The Scientific Advice that FDA Ignored – A Compilation
The United States claims to have the most rigorous regulation for GMOs.
But the Bio-Integrity lawsuit against the US Food and Drug Administration
uncovered secret memoranda showing how the FDA has ignored all the strongly worded
advice given by its own scientists;
New and unique risks from GMOs
- unintended effects due to random insertion of foreign DNA
- rearrangements of foreign DNA
- unexpected activation of metabolic pathways to produce toxins and allergens
- horizontal transfer of antibiotic resistance marker genes
The first GMO to be approved, Calgene’s Flavr Savr tomato, failed FDA’s toxicological
tests, and the question of safety was never resolved by the agency.
The records show that the agency has known all along that chemical analysis is
inadequate for proving the safety of GMOs. Furthermore, the potential health hazards
posed by the use of antibiotic resistance marker genes was also ignored, despite
clear warnings from FDA Public Health Services.
These records make scandalous reading and prove that I-SIS and other groups of
scientists were not the first to highlight GM food safety issues. US Government needs to
resolve these safety issues, raised by his own scientists in the first place, and which
remain outstanding to this day.
Scientific Advice given by FDA Scientists 1991-93
October 28 1991- Comments made by Dr Edwin J Mathews, FDA Director of Toxicology Review
and Evaluation, Dept of Health and Human Services to James Maryanski, Biotechnology
Coordinator on the revision of toxicology section of the ‘Statement of Policy: Foods
Derived from Genetically Modified Plants’.
On the ‘Safety of whole food plants transformed by technology methods’ he writes;
- 'An analysis of all major toxins that have been identified to occur naturally in
the edible part of the plant that has been transformed, or of its close relatives, should
be done to show that no change has occurred as compared to the natural parent or
- 'Results from an appropriately designed 28-day feeding study in swine that show
that the edible portion of the transformed plant causes no acute toxicity. End points to
be examined include the usual general screen done for 28-day animal studies. These include,
but are not limited to effects on 1) weight gain 2) organ function, 3) electrolyte levels,
4) metabolism and 5) gastrointestinal tract.
On the ‘Analysis of Major Plant Toxins’ he writes;
- 'A GE plant may contain an identical profile of expected plant toxicant levels
(i.e. expected toxicants) as is normally found in a closely related, natural plant.
However, genetically modified plants could also contain unexpected high concentrations of
plant toxicants. The presence of high levels of toxicants could be amplified through
enhancement of toxicant gene transcription and translation. This might occur as a result
of up-stream or down stream promotion of gene activities in the modified plant DNA.
In addition, plant toxicant genes, which were normally inactive, could be expressed in the
modified plant gene as a result of insertion of the new genetic material (i.e. positional
mutagenesis). Thus, the task of analysis of all major toxins in GE plants food include
the assessment of both expected toxicants and unexpected toxicants that could occur in the
modified plant food. The unexpected toxicant could be closely related chemicals produced
by common metabolic pathways in the same plant genus/species; however, unexpected toxicants
could also be uniquely different chemicals that are usually expressed in unrelated plants.
- 'The task of assessing the presence or the absence of expected and unexpected plant
toxicants…could be very difficult, because thousands of plant biochemicals have been shown
to have toxic effects on animals and microorganisms. While all these plant toxicants could
conceivably be harmful to man by direct ingestion of plant food, or indirectly by ingestion
of animal by products that had consumed plants containing toxicants, the agency’s primary
concern is for plant toxicants that could be present in common plants foods.'
- 'Analysis of expected and unexpected plant toxicants can be achieved using either
chemical/biochemical methods of toxicological bioassays. Chemical/biochemical methods have
a high sensitivity for detecting the level of an individual toxicant, but their
quantification of toxicant levels require extraction and purification of toxicants from
plant cell homogenates. Unfortunately, purification procedures permit the detection of
one toxicant while simultaneously destroying or excluding the detection of additional
toxicants. Furthermore current technology has purification procedures for only a fraction
of known plant toxicants.'
