Vol. 57 No. 104 Friday, May 29, 1992 p 22984
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 August 27, 1992.
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{1} derived from
new plant varieties,{2} including but not limited to plants
developed by new methods of genetic modification.{3}
³{1} "Food" means (1) Articles used for food or drink
³for man or other animals, (2) chewing gum, and (3) articles
³used for components of any such article (section 201(f)
³of the act (21 U.S.C. 321(f))). "Food" includes human
³food, substances migrating to food from food-contact
³articles, pet food, and animal feed (21 CFR 170.3(m)).
³"Animal feed" means "an article which is intended for
³use for food for animals or other than man and which
³is intended for use as a substantial source of nutrients
³in the diet of the animal, and is not limited to a mixture
³intended to be the sole ration of the animal" (section
³201(x) of the act (21 U.S.C. 321(x)).
³{2} "Variety" is used here as a general term to describe
³subgroups (whether varieties or cultivars) of plants
³within a species developed for desirable traits.
³{3} "Genetic modification" means the alteration of the
³genotype of a plant using any technique, new or traditional.
³"Modification" is used in a broad context to mean the
³alteration in the composition of food that results from
³adding, deleting, or changing hereditary traits, irrespective
³of the method. Modifications may be minor, such as a
³single mutation that affects one gene, or major alterations
³of genetic material that affect many genes. Most, if
³not all, cultivated food crops have been genetically
³modified.
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 the 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 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 commerical 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(TM) 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 to 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{4} 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.
³{4} A line is a group of individuals from a common ancestry.
³It is a more narrowly defined group than a variety. (Breeding
³Field Crops, J.M. Poehlman, Van Nostrand Reinhold, New
³York, 1987.
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 amendable 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 conferee
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 potential to create
unexpected (including pleiotropic{5} 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.
³{5} Pleiotropic effects refer to multiple effects resulting
³from a single genetic change.
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 acuate 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 seek 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 allergencity
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 of 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 inactives 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. 1 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 required 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
regulary 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 U.S.C. 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.
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.
>>>> See the accompanying hardcopy volume for non-machine-readable
data that appears at this point. (Figure 1. Safety Assessment of
New Varieties: Summary) <<<<
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.
>>>> See the accompanying hardcopy volume for non-machine-readable
flow chart that appears at this point. <<<<
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 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 characteristic
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 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 are
needed 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.
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.
>>>> See the accompanying hardcopy volume for non-machine-readable
flow chart that appears at this point. <<<<
Notes to Figure 3
6-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 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.
>>>> See the accompanying hardcopy volume for non-machine-readable
flow chart that appears at this point. <<<<
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:
a. The introduced protein is not derived from a food source,
or is not substantially similar to an edible protein;{6}
³{6} The issue of potential allergenicity of any new protein
³(as opposed to the allergenicity of a protein derived
³from a known source of allergens) is frequently raised.
³FDA recognizes that routine procedures for testing foods
³derived from new plant varieties for the presence of
³unknown allergens are not currently available. If the
³donor has no history of use in food, the issue of allergenicity
³cannot be addressed at this time. Comparison of gene
³sequences to data banks of known allergens may become
³increasingly useful as the information on such proteins
³expands. FDA invites comments on methods that may be
³available to address the issue of allergenicity of new
³proteins in foods.
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{7} 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).
³{7} Pariza and Foster (Ref. 7) note that very few toxic
³agents have enzymatic properties. Exceptions include
³diphtheria toxin and certain enzymes in the venom of
³poisonous snakes.
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 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){8} 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.
³{8} The nutritional content of seed storage proteins
³from some crops is particularly important in the case
³of animal feed, where one crop may furnish a substantial
³portion of the diet.
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.
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.
>>>> See the accompanying hardcopy volume for non-machine-readable
flow chart that appears at this point. <<<<
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.
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.
>>>> See the accompanying hardcopy volume for non-machine-readable
flow chart that appears at this point. <<<<
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 Consideration: 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 August 27, 1992, 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, 1991 (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.
Dated: April 2, 1992.
David A. Kessler,
Commissioner of Food and Drugs.
[FR Doc. 92-12660 Filed 5-26-92; 3:57 pm]
BILLING CODE 4160-01-M
| File Type | application/msword |
| File Title | Vol |
| Author | ATaylor |
| Last Modified By | DPresley |
| File Modified | 2011-07-06 |
| File Created | 2011-07-06 |