[Federal Register Volume 76, Number 55 (Tuesday, March 22, 2011)]
[Rules and Regulations]
[Pages 15841-15852]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2011-6625]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Part 179
[Docket No. FDA-1999-F-0056; Formerly Docket No. 1999F-4372]
Irradiation in the Production, Processing, and Handling of Food;
Confirmation of Effective Date
AGENCY: Food and Drug Administration, HHS.
ACTION: Final rule; denial of requests for a stay of effective date and
for a hearing; response to objections; confirmation of effective date.
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SUMMARY: The Food and Drug Administration (FDA) is denying requests for
a hearing on the final rule that amended the food additive regulations
to provide for the safe use of ionizing radiation for the control of
Vibrio species and other foodborne pathogens in fresh or frozen
molluscan shellfish. After reviewing objections to the final rule and
requests for a hearing, FDA has concluded that the objections do not
justify a hearing or otherwise provide a basis for revoking the
regulation. FDA also is denying the request for a stay of the effective
date of the amendment to the food additive regulations.
DATES: The August 16, 2005, effective date for the final rule published
at 70 FR 48057 is confirmed.
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.
SUPPLEMENTARY INFORMATION:
Table of Contents
I. Introduction
II. Objections, Requests for a Hearing, and Requests for a Stay
III. Standards for Granting a Hearing
IV. Analysis of Objections and Response to Hearing Requests
A. Studies on Animals Fed Clams
B. Microbiological Safety of Molluscan Shellfish
C. Reasonable Certainty of No Harm
D. Factors Unique to Molluscan Shellfish
E. Application of 100-Fold Safety Margin for 2-
Alkylcyclobutanones
F. Alleged Rejection of Published Evidence
G. Alleged Warnings on Potential Risks
H. Alleged Failure to Follow Critical Guidelines for Food
Additives
I. Wholesomeness
J. FDA Review Memoranda
K. Chemicals Formed in Irradiated Foods
V. Summary and Conclusion
VI. References
I. Introduction
FDA published a notice in the Federal Register of October 19, 1999
(64 FR 56351), announcing the filing of a food additive petition (FAP
9M4682) by the National Fisheries Institute and the Louisiana
Department of Agriculture and Forestry. In the Federal Register of
August 16, 2005 (70 FR 48057), FDA issued a final rule permitting the
irradiation of fresh or frozen molluscan shellfish for the control of
Vibrio spp. and other food-borne pathogens. FDA based its decision on
data in the petition and in its files. In the preamble to the final
rule, FDA outlined the basis for its decision and responded to
questions raised in several comments from Public Citizen and the Center
for Food Safety (PC/CFS). The preamble to the final rule advised that
objections to the final rule and requests for a hearing were due within
30 days of the publication date (i.e., by September 15, 2005).
II. Objections, Requests for a Hearing, and Requests for a Stay
Section 409(f)(1) of the Federal Food, Drug, and Cosmetic Act (the
FD&C Act) (21 U.S.C. 348(f)(1)) provides that, within 30 days after
publication of an order relating to a food additive regulation, any
person adversely affected by such order may file objections, specifying
with particularity the provisions of the order ``deemed objectionable,
stating reasonable grounds therefore, and requesting a public hearing
upon such objections.''
Under part 171 (21 CFR part 171) in Sec. 171.110 of the food
additive regulations, objections and requests for a hearing are
governed by part 12 (21 CFR part 12) of FDA's regulations. Under Sec.
12.22(a), each objection must meet the following conditions: (1) Must
be submitted on or before the 30th day after the date of publication of
the final rule; (2) must be separately numbered; (3) must specify with
particularity the provision of the regulation or proposed order
objected to; (4) must specifically state each objection on which a
hearing is requested; failure to request a hearing on an objection
constitutes a waiver of the right to a hearing on that objection; and
(5) must include a detailed description and analysis of the factual
information to be presented in support of the objection if a hearing is
requested; failure to include a description and analysis for an
objection constitutes a waiver of the right to a hearing on that
objection.
Following publication of the final rule permitting the irradiation
of fresh or frozen molluscan shellfish for the
[[Page 15842]]
control of Vibrio spp. and other food borne pathogens, FDA received
numerous submissions within the 30-day objection period. All but two of
these timely submissions express general opposition to the final rule,
and are form letters urging the FDA to conduct additional studies on
irradiating molluscan shellfish specifically and food in general.
Although most of these letters request a hearing, no evidence is
identified in support of these objections that could be considered in
an evidentiary hearing (Sec. 12.22(a)(5)). Therefore, they have waived
their right to a hearing. The Agency will not discuss these submissions
further. FDA received two submissions that met the requirements of
Sec. 12.22(a), One of these two submissions is a letter sent jointly
by PC/CFS containing 10 numbered objections to the final rule and
requesting a hearing on each one. The second is a letter sent by Samuel
Epstein (Dr. Epstein), containing six numbered objections, requesting a
hearing on each. All but one of the issues raised by Dr. Epstein are
identical to certain of those raised in the PC/CFS submission. Both PC/
CFS and Dr. Epstein also requested a stay of action on the final rule.
FDA addresses the PC/CFS and Dr. Epstein objections and hearing
requests in section IV of this document.
FDA also received a large number of submissions after the close of
the objection period; their content was identical or similar to the
form letters expressing general opposition to the final rule. These
tardy submissions failed to satisfy the requirements of 21 U.S.C.
348(f)(1) and need not be considered further by the Agency (see ICMAD
v. HEW, 574 F.2d 553, 558 n.8 (DC Cir), cert. denied, 439 U.S. 893
(1978)).
Additionally, most of the issues raised in the PC/CFS and Dr.
Epstein objections are similar or identical to issues that have been
raised previously and that have been previously addressed in the rule
being objected to (70 FR 48057) and in other Agency rulemaking
concerning irradiation. The Agency will address these issues briefly;
please refer to the cited Federal Register documents for a more
comprehensive discussion.
III. Standards for Granting a Hearing
Specific criteria for deciding whether to grant or deny a request
for a hearing are set out in Sec. 12.24(b). Under that regulation, a
hearing will be granted if the material submitted by the requester
shows, among other things, the following: (1) There is a genuine and
substantial factual issue for resolution at a hearing; a hearing will
not be granted on issues of policy or law; (2) the factual issue can be
resolved by available and specifically identified reliable evidence; a
hearing will not be granted on the basis of mere allegations or denials
or general descriptions of positions and contentions; (3) the data and
information submitted, if established at a hearing, would be adequate
to justify resolution of the factual issue in the way sought by the
requestor; a hearing will be denied if the data and information
submitted are insufficient to justify the factual determination urged,
even if accurate; and (4) resolution of the factual issue in the way
sought by the person is adequate to justify the action requested; a
hearing will not be granted on factual issues that are not
determinative with respect to the action requested (e.g., if the action
would be the same even if the factual issue were resolved in the way
sought).
A party seeking a hearing is required to meet a ``threshold burden
of tendering evidence suggesting the need for a hearing'' (Costle v.
Pacific Legal Foundation, 445 U.S. 198, 214-215 (1980), reh. denied,
446 U.S. 947 (1980), citing Weinberger v. Hynson, Westcott & Dunning,
Inc., 412 U.S. 609, 620-621 (1973)). An allegation that a hearing is
necessary to ``sharpen the issues'' or to ``fully develop the facts''
does not meet this test (Georgia Pacific Corp. v. U.S. EPA, 671 F.2d
1235, 1241 (9th Cir. 1982)). If a hearing request fails to identify any
factual evidence that would be the subject of a hearing, there is no
point in holding one. In judicial proceedings, a court is authorized to
issue summary judgment without an evidentiary hearing whenever it finds
that there are no genuine issues of material fact in dispute and a
party is entitled to judgment as a matter of law (see Rule 56, Federal
Rules of Civil Procedure). The same principle applies in administrative
proceedings (see Sec. 12.28).
A hearing request must not only contain evidence, but that evidence
should raise a material issue of fact concerning which a meaningful
hearing might be held (Pineapple Growers Association v. FDA, 673 F.2d
1083, 1085 (9th Cir. 1982)). Where the issues raised in the objection
are, even if true, legally insufficient to alter the decision, the
Agency need not grant a hearing (see Dyestuffs and Chemicals, Inc. v.