- 'Alternatively, toxicological bioassays could be used to simultaneously detect
both expected and unexpected toxicants. Based on our current knowledge…these toxicants
should elicit toxic effects in two types of assays….First, a portion of the plant toxicants
would …be mutagenic in Salmonella typhlmurium reverse mutagenesis assay…Second,
rats and swine would be expected to be sensitive to the toxicological effects of most
plant glycoside-,alkaloid-,protein and phenolic-toxicants….Furthermore, the 28-day study
should be optimised to detect hepatotoxicity, toxicity to certain sensitive organs (i.e.
gastrointestinal tract, pancreas, spleen and thyroid), anti-nutritive effects (e.g. growth
retardation) , and specific clinical chemistry tests (anemia, electrolytes etc).
November 1st 1991 - Comments from the Division of Food Chemistry and
Technology and Division of Contaminants Chemistry on the points to consider for safety
evaluation of GM foods, to James Maryanski, Biotechnology Coordinator.
- 'All the above marker genes produce proteins that are new with respect to
plants… They should be considered to be new proteins in the human diet and be subjected
to safety evaluation. Because the marker genes are inserted randomly in the plant genome,
each insert behaves essentially as a separate gene. As a result, subsequent crosses between
two independently obtained transformants may lead to the amplification of a marker gene
in the progeny. This possibility should be taken into account in the projections of
exposure to any protein, especially however, to proteins produced by the marker genes
because they are used repeatedly within the same species.'
- 'The insertion of any DNA into the plant genome may result in various phenotypic
changes (desirable or undesirable) referred to as pleiotropic effects. Undesirable
phenotypes may include, for example, poor growth, reduced levels of nutrients, increased
levels of natural toxicants etc. Pleiotropic effects occur in GE plants obtained with
Agrobacterium-mediated transformation at frequencies up to 30%….Some undesirable effects
such as increased levels of known naturally occurring toxicants, appearance of new, not
previously identified toxicants; increased capability for concentrating toxic substances
from the environment e.g. pesticides or heavy metals and undesirable alterations in the
levels of nutrients may escape breeders attention unless GE plants are evaluated
specifically for these changes. Such evaluations should be performed on a case-by-case
basis, i.e. every transformant should be evaluated before it enters the marketplace.
[A similar approach was recommended by the International Food Biotechnology
- 'Toxicological evaluation of the edible plant tissue may be more appropriate
than using chemical identification and quantitative procedures.'
Jan 3 1992 - Dr Linda Kahl writes to Dr James Maryanski, the FDA Biotechnology
Coordinator and comments on the Federal Register document 'Statement of Policy:
Foods from genetically modified plants'.
- 'The current document (particularly the section on scientific issues and the
appendix) is very schizophrenic in regard to the objective. The June 1986 Coordinated
Framework does not seem to be so concerned with traditional methods and makes no apologies
for discussing only biotechnology….It notes that the framework seeks to distinguish
those organisms that need review and those that do not…So why can’t that current appendix
deal only with new biotechnology? Why try to make it appear that we are discussing all
- 'I believe that there are at least two situations, relative to this document, in
which it (FDA) is trying to fit a square peg into a round hole. The first square peg in
the round hole is that the document is trying to force an ultimate conclusion that there
is no difference between foods modified by GE and food modified by traditional breeding
- 'The processes of GE and traditional breeding are different, and according to the
technical experts in the agency, they lead to different risks.'
- 'The ‘Points to consider’ for products of GE must be different than the '
points to consider' for products of traditional breeding. How can you expect a
traditional breeder to have the most basic molecular data (e.g. DNA sequences of the
inserted material), when he has no idea of the molecular identity of the genetic material
being introduced? Are we to insinuate that practitioners of GE do not need to adhere to
the most basic level of good laboratory techniques simple because the traditional breeding
community cannot also provide that data?'
- 'The second square peg in a round hole is that the approach, of at least part of
the document, to use a scientific analysis of the issues involved to develop the policy
statement. In the first place, are we asking the scientific experts to generate the basis
for this policy statement in the absence of any data?…It’s an exercise in hypothesis
forced on individuals whose jobs and training ordinarily deal with facts'.
