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DEPARTMENT OF HEALTH AND HUMAN SERVICES
FOOD AND DRUG ADMINISTRATION
DOCKET NO. 92N-0139
STATEMENT OF POLICY: FOODS DERIVED FROM NEW PLANT VARIETIES
AGENCY: Food and Drug Administration, HHS.
ACTION: Notice.
SUMMARY: The Food and Drug Administration (FDA) is issuing a
policy statement on foods derived from new plant varieties,
including plants developed by recombinant deoxyribonucleic acid
(DNA) techniques. This policy statement is a clarification of
FDA's interpretation of the Federal Food, Drug, and Cosmetic Act
(the act), with respect to new technologies to produce foods, and
reflects FDA's current judgment based on new plant varieties now
under development in agricultural research. This action is being
taken to ensure that relevant scientific, safety, and regulatory
issues are resolved prior to the introduction of such products
into the marketplace.
DATES: Written comments by (insert date 90 days after date of
publication in the FEDERAL REGISTER).
ADDRESSES: Submit written comments to the Dockets Management
Branch (HFA-305), Food and Drug Administration, Rm. 1-23, 12420
Parklawn Dr., Rockville, MD 20857.
FOR FURTHER INFORMATION CONTACT:
Regarding Human Food Issues:
James H. Maryanski,
Center for Food Safety and Applied Nutrition (HFF-300),
Food and Drug Administration,
200 C St. SW.,
Washington, DC 20204,
202-485-3617,
Regarding Animal Feed Issues:
William D. Price,
Center for Veterinary Medicine (HFV-221),
Food and Drug Administration,
7500 Standish Pl.,
Rockville, MD 20855,
301-295-8724.
SUPPLEMENTARY INFORMATION:
TABLE OF CONTENTS
I. Background and Overview of Policy
II. Responsibility for Food Safety
III. Scope of this Document
IV. Scientific Issues Relevant to Public Health
A. Unexpected Effects
B. Known Toxicants
C. Nutrients
D. New Substances
E. Allergenicity
F. Antibiotic Resistance Selectable Markers
G. Plants Developed to Make Specialty Nonfood Substances
H. Issues Specific to Animal Feeds
V. Regulatory Status of Foods Derived from New Plant Varieties
A. The Statutory Framework for New Foods and Food Ingredients
B. The Application of Section 402(a)(1) of the Act
C. The Application of Section 409 of the Act
VI. Labeling
VII. Guidance to Industry for Foods Derived from New Plant
Varieties
A. Introduction
B. Flow Charts
C. Effects of Processing
D. The Host Plant
E. The Donor(s)
1. Donor plants
2. Fragments of donor genetic material
F. Substances Introduced into the Host Plant from the
Donor(s)
1. Proteins
2. Carbohydrates
3. Fats and oils
G. Toxicology
H. Other Information
1. Nucleic acids
2. Metabolic considerations
3. Stability
I. Future Workshop on Scientific Issues
VIII. Environmental Considerations: Applicability of NEPA
IX. Coordination with EPA: Pesticide Considerations
X. Environmental Impact
XI. Comments
XII. References
I. BACKGROUND AND OVERVIEW OF POLICY
New methods of genetically modifying plants are being used
to develop new varieties that will be sources of foods. These
methods, including recombinant DNA techniques and cell fusion
techniques, enable developers to make genetic modifications in
plants, including some modifications that would not be possible
with traditional plant breeding methods. This policy discusses
the safety and regulatory status of foods derived from new plant
varieties, including plants developed by the newer methods of
genetic modification.
FDA has received numerous inquiries from industry,
government agencies, academia, and the public requesting
clarification of the regulatory status of foods, such as fruits,
vegetables, grains and their byproducts, derived from new plant
varieties developed using recombinant DNA techniques. The
questions that FDA has received center on issues such as whether
the agency will conduct premarket review of these new foods,
whether such foods introduced into interstate commerce would be
challenged by FDA on legal grounds, which new plant varieties
might come under the jurisdiction of FDA, what scientific
information may be necessary to satisfy FDA that such foods are
safe and comply with the law, whether petitions would be required
by the agency, and whether special labeling would be required.
Representatives of the food biotechnology industry have
expressed to FDA the need for strong but appropriate oversight by
Federal agencies to ensure public confidence in foods produced by
the new techniques. FDA has received several specific comments
and suggestions from the industry and from the public concerning
Federal oversight of foods developed through new methods of
genetically modifying plants (Refs. 1 through 4). The agency has
considered these and other documents, including scientific
research papers, in developing this notice, and is setting forth
this policy statement to clarify its interpretation of the act
with respect to human foods and animal feeds derived from new
plant varieties, including but not limited to plants developed
by new methods of genetic modification.
Under this policy, foods, such as fruits, vegetables,
grains, and their byproducts, derived from plant varieties
developed by the new methods of genetic modification are
regulated within the existing framework of the act, FDA's
implementing regulations, and current practice, utilizing an
approach identical in principle to that applied to foods
developed by traditional plant breeding. The regulatory status
of a food, irrespective of the method by which it is developed,
is dependent upon objective characteristics of the food and the
intended use of the food (or its components). The method by
which food is produced or developed may in some cases help to
understand the safety or nutritional characteristics of the
finished food. However, the key factors in reviewing safety
concerns should be the characteristics of the food product,
rather than the fact that new methods are used.
The safety of a food is regulated primarily under FDA's
postmarket authority of section 402(a)(1) of the act (21 U.S.C.
342(a)(1)). Unintended occurrences of unsafe levels of toxicants
in food are regulated under this section. Substances that are
expected to become components of food as a result of genetic
modification of a plant and whose composition is such or has been
altered such that the substance is not generally recognized as
safe (GRAS) or otherwise exempt are subject to regulation as
"food additives" under section 409 of the act (21 U.S.C. 348).
Under the act, substances that are food additives may be used in
food only in accordance with an authorizing regulation.
In most cases, the substances expected to become components
of food as a result of genetic modification of a plant will be
the same as or substantially similar to substances commonly found
in food, such as proteins, fats and oils, and carbohydrates. As
discussed in more detail in section V.C., FDA has determined that
such substances should be subject to regulation under section 409
of the act in those cases when the objective characteristics of
the substance raise questions of safety sufficient to warrant
formal premarket review and approval by FDA. The objective
characteristics that will trigger regulation of substances as
food additives are described in the guidance section of this
notice (section VII.).
The guidance section also describes scientific
considerations that are important in evaluating the safety and
nutritional value of foods for consumption by humans or animals,
regardless of whether the food is regulated under section
402(a)(1) or section 409 of the act. The guidance section
outlines a "decision tree" approach to safety assessment of foods
derived from new plant varieties that FDA believes is compatible
with current practice among scientists knowledgeable in this
area. The guidance section also identifies certain scientific
questions that may raise sufficient safety concern to warrant
consultation with FDA.
Finally, this notice addresses FDA's responsibility under
the National Environmental Policy Act (NEPA) and the food
labeling provisions of the act as such provisions affect labeling
of foods derived from new plant varieties.
This policy statement reflects FDA's current judgment based
on the new plant varieties now under development in agricultural
research. FDA invites comments on this document. Because
scientific developments in this field are occurring rapidly, FDA
will refine its policy, if circumstances warrant, in a future
FEDERAL REGISTER notice. Additionally, FDA plans to announce in
a future FEDERAL REGISTER notice a workshop to discuss specific
scientific issues. FDA invites comment on topics that might be
addressed at such a workshop.
II. RESPONSIBILITY FOR FOOD SAFETY
FDA is the primary Federal agency responsible for ensuring
the safety of commercial food and food additives, except meat and
poultry products. FDA works closely on food safety matters with
the U.S. Department of Agriculture (USDA), which regulates meat
and poultry products, and with the U.S. Environmental Protection
Agency (EPA), which regulates pesticides and sets tolerances for
pesticide residues in food. FDA's authority is under the act,
the Public Health Service Act, and FDA's implementing regulations
codified in Title 21 of the CFR. The act gives FDA broad
authority to initiate legal action against a food that is
adulterated or misbranded within the meaning of the act.
Producers of new foods have an obligation under the act to
ensure that the foods they offer consumers are safe and in
compliance with applicable legal requirements. Because in some
cases the regulatory jurisdiction of a new food product including
those produced using innovative methods may not be clear,
producers can informally consult with FDA prior to marketing new
foods to ensure that the safety and regulatory status of a new
food is properly resolved.
Elsewhere in this issue of the FEDERAL REGISTER, FDA
announces the filing of the first request by a producer for
consultation with FDA concerning a new plant variety developed by
recombinant DNA techniques. The request submitted by Calgene,
Inc., (Calgene) concerns the FLAVR SAVR tomato, a new variety
claimed to exhibit improved fruit ripening and other properties.
Because Calgene made this request prior to the finalization of
this policy statement, FDA advised the firm to submit the
information about the tomato initially as a request for advisory
opinion under 10.85 (21 CFR 10.85) to permit the agency to
consider the status of the new variety, and to utilize an
evaluation process that is open to public comment and permits the
agency to make its decision known to the public. Future requests
for FDA consultation should be made consistent with the
principles outlined in this notice. Thus, FDA does not
anticipate that future requests of this nature will be filed
under 10.85.