Flemming, 271 F.2d 281, 286 (8th Cir. 1959), cert. denied, 362 U.S. 911
(1960)). FDA need not grant a hearing in each case where an objector
submits additional information or posits a novel interpretation of
existing information (see United States v. Consolidated Mines &
Smelting Co., 455 F.2d 432 (9th Cir. 1971)). In other words, a hearing
is justified only if the objections are made in good faith and if they
``draw in question in a material way the underpinnings of the
regulation at issue'' (Pactra Industries v. CPSC, 555 F.2d 677 (9th
Cir. 1977)). Finally, courts have uniformly recognized that a hearing
need not be held to resolve questions of law or policy (see Citizens
for Allegan County, Inc. v. FPC, 414 F.2d 1125 (DC Cir. 1969); Sun Oil
Co. v. FPC, 256 F.2d 233, 240 (5th Cir.), cert. denied, 358 U.S. 872
(1958)).
Even if the objections raise material issues of fact, FDA need not
grant a hearing if those same issues were adequately raised and
considered in an earlier proceeding. Once an issue has been so raised
and considered, a party is estopped from raising that same issue in a
later proceeding without new evidence. The various judicial doctrines
dealing with finality can be validly applied to the administrative
process. In explaining why these principles ``self evidently'' ought to
apply to an Agency proceeding, the U.S. Court of Appeals for the
District of Columbia Circuit wrote: ``The underlying concept is as
simple as this: Justice requires that a party have a fair chance to
present his position. But overall interests of administration do not
require or generally contemplate that he will be given more than a fair
opportunity.'' Retail Clerks Union, Local 1401 v. NLRB, 463 F.2d 316,
322 (DC Cir. 1972). (See Costle v. Pacific Legal Foundation, supra at
215-220. See also Pacific Seafarers, Inc . v. Pacific Far East Line,
Inc., 404 F.2d 804 (DC Cir. 1968), cert. denied, 393 U.S. 1093 (1969)).
IV. Analysis of Objections and Response to Hearing Requests
The letter from PC/CFS contains 10 numbered objections and requests
a hearing on each of them. The letter from Dr. Epstein includes six
numbered objections and requests a hearing on each. The issues raised
in five of the six objections in the letter from Dr. Epstein are
identical to issues raised in the letter from PC/CFS; in those cases,
the issues will be considered together. FDA addresses each of the
objections, as well as the evidence and information filed in support of
each, comparing each objection and the information submitted in support
of it to the standards for granting a hearing in Sec. 12.24(b) as
follows:.
A. Studies on Animals Fed Clams
One objection raised by PC/CFS and Dr. Epstein states that the
Agency failed
[[Page 15843]]
to consider two animal feeding studies that include toxicological
evidence of harmful effects from consumption of irradiated molluscan
shellfish. In support of this objection, PC/CFS submitted copies of
brief summary reports of the two studies.
The first study is a 1976 reproduction study \1\ in which
irradiated (4 kiloGray (kGy) and 8 kGy) soft-shell clams were fed to
chickens for 2 years. In a note appended to the summary report, the
study authors state that the study was replicated (for differing
durations) in the F1 and F2 generation birds (i.e., the second and
third generation birds bred from the parent generation used in the
original study). The objection notes that FDA did not include this
study on chickens in the Agency's September 15, 1982, master
bibliography of more than 400 studies on the safety of irradiated foods
and, that therefore, this study was not assessed by the Task Group for
the Review of Toxicology Data on Irradiated Food.\2\
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\1\ Fegley, H.C. and Edmonds, R.E., in Food Irradiation
Information, International Project in the Field of Food Irradiation,
Karlsuhe, Germany, No. 6 (Supplement), 113-115, June 1976.
\2\ The Bureau of Foods Irradiated Food Task Group consisted of
toxicologists in the Bureau of Foods who reviewed many studies on
food irradiation in the early 1980s.
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The objection goes on to describe certain of the reported results
from the study on chickens, specifically results in the F1 and F2
generations, including the following: Higher hemoglobin values and
smaller gonad weights in males of the F1 generation fed irradiated
clams; and a decrease in ``hatchability'' of eggs, enlargement of
kidneys in females (an effect that increased with increasing
irradiation dose), decreases in egg fertility and embryonic viability,
and lower body weights in females, in the F2 generation.
FDA acknowledges that this study was not included in the inventory
of studies reviewed by the Bureau of Foods Irradiated Food Task Group
in the early 1980s, and agrees that the endpoints cited in the
objection were reported by the study authors. However, the Agency does
not agree that FDA's failure to assess the study calls into question
the safety of irradiated molluscan shellfish, as the objectors contend.
The objection fails to note that many of the findings cited in the
experimental report were observed both in chickens fed irradiated clams
and in chickens fed unirradiated clams, and that the report discusses
the need to supplement the diets of the clam-fed chickens with
thiamine. Therefore, the observed effects may have been related to the
nutritional effects of feeding diets consisting of 50 percent wet-
weight of soft-shell clams to chickens. More importantly, if the
negative effects cited by the objectors were due to the consumption of
irradiated food, one would expect the findings to be reproducible in
other studies on irradiated foods; however, such reproducibility is not
seen in the large number of feeding studies that have been reviewed by
FDA.
The objection also cites a second paper by the same researchers \3\
describing a study on feeding clams irradiated at 4 kGy or 8 kGy to
beagle dogs. According to the objection, the study showed a significant
inverse correlation between the irradiation dose applied to the clams
and the blood urea nitrogen (BUN) level of male dogs fed on them. PC/
CFS and Dr. Epstein both go on to state that ``[t]hough the researchers
did not speculate, low blood urea nitrogen levels are usually a symptom
of liver damage.''
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\3\ Fegley, H.C. and Edmonds, R.E., in Food Irradiation
Information, International Project in the Field of Food Irradiation,
Karlsruhe, Germany, No. 6 (Supplement), 111-112, June, 1976.
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The Agency included this beagle dog study in the review of
toxicology studies conducted in the early 1980s. The FDA reviewer noted
the reported BUN results and also noted that, although the researchers
indicated that organs were weighed and examined histopathologically, no
results of the histopathological examination were included in the
report. This suggests that the researchers did not find any evidence of
liver (or other organ) damage, and in fact the study report includes no
information that supports the objectors' contention that liver damage
was an underlying condition in the animals tested. Furthermore, the
Agency, as part of its rulemaking pertaining to the irradiation of meat
and meat products, re-examined the findings reported in this study. As
stated in the December 3, 1997, final rule (62 FR 64107 at 64113), FDA
concluded that the decrease in BUN levels in this study was not of
toxicological significance, and laid out its reasoning in that document
and in a memorandum to the record (Ref. 1). Thus, the Agency disagrees
with PC/CFS' and Dr. Epstein's contention that this study ``* * * found
serious toxicity concerns associated with irradiated molluscan
shellfish.''
A hearing will be denied if the data and information are
insufficient to justify the factual determination urged, even if
accurate (Sec. 12.24(b)(3)). FDA concludes the data and information
are insufficient and, therefore, FDA is denying the request for a
hearing on this issue.
B. Microbiologic Safety of Molluscan Shellfish
PC/CFS' second objection asserts that the final rule fails to
ensure that the irradiation of molluscan shellfish will result in a
product that is microbiologically safe. In support of this objection,
PC/CFS cites a 1996 PhD dissertation by Dustin W. Dixon on the effects
of irradiation on Vibrio vulnificus in shellstock oysters (raw oysters
in their shell) harvested in Florida and Texas (Ref. 2). The objection
states that there is a potential for microbial outgrowth post-
irradiation, and cites Dixon's observation that the V. vulnificus count
in oysters irradiated at 1.0 kGy and 3.0 kGy rose nearly to the level
of that in unirradiated oysters after 2 and 9 days of storage,
respectively. The objection states that Dixon concluded that ``* * *
irradiation processing cannot be considered as a method to sterilize
shellstock oysters, and provide a shelf-stable product.''
The objection also notes the potential for improper temperature
control of irradiated molluscan shellfish prior to consumption by the
consumer. The objection states that there is no guarantee that
temperature conditions will be properly maintained and asserts that FDA
is assuming that Hazard Analysis and Critical Control Point (HACCP)
plans \4\ will ensure consistent and adequate temperature control.
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\4\ FDA has established regulations for seafood HACCP in 21 CFR
part 123.
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As noted by PC/CFS, the Dixon dissertation was submitted to the
Agency as part of the molluscan shellfish petition. The stated
objectives of the research presented in that document were to determine
the effects of gamma irradiation on Florida and Texas shellstock
oysters in terms of shelf life and microbial consequences. FDA does not
dispute the findings of Dr. Dixon, and agrees that irradiation of
molluscan shellfish to an absorbed dose of 5.5 kGy will not sterilize
molluscan shellfish or create a shelf-stable product. FDA also agrees
with Dr. Dixon's conclusion in his dissertation that irradiation may
not be sufficient by itself to eliminate V. vulnificus in molluscan
shellfish and that proper conditions of storage must be maintained
after shellfish have been irradiated.
