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March 13, 2002


The Safety of Foods Produced Through Biotechnology: 'Society for Toxicology'


March 14, 2002 AgBioView at http://www.agbioworld.org/

The Safety of Foods Produced Through Biotechnology

- 'Society of Toxicology' Position Paper


"There is no reason to suppose that the process of food production
through biotechnology leads to risks of a different nature than those
already familiar to toxicologists or that cannot also be created by
conventional breeding practices.."

"The changes in composition of existing foods produced through
biotechnology are slight."

Executive Summary
The Society of Toxicology (SOT) is committed to protecting and
enhancing human, animal and environmental health through the sound
application of the fundamental principles of the science of
toxicology. It is with this goal in mind that the SOT defines here
its position on the safety of foods produced through biotechnology
(genetic engineering). These products are commonly termed
genetically-modified foods, but this is misleading since conventional
methods of microbial, crop and animal improvement also produce
genetic modifications and these are not addressed here.

1. There is no reason to suppose that the process of food production
through biotechnology leads to risks of a different nature than those
already familiar to toxicologists or that cannot also be created by
conventional breeding practices for plant, animal or microbial
improvement. It is therefore important to recognize that it is the
food product itself, rather than the process through which it is
made, that should be the focus of attention in assessing safety.

2. We support the use of the substantial equivalence concept as part
of the safety assessment of biotechnology-derived foods. This seeks
to establish whether the new food is significantly different from
existing foods that are generally considered to be safe for
consumers, and it provides critical guidance as to the nature of any
increased health hazards in the new food. To establish substantial
equivalence, it is necessary to conduct extensive comparative studies
of the chemical composition, nutritional quality, and levels of
potentially toxic components in both the engineered and conventional
crop or animal. Any notable differences between the existing and new
organism would require further evaluation to determine whether there
is a likely to be a higher level of risk from the consumption of the
foods derived from the engineered form. Through this approach, the
safety of current biotechnology-derived foods compared to their
conventional counterparts can be assessed with reasonable certainty
using established and accepted methods of analytical, nutritional and
toxicological research.

3. Extensive studies of this type have established that the level of
safety to consumers of current genetically engineered foods is likely
to be equivalent to that of traditional foods. Verified records of
adverse health effects are absent, although the current passive
reporting system probably would not detect minor or rare adverse

4. The changes in composition of existing foods produced through
biotechnology are slight. Assessing safety may be more difficult in
the future if genetic engineering projects cause more substantial and
complex changes in a foodstuff. Toxicologists are currently limited
in their ability to assess the risks presented by complex mixtures,
and they have not yet developed methods by which whole foods (as
compared to single chemical components) can be fully evaluated for
safety. Progress also needs to be made in developing definitive
methods for the identification and characterization of proteins that
are potential allergens and this is currently a major focus of
research. A continuing evolution of toxicological methodologies and
regulatory strategies will be necessary to ensure that the present
level of safety of biotechnology-derived foods is maintained in the
BD foods = Biotechnology-derived (BD) foods.


The Society of Toxicology (SOT) is committed to protecting and
enhancing human, animal and environmental health through the sound
application of the fundamental principles of the science of
toxicology. It is with this goal in mind that the SOT defines here
its position on the safety of foods produced through biotechnology.
In this context, biotechnology is taken to mean those processes
whereby foreign genes (transgenes) are transferred to microorganisms,
plants or animals employed in food production, or where the
expression of existing genes is permanently modified, using the
techniques of genetic engineering. We intentionally avoid using the
term genetically modified organisms (GMOs) or foods in this context
since conventional techniques of plant and animal breeding, which are
not considered here, also involve genetic modification. The extent of
the genetic changes resulting from such conventional breeding
techniques, which is generally undefined, far exceeds that typically
produced by transgenic methods. Consequently, it is important to
recognize that it is the product, and not the process of
modification, that is the focus of concern regarding the human or
environmental safety of biotechnology-derived (BD) foods.

