CU’s comments on Premarket Notice Concerning Bioengineered Foods

Consumers Union’s comments on Docket No. 00N-1396,
Premarket Notice concerning Bioengineered Foods

1, 2001

,* the non-profit publisher of Consumer Reports
magazine, appreciates the opportunity to comment on the FDA’s proposed
policy to require premarket notification for genetically engineered food.


FDA’s proposal to require a Premarket
Biotechnology Notification (PBN) is a very positive step. We agree that FDA
should be notified of any genetically engineered foods that may be introduced
into the marketplace and that sufficient data should be provided with that notification
so that FDA can determine whether the food is safe. This will be increasingly
important as genetically engineered foods are developed in other countries,
potentially including countries without safety assessment programs.

We also agree with FDA’s intent that
these notifications should be made publicly available so that consumers can
have greater confidence in the assessment process. However the proposal that
even the existence of a PBN could be kept confidential seriously undermines
the effectiveness of this system for reassuring consumers. If the existence
of the PBN can be kept secret, then consumers will have no confidence as to
whether the PBNs they are seeing are all, some or only a few of those actually
before the FDA. Consumers may incorrectly assume that the most controversial
PBNs will be the ones that are kept secret. We know of no precedent under the
Freedom of Information Act for keeping the fact of the existence of a document
secret, although FOIA does allow the contents of a document to be withheld as
confidential business information. We therefore urge FDA not to keep the mere
existence of any PBNs confidential.

Beyond this issue, the policies and
procedures which FDA has proposed for what it will require in a PBN, as well
as how it will evaluate those data, need significant strengthening if US consumers,
and the consumers in other countries with whom we want to trade, are to have
confidence in these products and to purchase them.

First, although FDA has indicated
much of the important data that should be submitted in a PBN, we urge some additions.
We urge FDA to pay particular attention to the data requirements listed in the
Proposed Draft Guidelines for the Conduct of Food Safety Assessment of Foods
Derived from Recombinant DNA Plants (Appendix III of ALINORM 01/34A, Draft Report
of the Second Session of the Codex Ad Hoc Intergovernmental Task Force on Foods
Derived from Biotechnology), now at Step 5 in the Codex process, which are under
development at the Codex Ad Hoc Committee on Foods Derived from Biotechnology.
Since this document is emerging as the international consensus for how to conduct
safety assessment, it would be beneficial to the US to include all the data
requirements that it includes, in order to avoid trade disputes in the future.

Second, FDA’s assessment procedure
should be at least as complete and thorough as that outlined in the Codex draft
document. It currently is lacking in a number of regards, as discussed below.
FDA should also make use of the excellent procedures outlined in the report
of the new Joint FAO/WHO Expert Consultation on Allergenicity of Foods Derived
from Biotechnology in assessing allergens. All of this will help assure safety,
increase harmonization with our trading partners, and reassure consumers.

Third, FDA says almost nothing in
this document about the criteria by which it will decide, after reviewing the
data, whether to send a letter indicating it has no further questions and regards
the bioengineered food as safe as a comparable food, or whether it will send
a letter indicating that the PBN does not provide a basis for saying that the
bioengineerd food is as safe as a comparable food. Some clear criteria are needed,
both to reassure the public that FDA has clear standards for safety and to indicate
clearly to companies what they can expect when they come to a safety review.
In our comments below we suggest some clear benchmarks, including:

1. GE foods should not have higher levels of natural toxins than their non-engineered
2. GE foods should not contain a known allergen which is not present in the
non-engineered counterpart.
3. GE foods should not contain an antibiotic marker gene in the finished product.
4. GE foods should not have significant reductions in levels of nutrients for
which the non-engineered counterpart is an important source in the diet.

Consumers Union continues to urge
the FDA to establish a mandatory process to assure the safety of genetically
engineered food, designed to achieve a standard of "reasonable certainty
of no harm." We believe the most practical way to do that would be to subject
all genetically engineered foods to a food additive review.

If FDA does not take this course,
however, then its proposed procedure must be strengthened in the manner we outline
above, and describe in more detail below.