FDA disagrees, however, with PC/CFS' assertion that the final rule
must ``[en]sure the microbiological safety of fresh oysters.'' The
standards for microbiological safety of molluscan
[[Page 15844]]
shellfish are independent of the final rule permitting the irradiation
of molluscan shellfish. Irradiation is but one measure for the control
of Vibrio spp. and other food-borne pathogens. The rule is not
predicated on the approved treatment, by itself, resulting in shellfish
that are sterile or shelf-stable. A hearing will not be granted on
factual issues that are not determinative with respect to the action
requested (Sec. 12.24(b)(4)). Therefore, FDA is denying the request
for a hearing based on this objection.
C. Reasonable Certainty of No Harm
PC/CFS' third objection states that ``there is no reasonable
certainty in the minds of competent scientists that irradiation is not
harmful as applied to molluscan shellfish.'' In support of this
objection, PC/CFS makes several assertions. First, PC/CFS refers to
several sets of comments that it submitted to the docket for the
molluscan shellfish rulemaking. PC/CFS states that those comments cite
11 ``peer-reviewed papers or other publications stating safety concerns
associated with irradiated foods'' and that these comments refer to
``at least 25 other highly `competent' Ph.D.s or MDs who have stated
that they have safety concerns in published literature.'' The objection
states that, although these comments and papers refer to irradiation of
food types other than molluscan shellfish, the Agency should have
specifically considered the statements of these authors. Second, PC/CFS
asserts that FDA misstated what is contained in its literature
reference numbered as ``Ref 20'' in the final rule. Third, PC/CFS, as
well as Dr. Epstein, asserts that FDA mischaracterized the findings of
the Raltech study. In support of this assertion, PC/CFS submitted a
copy of two summary reports from the ``Raltech studies'' and a 1984
trade press article that quotes Dr. Thayer of USDA. Finally, PC/CFS
states that neither FDA's final rule nor the underlying petition
actually contains data from, or references to, any toxicity studies on
irradiated mollusks.
As evidence that there is not a ``reasonable certainty of safety in
the minds of competent scientists'' PC/CFS notes that they have
submitted comments including journal articles and other publications
that express concerns with food irradiation. However, the articles do
not contain any evidence that could be resolved at a hearing, nor has
PC/CFS pointed to any evidence in the cited articles. Nor has PC/CFS
pointed to any specific factual information in the cited articles on
foods analogous to molluscan shellfish, which the Agency has ignored
and which would call into question the Agency's conclusions. A hearing
will not be granted on the basis of mere allegations or general
descriptions of positions and contentions (Sec. 12.24(b)(2)).
Therefore, FDA is denying the request for a hearing based on this
objection.
The Agency agrees that reference 20 as cited in the final rule is
incorrect. The proper reference is: S.G. Armstrong, S.G. Wylie, and D.
N. Leach, ``Effects of Preservation by Gamma Irradiation on the
Nutritional Quality of Australian Fish,'' Food Chemistry 50 (1994) 351-
357. This error does not demonstrate a lack of reasonable certainty of
safety. A hearing will be denied if the information submitted is
insufficient to justify the factual determination urged (Sec.
12.24(b)(3)).
The Agency disagrees with PC/CFS' and Dr. Epstein's assertion that
the final rule mischaracterizes the findings of the ``Raltech study.''
The Raltech studies were sponsored by the United States Department of
Agriculture and conducted by Raltech Scientific Services. In this
series of studies, conducted in the late 1970s and early 1980s,
irradiation-sterilized chicken (doses ranged from 45-59 kGy) was fed to
various types of animals. PC/CFS alleges that there were several
negative health effects seen in these studies, including a significant
dose-related decrease in the number of offspring of Drosophila
melanogaster (fruit flies), and a high incidence of testicular tumors
and significantly reduced survival in mice.
The Agency evaluated the results of the Raltech studies and has
extensively discussed its conclusions regarding these studies in
previous rulemaking documents (see 51 FR 13376 at 13386, 53 FR 53176 at
53188, and 55 FR 18538 at 18540). The Agency specifically discussed the
results of the feeding study in mice and the mutagenicity study in
fruit flies (see, e.g., 55 FR 18538 at 18540). The Agency has described
its reasoning in finding no evidence in any of the Raltech studies of
adverse effects that could be attributed to consumption of irradiation-
sterilized chicken. The Agency has found that the quantity and breadth
of testing and the number and significance of endpoints assessed would
have identified meaningful risks, if any existed. On those few
occasions where adverse effects were reported, FDA found that those
effects were not attributable to irradiation. PC/CFS does not submit or
otherwise identify any factual data that would cause the Agency to
alter its conclusions about these studies. Accordingly, FDA is denying
the request for a hearing based on this objection (Sec. 12.24(b)(2)).
Finally, the Agency agrees that there were no toxicological studies
conducted using irradiated molluscan shellfish submitted in the
petition. As noted in the molluscan shellfish final rule (70 FR 48057
at 48068), the Agency has reviewed a large body of data that are
relevant to the assessment of the potential toxicity of irradiated
flesh foods. FDA has consistently taken the position that various
scientifically validated types of data may properly support a safety
determination for a proposed use of a food additive (see part 170 (21
CFR part 170) in Sec. 170.20). For example, in the case of food
irradiation, the Agency has taken advantage of the extensive research
and large body of knowledge concerning the principles of radiation
chemistry and the chemical composition of foods. PC/CFS' suggestion
that data and information derived from studies of analogous irradiated
foods are not sufficient to support a determination that irradiated
molluscan shellfish are safe, is unsupported by specific data or other
factual information. Further, the question of whether safety has been
shown requires the application of the legal standard of safety as
defined by FDA's regulations (``reasonable certainty of no harm'') to a
set of facts (see Sec. 170.3(i)). As such, FDA concluded as a matter
of law that the proposed use of irradiation to treat fresh and frozen
molluscan shellfish with absorbed doses not to exceed 5.5 kGy is safe.
A hearing will not be granted on issues of policy or law (Sec.
12.24(b)(1)). Therefore, FDA is denying the request for a hearing based
on this objection.
D. Factors Unique to Molluscan Shellfish
PC/CFS objects to the molluscan shellfish final rule on the grounds
that the Agency and the underlying petition failed to consider several
factors that could make irradiated molluscan shellfish unsafe. These
factors are: (1) Safety of irradiated salt water; (2) chemicals that
irradiated molluscan shells may `off-gas' \5\; (3) effects of
irradiation on undigested shellfish stomach contents such as plankton
and algae; (4) attenuation of irradiation effects from shell thickness
(i.e., that thicker shells may attenuate the effectiveness of
irradiation); and (5) lack of data on furan creation from the shells.
Dr. Epstein also objects on the basis of the issues relating to
chemical byproducts from irradiated molluscan
[[Page 15845]]
shells, and the attenuation of irradiation effects from shell
thickness.
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\5\ ``Off-gassing'' refers to volatile chemicals that may be
emitted over time from a source.
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First, the Agency notes that there is no basis to suggest that the
presence of salts in water will affect the irradiation of molluscan
shellfish because ionizing radiation, under the petitioned conditions,
does not affect inorganic salts (Ref. 3). Second, the objection
provides no information to show that mollusk shells (composed of
approximately 95 percent calcium carbonate and 5 percent protein), when
irradiated, would produce any chemicals that may off-gas into the meat,
nor is there any information to suggest that such chemicals, were they
to be formed, would render the food unsafe. Third, the objection
provides no evidence that the stomach contents of irradiated molluscan
shellfish are materially different from any other irradiated food
(i.e., composed predominantly of protein, fat, and carbohydrate).
Fourth, the Agency agrees that varying shell thickness may attenuate
the effectiveness of irradiation, and that this attenuation would
increase with shell thickness. However, the objection provides no
evidence that would cause the Agency to find that consumption of
irradiated molluscan shellfish is not safe. As explained in section
IV.B of this document, it is not necessary that irradiation ``[en]sure
the microbiological safety of fresh oysters.'' Parties irradiating
molluscan shellstock are responsible for ensuring that treated food
receives the minimum irradiation dose reasonably required to accomplish
its intended technical effect and not more than the maximum dose
specified by the applicable regulation (see 21 CFR 179.25(b)) .