III. SCOPE OF THIS DOCUMENT
This notice discusses scientific and regulatory
considerations for foods derived from new plant varieties. This
notice does not address foods and food ingredients regulated by
FDA that have been derived from algae, microorganisms, and other
nonplant organisms, including: (1) Foods produced by
fermentation, where microorganisms are essential components of
the food (e.g., yogurt and single cell protein); (2) food
ingredients produced by fermentation, such as many enzymes,
flavors, amino acids, sweeteners, thickeners, antioxidants,
preservatives, colors, and other substances; (3) substances
produced by new plant varieties whose purpose is to color food,
and (4) foods derived from animals that are subject to FDA's
authority, including seafood. FDA is considering whether to
address these issues in future FEDERAL REGISTER notices.
Finally, the principles discussed in this notice do not
apply to "new drugs" as defined by section 201(p) of the act (21
U.S.C. 321(p)), "new animal drugs" as defined by section 201(w)
of the act (21 U.S.C. 321(w)), or to "pesticide chemicals" as
defined by section 201(q) of the act. As discussed in section
IX., EPA is responsible for pesticide chemicals, including those
produced in plants as a result of genetic modification.
IV. SCIENTIFIC ISSUES RELEVANT TO PUBLIC HEALTH
Plant breeding is the science of combining desirable genetic
traits into a variety that can be used in agriculture. The
desired traits can be broadly divided into two classes: Those
that affect agronomic characteristics of the plant, and those
that affect quality characteristics of the food. Agronomic
characteristics include those affecting yield; resistance to
diseases, insects, and herbicides; and ability to thrive under
various adverse environmental conditions. Quality
characteristics include those affecting processing, preservation,
nutrition, and flavor.
The genetic modification techniques used to develop new
plant varieties constitute a continuum. Traditional breeding
typically consists of hybridization between varieties of the same
species and screening for progeny with desired characteristics.
Such hybridizations only can introduce traits found in close
relatives. Breeders have developed or adopted a number of
techniques to expand the range of genetic variation available to
them. These techniques introduce variation either by using
mutagenesis to alter the genome or by introducing or modifying
DNA segments, including DNA segments derived from other
organisms.
Mutagenic techniques include both random mutagenesis,
resulting from treatment with chemical and physical mutagens, and
somaclonal variation, whereby, with the use of tissue culture
techniques, plants are regenerated from callus or leaf tissue
explants. The regenerated plants often have properties not found
in the progenitor plant, reflecting both preexisting cellular
genetic differences and tissue-culture induced mutations. The
mutations range from single gene changes to chromosomal
rearrangements. Mutagenesis techniques are limited, however, by
their inability to target a desired trait. Somaclonal variants
also frequently are unstable or infertile.
Techniques for gene transfer between plants that belong to
different species or genera fall under the general heading of
"wide crosses." These "crosses" have been accomplished using
hybridization, and protoplast fusion. Traditional wide crosses
involve hybridization between closely related species or genera,
frequently requiring the use of special techniques such as embryo
rescue and chromosome doubling to overcome physical or genetic
barriers to the production of fertile progeny. They permit the
transfer of genetic traits that are not present in close
relatives of the modern plant varieties but are found in more
distant wild relatives. Traits that confer resistance to a
number of diseases have been introduced this way.
All of the techniques described above require extensive back
crossing with the parent line to eliminate mutations unlinked to
that responsible for the desired phenotype and undesirable traits
in extraneous genetic material introduced along with that
encoding the desired trait.
Recombinant DNA techniques involve the isolation and
subsequent introduction of discrete DNA segments containing the
gene(s) of interest into recipient (host) plants. The DNA
segments can come from any organism (microbial, animal, or
plant). In theory, essentially any trait whose gene has been
identified can be introduced into virtually any plant, and can be
introduced without extraneous unwanted genetic material. Since
these techniques are more precise, they increase the potential
for safe, better-characterized, and more predictable foods.
DNA segments introduced using the new techniques insert
semi-randomly into the chromosome, frequently in tandem multiple
copies, and sometimes in more than one site on the chromosome.
Both the number of copies of the gene and its location in the
chromosome can affect its level of expression, as well as the
expression of other genes in the plant. To ensure homozygosity
and to enhance the stability of the line and the ability to cross
the trait into other lines, the breeder will often perform a
limited number of back crosses to ensure that the plant line has
the new trait inserted in only one location in the chromosome.
Additionally, as with other breeding techniques, the
phenotypic effects of a new trait may not always be completely
predictable in the new genetic background of the host.
Therefore, it is common practice for breeders using recombinant
DNA techniques to cross the new trait into a number of hosts to
find the best genetic background for expression of the new trait.
Currently, for most crops only a few lines or varieties of any
species are amenable to the use of recombinant DNA techniques.
Once the desired trait is introduced into a line amenable to the
technique, it must then be crossed by traditional means to other
desired lines or varieties.
Regardless of the particular combination of techniques used,
the development of a new plant variety typically will require
many site-years (number of sites x number of years of plant
testing) of performance trials before introduction into
agricultural practice. These range from as few as 10 to 20
site-years for some plants to 75 to 100 site-years for others (some 5
to 10 years). The time of evaluation and the size and number of
sites will vary as necessary to confirm performance; to reveal
vulnerabilities to pests, diseases, or other production hazards;
to evaluate stability of the phenotype; to evaluate
characteristics of the food; to evaluate environmental effects;
and to produce the required amount of seed before the new plant
variety can be grown commercially by farmers. In the course of
this intensive assessment, individual plants exhibiting
undesirable traits are eliminated.
Recombinant DNA techniques are used to achieve the same
types of goals as traditional techniques: The development of new
plant varieties with enhanced agronomic and quality
characteristics. Currently, over 30 different agricultural crops
developed using recombinant DNA techniques are in field trials.
Food crops have been developed using these techniques to exhibit
improved resistance to pests and disease and to chemical
herbicides. For example, a plant's ability to resist insect
infestation reportedly has been improved by transferring
bacterial genetic material that encodes proteins toxic to certain
insects (e.g., Bacillus thuringiensis delta endotoxin). Other
plants have been given viral coat-protein genes that confer
cross-protection to viral pathogens.
Other new plant varieties have been developed that exhibit
traits for improved food processing, improved nutritional
content, or enhanced protection against adverse weather
conditions. For example, genetic modifications of plant enzymes
involved in fruit ripening may yield tomatoes with improved
ripening characteristics, texture, and flavor. Scientists have
used recombinant DNA techniques to transfer genetic material for
the production of seed storage protein conferring improvements in
nutritional balance of important amino acids in the new plant
varieties. Scientists have also identified genes in certain fish
that encode proteins that confer increased resistance to cold.
Copies of these genes have been introduced into agricultural
crops with the goal of producing new plant varieties that show
improved tolerance to cold weather conditions.
These examples illustrate only a few of the many improved
agronomic and food processing traits currently being introduced
into plants using recombinant DNA techniques. Any genetic
modification technique has the potential to alter the composition
of food in a manner relevant to food safety, although, based on
experience, the likelihood of a safety hazard is typically very
low. The following paragraphs describe some potential changes in
composition that may require evaluation to assure food safety.
A. Unexpected Effects
Virtually all breeding techniques have the potential to
create unexpected (including pleiotropic) effects. For example,
mutations unrelated to the desired modification may be induced;
undesirable traits may be introduced along with the desired
traits; newly introduced DNA may physically insert into a
transcriptionally active site on the chromosome, and may thereby
inactivate a host gene or alter control of its expression; the
introduced gene product or a metabolic product affected by the
genetic change may interact with other cellular products to
produce a deleterious effect. Plant breeders using well
established practices have successfully identified and eliminated
plants that exhibit unexpected, adverse traits prior to
commercial use.
B. Known Toxicants
Plants are known to produce naturally a number of toxicants
and antinutritional factors, such as protease inhibitors,
hemolytic agents, and neurotoxins, which often serve the plant as
natural defense compounds against pests or pathogens. For
example, most cereals contain protease inhibitors, which can
diminish the nutritive value of proteins. Many legumes contain
relatively high levels of lectins and cyanogenic glycosides.
Lectins, if not destroyed by cooking or removed by soaking, can
cause severe nausea, vomiting, and diarrhea. Cyanogenic
glycosides can be hydrolyzed by specific enzymes in the plant to
release cyanide if food from the plant is improperly prepared.
The levels of cyanogenic glycosides in cassava and some legumes
can lead to death or chronic neurological disease if these foods
are eaten uncooked. Cruciferae contain glucosinolates which may
impair thyroid function. Squash and cucumber contain
cucurbiticin, an acute toxicant. Chickpeas contain lathyrogens,
which are neurotoxins.
Many of these toxicants are present in today's foods at
levels that do not cause acute toxicity. Others, such as in
cassava and some legumes, are high enough to cause severe illness
or death if the foods are not properly prepared. FDA seeks to
assure that new plant varieties do not have significantly higher
levels of toxicants than present in other edible varieties of the
same species.