Basis for Rule

The FDA’s proposal is a significant
step forward from the 1992 Policy in that it explicitly recognizes that genetic
engineering does differ from traditional breeding in a number of ways that can
affect food safety and so requires greater scrutiny of foods developed via biotechnology
or genetic engineering. Further it acknowledges that the results of each transformation
event are unique, so that data should be submitted for each transformational

Consumers Union agrees with the
FDA that it should require a premarket notification, as well as requiring "the
submission to the agency of data and information regarding plant-derived bioengineered
foods that would be consumed by humans or animals." We do not think that
it is adequate to have a voluntary consultation regarding these data, however.
Instead there should be a mandatory review and approval process.

Detailed comments on the various
sections of the proposed rule follow.

Sec. 192.1 Definitions

Consumers Union believes that the
five definitions proposed by FDA are clear and are consistent with the agency’s
intent that the proposed notification program applies just to plant foods derived
from genetic engineering/ bioengineering.

192.5 Requirement for premarket
biotechnology notice

We agree with the agency that companies
should be required to notify FDA about bioengineered foods derived from a new
plant variety engineered to contain a pesticidal substance, even though EPA
has regulatory control of such substances. This is a reasonable request as it
would facilitate discussion between FDA and EPA about such crops and what scientific
and regulatory issues are within the scope of EPA’s authority under FIFRA and
which are not.

We agree with the agency that notice
should be required for foods from each separate transformational event for exactly
the reason that FDA states: "[B]ecause some rDNA-induced unintended changes
are specific to a transformational event (e.g. those resulting from insertional
mutagenesis), FDA believes that it needs to be provided with information about
foods from all separate transformational events, even when the agency has been
provided with information about foods from rDNA-modified plants with the same
intended trait and has had no questions about such foods" (FR 66(12), pg.
4711). This is a scientifically sound approach to the issue.

We also agree with the agency that,
in general, foods derived from narrow crosses should not be subject to the mandatory
notification program. However, we do not believe that this exemption should
include narrow crosses between different rDNA-modified lines or between a rDNA-modified
line and an untransformed line. Since it is known that the genetic background
of a given crop line can influence expression levels, stability, etc. of a transgene
(that’s why the transformational events are more successful with certain plant
lines or varieties than with others), it’s possible that even though a transgene
is stable in one plant line or variety, crossing that line with another non-engineered
line, could lead to the genetic insert becoming unstable or to altered expression
levels (see Hansen, 2000 or Ho, 2000 for further discussion of this point).

Since we do not believe that narrow
crosses between different rDNA-modified lines or between a rDNA-modified line
and an untransformed line should be exempted from the mandatory notification
program, we do not agree with FDA’s proposal to exclude from the notification
requirement a bioengineered food that satisfies the three conditions that: i)
the bioengineered food derives from a plant line that represents a transformation
event addressed in a PBN previously submitted to FDA, ii) the use of the engineered
food has already been addressed in a previous PBN, and that iii) FDA provided
a letter saying that they have evaluated the use of the bioengineered food and
have no questions about it. All bioengineered foods should be subject to the
requirement and there should be no exemptions.

192.10 Recommendation for presubmission consultation

We disagree with FDA’s proposal to
allow the fact that a company is consulting with the FDA to be confidential,
along with all the data or other information in the administrative file. Allowing
the fact that a company is consulting with the FDA to be confidential will not
ensure the trust of consumers. Indeed, allowing both the fact that a company
is consulting with the FDA and the existence of a PBN to be confidential will
seriously undermine public trust in the actions of the agency.

192.20 Premarket biotechnology notice: Administrative information

We think it is a good idea for the
FDA to require an electronic copy of a disclosure PBN formatted in such a way
to facilitate the FDA making it available in an electronic reading room for
public access. We do not believe that any exemptions should be granted. We believe
that the FDA’s argument that "it is possible that a firm that develops
a bioengineered food would not have access to the particular [computer] technology
that will be needed" to produce an electronic copy strains credibility
to the breaking point. Surely, if a company has the technology to create a genetically
engineered/bioengineered food, they also must have computers and the appropriate
software to create an electronic copy.

192.25 Premarket biotechnology notice–required parts:

FDA should dramatically change section
192.25(a)(4). We do not believe that the existence of a PBN or "all of
the data or other information in your PBN" should be confidential. While
it is conceivable that some data or information in the PBN may be confidential,
we don’t think that blanket confidentiality should be permitted as this will
only undermine what credibility the FDA has with consumers. In addition, none
of the health or safety data should be confidential.