Finally, the Agency discussed the potential generation of furan in the
final rule (70 FR 48057 at 48059) and concluded that irradiated
molluscan shellfish do not generate furan at a rate that is higher than
the background generation of furan in un-irradiated molluscan shellfish
(Ref. 4). Although in the final rule the Agency cited data concerning
furan formation from shucked oysters, the objection points to no
factual data to suggest that irradiation of mollusks in the shell
(which is approximately 95 percent calcium carbonate) would lead to
furan formation from irradiation of the shell.
A hearing will not be granted on the basis of mere allegations or
general descriptions of positions and contentions (Sec. 12.24(b)(2)).
Neither PC/CFS nor Dr. Epstein has provided a basis for a hearing and
FDA is denying the request for a hearing on this objection.
E. Application of 100-Fold Safety Margin for 2-Alkylcyclobutanones
PC/CFS and Dr. Epstein cite 21 CFR 170.22 \6\ and object to the
molluscan shellfish final rule (70 FR 48057) on the basis that FDA
improperly failed to apply a 100-fold safety factor regarding the
production of 2-alkylcyclobutanones (2-ACBs) from the irradiation of
esterified fatty acids in considering the safety of irradiated
molluscan shellfish. In support of their contention that the Agency
should have applied a 100-fold safety factor to 2-ACBs, PC/CFS and Dr.
Epstein make several assertions. First, the objection asserts that 2-
ACBs are found only in irradiated foods and are known to be potentially
toxic at certain concentrations and to promote tumor formation in the
presence of known carcinogenic substances. The objection also asserts
that the flesh of molluscan shellfish is distinct from that of other
flesh foods because it contains a ``unique combination'' of fatty acids
and that these fatty acids, when irradiated, produce a unique
combination of 2-ACBs. The objection, therefore, maintains that FDA's
reliance on the Raltech study to address concerns about 2-ACBs is
flawed because that study involved chicken which has a lower stearic
acid content than oysters. Finally, the objection asserts that ``there
are no adequate long-term safety studies that assist in assessing the
overall health hazards that consuming 2-ACBs could pose, including
likely variations in sensitivities to 2-ACBs among the human consumer
population'' and refers particularly to children and other vulnerable
populations. In relation to this last point, PC/CFS submitted a
publication on the susceptibility of children to environmental
substances by William Au.\7\
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\6\ That section provides in relevant part 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. * * *'' 21 CFR 170.22.
\7\ Au, W., Susceptibility of Children to Environmental Toxic
Substances, International Journal of Hygiene Environmental Health;
205:1-3, 2002.
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The applicability of Sec. 170.22 is a legal issue, and a hearing
will not be granted on issues of law. The Agency notes that Sec.
170.22 refers to safety factors to be used in determining whether a
proposed use of a food additive will be safe. In the present instance,
2-ACBs are not the food additive that is the subject of the rulemaking.
Therefore, the 100-fold safety factor discussed in Sec. 170.22 does
not apply to 2-ACBs. Further, as noted in the molluscan shellfish final
rule (70 FR 48057 at 48066), applying a 100-fold safety factor to a
processed food or to individual components of a processed food is not
feasible or appropriate.
The Agency agrees that 2-ACBs have been reported to be formed in
small quantities as a result of irradiation of fats and that these
compounds have been identified in irradiated meat and poultry. In the
final rule permitting the irradiation of molluscan shellfish, the
Agency described in detail its assessment of the significance of the
formation of 2-ACBs to a safety assessment of molluscan shellfish,
which like poultry and meat, contain appreciable amounts of
triglycerides. This assessment included a discussion of the contentions
that 2-ACBs may cause DNA damage and may be tumor promoters at certain
concentrations (70 FR 48057 at 48065 to 48067). While the objection
repeats assertions made in comments to the final rule about the
toxicity of 2-ACBs and the failure of the Agency to apply a 100-fold
safety factor for 2-ACBs, the objection includes no new information or
analysis that would call into question the Agency's rationale for its
decision.
The objection states that molluscan shellfish contain a unique
combination of fatty acids that differ from those in poultry, and that
therefore, the Agency's reliance on the Raltech study to address
concerns about 2-ACBs is flawed. In particular, the objection states
that chicken meat contains less stearic acid than do oysters. It is
true that the Agency considers the Raltech studies useful in assessing
the effects of 2-ACBs in animals fed irradiated flesh foods (70 FR
48057 at 48066). In the Raltech studies, animals were fed chicken
irradiated at a dose approximately 10 times the dose permitted in the
molluscan shellfish final rule, at a level of 35 percent of the diet,
for their lifetime. Thus, although the concentration of stearic acid in
chickens is lower than in molluscan shellfish, the amount of 2-ACBs in
the diets of the animals in the Raltech studies, including those formed
from irradiation of stearic acid is likely to be higher than the amount
in the human diet from irradiated molluscan shellfish (70 FR 48057 at
48066). As noted previously, there were no adverse toxicological
effects seen in the Raltech studies that could be attributed to the
consumption of irradiated chicken. In addition, it is important to note
that the Agency has not relied solely on the Raltech studies in
concluding that irradiation of molluscan shellfish under the conditions
permitted in the final rule is safe. As pointed out in the final rule
(70 FR 48057 at 48066), the Agency's review included studies in which
animals were
[[Page 15846]]
fed diets containing irradiated beef, pork, poultry, horse meat, and
fish, and found no evidence of toxicity attributed to the consumption
of these foods, which contain various levels and combinations of fatty
acids that may potentially form 2-ACBs. The objection has thus
misrepresented the basis for the Agency's decision when it contends
that the final rule relies on the Raltech studies to discount concerns
about 2-ACBs in irradiated molluscan shellfish.
In the molluscan shellfish final rule, the Agency noted that it had
reviewed a multitude of studies on irradiated foods that would have
contained radiolytic products including 2-ACBs, and which include long-
term safety studies. FDA noted that it had previously concluded that
``The results of the available toxicological studies of irradiated
flesh foods * * * demonstrate 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). Although the objection
alleges that there are no ``adequate long-term safety studies that
assist in assessing the overall health hazards that consuming 2-ACBs
could pose,'' the objection provides no factual information to call
into question the studies on which the Agency has relied, nor does it
provide any new information or data to refute the analysis set out in
the molluscan shellfish final rule.
The objection also cites the FDA's ``rejection'' of the 100-fold
safety margin as inappropriate, given the need to ``protect children
and other vulnerable consumers.'' The paper by Dr. Au, which was
submitted in support of this objection, is a commentary discussing the
need to consider data and information that indicate that children are
more susceptible to toxic contaminants than are adults in setting
guidelines for protecting children's health. The objection provides no
evidence to show that the Agency's conclusion that molluscan shellfish,
irradiated under the conditions permitted by the regulation, are safe,
fails to protect children and other vulnerable consumers. The submitted
commentary includes no information or data relevant to the safety of
irradiated molluscan shellfish.
In sum, the Agency is denying a hearing on the objection that FDA
improperly rejected application of the 100-fold safety factor in Sec.
170.22 to 2-ACBs produced in irradiated molluscan shellfish. The
interpretation of the applicability of this regulation is a legal
issue, and a hearing will not be granted on issues of law. Moreover,
PC/CFS and Dr. Epstein have not presented any evidence supporting their
contention that the potential levels of 2-ACBs in irradiated molluscan
shellfish may render the food unsafe. PC/CFS' request for a hearing
merely alleges that there is potential for harm, without providing any
evidence that the Agency has not already considered. An objector must
make an adequate proffer of evidence to support its allegations and to
show that they provide a basis on which to call into question the
Agency's conclusions (Sec. 12.24(b)(2)). Thus, neither PC/CFS nor Dr.
Epstein has provided a basis for a hearing and FDA is denying their
requests for a hearing based on this objection.
F. Alleged Rejection of Published Evidence
PC/CFS cites their comment submitted on May 14, 2001, and repeats
the assertion made in that comment that the Agency ignored or
improperly discounted a number of positive in vivo and in vitro
mutagenicity studies, including five peer-reviewed published studies
performed by the Indian National Institute of Nutrition (NIN) in which
purported mutagenic effects were found in mice, rats, and monkeys, and
in malnourished children, consuming freshly-irradiated wheat. In
support of the objection, PC/CFS submitted excerpts from 1987
Congressional testimony by S.G. Srikantia, the former Director of NIN,
who testified that FDA committed an error of judgment in accepting a
report by a committee of Indian scientists discrediting the NIN studies
(see 53 FR 53176 at 53182). The objection also asserts that FDA
neglected to consider a statement made in 1988 by an Australian
genotoxicity expert to a Committee of the Australian House of
Representatives, stating that the malnourished children study's results
seemed reasonable. In addition, the objection refers to two later
publications by the NIN researchers rebutting criticisms of the study,
and cites a statement by the former Director of NIN stating that the
NIN's results were mirrored in a study on hamsters (Ref. 5) that found
that polyploidy cells occurred five times more frequently in animals
fed irradiated wheat in their diet, and that this increased incidence
of polyploidy was related to irradiation dose.