The principal responsibilities of toxicologists are to define and
characterize the potential for natural and manufactured materials to
cause adverse health effects and to assess, as accurately as
possible, the plausibility and level of risk for human or animal
health or for environmental damage under a defined set of
circumstances. It is not the task of the Society of Toxicology to
determine the overall value of a product or process by balancing
health or environmental risks with potential benefits, or to choose
between different strategies to manage risk, although toxicological
considerations are important in both processes. Our purpose here is
rather to identify and consider the primary toxicological issues
associated with BD foods. Major areas of concern in the development
and application of such foods in agriculture relate to the
possibility of deleterious effects on both human health and the

Types of Toxicological Hazards to Consumers and Producers Associated
with BD Foods

Current techniques of developing organisms used in the production of
BD foods typically involve the transfer to the host of the desired
gene or genes in combination with a promoter and a gene for a
selectable marker trait that allows the efficient isolation of cells
or organisms that have been transformed from those that have not.
Common selectable markers have included antibiotic or herbicide

Several key issues have been raised with respect to the potential
toxicity associated with BD foods, including the inherent toxicity of
the transgenes and their products, and unintended (pleiotropic or
mutagenic) effects resulting from the insertion of the new genetic
material into the host genome. Unintended effects of gene insertion
might include an over-expression by the host of inherently toxic or
pharmacologically-active substances, silencing of normal host genes,
or alterations in host metabolic pathways. It is important to
recognize that, with the exception of the introduction of marker
genes, the process of genetic engineering does not, in itself, create
new types of risk. Most of the hazards listed above are also inherent
in conventional breeding methods and have historically been accepted
with minimal public concern.

The Concept of Substantial Equivalence

The guiding principle in the evaluation of BD foods by regulatory
agencies in Europe and the USA is that their human and environmental
safety is most effectively considered relative to comparable products
and processes currently in use. From this arises the concept of
"substantial equivalence." If a new food is found to be substantially
equivalent in composition and nutritional characteristics to an
existing food, it can be regarded as being as safe as the
conventional food (FDA, 1992; OECD, 1993; Maryanski, 1995) and does
not require extensive safety testing. Evaluation of substantial
equivalence includes consideration of the characteristics of the
transgene and its likely effects within the host, metabolic
profiling, and measurements of protein, fat and starch content, amino
acid composition and vitamin and mineral equivalency together with
levels of known allergens and other potentially toxic components.

BD foods can either be substantially equivalent to an existing
counterpart, substantially equivalent except for certain defined
differences (on which further safety assessments would then focus),
or be non-equivalent, which would mean that more extensive safety
testing would be necessary. The examination of substantial
equivalence therefore may only be the starting point of the safety
assessment. It provides a valuable guide to the definition of
potential hazards from BD foods and illuminates necessary areas for
further study (FAO/WHO, 2000). While there is some concern relative
to the definition of the meaning of "substantial" and debate over the
concept continues (e.g. see Millstone et al., (1999) and following
correspondence, and Royal Society of Canada, 2001), the concept
appears to be logical and robust (FAO/WHO, 2000). If it can be
established with reasonable certainty that a BD food is not more
hazardous than its conventional counterpoint, it provides a standard
likely to be satisfactorily protective of public health. It is also
an approach that has the flexibility to evolve in concert with the
field of transgenic technology.

Key issues with respect to human health effects of BD Foods

1. Is the transgene itself toxic? Can it be transferred to the genome
of a consumer?

Humans typically eat several grams of DNA in their diet each day.
Therefore, the transgene in a genetically engineered plant is not a
new type of material to our digestive systems and it is present in
extremely small amounts. In transgenic corn, the transgenes represent
about 0.0001% of the total DNA (Lemaux and Frey, 2002). Decades of
research indicate that dietary DNA has no direct toxicity itself. On
the contrary, exogenous nucleotides have been shown to play important
beneficial roles in gut function and the immune system (Carver,
1999). Likewise, there is no compelling evidence for the
incorporation and expression of plant-derived DNA, whether a
transgene or not, into the genomes of consuming organisms. Defense
processes have evolved, including extensive hydrolytic breakdown of
the DNA during digestion, excision of integrated foreign DNA from the
host genome, and silencing of foreign gene expression by targeted DNA
methylation that prevent the incorporation or expression of foreign
DNA (Doerfler, 1991). Therefore, the possibility of adverse effects
arising from the presence of foreign DNA by either direct toxicity or
gene transfer is minimal (FAO/WHO, 2000; Royal Society, 2002).