Section 192.25(b)(5) needs to explicitly
recognize that significant changes, due to insertional mutagenesis, may be unexpected
as well as expected. Thus, FDA should alter the second sentence so that it reads
(suggested changes in bold): "This includes expected and unexpected significant
changes in the composition or characteristic properties of food derived from
the plant as a result of a transformation event, regardless of whether these
changes result from the insertion of new genes or from the modification in the
expression of endogenous genes or from any unexpected effect due to insertional
mutagenesis or pleiotropy." We feel these changes are needed as the sentence,
as originally written, is a bit ambiguous and could be interpreted in such a
way that the company may not realize that they need to look for effects of pleitropy
or insertional mutagenesis.

Section 192.25(c) We agree with
the FDA that the PBN should include
the status of the engineered food at other Federal agencies and foreign
governments as well. We are particularly glad that the FDA will require
that foods imported from other countries go through the same process as
foods grown in this country as this is very important to safety in the marketplace,
and there is no other review that imported food products would have to go through
in the US.

Section 192.25(d). This section
on the data or information about the method of development of the food should
be expanded and should be made consistent with the material laid out in paragraphs
20 to 31 of Appendix III of ALINORM 01/34A, (Proposed Draft Guideline for the
Conduct of Food Safety Assessment of Foods Derived from Recombinant DNA Plants)
included in the "Draft Report of the Second Session of the Codex Ad Hoc
Intergovernmental Task Force on Foods Derived From Biotechnology." Paragraphs
20 to 31 in Section 4 cover General Considerations, Description of the New Variety
(para 20), Description of the Host Plant and its Use as a Food (para 21-23),
Description of the Donor Organism (para 24), Description of the Genetic modification(s)
(paras 25-27) and Characterization of the Genetic Modification(s) (paras 28-31).
By requiring these data and information, FDA could harmonize their requirements
with those that are being proposed at a global level through Codex, thus reducing
the potential for trade disputes. The US data requirements should not in any
case be less stringent than those for other countries, given that it has always
been the goal of US food safety regulators to have the safest food supply in
the world.

Section 192.25(d)(3) and (4). In
section (3), in addition to the material presented above, we feel that the FDA
should also require data indicating the location of the introduced genetic material
and the identity of the flanking DNA sequences. In particular, FDA should require
the identity of flanking sequences 10kb upstream and downstream at each insertion
site including methylation patterns (see Hansen, 2000 for more details). For
section (4), on inheritence and genetic stability of the introduced material,
we feel the FDA should be more specific about what they will require. To determine
stability, FDA needs data on both functional stability (level of expression
remains constant over time and over successive generations) and structural stability
(location in the genome and structural arrangement of the insert). For functional
stability, FDA would need data on the level of expression of the transgene over
time-throughout the lifetime of the plant as well as over a number of generations
(say 3 to 5 generations). For structural stability, the FDA would need data
on the physical location of the insert in the genome as well as the structure
of the insert-throughout the lifetime of the plant as well as over successive
generations (say 3 to 5). In addition, the FDA should require appropriate molecular
probes for each insert with flanking host genome (organelle sequence) sequences
in order to monitor the structural stability of the insert.

Section 192.25(e) We do not believe
that genes that encode for resistance to antibiotics should be permitted in
the plant approved for planting. There is no reason why such added genes need
to be in the released plant variety. Not only are there other marker genes that
can be used, but the technology also exists that to remove the marker gene prior
to commercialization. Also, we note that the EU is planning on phasing out antibiotic
resistance marker genes by 2005.

Section 192.25(f). Between sections
(3) and (4), on dietary exposure levels and allergenicity respectively, a new
section should be added on toxicity assessment of introduced substances (non-nucleic
acid substances). We feel that a number of toxicity studies should be required,
including acute toxicity, chronic toxicity/carcinogenicity, impact on reproductive
function including endocrine disruption, teratogenicity and neurobehavioral
effects. For these toxicity studies, the new substance should be isolated from
the recombinant DNA plant and not synthesized or produced from an alternative
source such as bacteria. The reasons for this are spelled out in our previous
comments to the agency (Hansen, 2000). If the engineered substance is a protein,
we know that post-translational processing, which consists of the modification
of a protein after it has been translated from the genetic message, can have
a significant impact on the structure and function of a gene product. Furthermore,
post-translational processing can differ between organisms, so that the same
gene expressed in different genetic backgrounds may have the same amino acid
sequence but may differ in structure and function, or it may have a different
amino acid sequence. Examples of such post-translational processing include
glycosylation and acetylation. Indeed, bacteria do not glycosylate proteins
while plants usually do. This is important as many allergens are glycoproteins.
Some bacteria, such as E. coli, may also acetylate some of the lysine to form
an amino acid, epsilon-N-acetyllysine, not usually found in plants or animals.