The Agency has previously considered all of the various in vitro
and in vivo mutagenicity studies cited by PC/CFS and discussed its
conclusions in detail in previous documents (see e.g., 51 FR 13376 at
13383 and 13385; 53 FR 53176 at 53181-3 and 53191-2; 70 FR 48057 at
48064 and 48067). Several of the studies cited in the comment refer to
reports of in vitro mutagenicity of irradiated sugars in solution. The
Agency previously has discussed in detail why it has concluded that the
irradiation of simple sugars in solution is not a suitable model for
predicting and extrapolating toxicity of irradiated foods. In the final
rule permitting additional uses of ionizing radiation for the treatment
of food, the Agency noted: ``In feeding studies where sugars are
present in a typically complex food matrix there is no increase in
mutagenicity after irradiation. Studies have demonstrated that when a
food containing sugars is irradiated, the food does not produce the
same toxic effects that occur when these sugars are irradiated in
simple solution. Thus, the Agency concluded that irradiated aqueous
sugar solutions are unsuitable models for predicting and extrapolating
toxicity of irradiated foods and that there is no evidence that
radiolytic products from sugars present in irradiated foods cause toxic
effects to animals or humans (51 FR 13376 at 13383).''
The objection provides no new evidence or rationale that provides a
basis on which to find that FDA's conclusion on the relevance of these
studies is incorrect.
The Agency also has previously repeatedly addressed in detail the
interpretation of the NIN studies using freshly irradiated wheat and
concluded that none of the studies on polyploidy done at NIN were
reliable and that the studies do not demonstrate that adverse effects
would be caused by ingestion of irradiated foods (51 FR 13376 at 13385;
53 FR 53176 at 53183; 70 FR 48057 at 48068). In the molluscan shellfish
final rule, the Agency noted, citing earlier rulemaking: ``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 Indian
scientists that the studies with irradiated foods do not demonstrate
that
[[Page 15847]]
adverse effects would be caused by ingesting irradiated foods.'' (70 FR
48057 at 44067 and 44068)
Dr. Srikantia's testimony states that the FDA was wrong to accept
the report of the committee of Indian scientists; he states that NIN
has not repudiated the studies on polyploidy and that the Director of
NIN submitted a rebuttal to the report of the committee of Indian
scientists, and that ``[h]ad it seen the Institute's rejoinder to the *
* * report, surely, it would have been in a better position to evaluate
that report.'' FDA previously has addressed all issues raised in Dr.
Srikantia's testimony (see e.g., 53 FR 53176 at 53182-3). As noted
previously (53 FR 53176 at 53183) FDA did not state that NIN had
repudiated the studies, nor did it base its own conclusions about the
studies on a finding that the data were repudiated by NIN. FDA
concluded that the available data from NIN did not provide an
appropriate basis on which to conclude that increased polyploidy was
caused by ingesting irradiated wheat. Furthermore, FDA in 1986 invited
Dr. Srikantia to submit any information to FDA that would be relevant.
Dr. Srikantia replied, but did not submit a copy of his rebuttal to the
Indian government or any other report (see footnote 1, 53 FR 53176 at
53183).
The hamster study by Renner referenced by PC/CFS also has been
discussed previously (53 FR 53176 at 53183 and 531834). The study
involved the irradiation of hamster diets (composed primarily of
carbohydrates) at high doses. The investigator concluded that at doses
above 30 kGy there was a ``[* * *] transitory effect [* * *] as
evidenced by an increased incidence of polyploidy cells'' but that
``there was no evidence of any mutagenic effect being produced as a
result of feeding an irradiated diet.'' He noted that no effects on
incidence of polyploidy were seen at doses below 20 kGy. The objection
contains no information that explains why this study is relevant to the
molluscan shellfish (composed primarily of protein and fats) irradiated
at doses up to 5.5 kGy.
In summary, all of the studies referenced by PC/CFS have been
considered previously by FDA and the Agency's rationale for its
conclusions on those studies has been discussed at length in previous
rulemakings. Neither the objection, nor the testimony of Dr. Srikantia,
nor the statement of the Australian expert, includes any new
information or data that would refute the Agency's findings about the
studies. PC/CFS' request for a hearing merely alleges that there is
potential for harm, without providing any evidence that the Agency has
not considered previously. An objector must make an adequate proffer of
evidence to support its allegations and to show that they provide a
basis on which to call into question the Agency's conclusions (Sec.
12.24(b)(2)). Thus, PC/CFS has not provided a basis for a hearing and
FDA is denying PC/CFS' request for a hearing based on this objection.
G. Alleged Warnings on Potential risks
PC/CFS' seventh objection alleges that the ``FDA misrepresents
important published and unpublished warnings from qualified scientists
calling for additional research on 2-ACBs.''
The Agency previously has addressed the allegations of the
potential harm of the long-term consumption of 2-ACBs that are produced
from the irradiation of esterified fatty acids (70 FR 48057 at 48066)
and the research performed on 2-ACBs. The Agency concluded: ``2-ACBs
have been reported as radiolysis products of fats (Refs. 6 and 7).
Studies performed by researchers have reported that certain
alkylcyclobutanones can cause single strand DNA breaks detectable by
the COMET assay (Ref. 8). 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.''
The objection provides no additional information on 2-ACBs that the
Agency has not addressed previously. The Agency does not consider the
statements in the cited papers on 2-ACBs to be warnings; rather, the
comments are statements presented by the authors that research should
continue on 2-ACBs. These statements do not affect the Agency's
determination that 2-ACBs do not cause the food to be unsafe at levels
present in irradiated food.
Moreover, PC/CFS' request for a hearing merely alleges that there
is potential for harm, without providing any evidence that the Agency
has not already considered and determined did not demonstrate a
potential for harm. An objector must make an adequate proffer of
evidence to support its allegations and to show that they provide a
basis on which to call into question the Agency's conclusions (Sec.
12.24(b)(2)). Thus, PC/CFS has not provided a basis for a hearing and
FDA is denying PC/CFS' request for a hearing based on this objection.
H. Alleged Failure To Follow Critical Guidelines for Food Additives
PC/CFS and Dr. Epstein allege that FDA failed to follow ``critical
guidelines'' for food additives. Specifically, the objections assert
that although use of an irradiation source is statutorily defined as a
food additive, 21 U.S.C. section 321(s), the final rule incorrectly
characterizes irradiated molluscan shellfish as ``processed foods'' (70
FR 48057 at 48069), and as such, applied a lower safety standard.
Second, the objections cite Sec. 170.20 and assert that the Agency
ignored provisions of that regulation. For example, the objections
assert that the rule provides no evidence to support FDA's decision to
ignore the current National Academy of Sciences-National Research
Council (NAS-NRC) publication ``Risk Assessment/Safety Evaluation of
Food Chemicals'' (see Sec. 170.20(a)). Also citing Sec. 170.20, the
objections assert that the final rule provides no evidence that FDA
gave due weight to anticipated levels and patterns of consumption of
irradiated molluscan shellfish (see Sec. 170.20 (a)). Third, the
objections cite Sec. 170.22 and state that the Agency failed to
justify not using a 100-fold safety factor in the final rule. Fourth,
the objection maintains that FDA failed to comply with the testing
protocols set forth in the Redbook.\8\ Finally, the objections state
that FDA ignored the recommendations put forth in 1980 by the Bureau of
Foods Irradiated Foods Committee (BFIFC) regarding the evaluation of
irradiated foods.
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\8\ Toxicological Principles for the Safety Assessment of Direct
Food Additives and Color Additives Used in Food, ``Red Book II,''
U.S. Food and Drug Administration, Center for Food Safety and
Applied Nutrition, (1993, revised 2001).
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A source of radiation used to process food is defined as a food
additive in section 201(s) of the FD&C Act (21 U.S.C. 321(s)); the
exposure of molluscan shellfish to ionizing radiation is what makes
irradiated molluscan shellfish a processed food. The FD&C Act requires
that a food additive, including a source of radiation used to process
food, must be shown to be safe under the proposed conditions of use
before the use can be approved. That is, the Agency must find that
there is a reasonable certainty that consumption of an irradiated food
is not harmful. FDA applied the same standards and guidelines that the
Agency uses to evaluate all food additives to evaluate the safety of a
source of ionizing radiation used to treat molluscan shellfish. The
Agency's reference to
[[Page 15848]]
irradiated molluscan shellfish as a ``processed'' food in the final
rule did not change the Agency's finding that such shellfish is safe.