- 'I do not think that the scientific analysis as presented is complete. The
scientific issues section of the document talks of the 'possibility of unintended,
accidental changes in GE plants' but I believe that in most cases the word
'risk' is avoided.'
- 'Surely the following series of events must all occur in order to present a
danger to the public health: (1) The accidental change must activate a pathway for
production of a toxin that was unanticipated, or for which there is no suitable analytical
method. (2) This unanticipated toxin must be expressed at a high enough level to exert an
effect. (3) This toxin must have serious adverse consequences to humans and or animals
that consume it. (4) The presence of this dangerous unanticipated toxin in amounts
sufficient to cause a public health problem must not manifest itself in any other way, so
that the first and only clue will be the 'body count' so to speak.'
- ' I wonder if part of the problems associated with this approach – using
scientific issues to set the stage for the policy statement – are due to the fact that
the scope of the technical experts assigned to the project did not include any whose
usual job is risk analysis.'
- 'Are there any alternatives to toxicology testing that could tip the scales to
a level where the modified food can meet a safety standard of reasonable no harm? My
impression is that the limitation of the number of insertion sites to one is not
sufficient – what does that actually tell you about safety?'
Jan 8th 1992 - Points made by Dr Mitchell Smith, FDA Department of Health
and Human Services to James Maryanski, biotechnology coordinator. Re; Comments of draft
Federal Register Notice on Food Biotechnology (Draft 12th Dec 1991).
- 'My general conclusion is that the issue turns the conventional connotation of
‘Food Additive’ on its head. It also conveys that the public need not know when it is
being exposed to ‘new food additives’, for lack of a better descriptor.'
- 'The statement ‘organisms modified by modern molecular and cellular methods are
governed by the same physical and biological laws as are organisms produced by classical
methods’ is somewhat erroneous because in the former, natural biological barriers to
breeding have been breached.'
- 'The statement 'to the extent that it is known' begs the question as to
what degree of identification and toxicological evaluation is sought or prudent. In this
instance ignorance is not bliss.'
Jan 31 1992 - Comments by Dr Samuel I Shibko, Director of Toxicological Review and
Evaluation, Dept of Health and Human Services (FDA), to Dr James Maryanski – the
biotechnology coordinator, on the Draft document - Revision of Toxicology Section of the
Statement of policy: foods derived from GM plants.
- 'At this time it is unlikely that molecular and compositional analysis can
reasonably detect or predict all possible changes in toxicant levels or the development of
new toxic metabolites as a result of GM. FDA believes that, until sufficient time and
experience with the new techniques of gene transfer have accumulated, the possibility of
unexpected, accidental changes in GE plants justifies a limited traditional toxicological
study. This study would provide the basis for assuring the absence of any new highly toxic
materials that are not present in the parental plant variety, and would establish the
wholesomeness of the food for subsequent limited studies in humans. Addition assurance of
safety would be provided by in vitro genotoxicity and digestion studies with the
food or appropriate extracts.'
Feb 5th 1992 - Points made by Dr Gerald B. Guest, Director, Centre of
Veterinary Medicine FDA to Jame Maryanski on the regulation of transgenic plants – FDA
draft Federal Notice on Food Biotechnology.
- 'It has always been our position that the sponsor needs to generate the appropriate
scientific information to demonstrate product safety to humans, animals and the environment
. … Generally, I would urge you to eliminate statements that suggest that the lack of
information can be used as evidence for no regulatory concern.'
- 'We believe that animal feeds derived from GM plants present unique animal and
food safety concerns.'
- 'Unlike the human diet, a single plant product may constitute a significant
portion of the animal diet. For instance, 50-75% 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
- ' Animals consume plants, plant parts and plant byproducts that are not consumed
by humans. For example, animals consume whole cotton seed meal, whereas humans consume
only small amount of cottonseed oil. Gossypol, a natural toxicant, is concentrated in the
cotton seed meal during the production of cotton seed oil. Since plant byproducts
represent an important food source for animals, it is important to determine if significant
concentrations of harmful plant constitutes or toxicants are present in the transgenic
- 'The use of antibiotic-resistance genes as selectable markers in transgenic
plants must be reviewed to determine the effect on animal therapeutics. For example, the
enzyme product of the kanamycin resistance gene… inactivates the antibiotic neomycin, which
is used in feed and drinking water of animals.'