Section 192.25(f)(4). For the testing
of potential allergenicity of the newly-expressed protein(s), the agency should
require the companies to perform the tests as proposed in the most recent Joint
FAO/WHO Expert Consultation on Allergenicity of Foods Derived from Biotechnology
(FAO 2001). At present, the agency uses a decision-tree strategy which relies
on various criteria used in combination, since no single criterion is sufficiently
predictive. The present decision-tree strategy used by FDA was proposed back
in 1992 and needs to be updated. The most recent Joint FAO/WHO Expert Consultation
on Allergenicity of Foods Derived from Biotechnology (FAO 2001) includes a strong
critique of the inadequacies of the older decision-tree strategy, particularly
the one being used by FDA, and suggest new criteria. Since this is the most
up-to-date thinking in the area, and given that the Joint FAO/WHO Expert Consultation
on Allergenicity was chaired by an American who is the head of the NIH’s National
Institute for Allergy and Infectious Disease, we feel that the decision-tree
proposed by this consultation should be the one used by FDA as well.

Section 192.25(g). This entire section
deals with information (composition and characteristics) about the whole food,
aside from the introduced substance, which is then compared to a "comparable
food." Sub-section (1) includes the justification for selecting a food
or foods as the "comparable food" to which the notifier (i.e. company)
will compare the genetically engineered food. It is essential that the comparator
should be a conventional counterpart and not consist of a genetically engineered
line. This is important because there are concerns about the potential unexpected
effects associated with insertional mutagenesis that we do not feel the agency
will adequately consider before approving an engineered plant. Indeed, the agency
required none of these data from the companies for the 45 products already on
the market (which we do not think have been adequately looked at vis-a-viz safety
issues). Ideally, the comparator(s) used in the assessment should be the near
isogenic parental line. If this is not feasible, a line as close as possible
to the isogenic parental line should be chosen. Furthermore, the comparator
should be grown and harvested under the same conditions. In some cases, a further
comparison with the recombinant DNA plant grown under its expected agronomic
condition should be required (e.g. application of an herbicide). Since the vast
majority of the acreage in transgenic crops in the US contain the trait for
herbicide tolerance, such testing is of crucial importance and has not been
required in the past.

Section 192.25(g)(3). This subsection
deals with specific composition and characteristics. Sub-subsection (i) and
(ii) "Levels of significant nutrients" and "levels of naturally
occurring toxicants and antinutrients" need to be more fully explained.
We feel that this should include both key nutrients and key anti-nutrients,
which may be defined as those components in a particular food that may have
a substantial impact in the overall diet. They may be major constituents (fats,
proteins, carbohydrates as nutrients or enzyme inhibitors as anti-nutrients)
or minor compounds (minerals, vitamins).

Section 192.25(g)(4). This sub-subsection,
"Any other information relevant to the safety, nutrition or other assessment
of the bioengineered food," is a bit vague. As FDA correctly points out,
genetic engineering can lead to unintended effects due to insertional mutagenesis.
Indeed, that is why the agency is requiring data from each separate transformational
event. So, the agency should require the company developing the new seeds to
look explicitly for such unintended consequences in the whole food. This could
be done by the use of metabolic and protein profiling, and DNA or mRNA profiling.
To capture this, the sub-subsection could be modified by adding the words "including
any unintended changes to the composition of the food" at the end of the
phrase, i.e. after "bioengineered food."