The Agency has previously addressed its reasoning in interpreting
and applying its own regulations at Sec. Sec. 170.20 and 170.22 in the
molluscan shellfish final rule, in response to comments submitted by
PC/CFS (70 FR 48057 at 48066 and 48068). The regulation at Sec.
170.20(a) reads in part: ``In reaching a decision on any petition filed
under section 409 of the Act, the Commissioner will give full
consideration to the specific biological properties of the compound and
the adequacy of the methods employed to demonstrate safety for the
proposed use, and 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. In reaching a decision, the Commissioner will give due
weight to the anticipated levels and patterns of consumption of the
additive specified or reasonably inferable.''
In the molluscan shellfish final rule, the Agency explained that
FDA has consistently taken the position that many scientifically valid
types of data may properly support a finding that a proposed use of a
food additive is safe. The Agency pointed out that NAS-NRC testing
standards and guidelines have been stated in relatively general terms
and that in practice, FDA has applied exposure and toxicological
criteria that were current for the time, and appropriate for assessing
the safety of a particular food additive (70 FR 48057 at 48068). In its
objection, PC/CFS repeats its assertion that FDA failed to properly
interpret its own regulation, but has provided no new information that
would refute the Agency's reasoning. The objection implies that the
Agency is obligated to explicitly discuss its consideration of NAS-NRC
guidelines in its rules, but there is nothing in Sec. 170.20 that
imposes such an obligation on the Agency. The regulation requires the
Commissioner of Food and Drugs (the Commissioner) to make a finding
that the procedures used by the petitioner give results that are as
reliable as, or more reliable than, those reasonably expected from use
of the NAS-NRC guidelines. Acceptance of a petition based on alternate
procedures implies that the Commissioner has made such a finding.
With respect to the assertion that FDA failed to give due weight to
anticipated levels and patterns of consumption of irradiated molluscan
shellfish, FDA previously has reviewed a large body of data relevant to
the assessment of potential toxicity of irradiated flesh foods. In its
evaluations of the safety of a source of radiation to treat food
intended for human consumption, the Agency has identified three areas
of concern to be addressed: (1) Potential toxicity, (2) nutritional
adequacy, and (3) potential microbiological risk from treated foods.
Each of these areas was discussed in detail in the molluscan shellfish
final rule. FDA asserted that the Agency ``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 (70 FR 48057 at 48059).'' In its
review of studies in which animals were fed diets containing beef
irradiated at 56 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 these foods.
FDA has concluded that products formed (typically oxidation
products of food constituents) following irradiation of molluscan
shellfish are the same as or similar to those found in non-irradiated
foods after cooking. Further, radiolysis products in shellfish are
essentially the same as those in red meat and poultry, since the
composition is roughly the same. Additionally, shellfish make a smaller
contribution to the average daily diet; therefore, exposure to
radiolysis products from shellfish will be smaller than that from foods
for which irradiation currently is regulated. Cooking and other heat
processing methods remain the principle means for introducing such
substances into the diet (Ref. 9). PC/CFS' assertion provides no basis
to challenge FDA's assessment of the safety of irradiated molluscan
shellfish.
In like manner, the assertions that FDA failed to follow its
regulation in Sec. 170.22, or to comply with recommendations in the
Redbook or set forth by the BFIFC committee, have been raised
previously by PC/CFS, Dr. Epstein, and others, and have been responded
to by the Agency in the molluscan shellfish final rule (70 FR 48057 at
48066 and 48069) and in other previous rulemakings (see e.g., 57 FR
6667 at 6669; 62 FR 64102 at 64105; and Section IV.E., above). The
Agency has described its reasoning for concluding that the data and
information considered in the evaluation of the petition to permit the
irradiation of molluscan shellfish, when considered in its entirety,
are sufficient to support the safety of molluscan shellfish irradiated
under the conditions specified in the regulation. Once the Agency makes
a finding of safety in a listing document, the burden shifts to an
objector to come forward with evidence that calls into question FDA's
conclusion (see Sec. 12.24(b)(2)). PC/CFS and Dr. Epstein provide no
new information on how the Agency failed to follow the regulations to
establish the safety of irradiating molluscan shellfish to an absorbed
dose of 5.5 kGy. A hearing will not be granted on the basis of mere
allegations or general descriptions of positions and contentions (Sec.
12.24(b)(2)). The objectors must, at a minimum, raise a material issue
concerning which a meaningful hearing might be held. Neither PC/CFS nor
Dr. Epstein has provided a basis for a hearing and FDA is denying their
request for a hearing based on this objection.
I. Wholesomeness
PC/CFS states that ``FDA's final rule fails to address recent
studies in its possession indicating that irradiation at low dose
levels in oysters may cause unpleasant--perhaps unwholesome--
byproducts.'' The objection discusses a report \9\ presented at the
2002 annual meeting of the Institute of Food Technologists that
suggests that molluscan shellfish irradiated at 2.0 kGy produced an
``unpleasant yellow exudate.'' The objection goes on to discuss other
potential organoleptic changes that may occur in irradiated molluscan
shellfish (such as ``grassy'' and ``oxidized'' odors) as noted in
Dixon's 1996 dissertation (Ref. 2). PC/CFS states that FDA's final rule
failed to address these issues of ``wholesomeness,'' and requests a
hearing on these issues.
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\9\ Andrews, L. S., ``Gamma Irradiation Processing to Reduce the
Risk of Vibrio Infections from Raw Oysters,'' (unpublished
presentation at the 2002 Annual Meeting), 2002.
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FDA previously has acknowledged that irradiation may cause
organoleptic changes in foods (62 FR 64107 at 64110). Such organoleptic
changes may make the food unappealing and unmarketable; however,
undesirable organoleptic changes do not render the food unsafe. Neither
the author of the
[[Page 15849]]
report cited by PC/CFS nor PC/CFS itself suggests that there is any
evidence that the noted ``unpleasant yellow exudate'' or other
organoleptic changes would render irradiated molluscan shellfish
unsafe.
PC/CFS' request for a hearing suggests that there is potential for
harm from possible organoleptic changes from irradiation of molluscan
shellfish, without providing any evidence to support this suggestion.
An objector must make an adequate proffer of evidence to support its
allegations and to show that they provide a basis on which to call into
question the Agency's conclusions. A hearing will be denied if the
Commissioner concludes that the data and information submitted are
insufficient to justify the factual determination urged, even if
accurate (Sec. 12.24(b)(3)). FDA concludes that the data and
information are insufficient; therefore, FDA is denying the request for
a hearing based on this objection.
J. FDA Review Memoranda
PC/CFS alleges that there are errors in some of the FDA review
memoranda used to support the final rule. The objection states that
these errors call into question the adequacy of the Agency's review
processes that led to the Agency's conclusion that irradiated molluscan
shellfish are safe. There are four parts to this objection; the Agency
will address each part below.
Part one of this objection asserts that ``FDA significantly
misrepresents published research on the tumor-promoting qualities of 2-
ACBs.'' Specifically, the objection states that an FDA memorandum in
the record (Ref. 10) mischaracterizes the findings of a publication
submitted by PC/CFS as part of a comment to the petition to irradiate
molluscan shellfish (Ref. 11). The objection states that these alleged
mischaracterizations ``severely bias the Agency's analysis of 2-ACBs.''
The disputed memorandum included a discussion of the Raul et al.
(2002) paper submitted to the Agency by PC/CFS as part of its comment
to the molluscan shellfish petition; the memorandum also discussed a
commentary on the paper that was submitted with the comment (Ref. 12).
The objection cited three selected sentence fragments from the
memorandum which PC/CFS maintains are incorrect. The memorandum
discussed the authors' observations and the limitations of the Raul, et
al. study and stated that those limitations and inconsistencies in the
data made it difficult to draw conclusions from the study. In the final
rule (70 FR 48057 at 48067) the Agency discussed the limitations of the
study and its reasoning in concluding that the results of long-term
feeding studies were more relevant to a finding of safety than the Raul
et al. study.
As FDA noted in the final rule (70 FR 48057 at 48067): ``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 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.''
The Agency maintains that the disputed memorandum taken as a whole,
including the sentence fragments highlighted by PC/CFS, accurately and
reliably reflects the information in the Raul and Rao publications.