Plants, like other organisms, have metabolic pathways that
no longer function due to mutations that occurred during
evolution. Products or intermediates of some such pathways may
include toxicants. In rare cases, such silent pathways may be
activated by mutations, chromosomal rearrangements, or new
regulatory regions introduced during breeding, and toxicants
hitherto not associated with a plant species may thereby be
produced. Similarly, toxicants ordinarily produced at low levels
in a plant may be produced at high levels in a new variety as a
result of such occurrences. The likelihood of activation of
quiescent pathways or increased expression from active pathways
is considered extremely low in food plants with a long history of
use that have never exhibited production of unknown or unexpected
toxins, since the genetic changes that can lead to such events
occur during growth and are induced with traditional breeding
manipulations. In the few cases where toxicants have been raised
to unsafe levels in a commercial plant variety, the toxicants
were known to occur in significant levels in one of the parent
species. Except in rare cases, plant breeders using well
established practices have successfully identified and eliminated
plants that express unacceptably high levels of toxicants prior
to commercial use.
C. Nutrients
Another unintended consequence of genetic modification of
the plant may be a significant alteration in levels of important
nutrients. In addition, changes in bioavailability of a nutrient
due to changes in form of the nutrient or the presence of
increased levels of other constituents that affect absorption or
metabolism of nutrients must be considered for potential
nutritional impact.
D. New Substances
Because plant breeders using the new techniques are able to
introduce essentially any trait or substance whose molecular
genetic identity is known into virtually any plant, it is
possible to introduce a protein that differs significantly in
structure or function, or to modify a carbohydrate, fat or oil,
such that it differs significantly in composition from such
substances currently found in food.
E. Allergenicity
All food allergens are proteins. However, only a small
fraction of the thousands of proteins in the diet have been found
to be food allergens. FDA's principal concern regarding
allergenicity is that proteins transferred from one food source
to another, as is possible with recombinant DNA and protoplast
fusion techniques, might confer on food from the host plant the
allergenic properties of food from the donor plant. Thus, for
example, the introduction of a gene that encodes a peanut
allergen into corn might make that variety of corn newly
allergenic to people ordinarily allergic to peanuts.
Examples of foods that commonly cause an allergenic response
are milk, eggs, fish, crustacea, molluscs, tree nuts, wheat, and
legumes (particularly peanuts and soybeans). The sensitive
population is ordinarily able to identify and avoid the offending
food. However, if the allergen were moved into a variety of a
plant species that never before produced that allergen, the
susceptible population would not know to avoid food from that
variety.
In some foods that commonly cause an allergic response, the
particular protein(s) responsible for allergenicity is known, and
therefore the producer may know whether the transferred protein
is the allergen. However, in other cases, the protein
responsible for a food's allergenicity is not known, and FDA
considers it prudent practice for the producer initially to
assume that the transferred protein is the allergen. Appropriate
in vitro or in vivo allergenicity testing may reveal whether food
from the new variety elicits an allergenic response in the
potentially sensitive population (i.e., people sensitive to the
food in which the protein is ordinarily found). Producers of
such foods should discuss allergenicity testing protocol
requirements with the agency. Labeling of foods newly containing
a known or suspect allergen may be needed to inform consumers of
such potential.
A separate issue is whether any new protein in food has the
potential to be allergenic to a segment of the population. At
this time, FDA is unaware of any practical method to predict or
assess the potential for new proteins in food to induce
allergenicity and requests comments on this issue.
F. Antibiotic Resistance Selectable Markers
In gene transfer experiments, only a small percentage of the
recipient plant cells will actually take up the introduced genes,
and many desirable traits (i.e., those that specify the intended
technical effect) are not easy to detect before the plant has
fully developed. Scientists, therefore, enhance their ability to
isolate plant cells that have taken up and stably incorporated
the desired genes by physically linking the desired gene to a
selectable marker gene, such as a gene that specifies the
production of a substance that inactivates antibiotics.
The kanamycin resistance gene is one of the most widely used
selectable marker genes. The kanamycin resistance gene specifies
the information for the production of the enzyme, aminoglycoside
3'-phosphotransferase II. The common name for this enzyme is
kanamycin (or neomycin) phosphotransferase II. The kanamycin
phosphotransferase II enzyme modifies aminoglycoside antibiotics,
including kanamycin, neomycin, and geneticin (G418), chemically
inactivating the antibiotic and rendering the cells that produce
the kanamycin resistance gene product refractory or resistant to
the antibiotic. Plant cells that have received and stably
express the kanamycin resistance gene survive and replicate on
laboratory media in the presence of the antibiotic, kanamycin.
Plant cells that did not take up and express the introduced
kanamycin resistance gene will be killed by the antibiotic. By
linking the selectable marker gene to another gene that specifies
a desired trait, scientists can identify and select plants that
have taken up and express the desired genes.
The kanamycin resistance gene has been used as a selectable
marker in more than 30 crops to develop varieties that exhibit
improved nutritional and processing properties, resistance to
pests and diseases, tolerance to chemical herbicides, and other
agronomic properties. Once the desired plant variety has been
selected, the kanamycin resistance gene serves no further useful
purpose, although it continues to produce the kanamycin
phosphotransferase II enzyme in the plant tissues. Thus, while
the kanamycin resistance gene is a research tool that is
important for developing new plant varieties through the current
recombinant DNA techniques of gene transfer, both the kanamycin
resistance gene and its product, the kanamycin phosphotransferase
II enzyme protein, are expected to be present in foods derived
from such plants, unless removed through recently developed
techniques (Ref. 5).
Selectable marker genes that produce enzymes that inactivate
clinically useful antibiotics theoretically may reduce the
therapeutic efficacy of the antibiotic when taken orally if the
enzyme in the food inactivates the antibiotic. FDA believes that
it will be important to evaluate such concerns with respect to
commercial use of antibiotic resistance marker genes in food,
especially those that will be widely used. FDA is now evaluating
this and other issues with respect to the use of the kanamycin
resistance marker in food. (See 56 FR 20004, May 1, 1991.)
G. Plants Developed to Make Specialty Nonfood Substances
New genetic modification techniques may develop plants that
produce nonfood chemicals, such as polymers and pharmaceuticals.
In many cases, the plant will not subsequently be used for food.
In such cases, the developer must ensure that food-use varieties
of the crop do not cross with or become mixed with the
nonfood-use varieties. This is not a new issue for breeders and growers.
For example, some varieties of rapeseed oil are grown for
industrial oil use, and have high levels of toxicants, such as
erucic acid and glucosinylates, while other varieties are grown
for food use and have low levels of these substances. Similarly,
potatoes grown for industrial uses can have higher levels of
solanine than those grown for retail food use. The producer of
the oil or potato must ensure that the edible plant variety is
not adulterated within the meaning of the act. Developers of
crops designed to produce specialty nonfood substances have a
comparable obligation.
If plants (or materials derived from plants) used to make
nonfood chemicals are also intended to be used for food,
producers should consult with FDA to determine whether the
nonfood chemical would be a food additive requiring an
authorizing regulation prior to marketing for food use.
H. Issues Specific to Animal Feeds
Unlike a food in the human diet, an animal feed derived from
a single plant may constitute a significant portion of the animal
diet. For instance, 50 to 75 percent of the diet of most
domestic animals consists of field corn. Therefore, a change in
nutrient or toxicant composition that is considered insignificant
for human consumption may be a very significant change in the
animal diet.
Further, animals consume plants, plant parts, and plant
byproducts that are not consumed by humans. For example, animals
consume whole cottonseed meal, whereas humans consume only cotton
seed oil. Gossypol, a plant toxicant, is concentrated in the
cotton seed meal during the production of cotton seed oil.
Because plant byproducts represent an important feed source for
animals, it is important to determine if significant
concentrations of toxicants or other harmful plant constituents
are present in new plant varieties.
Nutrient composition and availability of nutrients in feed
are important safety considerations for animal health. For
example, if a genetic modification in soybeans caused an increase
in phytin content, the soybean feed may need to be supplemented
with phosphorous to avoid problems of animal health.
V. REGULATORY STATUS OF FOODS DERIVED FROM NEW PLANT VARIETIES
A. The Statutory Framework for New Foods and Food Ingredients
The United States today has a food supply that is as safe as
any in the world. Most foods derived from plants predate the
establishment of national food laws, and the safety of these
foods has been accepted based on extensive use and experience
over many years (or even centuries). Foods derived from new
plant varieties are not routinely subjected to scientific tests
for safety, although there are exceptions. For example, potatoes
are generally tested for the glycoalkaloid, solanine. The
established practices that plant breeders employ in selecting and
developing new varieties of plants, such as chemical analyses,
taste testing, and visual analyses, rely primarily on
observations of quality, wholesomeness, and agronomic
characteristics. Historically, these practices have proven to be
reliable for ensuring food safety. The knowledge from this past
experience coupled with safe practices in plant breeding has
contributed to continuous improvements in the quality, variety,
nutritional value, and safety of foods derived from plants
modified by a range of traditional and increasingly sophisticated
techniques (Ref. l at xvi). Based on this record of safe
development of new varieties of plants, FDA has not found it
necessary to conduct, prior to marketing, routine safety reviews
of whole foods derived from plants.
Nevertheless, FDA has ample authority under the act's food
safety provisions to regulate and ensure the safety of foods
derived from new plant varieties, including plants developed by
new techniques. This includes authority to require, where
necessary, a premarket safety review by FDA prior to marketing of
the food. Under section 402(a)(1) of the act, a food is deemed
adulterated and thus unlawful if it bears or contains an added
poisonous or deleterious substance that may render the food
injurious to health or a naturally occurring substance that is
ordinarily injurious. Section 402(a)(1) of the act imposes a
legal duty on those who introduce food into the market place,
including food derived from new crop varieties, to ensure that
the food satisfies the applicable safety standard. Foods that
are adulterated under section 402(a)(1) of the act are subject to
the full range of enforcement measures under the act, including
seizure, injunction, and criminal prosecution of those who fail
to meet their statutory duty.