We also feel that the agency should
require that the PBN include methods by which the bioengineered food could be
detected. This would include a method for detecting the inserted DNA sequence
as well as a method for detecting the introduced substance. Such a requirement
would be very useful in traceability of the food, as well as serving to tell
when there is unexpected gene flow. Since there is a developing market for non-transgenic
or non-engineered food, and since organic foods cannot contain any genetically
engineered ingredients, a test would be needed to determine when the foods destined
for GE-free markets have been contaminated. In addition, many countries have
not approved genetically engineered foods and have laws that state that unless
such foods are explicitly approved, it is illegal for them to be on the market.
Since the US has approved more engineered varieties than any other country,
some of it may be illegal to ship to other countries. For example, not all the
varieties of engineered corn approved in the US have been approved in the EU.
The result is that the US has lost a $300 million corn export market to the
EU. Shipments of food have already been rejected at foreign ports due to contamination
with unapproved varieties, eg., the StarLink fiasco. So detection methods should
absolutely be required. Furthermore, the detection methods should be available
for the raw agricultural commodity as well as the representative finished product.
We feel that the detection methods should include one for testing the presence
of the inserted DNA as well as one for the expressed product. For the former,
we suggest the use of a PCR (polymerase chain reaction) test as this is the
most sensitive test to date. To facilitate such testing, the agency should require
that the complete identity of the primer sequences be made available so that
technically-proficient non-governmental laboratories can use them. The agency
should require that the detection methods are adequate for detecting the presence
of the inserted DNA and its expression products at the level at which it will
appear in the food and that the test is of a reasonable cost. This requirement
could be done along the lines of the detection method that is required when
a new drug or pesticide is put on the market.

Section 192.30 FDA evaluation and response

In 192.30(d), the agency lays out
the four types of letters that it may send to a notifier. In 192.30(d)(2), the
agency would send a letter stating that "the premarket notice doesn’t provide
a basis for your [the notifier] view that the bioengineered food is as safe
as comparable food or is otherwise in compliance with all applicable requirements
of the act" (FR 66(12), pg. 4733). With the present proposed mandatory
notice and voluntary consultation process, there are no criteria or endpoints
indicated for the review. FDA should explicitly state what data might lead it
to the conclusion that the product is "not as safe as" its conventional
(comparable) counterpart. There is no indication of what data would cause FDA
to say that the bioengineered plant was not as safe as its traditional counterpart
for consumption. FDA does foresee both the possibility of inadequate data to
make a safety determination and the possibility that the submitted data are
adequate but demonstrate lack of safety (Section 192.30(d)(2)), but FDA does
not lay out the criteria that would cause is to say the latter.

We suggest inclusion of a number
of criteria data that would indicate lack of safety, including: animal feeding
studies, or other laboratory studies, that show the introduced substance is
a mutagen, teratogen, reproductive toxin, carcinogen, or endocrine disruptor;
animal feeding studies of the introduced substance or whole food that show acute
toxicity; the final product containing an antibiotic resistance gene (i.e. it
has not been removed prior to approval); the product contains a known allergen
which isn’t present in the traditional counterpart; and the food or plant showing
statistically significant reduction in levels of a nutrient important in the
diet for which the food is a major source of that nutrient.

The lack of explicit criteria for
deciding when a food is not as safe as its traditional counterpart is good neither
for the public nor for the companies themselves. The lack of explicit criteria
does not reassure the public that the FDA has adequately determined whether
the food is as safe as its conventional counterpart. This lack is also not in
the interests of the companies that want to commercialize this technology as
they do not get a clear idea of what FDA’s criteria for evaluating the data
are or even what the pass/fail criteria may be.

Section 192.40 Public Disclosure

We strongly disagree with FDA’s
proposal to allow the fact that a company is consulting with the FDA to be confidential,
along with all the data or other information in the administrative file. Allowing
the fact that a company is consulting with the FDA to be confidential will not
ensure the trust of consumers. Indeed, allowing both the fact that a company
is consulting with the FDA and the existence of PBN to be confidential will
only undermine public trust in the actions of the agency. We are unaware of
other examples where the existence of a consultation can be kept confidential.
The only case we can think of is that until a decision is made on a new human
or animal drug, the FDA keeps all the information confidential and will neither
confirm nor deny that a particular drug is going through the approval process.
Furthermore, none of the health or safety data submitted to FDA should be allowed
to be considered confidential business information (CBI).


Hansen, M. 2000. Consumers Union’s
comments on Docket No. 99N-4282, Biotechnology in the Year 2000 and Beyond;
Public meetings. January 13, 2000; 21 pp.


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