2. Does the product encoded by the transgene present a risk to
consumers or handlers?

The potential toxicity of the transgene product must be considered on
a case-by-case basis. Particular attention must be paid if the
transgene produces a known toxin (such as the Bacillus thuringiensis
(Bt) endotoxins) or a protein with allergenic properties.

2a. Production of toxins. The level of risk of these gene products to
consumers and those involved in food production can be and is
evaluated by standard toxicological methods. The toxicology testing
for the Bt endotoxins typifies this approach and has been described
in detail by USEPA (2000, 2001). The safety of most Bt toxins is
assured by their easy digestibility as well as by their lack of
intrinsic activity in mammalian systems (Betz et al., 2000: Siegel,
2001). However, each new transgenic product must be considered on its
own merits based on exposure levels and its potency in causing any
toxic effects, as is typical of current risk assessment paradigms for
chemical agents.

2b. Production of allergens. Allergenicity is one of the major
concerns about food derived from transgenic crops. However, it is
important to keep in mind that eating conventional food is not
risk-free; allergies occur with many known and even new conventional
foods. For example, the kiwi fruit was introduced into the U.S. and
the European market in the 1960's with no known human allergies;
however, today there are people allergic to this fruit (Pastorello et
al., 1998).

The issues that have to be addressed regarding the potential
allergenicity of BD foods are: do the products of novel genes
engineered into food plants have the ability to induce de novo
sensitization among susceptible individuals. do the products of novel
genes have the ability to elicit allergic reactions in individuals
who are already sensitized to the same, or a structurally similar,
protein will transgenic techniques alter the level of expression of
existing protein allergens in the host crop plant. These are
legitimate concerns and considerable scientific resources are being
committed to determine the most appropriate and accurate approaches
for identifying and characterizing potentially allergenic proteins.
The first systematic approach to allergenicity assessment was
developed by the International Life Sciences Institute (ILSI) in
collaboration with the International Food Biotechnology Council and
published in 1996 (Metcalfe et al., 1996). The hierarchical approach
described therein has been reviewed and revised by the World Health
Organization (WHO) and the Food and Agriculture Organization of the
United Nations (FAO) (FAO/WHO, 2001). The main approaches currently
used in the evaluation of allergenicity are:

(i) Determinations of structural similarity, sequence homology and
serological identity: The objective is to determine whether, and to
what extent, the novel protein of interest resembles other proteins
that are known to cause allergy among human populations. There are
essentially three generic approaches. The first is to examine the
overall structural similarity between the protein of interest and
known allergens. The second is to determine, using appropriate
databases, whether the novel protein is similar to known allergens
with respect to either overall amino acid homology, or with respect
to discrete areas of the molecule where complete sequence identity
with a known allergen may indicate the presence of shared epitopes.
The third approach is to determine whether specific IgE antibodies in
serum drawn from sensitized subjects are able to recognize the
protein of interest.

(ii) Assessment of proteolytic stability: There exists a good, but
incomplete, correlation between the resistance of proteins to
proteolytic digestion and their allergenic potential; the theory
being that relative resistance to digestion will facilitate induction
of allergic responses provided the protein possesses allergenic
properties (Astwood et al., 1996). One approach therefore is to
characterize the susceptibility of the protein of interest to
digestion by pepsin or in a simulated gastric fluid. However, this
approach alone may not be sufficient to identify cross-reactive
proteins with the potential to elicit allergic responses in food- or
latex-sensitized individuals as in the case of oral allergy syndrome
or latex-fruit syndrome (Yagami et al., 2000). Nor are considerations
of stability to digestion necessarily relevant for allergens that act
through dermal or inhalation exposure and that may have significance
for worker health.

(iii) Use of animal models: Currently there are available no widely
accepted or thoroughly evaluated animal models for the identification
of protein allergens. Nevertheless, progress is being made and
methods based on the characterization of allergic responses or
allergic reactions in rodents and other species have been described
(Kimber and Dearman, 2001).