FDA has relied almost exclusively on section 402(a)(1) of
the act to ensure the safety of whole foods. Toxins that occur
naturally in food and that render the food ordinarily injurious
to health (such as poisons in certain mushrooms), and thus
adulterated, rarely require FDA regulatory action because such
cases are typically well known and carefully avoided by food
producers.
FDA regards any substance that is not an inherent
constituent of food or whose level in food has been increased by
human intervention to be "added" within the meaning of section
402(a)(1) of the act. See United States v. Anderson Seafoods,
Inc., 622 F.2d 157 (5th Cir. 1980). Added substances are subject
to the more stringent "may render [the food| injurious" safety
standard. Under this standard, the food is adulterated if, by
virtue of the presence of the added substance, there is a
"reasonable possibility" that consumption of the food will be
injurious to health. United States v. Lexington Mill & Elevator
Co., 232 U.S. 399 (1914). The "may render injurious" standard
would apply to a naturally occurring toxin in food if the level
of the toxin in a new plant variety were increased through
traditional plant breeding or some other human intervention.
Section 402(a)(1) of the act would have been the legal basis
under which FDA could have blocked marketing in the 1970's of a
new variety of potato that had been found during its development
to contain elevated and potentially harmful levels of solanine as
a result of a cross with an inedible wild potato.
Section 402(a)(1) of the act is most frequently used by FDA
to regulate the presence in food of unavoidable environmental
contaminants such as lead, mercury, dioxin, and aflatoxin. FDA
regularly establishes action levels and takes enforcement action
to prevent the sale of foods that contain unacceptable levels of
such unintended and undesired contaminants.
Section 402(a)(1) of the act was signed into law in 1938 and
has its origins in a similar provision in the Federal Food and
Drugs Act of 1906. Until 1958, this authority was the principal
tool relied upon by FDA to regulate the safety of food and food
ingredients. In 1958, in response to public concern about the
increased use of chemicals in foods and food processing and with
the support of the food industry, Congress enacted the Food
Additives Amendment (the amendment) to the act. Among other
provisions, the amendment established a premarket approval
requirement for "food additives." The basic thrust of the
amendment was to require that, before a new chemical additive
(such as a preservative, antioxidant, emulsifier, or artificial
flavor) could be used in food processing, its producer must
demonstrate the safety of the additive to FDA. Congress
recognized under this new scheme that the safety of an additive
could not be established with absolute certainty or under all
conditions of use. Congress thus provided for a science-based
safety standard that requires producers of food additives to
demonstrate to a reasonable certainty that no harm will result
from the intended use of the additive. See 21 CFR 170.3(i). If
FDA finds an additive to be safe, based ordinarily on data
submitted by the producer to the agency in a food additive
petition, the agency promulgates a regulation specifying the
conditions under which the additive may be safely used. Food
additives that are not the subject of such a regulation are
deemed unsafe as a matter of law, and the foods containing them
are adulterated under section 402(a)(2)(C) of the act (21 U.S.C.
342(a)(2)(C)) and are thus unlawful.
In enacting the amendment, Congress recognized that many
substances intentionally added to food do not require a formal
premarket review by FDA to assure their safety, either because
their safety had been established by a long history of use in
food or because the nature of the substance and the information
generally available to scientists about the substance are such
that the substance simply does not raise a safety concern worthy
of premarket review by FDA. Congress thus adopted a two-step
definition of "food additive." The first step broadly includes
any substance the intended use of which results in its becoming a
component of food. The second step, however, excludes from the
definition of food additive substances that are GRAS. It is on
the basis of the GRAS exception of the "food additive" definition
that many ingredients derived from natural sources (such as salt,
pepper, vinegar, vegetable oil, and thousands of spices and
natural flavors), as well as a host of chemical additives
(including some sweeteners, preservatives, and artificial
flavors), are able to be lawfully marketed today without having
been formally reviewed by FDA and without being the subject of a
food additive regulation. The judgment of Congress was that
subjecting every intentional additive to FDA premarket review was
not necessary to protect public health and would impose an
insurmountable burden on FDA and the food industry.
Congress' approach to defining food additives means,
however, that companies developing new ingredients, new versions
of established ingredients, or new processes for producing a food
or food ingredient must make a judgment about whether the
resulting food substance is a food additive requiring premarket
approval by FDA. In many cases, the answer is obvious, such as
when the ingredient is a man made chemical having no widely
recognized history of safe use in food. Such an ingredient must
be approved prior to its use by the issuance of a food additive
regulation, based on information submitted to FDA in a food
additive petition.
In other cases, the answer is less obvious, such as when an
established ingredient derived from nature is modified in some
minor way or produced by a new process. In such cases, the
manufacturer must determine whether the resulting ingredient
still falls within the scope of any existing food additive
regulation applicable to the original ingredient or whether the
ingredient is exempt from regulation as a food additive because
it is GRAS. The GRAS status of some substances is recognized in
FDA'S regulations (21 CFR Parts 182, 184, 186, 582, and 584), but
FDA has not attempted to include all GRAS substances in its
regulations.
FDA has traditionally encouraged producers of new food
ingredients to consult with FDA when there is a question about an
ingredient's regulatory status, and firms routinely do so, even
though such consultation is not legally required. If the
producer begins to market the ingredient based on the producer's
independent determination that the substance is GRAS and FDA
subsequently concludes the substance is not GRAS, the agency can
and will take enforcement action to stop distribution of the
ingredient and foods containing it on the ground that such foods
are or contain an unlawful food additive.
FDA considers the existing statutory authority under
sections 402(a)(1) and 409 of the act, and the practical
regulatory regime that flows from it, to be fully adequate to
ensure the safety of new food ingredients and foods derived from
new varieties of plants, regardless of the process by which such
foods and ingredients are produced. The existing tools provide
this assurance because they impose a clear legal duty on
producers to assure the safety of foods they offer to consumers;
this legal duty is backed up by strong enforcement powers; and
FDA has authority to require premarket review and approval in
cases where such review is required to protect public health.
In the FEDERAL REGISTER of June 26, 1986 (51 FR 23302) (the
June 1986 notice), FDA, in conjunction with the Office of Science
and Technology Policy in the Executive Office of the President,
described FDA's current food safety authorities and stated the
agency's intention to regulate foods produced by new methods,
such as recombinant DNA techniques, within the existing statutory
and regulatory framework. This notice reaffirms that intention.
The following paragraphs explain briefly how the current
framework will apply specifically to foods derived from new plant
varieties, including plants developed by recombinant DNA
techniques.
B. The Application of Section 402(a)(1) of the Act
Section 402(a)(1) of the act will continue to be FDA's
primary legal tool for regulating the safety of whole foods,
including foods derived from plants genetically modified by the
new techniques. Section 402(a)(1) of the act will be applied to
any substance that occurs unexpectedly in the food at a level
that may be injurious to health. This includes a naturally
occurring toxicant whose level is unintentionally increased by
the genetic modification, as well as an unexpected toxicant that
first appears in the food as a result of pleiotropic effects.
Such substances are regarded by FDA as added substances whose
presence adulterates the food if present at a level that "may
render" the food injurious to health.
It is the responsibility of the producer of a new food to
evaluate the safety of the food and assure that the safety
requirement of section 402(a)(1) of the act is met. In section
VII., FDA provides guidance to the industry regarding prudent,
scientific approaches to evaluating the safety of foods derived
from new plant varieties, including the safety of the added
substances that are subject to section 402(a)(1) of the act. FDA
encourages informal consultation between producers and FDA
scientists to ensure that safety concerns are resolved. However,
producers remain legally responsible for satisfying section
402(a)(1) of the act, and they will continue to be held
accountable by FDA through application of the agency's
enforcement powers.
C. The Application of Section 409 of the Act
When Congress enacted the amendment in 1958, it did not
explicitly address the possible application of the food additive
approval process to foods derived from new plant varieties. As
previously discussed, such foods have historically been regulated
successfully under section 402(a)(1) of the act. The new methods
of genetic modification have focused attention, however, on the
possibility that intended changes in the composition of food
resulting from genetic modification might be of a nature
sufficient as a legal and public health matter to trigger
regulation of a component of the food under section 409 of the
act.
As discussed above, the food additive definition broadly
encompasses any substance that has an intended use in food,
unless the substance is GRAS. It was on this basis that the June
1986 notice indicated that, in some cases, whole foods derived
from new plant varieties, including plants developed by new
genetic modification techniques, might fall within the scope of
FDA's food additive authority. Indeed, FDA's regulations have
long recognized that it might be appropriate in some
circumstances to review the GRAS (and implicitly food additive)
status of foods or substances of natural biological origin that
have a history of safe use but which subsequently have had
"significant alteration by breeding and selection." (See 21 CFR
170.30(f).) As already discussed, however, FDA has rarely had
occasion to review the GRAS status of foods derived from new
plant varieties because these foods have been widely recognized
and accepted as safe.
