to additional amounts of radiation.
BFIFC ``* * *cautioned that even if 10 percent of the food supply were
irradiated: `When irradiation results in the significant loss of
micronutrients, enrichment may be considered appropriate.''' The
comment goes on to state that to date, FDA has authorized the
irradiation of several classes of food that comprise more than half of
the U.S. food supply. ``If the FDA approves the pending `ready-to-eat'
petition [FAP 9M4697], an estimated 80-90 percent of the U.S. food
supply would be eligible for irradiation.'' The comment further states
that ``no analysis has been done of the nutritional deficiencies that
would be created among the populace should 80-90 percent of the food
supply be irradiated.''
The comment provides no information to conclude that irradiating
80-90 percent of the diet is probable or feasible. Additionally,
molluscan shellfish are a small part of the food supply. The comment
provides no basis for the statement that consumers will suffer
nutritional deficiencies from being exposed to irradiated food.
FDA agrees that treatment of food with ionizing radiation, as with
heat processing, decreases the levels of some nutrients and irradiation
must be evaluated by considering the nutritional consequences on the
diet as a whole. The agency has specifically addressed the impact of
irradiation on vitamins and other nutritional components in the
Nutrition section in this document. Irradiation has essentially no
effect on the quantity of fatty acids, amino acids, and carbohydrates
in foods and no effect on the overall dietary intake of these
macronutrients. While irradiation may reduce the levels of some
vitamins, similar to heat processing, the agency concludes that the
irradiation treatment of shellfish would have no significant effect on
dietary intake of vitamins. The comment provides no evidence to refute
the agency's conclusion that the consumption of irradiated molluscan
shellfish would not result in nutritional deficiencies. The effects of
ionizing radiation on the nutritional qualities of the foods that are
the subject of other petitions, such as FAP 9M4697, will be evaluated
as part of the safety evaluation for those petitions.
Another comment states that a statement by D. R. Murray in Biology
of Food Irradiation\9\ suggests that ``disproportionate and selective
losses of nutrients occur in foods as consequence of irradiation.''
\9\ Murray, D. R., Biology of Food Irradiation, Research Studies
Press Ltd. Staunton, UK, Chapter 4, Radiolytic products and
selective destruction of nutrients, 1990.
The comment provided the bulk of a chapter from this book and
states that FDA must address the negative impact on fatty acids,
vitamins, amino acids, carbohydrates and other essential components on
food as a consequence of irradiation and in combination with cooking.
The comment requests that the agency respond to the following four
questions regarding the nutritional impact of irradiated foods.
<BULLET> ``What would be the impacts of irradiation as proposed on
each important vitamin and other nutritional component in each
different food type that is included?''
<BULLET> ``What would be the projected national rates of
consumption of each different food type included in the petition after
foreseeable market penetration of the product, e.g., after 5-10 years
of marketing?''
<BULLET> ``How would this projected future consumption vary across
age, ethnic, gender, economic status, education status, and other
variables in the American population?''
<BULLET> ``To what extent would the various population groups
likely be affected by the nutritional/vitamin impacts identified under
question 1, above?''
In the review of this petition (FAP 9M4682), FDA considered whether
the nutritional quality of irradiated molluscan shellfish would differ
in any meaningful way from that of non-irradiated molluscan shellfish
and concludes that consumption of irradiated molluscan shellfish will
not result in nutritional deficiencies. FDA notes that foods are
commonly processed more than once, such as by heating in the factory
cooking one or more times in the home, without an adverse effect on the
diet. The comment provides no rationale as to why irradiation should be
considered differently from heat processing in this regard, nor why the
major data research projects envisioned in the final three questions
are necessary to evaluate the safety of irradiated shellfish.
Based on the data and studies submitted in the petition and other
information in the agency's files, FDA concludes that the proposed use
of irradiation to treat fresh and frozen molluscan shellfish with
absorbed doses that will not to exceed 5.5 kGy is safe, and therefore,
the regulations in Sec.  179.26 should be amended as set forth in this
In accordance with Sec.  171.1(h), the petition and the documents
that FDA considered and relied upon in reaching its decision to approve
the petition are available for inspection at the Center for Food Safety
and Applied Nutrition by appointment with the Information contact
person (see FOR FURTHER INFORMATION CONTACT). As provided in Sec.
171.1(h), the agency will delete from the documents any materials that
are not available for public disclosure before making the documents
available for inspection.
This final rule contains no collections of information. Therefore,
clearance by the Office of Management and Budget under the Paperwork
Reduction Act of 1995 is not required.
The agency has carefully considered the potential environmental
effects of this action. The agency has determined under 21 CFR 25.32(j)
that this action is of a type that does not individually or
cumulatively have a significant effect on the human environment.
Therefore, neither an environmental assessment nor an environmental
impact statement is required.