- 'Nutrient composition and availability of nutrients in feed are extremely
important to the animal industry and animal health. If GM makes a higher percentage of a
nutrient unavailable…for example, if an unintended effect of modification of soybeans was
increased content of phytin, the amount of phosphorus available could be greatly reduced.
Animal health problems could result unless the diet were supplemented with phosphorus.
- 'Residues of plant constituents or toxicants in meat and milk products may pose
human food safety problems.'
On Toxicology – Target animal safety feeding study
- 'Sponsors with products to be incorporated into animals feeds should conduct
appropriately controlled feeding studies in the target animal comparing the new plant
variety to the conventional plant. The study should be of sufficient size and duration to
provide adequate statistical power to detect adverse effects should they occur.'
27 Feb 1992 - Comments on FDA ‘Biotechnology Draft Document’ by Dr Louis J. Pribyl.
- 'What has happened to the scientific elements of this document?. Without a
sound scientific base to rest on, this becomes a broad, general ‘what do I have to do to
avoid trouble - type document. The examples do not supply the scientific rational that
is needed. A scientific document is needed, because there is very little (even when
things are called scientific) scientific information supplied. If the FDA wants to have
a document based upon scientific principles these principles must be included, otherwise
it will look like and probably be just a political document.'
- 'It reads very pro-industry, especially in the area of unintended effects'.
- 'There is a profound difference between the types of unexpected effects from
traditional breeding and genetic engineering, which is just glanced over in this
- 'The flow charts are just a version of a Redbook, hoops through which industry
must jump, and are not scientific considerations. Industry will do what it HAS to do to
satisfy the FDA 'requirements' and not do the tests that they would normally do
because they are not on the FDA’s list'.
- ' How many 'first' examples will have to be examined? First examples
of what – new genes; new types of modifications: genes from organisms from other kingdoms:
first submissions. Also in order not to be sued by the 'first' group of
submitting biotech companies, who will be required to submit data when others later on
will not. What will they receive for being the guinea pigs? (After all even those who do
not submit will also have the implicit seal of approval from the FDA if they 'follow
' the code of practice.) … 'First' examples again, who decides when enough
is enough? Industry? FDA? Congress? Safety? The president? The council for Competitiveness?
- 'If there is no difference between traditional foods and genetically engineered
foods, then why would that FDA even bother to challenge them: unless it is really saying
that they are in fact different.'
- 'Is it really feasible to think that breeders would freely (without some sort of
urging) back-cross to get only one chromosomal location, unless there was interference
with the desired outcome. And besides multiple copies inserted at one site could become
potential sites for rearrangements, especially if used in future gene transfer experiments,
and as such may be more hazardous.'
- 'Unexpected effects - This is industries pet idea, namely that there are no
unintended effects that will raise the FDA’s level of concern. But time and time again
there is no data to back up this contention, while the scientific literature does contain
many examples of naturally pleiotropic effects. When the introduction of genes into plant’s
genome randomly occurs, as is the case with the current technology (but not traditional
breeding), it seems apparent that many pleiotrophic effects will occur. Many of these
effects might not be seen by the breeder because of the more or less similar growing
conditions, in the limited trials that are performed. Until more of these experimental
plants have a wider environmental distribution, it would be premature for the FDA to
summarily dismiss pleiotropy as it has done here.'
- 'The potential for activating cryptic pathways has NOT 'been
effectively managed in the past by sound agricultural practices', because the
breeders have not had to face the issue of new, powerful regulatory elements being
randomly inserted into the genome. So there is no certainty that they will be able to
pick up effects that might not be obvious, such as cryptic pathway activation. This
situation IS different than that experienced by traditional breeding techniques.'