FDA has reviewed its position on the applicability of the
food additive definition and section 409 of the act to foods
derived from new plant varieties in light of the intended changes
in the composition of foods that might result from the newer
techniques of genetic modification. The statutory definition of
"food additive" makes clear that it is the intended or expected
introduction of a substance into food that makes the substance
potentially subject to food additive regulation. Thus, in the
case of foods derived from new plant varieties, it is the
transferred genetic material and the intended expression product
or products that could be subject to food additive regulation, if
such material or expression products are not GRAS.
In regulating foods and their byproducts derived from new
plant varieties, FDA intends to use its food additive authority
to the extent necessary to protect public health. Specifically,
consistent with the statutory definition of "food additive" and
the overall design of FDA's current food safety regulatory
program, FDA will use section 409 of the act to require food
additive petitions in cases where safety questions exist
sufficient to warrant formal premarket review by FDA to ensure
public health protection.
With respect to transferred genetic material (nucleic
acids), generally FDA does not anticipate that transferred
genetic material would itself be subject to food additive
regulation. Nucleic acids are present in the cells of every
living organism, including every plant and animal used for food
by humans or animals, and do not raise a safety concern as a
component of food. In regulatory terms, such material is
presumed to be GRAS. Although the guidance provided in section
VII. calls for a good understanding of the identity of the
genetic material being transferred through genetic modification
techniques, FDA does not expect that there will be any serious
question about the GRAS status of transferred genetic material.
FDA expects that the intended expression product or products
present in foods derived from new plant varieties will typically
be proteins or substances produced by the action of protein
enzymes, such as carbohydrates, and fats and oils. When the
substance present in the food is one that is already present at
generally comparable or greater levels in currently consumed
foods, there is unlikely to be a safety question sufficient to
call into question the presumed GRAS status of such naturally
occurring substances and thus warrant formal premarket review and
approval by FDA. Likewise, minor variations in molecular
structure that do not affect safety would not ordinarily affect
the GRAS status of the substances and, thus, would not ordinarily
require regulation of the substance as a food additive.
It is possible, however, that the intended expression
product in a food could be a protein, carbohydrate, fat or oil,
or other substance that differs significantly in structure,
function, or composition from substances found currently in food.
Such substances may not be GRAS and may require regulation as a
food additive. For example, if a food derived from a new plant
variety contains a novel protein sweetener as a result of the
genetic modification of the plant, that sweetener would likely
require submission of a food additive petition and approval by
FDA prior to marketing. FDA invites comments on substances, in
addition to proteins, carbohydrates, and fats and oils, that in
the future may be introduced into foods by genetic modification.
Section VII. of this notice provides guidance to producers
of new foods for conducting safety evaluations. This guidance is
intended to assist producers in evaluating the safety of the food
that they market, regardless of whether the food requires
premarket approval by FDA. This guidance also includes criteria
and analytical steps that producers can follow in determining
whether their product is a candidate for food additive regulation
and whether consultation with FDA should be pursued to determine
the regulatory status of the product. Ultimately, it is the food
producer who is responsible for assuring safety.
FDA has long regarded it to be a prudent practice for
producers of foods using new technologies to work cooperatively
with the agency to ensure that the new products are safe and
comply with applicable legal requirements. It has been the
general practice of the food industry to seek informal
consultation and cooperation, and this practice should continue
with respect to foods produced using the newer techniques of
genetic modification.
VI. LABELING
FDA has received several inquiries concerning labeling
requirements for foods derived from new plant varieties developed
by recombinant DNA techniques. Section 403(i) of the act (21
U.S.C. 343(i)) requires that a producer of a food product
describe the product by its common or usual name or in the
absence thereof, an appropriately descriptive term (21 CFR Part
101.3) and reveal all facts that are material in light of
representations made or suggested by labeling or with respect to
consequences which may result from use (21 U.S.C. 343(a); 21
U.S.C. 321(n)). Thus, consumers must be informed, by appropriate
labeling, if a food derived from a new plant variety differs from
its traditional counterpart such that the common or usual name no
longer applies to the new food, or if a safety or usage issue
exists to which consumers must be alerted.
For example, if a tomato has had a peanut protein introduced
into it and there is insufficient information to demonstrate that
the introduced protein could not cause an allergic reaction in a
susceptible population, a label declaration would be required to
alert consumers who are allergic to peanuts so they could avoid
that tomato, even if its basic taste and texture remained
unchanged. Such information would be a material fact whose
omission may make the label of the tomato misleading under
section 403(a) of the act (21 U.S.C. 343(a)).
FDA has also been asked whether foods developed using
techniques such as recombinant DNA techniques would be required
to bear special labeling to reveal that fact to consumers. To
date, FDA has not considered the methods used in the development
of a new plant variety (such as hybridization, chemical or
radiation-induced mutagenesis, protoplast fusion, embryo rescue,
somaclonal variation, or any other method) to be material
information within the meaning of section 201(n) of the act (21
U.S.C. 321(n)). As discussed above, FDA believes that the new
techniques are extensions at the molecular level of traditional
methods and will be used to achieve the same goals as pursued
with traditional plant breeding. The agency is not aware of any
information showing that foods derived by these new methods
differ from other foods in any meaningful or uniform way, or
that, as a class, foods developed by the new techniques present
any different or greater safety concern than foods developed by
traditional plant breeding. For this reason, the agency does not
believe that the method of development of a new plant variety
(including the use of new techniques including recombinant DNA
techniques) is normally material information within the meaning
of 21 U.S.C. 321(n) and would not usually be required to be
disclosed in labeling for the food.
The guidance section (section VII.) of this notice discusses
certain circumstances where questions may arise about the proper
labeling of foods derived from new plant varieties. FDA requests
comments on the labeling of foods derived from new plant
varieties, including plants developed with recombinant DNA
techniques.
VII. GUIDANCE TO INDUSTRY FOR FOODS DERIVED
FROM NEW PLANT VARIETIES
A. Introduction
This guidance section describes many of the scientific
considerations for evaluating the safety and nutritional aspects
of food from new plant varieties derived by traditional methods
(such as hybridization or mutagenesis), tissue culture methods
(such as somaclonal variation and protoplast fusion), and
recombinant DNA methods. Although some of the safety
considerations are specific to individual technologies, many
safety considerations are similar regardless of the technology
used. This guidance section does not attempt to delineate
acceptable practices for each specific technology. FDA expects
plant breeders to adhere to currently accepted scientific
standards of practice within each technology. This guidance
section is based on existing practices followed by the
traditional plant breeders to assess the safety and nutritional
value of new plant varieties and is not intended to alter these
long-established practices, or to create new regulatory
obligations for them.
This guidance section describes food safety and nutritional
concerns, rather than performance characteristics for which the
new plant varieties may have been developed. However, this
guidance section cannot identify all safety and nutritional
questions that could arise in a given situation and, while
comprehensive, should not be viewed as exhaustive. In some
cases, additional factors may need to be considered, while in
other situations, some of the factors may not apply. Therefore,
this guidance section also describes situations in which
producers should consult with FDA on scientific issues, the
design of appropriate test protocols, requirements for labeling,
and whether a food additive petition may be required.
Genetic modifications of plants can have unintended or
unexpected effects on the phenotype of the plant, such as poor
growth or reduced tolerance to conditions of environmental
stress, that are readily apparent and can be effectively managed
by appropriate selection procedures. However, effects such as an
alteration in the concentration of important nutrients, increases
in the level of natural toxicants, or the transfer of allergens
from one species to another may not be readily detected without
specific test procedures. FDA believes that a scientific basis
should exist to establish that new plant varieties do not exhibit
unacceptable effects with respect to toxicants, nutritional
value, or allergens. In cases where the host plant has little or
no history of safe use, the assessment of new plant varieties
should include evidence that unknown toxicants are not present in
the new plant variety at levels that would be injurious to
health.
In addition, by using recombinant DNA techniques, plant
breeders are now capable theoretically of introducing essentially
any trait (and thus substance) whose molecular genetic identity
is known into virtually any plant due to the increased power and
precision of recombinant DNA techniques. This guidance section,
however, discusses only proteins, carbohydrates, and fats and
oils, in the belief that these are the principal substances that
are currently being intentionally modified or introduced into new
plant varieties. Using the new techniques, it is possible to
introduce a gene that encodes a protein that differs
significantly in structure or function, or to modify a
carbohydrate, or fat or oil, such that it differs significantly
in composition from such substances currently found in food. FDA
believes that plant breeders must carefully evaluate the
potential for adverse effects that could result from the presence
of these substances in new plant varieties.
Theoretically, genetic modifications have the potential to
activate cryptic pathways synthesizing unknown or unexpected
toxicants, or to increase expression from active pathways that
ordinarily produce low or undetectable levels of toxicants.
However, this potential has been effectively managed in the past
by sound agricultural practices. The agency believes that the
use of host plants with a history of safe use, coupled with a
continuation of sound agricultural practice, will minimize the
potential for adverse public health consequences that may arise
from increased levels of unknown or unexpected toxicants.
This guidance section provides a basis for determining
whether new plant varieties are as safe and nutritious as their
parental varieties. The assessment scheme focuses on
characteristics of the new plant variety, based on
characteristics of the host and donor species, the nature of the
genetic change, the identity and function of newly introduced
substances, and unexpected or unintended effects that accompany
the genetic change. The assessment focuses on the following
considerations:
1. Toxicants known to be characteristic of the host and
donor species;
2. The potential that food allergens will be transferred
from one food source to another;
3. The concentration and bioavailability of important
nutrients for which a food crop is ordinarily consumed;
4. The safety and nutritional value of newly introduced
proteins; and
5. The identity, composition and nutritional value of
modified carbohydrates, or fats and oils.