Any person who will be adversely affected by this regulation may
file with the Division of Dockets Management (see ADDRESSES) written or
electronic objections. Each objection shall be separately numbered, and
each numbered objection shall specify with particularity the provisions
of the regulation to which objection is made and the grounds for the
objection. Each numbered objection on which a hearing is requested
shall specifically so state. Failure to request a hearing for any
particular objection shall constitute a waiver of the right to a
hearing on that objection. Each numbered objection for which a hearing
is requested shall include a detailed description and analysis of the
specific factual information intended to be presented in support of the
objection in the event that a hearing is held. Failure to include such
a description and analysis for any particular objection shall
constitute a waiver of the right to a hearing on the objection. Three
copies of all documents are to be submitted and are to be identified
with the docket number found in brackets in the heading of this
document. Any objections received in response to the regulation may be
seen in the Division of Dockets Management between 9 a.m. and 4 p.m.,
The following sources are referred to in this document. References
marked with an asterisk (*) have been placed on display at the Division
of Dockets Management (see ADDRESSES) and may be seen by interested
persons between 9 a.m. and 4 p.m., Monday through Friday. References
without asterisks are not on display; they are available as published
articles and books.
1. WHO, ``Wholesomeness of Irradiated Food: Report of a Joint
FAO/IAEA/WHO Expert Committee,'' World Health Organization Technical
Report Series, No. 659, World Health Organization, Geneva, 1981.
2. Codex 2003, ``Codex General Standard for Irradiated Foods
(CODEX STAN 106-1983, Rev.-2003)'' and ``Recommended Code of
Practice for the Operation of Radiation Facilities Used for the
Treatment of Foods (CAC/RCP 19-1979, Rev.-2003).'' Codex
Alimentarius Commission, Food and Agriculture Organization and World
Health Organization, Rome, 2003.
3. Safety and Nutritional Adequacy of Irradiated Food, World
Health Organism, Geneva, 1994.
*4. Memorandum for FAP 9M4682 from D. Folmer, FDA, to L.
Highbarger, FDA, August 2, 2002.
5. Diehl, J.F., Safety of Irradiated Foods, Second Edition,
Marcel Dekker, Inc., New York, 1995.
6. Seibersdorf Project Report, International Programme on
Irradiation of Fruit and Fruit Juices, Chemistry and Isotopes
Department, National Centre for Nuclear Energy, Madrid, Spain, vol.
8, 1966.
*7. Memorandum for FAP 9M4682 from K. Morehouse, FDA, to L.
Highbarger, FDA, July 15, 2005.
*8. Memorandum for FAP 9M4695 from I. Chen, FDA, to L.
Highbarger, FDA, April 7, 2003.
*9. Uderdal, B., J. Nordal, G. Lunde, and B. Eggum, ``The Effect
of Ionizing Radiation on the Nutritional Value of Fish (Cod)
Protein,'' Lebensmittel-Wissenschaft Technologie, 6:90-93, 1973.
10. Von Sonntag, C., ``Free-radical Reactions of Carbohydrates
as Studies by Radiation Techniques, ''Advances in Carbohydrate
Chemistry Biochemistry, 37:7-77, 1980.
11. WHO, ``High-dose Irradiation: Wholesomeness of Food
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of Agriculture and Food Chemistry, 40(10), 1963-1971, 1992.
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Feeding Study on Irradiated Strawberries; Food Irradiation; 7 (1-2);
pp. A17-A21, 1966.
*35. Memorandum from Food Additives Evaluation Branch, HFF-156
to C. Takaguchi, Petition Control Branch, December 28, 1982.
*36. Bureau of Foods Irradiated Foods Committee, Recommendations
for Evaluating the Safety of Irradiated Food, Prepared for the
Director, Bureau of Foods, FDA, July 1980.
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Applied Nutrition, 1993, revised 2001.
*38. Organisation for Economic Co-Operation and Development,
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by Irradiated Foods and Food Components, Scarascia-Mugnozza, G.T.,
A.T. Natarajan, and L. Ehrenberg, 1965.
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in Potato Tubers and Some Highber Plants Caused by Ionizing
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List of Subjects in 21 CFR Part 179
Food additives, Food labeling, Food packaging, Radiation
protection, Reporting and record keeping requirements, Signs and
Therefore, under the Federal Food, Drug, and Cosmetic Act and under
authority delegated to the Commissioner of Food and Drugs, 21 CFR part
179 is amended as follows:
PART 179--IRRADIATION IN THE PRODUCTION, PROCESSING AND HANDLING OF
1. The authority citation for 21 CFR part 179 continues to read as
Authority: 21 U.S.C. 321, 342, 343, 348, 373, 374.
2. Section 179.26 is amended in the table in paragraph (b) by adding a
new item ``11.'' under the headings ``Use'' and ``Limitations'' to read
as follows:
Sec. 179.26  Ionizing radiation for the treatment of food.
(b) * * *
Use                              Limitations
11. For the control of Vibrio         Not to exceed 5.5 kGy.
bacteria and other foodborne
microorganisms in or on fresh or
frozen molluscan shellfish.
Dated: August 11, 2005.
Jeffrey Shuren,
Assistant Commissioner for Policy.
[FR Doc. 05-16279 Filed 8-12-05; 1:19 pm]
BILLING CODE 4160-01-S
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