- 'All plants produce toxicants…at their native dose range, they might be benign,
but if they are increased by unintended effects, their effect(s) are unknown. So to just
say 'No problem' would be premature and potentially unsafe.'
- ' Is there clear evidence that allergens have not been transfer to host? Since
there are very few allergens that have been identified at the protein or gene level, this
question can only be answered 'No' when the gene comes from a plant which
produced allergies. So the companies are going to have to consult FDA on tomatoes,
peanuts, wheat and every other plant which produce allergic reactions. Also the only
definitive test for allergies is human consumption by affected peoples, which can have
- 'Newly introduced proteins present in the plant?’, this does not take into
account, nor does the document as a whole, those introduced proteins (enzymes), that
while acting on one specific substrate, intended substrate to produce the desired effect,
will also affect other cellular molecules. Either as substrates, or by swapping the
plants regulatory/metabolic systems and depriving the plant of resources needed for other
- ' The toxicity section is going to be a problem. Industry will say it is too
much and the environmental/consumer groups will say it is not enough. A more complete
presentation of the scientific concerns…, as well as a more forceful show of reliance on
the usefulness of molecular biology would have reduced this problem by spelling out the
need for toxicity tests, in limited circumstances. Better yet, a separate (Federal
Register) presentation of the scientific concerns with an analysis of comments before
ever producing flow charts of guidelines (as currently presented) would produce better
- ' A recent report in the Feb 8;1992 issue of new Scientists (pg 40-44) By C.
Heron, implies that plants can form hybrid chains that include plants that are not often
considered capable of making such hybrids. There are many things about hybridization that
are not known that could cause the transfer of introduced genes into unintended species.
This possibility should not be written off so easily.'
March 10th 1992- Points made by Dr Steven Gindel, Chief, Biotechnology
Section, Food Engineering Branch, FDA Dept of Health and Human Services, to Dr James
Maryanski, Biotech coordinator.
- 'Regarding silent metabolic pathways. I would like to see this paragraph include
a mention of the fact that a ‘silent pathway’ can become ‘activated’ due to an increased
concentration of some metabolic intermediate, allowing mass flow into a low affinity
pathway. This apparent activation of a silent pathway can occur without direct mutational
change in the pathway involved, and might result in the production of a toxicant.'
March 18th 1992 Dr Louis J Pribyl comments on the March 1992 version of the
'I can see many ways that a protein (enzyme) could modify a plant without the
protein being toxic; e.g. a protein could modify secondary substrates (non-primary,
intended substrates) such that they change the nutritional value of the food. There
is also the potential for the newly introduced gene (or gene product) to swamp the plants
resources, be they proteins binding to regulatory regions, thereby shutting down other
genes (as has occurred when two separate T-DNA have been introduced separately [at
different times] into the same plant, Matzke, et al (1990) Dev Genetics 11:214-223).
1st Aug 1992 - Points made by Dr Carl B Johnson on the draft ‘Statement
of Policy for Biotechnology’.
- 'Unintended effects. The nature of unintended effects on gene expression may
vary depending on; the site of integration in the genome of the host plant; the number of
integration sites; the number of copies of the introduced DNA at each integration site;
the source and nucleotide sequence of all introduced DNA.'
- ' Line 9-7 appear to provide a justification for the use of toxicological studies
in safety assessment, citing as an example the inability of analytical or molecular
methods to detect the presence of an unknown toxin produced by activation of a previously
cryptic gene. However, lines B-end of paragraph says that toxicological studies will not
be needed if DNA insertion is limited to only a single site of known genomic location.
This discussion implies that pleiotropy (i.e. the production of an unknown toxin due to
activation of a previously cryptic gene) will disappear or be negligible if gene insertions
are limited to a single copy at a known genomic location. Evidence should be provided to
support this position.'
- ' What if the inserted DNA is from a non-food source and encodes a protein that
is toxic to certain organisms (e.g. Bt toxin)? Wouldn’t knowledge of the toxicity of this
protein product be necessary to ensure safety?'