The scientific concepts described in this guidance section
are consistent with the concepts of substantial equivalence of
new foods discussed in a document under development by the Group
of National Experts on Safety in Biotechnology of the
Organization for Economic Cooperation and Development (OECD).
This guidance section is also consistent with the principles for
food safety assessment discussed in the Report of a Joint Food
and Agriculture Organization/World Health Organization
Consultation (Ref. 6).
B. Flow Charts
The flow charts presented in sections VII.D. through VII.F.
(Figures 2 through 6) outline a series of questions related to
the safety and nutritional value of foods derived from the new
plant variety, and are intended to provide general guidance to
breeders and developers. FDA intends that these flow charts be
used in conjunction with other information and practices that
breeders and developers rely on to develop new plant varieties.
These reflect the current state of scientific information and are
not intended as regulatory requirements. As new information is
developed, FDA anticipates that the flow charts may require
modification.
The summary flow chart (Figure 1) presented in this section
is a synopsis of FDA's safety assessment process. It describes,
in a general way, the assessment for unexpected or unintended
effects that may arise as a result of the specific
characteristics that are associated with the host plant and
donor(s), as well as the assessment of the expected or intended
effects. Because Figure 1 is a summary, it should not be relied
upon for a safety assessment. The boxes labeled Figure 2, Figure
3, Figure 4, and Figures 5 and 6, respectively, refer to more
specific flow charts that describe, in appropriate detail, the
safety assessment from the perspective of the host, donor, and
new substances that are introduced into the new plant variety.
Sections VII.D. through VII.F. address the scientific
considerations pertaining to the host plant, donor(s), and new
substances in more detail. Each section describes information
that relates to the safety assessment, presents a flow chart that
summarizes the safety assessment, discusses each of the questions
in that flow chart, and describes the endpoints that are reached
in that flow chart.
There are three endpoints in the flow charts in this notice:
(1) No concerns, (2) new variety not acceptable, and (3) consult
FDA. The notes to each individual flow chart discuss the
interpretation of these endpoints in relation to that particular
flow chart. In general, the interpretation of "no concerns" or
"new variety not acceptable" is similar for each flow chart. The
endpoint "consult FDA" means that producers may need to consult
FDA on regulatory questions, such as whether a food additive
petition or special labeling is needed, or on technical
questions, such as appropriate testing protocols or specific
scientific issues.
C. Effects of Processing
Processing (e.g., cooking) may affect the safety of a
substance. This is particularly important in the safety
assessment of proteins transferred from one food source to
another. For example, lectins, which are inactivated by cooking,
would raise a safety concern if transferred from kidney beans,
which are eaten cooked, to tomatoes, which may be eaten raw. The
effects of any potential differences in food processing between
the donor and the new plant variety should be carefully
considered at each stage in the safety assessment.
D. The Host Plant
A premise basic to this guidance section is that a long
history of safe use of the host species in food provides much
information regarding the potential of new plant varieties to
produce toxicants and antinutrients (substances that adversely
affect the nutritional quality of food). In assessing the
potential of the host plant to contribute unexpected harmful
substances, producers should consider attributes of the host
plant and its progenitors such as the following:
1. Taxonomy
a. Variety name
b. Known phenotypes and relevant genotypes
2. Other species or varieties that have previously
contributed genetic information to the host
3. History of safe use
a. Extent of previous experience
b. The part of the plant used as food
c. The presence and identity of potentially harmful
constituents such as toxicants and antinutrients
d. Typical methods of processing and the impact of
this processing on the reduction or enhancement of
effects from potentially harmful constituents
4. The identity and level of nutrients for which the food
is consumed
Figure 2
The numbers above each box in the flow chart refer to
accompanying notes that immediately follow the flow chart.
Notes to Figure 2
1--Does the host species have a history of safe use?
This guidance section is primarily designed for the
development of new varieties of currently consumed food plants
whose safety has been established by a history of use. If exotic
species are used as hosts, testing may be needed to assure the
safety and wholesomeness of the food.
2--Do characteristics of the host species, related species, or
progenitor lines warrant analytical or toxicological tests?
It is not possible to establish a complete list of all
toxicants that should be considered for each plant species. In
general, the toxicants that are of highest concern in any
particular species are those that have been documented to cause
harm in normal human or animal diets, or that have been found at
unsafe levels in some lines or varieties of that species or
related species.
In many cases, characteristic properties (such as a bitter
taste associated with alkaloids) are known to accompany elevated
levels of specific natural toxicants. If such characteristics
provide an assurance that these toxicants have not been elevated
to unsafe levels, analytical or toxicological tests may not be
necessary.
3--Do test results provide evidence that toxicant levels in the
new plant variety do not present a safety concern?
If a host plant or related species is known to contain
toxicants whose presence must be assessed, analytical tests may
Notes to Figure 2--continued
be appropriate to establish that the toxicant levels are in a
safe range. There is, however, a wide variation in the level of
natural toxicants within and between varieties of a species, due
to differences in genetic makeup and in environmental conditions
during growth, harvest, and storage. Due to this natural
variation, analytical tests, if necessary, should be performed
using as a control the parental variety that has been grown,
harvested, and stored under the same conditions as the new plant
variety.
In some cases, analytical methods alone may not be
available, practical, or sufficient for all toxicants whose
levels need to be assessed. In such situations, comparative
toxicological tests on the new and parental plant varieties may
provide assurance that the new variety is safe. FDA encourages
producers of new plant varieties to consult informally with the
agency on testing protocols for whole foods when appropriate.
4--Is the concentration and bioavailability of important
nutrients in the new variety within the range ordinarily seen in
the host species?
If the native levels of important nutrients for which a food
is widely consumed are not within the range ordinarily seen in
the host species, appropriate labeling may be required. In
addition, changes in bioavailability of a nutrient due to changes
in form of the nutrient or the presence of increased levels of
other constituents that affect absorption or metabolism of
nutrients must be considered for potential nutritional impact.
Notes to Figure 2--continued
5--Endpoints in Figure 2
5a--No concerns
When this endpoint is reached, safety and nutritional
concerns relative to the host plant will generally have been
satisfied.
5b--New variety not acceptable
This endpoint is reached when test results indicate that
food derived from the new plant variety may be unsafe - e.g., if
it contains unacceptable levels of toxicants.
5c--Consult FDA
Producers should consult informally with FDA when the
concentration or bioavailability of important nutrients is not
within the range ordinarily seen in the host species. FDA will
work with the producers on a case-by-case basis to address
requirements such as labeling, or other issues relating to
nutritional concerns.
E. The Donor(s)
In some cases, the donor will not have a history of safe use
in food. For example, the donor may be a wild species that is
related to the host plant, or may be a microorganism with no
history of use in food. The potential of the donor(s) to
contribute undesirable characteristics to the new plant variety
should be assessed. In assessing the potential of the donor to
contribute unexpected harmful substances, producers should
consider attributes of the donor plant, or of fragments of
genetic material from one or multiple donors, to the extent that
such information is available (see Figure 3).
1. Donor plants
Attributes of the donor plant and its progenitors, such as
the following, should be considered:
1. Taxonomy
a. Variety name
b. Known phenotypes and relevant genotypes
2. Other species or varieties that have previously
contributed genetic information to the donor plant
3. History of use (as applicable)
a. The part of the plant used as food
b. The presence and identity of potentially harmful
constituents such as toxicants, antinutrients, and allergens
c. Typical methods of processing and the impact of
this processing on the reduction or enhancement of effects
from potentially harmful constituents
2. Fragments of donor genetic material
Attributes of each donor, and its progenitors when
appropriate, such as the following, should be considered:
1. Taxonomy
2. Other species or varieties that have previously
contributed genetic information to the donor(s)
3. History of use (as applicable)
a. The part of the donor(s) used as food
b. The presence and identity of potentially harmful
constituents, such as toxicants, antinutrients, and
allergens
c. Typical methods of processing and the impact of
this processing on the reduction or enhancement of effects
from potentially harmful constituents
d. The association of the transferred genetic material
with harmful constituents
4. Additional information consistent with currently
accepted scientific practices, such as:
a. History and derivation of molecular constructs,
such as passage through microbial hosts
b. Known activities of any introduced regulatory
sequences, such as environmental, developmental and
tissue specific effects on promoter activity
c. The presence of extraneous open reading frames, and
the potential for transcription and expression of these
additional open reading frames
Figure 3
The numbers above each box in the flow chart refer to
accompanying notes that immediately follow the flow chart.
Notes to Figure 3
--Is food from the donor commonly allergenic? If yes, can it be
demonstrated that the allergenic determinant has not been
transferred to the new variety of host plant?
Some examples of foods that commonly cause an allergenic
response are milk, eggs, fish, crustacea, molluscs, tree nuts,
wheat, and legumes (particularly peanuts and soybeans).
Allergens from these common sources may be knowingly or
unknowingly transferred from a donor to a new variety of host
plant. Knowledge of the identity of the allergenic determinant
of the donor, coupled with appropriate knowledge of the genetic
fragment that has been transferred from the donor to the new
plant variety, may provide sufficient evidence that the
allergenic determinant has not been transferred to the new
variety of the host plant.
7--Do characteristics of the donor species, related species, or
progenitor lines warrant analytical or toxicological tests?