Although testing strategies for allergens are still evolving and no
single test is fully predictive of human responses, the approaches
outlined above, when used in combination, allow scientists to address
questions of potential allergenicity and these will increase in
precision and certainty with time. Considerations of this type led
the US federal agencies to deny approval of StarLink corn for human
consumption because of the possibility that its Bt protein, Cry9C,
may be a human allergen. This protein had been modified to slow its
digestion and prolong its effect in the insect gut and this change
rendered the protein less digestible in the human gut as well. With
the exception of Cry9C, none of the new proteins in foods evaluated
through the FDA consultation process has the characteristics of an
allergen. There is currently no evidence that the health of any
consumer has been affected by exposure to StarLink corn (CDC, 2001)
or any other BD food.

The only documented case where a human allergen was introduced into a
food component by genetic engineering occurred when attempts were
made to improve the nutritional quality of soybeans using a Brazil
nut protein, the methionine-rich 2S albumin. Allergies to the Brazil
nut have been documented (Arshad et al., 1991), and while still in
pre-commercial development, testing of these new soybeans for
allergenicity was conducted in university and industrial
laboratories. It was found that serum from people allergic to Brazil
nuts also reacted to the new soybean (Nordlee et al., 1996). Once
this was discovered, further development of the new soybean variety
was halted and it was never marketed. This work led to the
identification of the major protein associated with Brazil nut
allergy which was previously unknown (Nordlee et al., 1996).

3. Will insertion of the transgene increase the potential hazard from
toxins or pharmacologically active substances present in the host?

Concern has been expressed about the randomness with which genes are
inserted into the host by current genetic engineering processes. This
could (and does) result in pleiotropic and insertional mutagenic
effects. The former term refers to the situation where a single gene
causes multiple changes in the host phenotype and the latter to the
situation where the insertion of the new gene induces changes in the
expression of other genes. Such changes due to random insertion might
cause the silencing of genes, changes in their level of expression
or, potentially, the turning on of existing genes that were not
previously being expressed. Pleiotropic effects could be manifested
as unexpected new metabolic reactions arising from the activity of
the inserted gene product on existing substrates or as changes in
flow rates through normal metabolic pathways (Conner and Jacobs,

Although it is possible to envision situations where transgenic
technology causes unexpected and potentially undesirable pleiotropic
or mutagenic changes in the genome of the host, these cases are
likely to be discovered by their effects on the development, growth
or fertility of the host or by the extensive testing of its chemical
composition compared to isogenic untransformed plants that is
typically conducted.

Over 5000 field trials with more than 70 different transgenic plant
species have been conducted since 1987 in the United States by the
USDA Animal and Plant Health Inspection Service (APHIS). In only one
instance has an unexpected result been seen. In this case a mutation
in a color gene and gene silencing through changes in the methylation
status of these genes led to unexpected color patterns in petunia
flowers. Both of these effects are also seen in conventional plant
breeding (Meyer et al., 1992). While the possibility of an undetected
increase in a toxic component in a new food cannot be entirely
eliminated, the current safeguards make this quite unlikely and no
toxicologically or nutritionally significant changes of this type are
evident in the transgenic plants so far marketed for food production.

A frequently-quoted example of the dangers of genetic engineering
relates to the production of the amino acid, tryptophan, used as a
dietary supplement. After genetic engineering of the microorganisms
used in this fermentation, a number of cases of eosinophilia-myalgia
syndrome (EMS) were reported among users of the supplement. However,
prior to these cases, the manufacturing process was also changed and
certain filtration and purification steps were removed. Although the
cause of the outbreak has, regrettably, never been clarified, and the
nature of the toxic impurity remains a matter of conjecture, it
appears much more likely that the changes in the manufacturing
process rather than genetic modifications in the microorganism were
to blame (Mayeno and Gleich, 1994).