- 'It is my understanding that pleiotropic effects are unpredictable, and may be
triggered by gene insertion at a single site, as well as at multiply sites, in the plant
genome. Restriction of foreign DNA insertion to a single site in the plant genome would
reduce, but not eliminate the chance that the insertion event might trigger pleiotropic
effects. The document does not present evidence that pleiotropic effects (e.g.
alterations in biosynthesis of unknown toxicants) can be controlled by restriction of
foreign DNA insertion to a single site in the plant genome. If such evidence exists,
it should be summarized in this document.'
Dec 17th 1992 - Dr Murray Lumpkin, Director, Anti-infective Drug
Products comments to Dr Bruce Burlington.
- 'The Division comes down fairly squarely against the use of the Kanamycin
resistance gene marker in the GM tomatoes (Calgene’s Flavr Savr – the first GM food
approved in the US). I know this could have serious ramifications.'
Taken from ‘The Medical Officer’s summary of final comments’:
- 'The Division representatives expressed that their main concern focussed on the
gene itself. Concern was expressed that the endogenous bacterial population could be
transformed by the insertion of the kanamycin resistance gene…The presence of these genes
in commensal intestinal bacteria could have far-reaching implications with respect to
antimicrobial treatment of patients and in particular, the immunosuppressed patient.
- 'Dr Flamm and Maryanski stated that the gene transfer from the eucaryotic tomato
plant genome to the procaryotic bacterial genome was improbably. Even if the gene
transfer were successful, in order to have expression of the gene product i.e. the enzyme;
the bacterial genome would require a procaryotic promoter region. The Kanamycin
resistance gene originates in a prokaryotic system, i.e. a plasmid; can it be assumed
that the prokaryotic promoter region is not available?'
- 'By ingesting the GM foodstuffs and thus increasing the background exposure of
the kanamycin resistant gene many fold, are we creating a selective pressure to induce
natural transformation of bacteria?'
- 'The author of the sponsor’s document presents clinical assumptions, which are
not entirely valid…namely the model that addresses that potential uptake and expression
of the Kanamycin resistance gene in humans consuming GE fresh tomatoes. In addition the
sponsor reports that the human intestinal microflora already has a substantial population
of organisms with kanamycin resistance… However, it is not clear from this statement
whether the sponsor clarified that the mechanism of kanamycin resistance was the same as
that which occurs with the kanamycin resistance gene.'
- 'The major issue of concern from a clinical standpoint is the introduction of
the kanamycin resistance gene into significant numbers of microorganisms in the general
population of human microflora. IT WOULD BE A SERIOUS HEALTH HAZARD TO INTRODUCE A GENE
THAT CODES FOR ANTIBIOTIC RESISTANCE INTO THE NORMAL FLORA OF THE GENERAL POPULATION.
- 'The sponsor should consider a brief controlled animal study designed to
determine the rate of transformation in the intestinal microflora after a dietary
challenge of gene modified food.'
- 'The sponsor should address the presence or absence of a bacterial promoter
region for Kanamycin resistance in the T-DNA region.'
- 'The sponsor should also consider implementing a program of post-marketing
surveillance, similar to a phase IV drug safety surveillance, to monitor for increases
in frequency in the kanamycin resistance gene.'
- 'Finally, the sponsor should seek an alternative gene marker, one that does not
involve antibiotics used in human therapy. Although there is, at present, no proof that
the introduction of the Kanamycin gene in the tomato genome will result in widespread
bacterial incorporation of the resistance gene, the potential risk of this happening
would have enormous implications.'
March 30th 1993 - Points made by Dr Albert Sheldon, FDA Department of Human
Health Services, Public Health Services, and FDA Centre for Drug Evaluation and Research,
to Dr James Maryanski, Biotechnology Coordinator on the use of Kanamycin Resistance Markers
- 'The sponsor contends that resistance to Kanamycin already exists in
microorganisms colonizing the gastrointestinal tract and utilization of the Kanamycin
marker in transgenic tomatoes (Calgene’s Flavr Savr) will not increase the genetic
burden in that environment.
Article first published 18/09/00
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