Importantly, the factual issues raised by the three disputed statements
were not determinative in the Agency's overall conclusions about the
relevance of the Raul et al. study or to its determination that the
irradiated molluscan shellfish under the conditions of the regulation
are safe. A hearing will not be granted on factual issues that are not
determinative with respect to the action requested (Sec. 12.24(b)(4)).
Thus, PC/CFS has not provided a basis for a hearing and FDA is denying
PC/CFS' request for a hearing based on this objection.
Part two of this objection asserts that FDA cites no evidence to
dismiss the COMET assay as a valid technique for testing genetic
toxicity. The objection asserts that the ``technique has broad support
within the scientific community'' and quotes excerpts from several
published reports that state that the COMET assay has utility, and is
being increasingly used in the screening of various substances.
The Agency does not dispute the statements quoted by the PC/CFS nor
the fact that the COMET assay is being increasingly studied and used to
study the cellular response to DNA damage and repair. In the final
rule, the Agency has addressed its conclusions pertaining to the COMET
assay results (70 FR 48057 at 48065), as they are presented with
respect to 2-ACBs and has determined that, when the totality of
evidence is examined with other more standard genotoxicity testing
methods, ``the potential risk of 2-DCB, if any, is very low.'' The
cited quotations do not provide any information related to the safety
of consumption of 2-ACBs that may be present in irradiated molluscan
shellfish that the Agency has not considered, and the objection
contains no information that would cause the Agency to change its
safety determination. A hearing will not be granted on factual issues
that are not determinative with respect to the action requested (Sec.
12.24(b)(4)).
Part three of this objection states that certain FDA review
memoranda (Chen to Highbarger, 12/21/2001, FAP 9M4697), (Morehouse to
Highbarger, 6/l/2002, 9M4697), and (Chen to Highbarger, 4/7/2003, FAP
9M4695) are irrelevant to the analysis of irradiated molluscan
shellfish, because they were written as part of the review of other
petitions to permit the irradiation of certain other foods. This
objection also states that one of the memoranda (Chen to Highbarger,
12/21/2001, FAP 9M4697) is inaccurate, because it states that ``the
radiolysis products of irradiated lipids and proteins are either the
same as, or structurally very similar to, compounds found in foods that
have not been irradiated.'' PC/CFS state that ``numerous published
articles show--and the FDA now admits--that 2-ACBs are fundamentally
unique from any naturally occurring food component.'' Additionally, the
objection states that this memorandum ignores the FDA Redbook's
statement that genotoxicity tests can contribute to safety assessments.
The Agency acknowledges that the review memoranda cited were
written as part of the review of two petitions to permit the
irradiation of certain foods (other than molluscan shellfish) that are
pending at the Agency: FAP 9M4695, submitted by the U.S. Department of
Agriculture (64 FR 71792) \10\ and FAP 9M4697, submitted by the
National Food Processors Association on behalf of the Food Irradiation
Coalition (65 FR 493 and 66 FR 23943).\11\ The objection
[[Page 15850]]
does not explain, however, why the information in those memoranda is
irrelevant to the irradiation of molluscan shellfish to an absorbed
dose of 5.5 kGy. These review memoranda describe chemistry and
toxicology information related to the irradiation of protein, fat, and
carbohydrate; these are components of molluscan shellfish. The Agency
has repeatedly noted that its conclusions on safety of irradiating
molluscan shellfish are based on the evaluation of the totality of
evidence before it, and in particular, that information related to the
irradiation of flesh foods is relevant to an evaluation of the safety
of irradiated molluscan shellfish. The objection provides no
information that would suggest the information in the cited memoranda
is irrelevant to the molluscan shellfish final rule except to point out
that they were written as part of the review of other petitions.
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\10\ FAP 9M4695 requests that 21 CFR part 179 be amended to
provide for the safe use of a 4.5 kiloGray (kGy) maximum dose of
ionizing radiation to treat unrefrigerated (as well as refrigerated)
uncooked meat, meat products, and certain meat food products to
reduce levels of foodborne pathogens and extend shelf-life.
\11\ FAP 9M4697 requests that 21 CFR part 179 be amended to
provide for the safe use of ionizing radiation for control of
foodborne pathogens, and extension of shelf-life, in a variety of
human foods up to a maximum irradiation dosage of 4.5 kGy for non-
frozen and non-dry products, and 10.0 kGy for frozen or dry
products, including: (1) Pre-processed meat and poultry; (2) both
raw and preprocessed vegetables, fruits, and other agricultural
products of plant origin; (3) certain multi-ingredient food
products. The notice stated that the petition does not cover
products composed in whole or in part of raw meat, poultry, or fish
nor does it cover ``ready-to-eat'' fish products or ingredients made
from fish.
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The objection also cites a statement from a memorandum written in
2001 that stated that `` * * * radiolysis products of irradiated lipids
and proteins are either the same as, or structurally very similar to,
compounds found in foods that have not been irradiated'' and points out
that the Agency has since acknowledged that 2-ACBs have thus far not
been found in food that has not been irradiated.\12\ As noted in the
objection itself, there is no factual issue in dispute, and the
objection points to no reason why the statement in the 2001 memorandum
calls into question the Agency's subsequent conclusions about the
safety of irradiated molluscan shellfish.
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\12\ We note that recent studies have demonstrated that 2-ACBs
are formed in certain foods that have not been irradiated (e.g.,
roasted nuts).
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Finally, this part of the objection alleges that the 2001
memorandum ignores the FDA Redbook's statement that genotoxicity tests
can contribute significantly to safety assessments. The Agency agrees
that genotoxicity testing can be useful in the assessment of the safety
of food additives. In the molluscan shellfish final rule the Agency
discussed the use of genotoxicity tests, and of long-term feeding
studies, in the context of the safety assessment of irradiated foods
(70 FR 48057 at 48064) concluding: ``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.''
Thus, the Agency has acknowledged the utility of genotoxicity
tests, but also states that when long-term animal feeding studies are
available, that these latter studies are more reliable for determining
the mutagenic potential of a compound consumed in food. Nothing in the
objection would suggest that the Agency's position is in contradiction
to the recommendations in the Redbook.
An objector must make an adequate proffer of evidence to support
its allegations and to show that they provide a basis on which to call
into question the agencies conclusions (Sec. 12.24(b)(2)). PC/CFS has
not provided a basis for a hearing and FDA is denying PC/CFS' request
for a hearing based on this objection.
Finally, part four of the objection states that an FDA memorandum
(Folmer-Jensen to Highbarger, 8/2/2002, FAP 9M4697) states that other
food processing methods (such as freezing, canning and drying) can
result in loss of vitamins, but neglects to consider the potential for
additional vitamin reduction if irradiated foods were to be
subsequently processed by freezing, canning or drying. This part
further cites a 1986 trade press article as evidence that irradiation,
when combined with other food processing techniques, has a greater
effect on reducing levels of vitamins than each process individually.
The objection then questions the Agency's conclusion that the
contribution of thiamine, niacin and vitamin B6 from fish and shellfish
represents an insignificant contribution to the nutritional needs of
Americans. The objection cites two studies that showed a substantial
reduction in thiamine level in irradiated cod.
The Agency agrees that irradiation may reduce some vitamins in
foods. Additionally, further processing may further reduce some
vitamins in foods. The extent to which vitamin loss is nutritionally
significant depends in part on the relative contribution of the food in
question to the overall dietary intake of the vitamin. The Agency has
concluded that the reductions of vitamins in molluscan shellfish will
cause negligible changes in total dietary intake of the affected
vitamins as a result of irradiating molluscan shellfish under the
conditions of the regulation. The objection questions the Agency's
analysis and conclusion, but offers no data or information to support a
contention that permitting the irradiation of molluscan shellfish would
have an adverse impact on the nutritional adequacy of the diet.
Moreover, the objection contains no information that would cause the
Agency to change its conclusion that the consumption of irradiated
molluscan shellfish to an absorbed dose of 5.5 kGy is safe.
A hearing will be denied if the Commissioner concludes that the
data and information submitted are insufficient to justify the factual
determination urged, even if accurate ((Sec. 12.24(b)(3)). FDA
concludes that the data and information are insufficient; therefore,
FDA is denying the request for a hearing based on this objection.