It is possible that a toxicant present in the donor may be
transferred to the host, e.g., during hybridization of a
cultivated variety with a wild, poisonous relative. However, it
is also possible to use a toxic donor safely. For example, a
gene coding for an enzyme that is not toxic and does not yield
toxic products may be isolated from pathogenic bacteria and
safely transferred to a plant.
The potential that toxicants known to exist in the donor,
related species, or progenitor lines will be present in the new
plant variety should be addressed as described previously for the
Notes to Figure 3--continued
host plant (section VII.D.). Unless there is sufficient evidence
that the toxicant has not been transferred to the new variety of
host plant, such transfer should be assumed, and analytical
and/or toxicological tests may be warranted.
8--Do test results provide evidence that toxicant levels in the
new variety do not present a safety concern?
When the presence of donor-associated toxicants must be
assessed, analytical or toxicological studies may provide
assurance that the new variety is safe as described previously
for the host species (section VII.D.). FDA encourages producers
of new plant varieties to consult with the agency on testing
protocols.
9--Endpoints in Figure 3
9a--No concerns
When this endpoint is reached, safety concerns relative to
the donor will generally have been satisfied.
9b--New variety not acceptable
This endpoint is reached when test results indicate that
food derived from the new plant variety may be unsafe, e.g., if
it contains unacceptable levels of toxicants.
9c--Consult FDA
Appropriately designed tests may provide evidence that the
suspected allergen in the donor was not transferred to the new
plant variety, or is not allergenic in the new variety.
Producers should consult informally with FDA on protocols that
are designed to assess allergenicity. FDA will work with the
producer on a case-by-case basis to address requirements such as
labeling.
F. Substances Introduced into the Host Plant from the Donor(s)
Safety assessment should address the specific risks
associated with the new substances introduced from the donor(s)
to a degree that is consistent with currently accepted scientific
practices.
1. Proteins
Depending upon the circumstances, safety assessment of an
introduced protein should be based on:
1. Presence and level in the food product
2. Origin
3. Known or suspected allergenicity
4. Evidence of consumption in other foods at similar levels
and under similar conditions of processing (e.g., eaten cooked or
uncooked)
5. Effects of processing (e.g., cooking)
6. Biological function
7. Known or potential toxicity
8. Chemical differences and similarities to edible proteins
9. The presence of host-specific posttranslational
modifications
Figure 4
The numbers above each box in the flow chart refer to
accompanying notes that immediately follow the flow chart.
Notes to Figure 4
10--Is the newly introduced protein present in food derived from
the plant?
For example, an enzyme introduced to alter the fatty acid
composition of an oil may be removed from the oil as a result of
processing. Alternatively, an enzyme introduced to confer
antibiotic resistance for use as a selectable marker may be
present in food products.
11--If an introduced protein is derived from a food source, the
question of allergenicity must be addressed in the same fashion
as was discussed from the perspective of the donor as a whole.
12--Is the introduced protein that is derived from a food source,
or is substantially similar to an edible protein, reported to be
toxic?
For example, some lectins are toxic unless inactivated by
cooking. If a protein whose safety is dependent on processing
such as cooking has been transferred from a species that is
commonly cooked before consumption to a species that may be eaten
raw, safety questions may arise.
13--If the intake of an introduced protein that is derived from a
food source, or that is substantially similar to an edible
protein, is not generally comparable to the intake of the same or
similar protein in the donor or other food, the biological
function of the protein should be assessed.
14--The biological function of the introduced protein should be
assessed if either of the following occur:
Notes to Figure 4--continued
a. The introduced protein is not derived from a food
source, or is not substantially similar to an edible protein;
b. The intake of the introduced protein in the new variety
is not comparable to the intake of the same or similar protein in
the donor or other food.
15--Does the biological function of the introduced protein raise
any safety concerns, or is the introduced protein reported to be
toxic?
In general, proteins that function as enzymes do not raise
concern. Exceptions include enzymes that produce substances
that are not ordinarily digested and metabolized by vertebrates,
or that produce toxic substances (e.g., the enzymes that convert
cyanogenic glycosides to cyanide).
Other functions that could raise concern include any
reported toxicity, such as known toxic activity toward
vertebrates, known toxic activity toward nonvertebrates when the
absence of toxic activity to vertebrates is not established, and
unusual properties that indicate that the protein is
Notes to Figure 4--continued
significantly different from other proteins found in the diet.
If the function of the protein is not known, see note 17d.
16--Is the introduced protein likely to be a macroconstituent in
the human or animal diet?
From a nutritional standpoint, the amount and quality of
total protein in the diet, rather than of any particular protein,
is of greatest significance. However, while most individual
proteins (e.g., enzymes) that might be introduced into food
derived from plants will be present at relatively low
concentrations, some proteins (e.g., seed storage proteins) may
become macroconstituents of the plant-derived food. Other
proteins (e.g., enzymes used as selectable marker genes) may be
introduced into many plants and therefore be consumed at a
substantial level. Dietary exposure to such proteins should be
considered.
17--Endpoints in Figure 4
17a--No concerns
When this endpoint is reached, safety concerns relative to
intentionally introduced proteins will generally have been
satisfied.
17b--Consult FDA: Allergens
Notes to Figure 4--continued
Producers should consult informally with FDA on protocols
that are designed to assess allergenicity. FDA will work with
the producer on a case-by-case basis to address requirements such
as labeling.
17c--Consult FDA: Toxicity
Producers should consult informally with FDA when a protein
is reported to be toxic or when the safety of an introduced
protein is dependent on processing such as cooking. FDA will
determine on a case-by-case basis whether it will review the food
additive status of these proteins, or whether the proteins are
unacceptable in the new plant variety.
17d--Consult FDA: Function and toxicity
Producers should consult informally with FDA on scientific
issues and design of appropriate test protocols when the function
of the protein raises concern or is not known, or the protein is
reported to be toxic. FDA will determine on a case-by-case basis
whether it will review the food additive status of these
proteins.
17e--Consult FDA: Macroconstituents in the diet
Producers should consult informally with FDA when a protein
is expected to become a macroconstituent of the diet, whether as
a result of its presence in high levels in one food or as a
result of its use in many foods. FDA will determine on a case-by-case
basis whether it will review the food additive status of
these proteins.
2. Carbohydrates
Safety assessment of a new or modified carbohydrate should
be based on the nature of the carbohydrate or modification.
Figure 5
The numbers above each box in the flow chart refer to
accompanying notes that immediately follow the flow chart.
Notes to Figure 5
18--Have any structural features or functional groups been
introduced into the carbohydrate that do not normally occur in
food carbohydrates?
For example, developments that affect carbohydrates will
frequently be modifications of food starches, presumably
affecting the content of amylose and amylopectin, as well as the
branching of amylopectin. Such modified starches are likely to
be functionally and physiologically equivalent to starches
commonly found in food and thus would not suggest any specific
safety concerns. However, if functional groups or structural
features that normally do not occur in food carbohydrates are
introduced, such modifications should be evaluated with respect
to any safety concerns that may arise.
19--Have there been any alterations that could affect
digestibility or nutritional qualities in a carbohydrate that is
likely to be a macroconstituent in the diet?
If a vegetable or a fruit is modified to produce high levels
of an indigestible carbohydrate that normally occurs at very low
levels, or to convert a normally digestible carbohydrate to an
indigestible form, nutritional questions may arise.
20--Endpoints in Figure 5
20a--No concerns
When this endpoint is reached, safety and nutritional
concerns relative to intentional modifications of food
carbohydrates will generally have been satisfied.
Notes to Figure 5--continued
20b--Consult FDA
Producers may consult informally with FDA on scientific
issues. FDA will determine on a case-by-case basis whether it
will review the food additive status of these carbohydrates, and
will work with the sponsor on a case-by-case basis to address
requirements such as labeling.
3. Fats and oils
Safety assessment of a new or modified fat or oil should be
based on its composition and the presence of any unusual
components at levels that would cause safety concern.
Figure 6
The numbers above each box in the flow chart refer to
accompanying notes that immediately follow the flow chart.
Notes to Figure 6
21--Has there been an intentional alteration in the identity,
structure, or composition of fats or oils that are likely to be a
macroconstituent in the diet?
Some alterations in the composition or structure of fats and
oils, such as an alteration in the ratio of saturated to
unsaturated fatty acids, may have significant nutritional
consequences, or result in marked changes in digestibility.
Other changes may produce a fat or oil that has been altered such
that it is no longer representative of fats and oils from the
host species.
22--Are any unusual or toxic fatty acids produced in the new
variety?
For example, safety questions may arise as a result of the
presence of fatty acids with chain length greater than C-22,
fatty acids with cyclic substituents, fatty acids with functional
groups not normally present in dietary fats and oils, and fatty
acids of known toxicity (e.g., erucic acid).
23--Endpoints in Figure 6
23a--No concerns
When this endpoint is reached, safety and nutritional
concerns relative to intentional modifications of fats and oils
will generally have been satisfied.
23b--Consult FDA
Producers may consult informally with FDA on scientific
issues. FDA will determine on a case-by-case basis whether it
will review the food additive status of these fats or oils, and
will work with the sponsor on a case-by-case basis to address
requirements such as labeling.
