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,

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

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

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.

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,

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

counterpart

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

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

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

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.

intent that the proposed notification program applies just to plant foods derived

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

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.

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

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

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

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

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

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

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

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

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

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

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

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

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

(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)

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

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

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

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

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

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

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