K. Chemicals Formed in Irradiated Foods
One objection submitted by Dr. Epstein alleges that FDA has
``ignore[d] the fact that irradiation can dramatically increase the
concentration of many potentially toxic chemicals.'' Dr. Epstein
specifically mentions benzene and toluene, quoting a statement from
D.U. Ahn of Iowa State University: ``[B]enzene and toluene * * * could
be formed from amino acids upon irradiation * * * Benzene has
deleterious effects on human health (Ref. 13).'' In support of the
quoted statement, the objection references a paper entitled ``Effects
of Electron Beam Irradiation and Antimicrobials on the Volatiles,
Color, and Texture of Ready-to-Eat Turkey Breast Roll.''
The Agency acknowledges that benzene, toluene, and other compounds
are formed, albeit in very small amounts, when meats are irradiated at
sterilizing doses (Ref. 14.). The formation of benzene and other
volatile compounds (including toluene) in irradiated foods and their
possible risk to human health has been extensively evaluated by FDA and
discussed in previous rulemaking (see 62 FR 64107 at 64110-64111, 55 FR
18538 at 18542-18543 and 53 FR 53176 at 53197).
[[Page 15851]]
Regarding benzene specifically, the Agency has stated: ``The select
Committee concluded that the small addition of benzene from radiation
sterilized beef would contribute only a trivial increment to the normal
body burden and is unlikely to increase significantly whatever hazard
exists from other sources. FDA is not aware of any evidence that call
this conclusion into question'' (53 FR 53176 at 53197).
The objection identifies no evidence that the Agency overlooked,
and does not provide any new evidence that would indicate benzene,
toluene, or other chemicals are formed in irradiated molluscan
shellfish in quantities that would pose a risk to human health. Thus,
Dr. Epstein's request for a hearing based on this objection is denied
because a hearing will not be granted on the basis of mere allegations
or general descriptions of positions and contentions (Sec.
12.24(b)(2)).
The objection also criticizes the Agency for making ``[a] blanket
statement which the Agency fails to explain further: ``FDA and food
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.'' Dr. Epstein also takes issue with the
Agency's statement that ``* * * identification of major radiolysis
products will aid in the interpretation of data.''
Contrary to Dr. Epstein's remarks, the Agency provided a detailed
explanation of its statement about safety testing of irradiated whole
foods versus the testing of individual components of those foods in the
context of its response to a comment expressing a different view about
requirements for testing irradiated food (see 70 FR 48057 at 48066).
Additionally, the Agency has provided detailed discussions of the role
of chemical identification of radiolysis products in the evaluation of
data from safety testing (see 70 FR 48507 at 48059 and 62 FR 64107 at
64110-64111 and section IV. H of this document).
In conclusion, the submitted objection contains no evidence that
the Agency has overlooked and no new evidence that would call into
question the Agency's previous conclusion that consumption of
irradiated molluscan shellfish is safe. The objection merely alleges
that there may possibly be formation of benzene and toluene and alleges
a potential of harm. A hearing will not be granted on the basis of mere
allegations or denials or general descriptions of positions and
contentions (Sec. 12.24(b)(2)); therefore, FDA is denying the request
for a hearing based on this objection.
V. Summary and Conclusion
The FD&C Act requires that a food additive be shown to be safe
prior to marketing under section 409 of the FD&C Act. Under Sec.
170.3(i), a food additive is ``safe'' if there is a reasonable
certainty in the minds of competent scientists that the substance is
not harmful under the intended conditions of use. In the Agency's
August 16, 2005, final rule approving the use of irradiation on fresh
or frozen molluscan shellfish, FDA concluded that the studies conducted
to establish the safety of this additive demonstrate that this use of
irradiation is safe for its intended use on fresh or frozen molluscan
shellfish.
The petitioner has the burden to demonstrate the safety of the
additive to gain FDA approval. Nevertheless, once FDA makes a finding
of safety in an approval document, the burden shifts to an objector,
who must come forward with evidence that calls into question FDA's
conclusion (American Cyanamid Co. v. FDA, 606 F.2d 1307, 1314-1315 (DC
Cir. 1979)).
Despite their many allegations, PC/CFS and Dr. Epstein have not
established that FDA overlooked significant information in the record
in reaching its conclusion that the use of irradiation on fresh or
frozen molluscan shellfish is safe. In such circumstances, FDA has
determined that the objections do not raise any genuine and substantial
issue of fact that can be resolved by an evidentiary hearing (Sec.
12.24(b)).
Accordingly, FDA is denying the requests for a hearing. In
addition, PC/CFS' and Dr. Epstein's requests for a stay of the
effectiveness of the August 16, 2005, regulation until a hearing is
held are moot because FDA is denying all hearing requests. Thus, FDA is
confirming August 16, 2005, as the effective date of the final rule
published at 70 FR 48057.
VI. References
The following references are on display at the Division of Dockets
Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane,
rm. 1061, Rockville, MD 20857, under Docket No. FDA-1999-F-0056
(formerly 1999F-4372), and may be seen by interested persons between 9
a.m. and 4 p.m., Monday through Friday.
1. Memorandum to the file, FAP 4M4428, from P. Hansen, FDA, dated
October 31, 1997.
2. Dixon, D.W., ``The Influence of Gamma Radiation Upon Shellstock
Oysters, and Culturable and Viable but Nonculturable Vibrio
vulnificus,'' a dissertation presented to the Graduate School of the
University of Florida, 1996.
3. Diehl, J.F., ``Safety of Irradiated Foods,'' second edition,
Marcel Dekker, Inc., New York, 1995.
4. Memorandum for FAP 9M4682 from K. Morehouse, FDA, to L.
Highbarger, FDA, July 15, 2005.
5. Renner, H.W., ``Chromosome Studies on Bone Marrow Cells of
Chinese Hamsters Fed a Radiosterilized Diet,'' Toxicology, 8:213-
222, 1977.
6. Miesch, M., Ndiye, B., Hasselmann, C., and E. Marchioni, ``2-
Alkylcyclobutanones as Markers for Irradiated Food Stuffs--I.
Synthesis of Saturated and Unsaturated Standards,'' Radiation
Physics and Chemistry, 55:337-344, 1999.
7. Horvatovich, P., M. Miesch, C. Hasselmann, and E. Marchioni,
``Supercritical Fluid Extractin of Hydrocarbons and 2-
Alkylcyclobutanones for the Detection of Irradiated Foodstuffs,''
Journal of Chromatography, 897:259-268, 2000.
8. Delinc[eacute]e H, B.L. Pool-Zobel, and G. Rechkemmer
``Genotoxicity of 2-Dodecyclcyclobutanone,'' Food Irradiation: Fifth
German Conference, Report BFE-R-99-01, Federal Nutrition Research
Institute, Karlsruhe, Germany (unpublished, 1998).
9. Memorandum for FAP 9M4682 and FAP 1M4727, from D. Folmer, FDA, to
L. Highbarger, August 2, 2002.
10. Memorandum for FAP 9M4682 from T. Twaroski, FDA, to L.
Highbarger, FDA, July 14, 2005.
11. Raul, F., F. Gosse, H. Delincee, A. Hartwig, E. Marchioni, M.
Miesch, D. Werner, and D. Burnouf, ``Food Borne Radiolytic Compounds
(2-Alkylcyclobutanones) May Promote Experimental Colon
Carcinogenesis,'' Nutrition and Cancer, 44(2):181-191, 2002.
12. Rao, C., ``Do Irradiated Foods Cause or Promote Colon Cancer?'',
Division of Nutritional Carcinogenesis, Institute for Cancer
Prevention, American Health Foundation--Cancer Center, Valhalla, NY
(Unpublished, 2003), FDA notes that this article has now been
published as a commentary in Nutrition and Cancer, 46(2):107-109,
2003.
13. Bureau of Food Irradiated Foods Committee, ``Recommendations for
Evaluation the Safety of Irradiated Food,'' prepared for the
Director, Bureau of Foods, FDA, July 1980.
14. Toxicological Principles for the Safety Assessment of Direct
Food Additives and Color Additives Used in Food, ``Red Book II,''
U.S. Food and Drug Administration, Center for Food Safety and
Applied Nutrition, 1993, revised 2001.
15. Zhu, M.J., et al., ``Effects of Electron Beam Irradiation and
Antimicrobials on the Volatiles, Color, and Texture of Ready-to-Eat
Turkey Breast Roll,'' Journal of Food Science, 69(5):C382-C387,
2004.
16. Federation of American Societies for Experimental Biology, Life
Sciences Research Office, Evaluation of the Health Aspects of
Certain Compounds Found in Irradiated Beef, Supplement 1979, 1977.
[[Page 15852]]
Dated: March 15, 2011.
Leslie Kux,
Acting Assistant Commissioner for Policy.
[FR Doc. 2011-6625 Filed 3-21-11; 8:45 am]
BILLING CODE 4160-01-P