G. Toxicology
Feeding studies or other toxicological tests may be
warranted when the characteristics of the plant or the nature of
the modification raise safety concerns that cannot be resolved by
analytical methods. FDA recognizes that feeding studies on whole
foods have limited sensitivity because of the inability to
administer exaggerated doses. Because of the difficulty of
designing meaningful studies, FDA encourages companies to consult
informally with the agency about test protocols.
H. Other Information
The information described below is not directly addressed in
the flow charts but should be considered during the development
of new plant varieties.
1. Nucleic acids
Introduced nucleic acids, in and of themselves, do not raise
safety concerns. Thus, for example, the introduction of a gene
encoding an anti-sense ribonucleic acid (RNA) would not raise
concerns about either the gene or the anti-sense RNA. Any safety
considerations would focus on the intended effects of the anti-sense RNA.
Hence, continuing the example, if the anti-sense RNA
were used to suppress an enzyme, then just as for any other
method intended to suppress an enzyme, such as deletion or
nonsense mutations, the metabolic effects on the host plant of
such enzyme suppression should be considered at the conceptual
stage of development and monitored, when appropriate and
feasible.
2. Metabolic considerations
The effects of an intentional alteration of a biochemical
pathway should be considered at the conceptual stage of
development, and monitored when appropriate and feasible. For
example, are there any toxic effects of a metabolic imbalance
with respect to enzyme substrate depletion and product
accumulation? Are any auxiliary pathways likely to be affected?
3. Stability
The genetic stability of the new plant variety and the
inheritance of the introduced genetic material as a single
Mendelian trait are important safety considerations. A safety
assessment of food derived from early generations of the new
variety may not be valid if the new genetic material is expressed
at substantially different levels in subsequent generations.
Factors that favor stability include a minimum number of copies
of the introduced genetic material, and insertion at a single
site.
I. Future Workshop on Scientific Issues
FDA recognizes the desirability of establishing consensus
within the industry, the scientific community, and the public on
the agency's scientific assessment approach to food safety
presented in this guidance section. For this reason, FDA plans
to announce, in a future FEDERAL REGISTER notice, a workshop to
discuss specific scientific issues. The notice announcing the
workshop will include a description of the scientific issues to
be discussed. FDA invites comment on topics that might be
addressed at such a workshop.
VIII. ENVIRONMENTAL CONSIDERATIONS: APPLICABILITY OF NEPA
NEPA requires FDA to consider in its decisionmaking the
environmental impact of its major Federal actions that
significantly affect the quality of the human environment. The
promulgation of a food additive regulation is an agency action
that ordinarily triggers the NEPA requirement for development of
an environmental assessment (21 CFR 25.22(a)(10)) and, if the
agency does not make a finding of no significant environmental
impact, an environmental impact statement is prepared (21 CFR
25.21(b)).
The Council on Environmental Quality (CEQ) regulations (40
CFR 1500 through 1508) provide that in complying with NEPA, an
agency should avoid unnecessary duplication and should tier its
NEPA statements with those of other agencies to eliminate
repetitive discussions of the same issues and to focus on the
actual issues ripe for decision at each level of environmental
review (40 CFR 1502.20 and 1508.28).
Other agencies, particularly USDA and EPA, may prepare NEPA
and other environmental documentation before products are
presented to FDA for a decision. FDA intends to rely on such
documentation to the maximum extent possible.
Under regulations administered by the Animal and Plant
Health Inspection Service (APHIS) in USDA (7 CFR Part 340), the
majority of plants developed by recombinant DNA techniques that
are being commercially developed have been considered "regulated
articles." The action that results in a permit for introduction
of a regulated article into the environment is subject to NEPA
review. At some stage of research and development of a regulated
article, an interested party will request from APHIS a
determination of the article's regulatory status. APHIS has
informed FDA that when APHIS receives a petition or other request
it intends to consult with other agencies. This should enable
FDA to identify the type of data that would be useful if any
subsequent environmental review is to be prepared for actions
under FDA jurisdiction.
EPA has authority, under the Federal Insecticide, Fungicide,
and Rodenticide Act (FIFRA) (7 U.S.C. 136 et seq.), to regulate
all pesticides, no matter how they are made or their mode of
action. Under the act, EPA has authority to regulate pesticide
residues in foods. Any relevant review that EPA conducts under
FIFRA, the act, or any other of its statutes, involving an
assessment of potential effects on human health and the
environment will be available to FDA.
FDA intends to work closely with USDA and EPA to minimize
duplication of environmental reviews. The agency will, to the
extent possible, invoke the tiering provisions in the CEQ
regulations and, in FDA's environmental assessments, rely on
APHIS NEPA reviews and other such documents, as well as relevant
environmental documents considered by EPA. Further, FDA will
provide informal guidance on environmental issues to assist
individuals who are preparing food additive petitions to meet
FDA's requirements for environmental assessments.
FDA does not consider that the activities it may undertake
with respect to foods from new plant varieties other than
promulgation of food additive regulations, such as consultation
with producers on safety issues and providing advice on the
regulatory status of foods from new plant varieties, will
constitute agency action under NEPA.
IX. COORDINATION WITH EPA: PESTICIDE CONSIDERATIONS
Questions have been raised concerning whether FDA or EPA
would have jurisdiction when plants are modified to express
pesticidal substances. FDA and EPA are agreed that substances
that are pesticides as defined by FIFRA (7 U.S.C. section
136(u)), are subject to EPA's regulatory authority. The agencies
also agree that FDA's authority under the act extends to any
nonpesticide substance that may be introduced into a new plant
variety and that is expected to become a component of food.
EPA and FDA are aware that there may be cases in which the
jurisdictional responsibility for a substance is not clear.
Because pesticides, as defined by FIFRA, are subject to EPA's
jurisdiction, the agencies encourage producers who have such
questions to contact EPA. FDA and EPA intend to consult closely
on such jurisdictional questions, as well as on scientific
matters where consultation will be helpful in resolving safety
questions.
The agencies are also aware that, in some circumstances,
evaluation of a particular substance introduced into a plant may
require the expertise of both EPA and FDA. Both agencies agree
that EPA will address under its regulatory jurisdiction the food
safety issues associated with the pesticide, including marker
genes used to confirm the presence of the pesticidal gene. Any
food safety questions beyond those associated with the pesticide,
such as those raised by unexpected or unintended compositional
changes, are under FDA's jurisdiction and should be addressed
under the policy set forth elsewhere in this notice.
Based upon the agencies' current knowledge, examples of
substances that fall under FDA's authority include: (1)
Substances intended to alter the nutritional composition of the
food (e.g., amino acids or carbohydrates); (2) substances
intended to enhance the plant's resistance to chemical herbicides
(e.g., bromoxynil, glyphosate, and sulfonylurea); and (3)
substances intended to alter the flavor or the texture of the
food.
Similarly, based upon the agencies' current knowledge of new
plant varieties being developed using the new technologies of
gene transfer, EPA is in the process of evaluating how or if it
will exert its oversight for the following examples subject to
its jurisdiction under FIFRA and therefore not under FDA's
jurisdiction: (1) Substances that are intended to kill insects
(e.g., Bacillus thuringiensis delta-endotoxin);
(2) substances intended to protect plants from viral, fungal, or
bacterial infection (e.g., cecropin); and (3) substances that
are plant regulators and thus "pesticides" under FIFRA.
X. ENVIRONMENTAL IMPACT
The agency has determined under 21 CFR 25.24(a)(8) 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.
This action is intended to provide guidance to developers by
describing the scientific considerations for the safe development
of foods derived from new plant varieties.
XI. COMMENTS
Interested persons may, on or before (insert date 90 days
after date of publication in the FEDERAL REGISTER), submit to the
Dockets Management Branch (address above) written comments
regarding this notice. Two copies of any comments are to be
submitted, except that individuals may submit one copy. Comments
are to be identified with the docket number found in brackets in
the heading of this document. Received comments may be seen in
the office above between 9 a.m. and 4 p.m., Monday through
Friday.
XII. REFERENCES The following references have been placed on display in the
Dockets Management Branch (address above) and may be seen by
interested persons between 9 a.m. and 4 p.m., Monday through
Friday.
1. Anonymous, "Biotechnologies and
Food: Assuring the Safety of Foods Produced
by Genetic Modification," International Food
Biotechnology Council, Regulatory Toxicology
and Pharmacology, Vol. 12, No. 3, Part 2 of 2
Parts, New York, December 1990.
2. Letter, Hopkins, D. D., R. J.
Goldburg, and S. A. Hirsch to Dr. David
Kessler, September 30, 1991, and enclosure,
"A Mutable Feast: Assuring Food Safety in
the Era of Genetic Engineering."
3. Letter, Richard D. Godown to James
H. Maryanski, January 3, 1992; Letter, W.
Douglas Crabb to Fred R. Shank, January 24,
1992.
4. Comments to Docket No. 90A-0416,
FEDERAL REGISTER, May 1, 1990 (56 FR 20004).
5. Dale, E. C. and D. W. Ow, "Gene
Transfer with Subsequent Removal of the
Selection Gene from the Host Genome,"
Proceedings of the National Academy of
Sciences USA, 88:10558-10562, 1991.
6. Anonymous, "Strategies for Assessing
the Safety of Foods Produced by
Biotechnology," World Health Organization,
Geneva, 1991.
7. Pariza, M. W. and E. M. Foster,
"Determining the Safety of Enzymes Used in
Food Processing," Journal of Food Protection,
46:453-468, 1983.