These examples indicate that careful analysis of the changes in BD
organisms is necessary to ensure against unexpected alterations in
the levels of toxins, allergens and essential nutrients. This will be
particularly critical if, as seems likely, engineering of the
synthetic pathways of secondary metabolites is undertaken in plants
e.g. to increase their resistance to insects and pathogens or produce
compounds of pharmaceutical value. Such changes might create new and
unanticipated secondary compounds with unknown toxic properties.

4. Does the possible transfer of antibiotic resistance marker genes
from the ingested BD food to gut microbes present a significant human

Organisms that contain DNA encoding for antibiotic resistance
proteins are common and of increasing prevalence in the environment.
However, a contribution of the antibiotic resistance markers in BD
foods to antibiotic resistance in gut bacteria has not been
documented and, for several reasons including efficient destruction
of the resistance gene in the human gut and the extremely low
intrinsic rate of plant-microbe gene transfer, it is expected to be
extremely small (Royal Society, 1998). In any case, such resistance
genes occur quite widely already and the antibiotics involved are not
widely used in medical practice (Nawaz et al., 2001). Finally, the
technology is now available to omit the use of such selection devices
(e.g. Goldsbrough et al. 1996; Koprek et al. 2000) and their use is
likely to diminish.

5. Will genetic transformation adversely affect the nutritional value
of the host?

In the USA, the FDA is entrusted with assuring that the nutritional
composition of BD foods is substantially equivalent to that of the
non-modified food. Studies are performed to determine whether
nutrients, vitamins and minerals in the new food occur at the same
level as in the conventionally-bred food sources (e.g. see Berberich
et al. (1996) and Sidhu et al. (2000)). A typical example is the case
of Roundup Ready soybeans. In this case, the protein, oil, fiber,
ash, carbohydrates and moisture content and the amino acid and fatty
acid composition in seeds and toasted soybean meal were compared to
conventional soybeans. Fatty acid compositions and protein or amino
acid levels of soybean oil were compared and special attention was
given to checking the levels of antinutrients typically found in
soybeans, e.g., trypsin inhibitors, lectins and isoflavones (Padgette
et al., 1996). The only difference between the conventional and
non-conventional soybeans was detected in defatted, non-toasted
soybean meal, the starting material for commercially utilized soybean
protein. In this form, trypsin inhibitor levels were 11 - 26% higher
in transgenic soybeans. The levels of the trypsin inhibitors were
similar in all lines in the seeds and in defatted, toasted soybean
meal, the form used in foods. The results of this study demonstrated
that, except for the trypsin inhibitors in non-toasted soybean meal,
which is not consumed, the composition of transgenic lines is
equivalent to that of conventional soybean cultivars. In addition,
the equivalence of the feeding value of these transgenic grains was
demonstrated in rats, chickens, catfish and dairy cattle (Hammond et
al., 1996).

6. Will the transgene product adversely affect non-target organisms?

In addition to the general concerns addressed under food safety,
additional attention is needed when the gene product is pesticidal or
otherwise may be toxic to non-target organisms that consume it. The
effects of each transgene product that is designed for pesticidal
effects must be evaluated on a case-by-case basis against target and
non-target organisms under specific field growth conditions for each
transgenic crop. The foremost current example of this is the
incorporation of Bt genes into crop plants for insect control. The
toxic properties of Bt endotoxins to both target and non-target
species of many kinds are well known (Betz et al., 2000). They show a
narrow range of toxicity limited to specific groups of insects,
primarily Lepidoptera, Coleoptera or Diptera, depending on the Bt
strain. Nevertheless, Bt-producing plants have been tested broadly to
determine whether any alteration in this limited spectrum of toxicity
has occurred, without the discovery of any unexpected results (see
Orr and Landis (1997), Pilcher et al., (1997), and Lozzia et al.
(1998) for examples of such studies). Exotoxins and enterotoxins,
which are much more broadly toxic than the endotoxins, are also
produced by some Bt strains, but these are not present in the
transformed plant.

In plants transformed with Bt genes to control lepidopterans,
toxicity to non-target lepidopterans would be expected if exposure
occurs by feeding on the transformed crop. A long and contentious
debate has ensued over the potential toxicity of the Bt toxin in corn
pollen to the Monarch butterfly after initial laboratory studies
showed increased mortality in larvae (Losey et al., 1999) . It is
unlikely that a substantial risk to these butterflies exists in the
field (e.g. see Sears et al., 2001), but the details of this
controversy are beyond the scope of this article. Beyond the question
of the potential toxicity of Bt corn to such valued insects, it is
also important to recollect that the common alternative is to spray
corn with insecticides, which are not as selective as Bt toxin.

Future Challenges in the Assessment of the Safety of BD Foods

Current safety assessment methodologies are focused primarily on the
evaluation of the toxicity of single chemicals. Food is a complex
mixture of many chemicals. Using animal models, the evaluation of
most aspects of the safety of single components of the diet, such as
a Bt toxin, is possible using widely accepted protocols. Future
projects may involve more complicated manipulations of plant
chemistry. In this case, safety testing will be more challenging.
Whole foods cannot be tested with the high dose strategy currently
used for single chemicals to increase the sensitivity in detecting
toxic endpoints (MacKenzie, 1999; Royal Society of Canada, 2001).
Also, the question of potential deleterious interactions between new,
or enhanced levels of known, toxic agents in BD foods will
undoubtedly be raised. The safety-testing of multiple combinations of
chemicals remains a difficult proposition for toxicologists. In view
of these challenges, there is a clear need for the development of
effective protocols to allow the assessment of the safety of whole
foods (NRC, 2000; Royal Society of Canada, 2001),


1. The responsibility of toxicologists is to assess whether foods
derived through biotechnology are at least as safe as their
conventional counterparts and to ascertain that any levels of
additional risk are clearly defined. In achieving this, it is
important to recognize that it is the food product itself, rather
than the process through which it is made that should be the focus of
attention. In assessing safety, the use of the substantial
equivalency concept provides guidance as to the nature of any new

2. There is no reason to suppose that the process of BD food
production leads to hazards of a different nature than those already
familiar to toxicologists. The safety of current BD foods compared to
their conventional counterparts can be assessed with reasonable
certainty using established and accepted methods of analytical,
nutritional and toxicological research.

3. A significant limitation may occur in the future if transgenic
technology results in more substantial and complex changes in a
foodstuff. Toxicologists are currently limited in their ability to
assess the hazard presented by complex mixtures, and have not yet
developed methods by which whole foods (as compared to single
chemical components) can be fully evaluated for safety. Progress also
needs to be made in developing definitive methods for the
identification and characterization of protein allergens and this is
currently a major focus of research.

4. The level of safety of current BD foods to consumers appears to be
equivalent to that of traditional foods. Verified records of adverse
health effects are absent although the current passive reporting
system would probably not detect minor or rare adverse effects .
However, this is no guarantee that all future genetic modifications
will have such apparently benign and predictable results. A
continuing evolution of toxicological methodologies and regulatory
strategies will be necessary to ensure that this level of safety is


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To: Members of the Society of Toxicology

I am pleased to announce the completion of the SOT Position Paper on
the subject of genetically-modified organisms.

You will recall that SOT Council convened a working group of experts
nominated through their respective Specialty Sections to draft this
statement. The authors of the report are Drs. Bob Hollingworth
(Michigan State University), Len Bjeldanes (UC-Berkeley), Mike Bolger
(USFDA), Ian Kimber (AstraZeneca), Barbara Meade (NIOSH), and Steve
Taylor (University of Nebraska).

As per Council policy, the document has been posted to the SOT
for your review and consideration. The working group has invested
considerable thought and discussion in formulating the draft paper. I
encourage you to review the document and to respond with your
comments by sending an Email message to SOT headquarters at
shawnl@toxicology.org. On behalf of Council and the members of the
Society, I want to personally and publicly thank the working group
members for all of the effort they devoted to this cause. I hope that
it was found to be intellectually stimulating and professionally

Kendall B. Wallace, Ph.D., DABT
Professor, Department of Biochemistry & Molecular Biology
University of Minnesota School of Medicine
1035 University Drive, Duluth, MN 55812

Tel: (218) 726-8899; FAX: (218) 726-8014; Email: kwallace@d.umn.edu