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Below is an excerpt from our published paper: Ho, M.W. and Steinbrecher,
R. (1998). Fatal flaws in food safety assessment: critique of the joint
FAO/WHO biotechnology and food safety report, Environmental &
Nutritional Interactions 2, 51-84. We are reproducing the Section on
the principle of substantial equivalence to show how rediculous it is.
The Principle of Substantial equivalence is Unscientific
and Arbitary
The most serious shortcomings of the report are in the
principle of "substantial equivalence" on which all safety
assessment is based.
The Principle is Intentionally Vague and Ill-Defined to
Be as Flexible, Malleable, and Open to Interpretation as Possible
"Substantial equivalence embodies the concept that if a new food or
food component is found to be substantially equivalent to an existing food
or food component, it can be treated in the same manner with respect to
safety (i.e., the food or food component can be concluded to be as safe as
the conventional food or food component)" (Joint FAO/WHO
Biotechnology and Food Safety Report, 1996, p. 4)
This principle is unscientific and arbitrary, encapsulating a
dangerously permissive attitude toward producers, and at the same time it
offers less than minimalist protection for consumers and biodiversity,
because it is designed to be as flexible, malleable, and open to
interpretation as possible.
"Establishment of substantial equivalence is not a safety
assessment in itself, but a dynamic, analytical exercise in the assessment
of the safety of a new food relative to an existing food. The comparison
may be a simple task or be very lengthy depending upon the amount
available knowledge and the nature of the food or food component under
consideration. The reference characteristics for substantial equivalence
comparisons need to be flexible and will change over time in accordance
with the changing needs of processors and consumers and with experience."
(Joint FAO/VMO Biotechnology and Food Safety Report, 1996, pp. 4 and 5)
In other words, one can choose to compare whatever is the most
convenient at a particular time, and for a particular purpose. And if on
one set of criteria the product is not substantially equivalent, a
different set of criteria could be used, always to the advantage of the
producers.
Comparisons Are Designed to Conceal Significant Changes
Resulting From Genetic Modifications
In practice, this principle allows comparison of the transgenic
line to any variety within the species, and even to an abstract entity
made up of the composite of selected characteristics from all varieties.
That is exemplified in the safety evaluation reported by the company
Calgene on several of their products (Redenbaugh et al., 1995). By a
judicious use of additional varieties, any changes from the control
recipient variety could be bracketed. In theory, a genetically engineered
line could have the worst features of every variety and still be
substantially equivalent. Such comparisons rather than comparing the
transgenic line to the parental nontransgenic line would rarely, if at
all, pick up significant changes resulting from the genetic modification
per se, which should alert conscientious researchers to a more careful
characterisation of the genetically modified organism-
Bernard Shaw was reputed to have been propositioned by a beautiful
though not too bright lady who wanted to have his child so it would have
his brains and her looks, 'but Shaw was said to have discouraged her by
pointing out that the child could end up having her brains and his looks
instead. So, it is the particular combination of characteristics that
makes all the difference. But under the present safety assessment regime,
both combinations would be deemed "substantially equivalent."
The danger is that particular combinations of nutrients or metabolises
might fall within the "equivalent" range determined in this
fashion, and yet be antinutritional, toxic or cumulative lethal.
And if that were not enough, producers are assured that, even when
products are not substantially equivalent, they can be shown to be
substantially equivalent except for defined differences, and "further
safety assessment should focus only on those defined differences"
(Joint FAO/W'HO Biotechnology and Food Safety Report, 15)96, p. 8).
Lest one is in any doubt, it is stated an page 11 of the
report that "UP to the present time, and probably for the near
future, there have been few, if any, examples of foods or food components
produced using genetic modification which could be considered to be not
substantially equivalent to existing foods or food components."
Calgene's genetically engineered Laurate canola oil should, by no stretch
of the imagination, be considered substantially equivalent to ordinary
canola oil. But, "other fatty acids components are Generally
Recognised as Safe (GRAS) when evaluated individually because they
are present at similar levels in other commonly consumed oils."
Similarly, "substitution of Laurate canola for coconut and palm
kernal oils does not raise any safety concerns for intended uses, in part
because the major components, the fatty acids laurate and myristate, are
identical" (Rodenbaugh et al., 1996)
In other words, it is already a foregone conclusion that most, if not
all, the products now and for the foreseeable future will be assessed as "substantially
equivalent," and if not, then considered GRAS by a judicious
choice of a comparator.
It is significant that the Dutch courts have recently ruled Monsanto's
genetically engineered soy beans not equivalent in quality to natural soy
beans, as was claimed in the advertisement of Albert Heijn, the
biggest supermarket chain in the Netherlands. Albert Heijn is itself part
of the Dutch multinational Ahold, which owns super- market chains
in many countries around the world. The complaint was filed by the Dutch
Natural Law Party (Storms, 1997).
The Principle Is Weak and Misleading Even When It Does
Not Apply, Effectively Giving Producers Carte Blanche
Given that "substantial equivalence" can be interpreted in the
widest possible sense--and if not, then by a judicious choice of
comparator the product can be considered as GRAS-it is difficult to
imagine which remaining products cannot pass muster.
The report recognised that "products could be developed which could
be considered to have no conventional counterpart and for which
substantial equivalence could not be applied" (Joint FAO/WHO
Biotechnology and Food Safety Report, 1996, p. 11). For example, one
phrase used is "products derived from organisms in which there has
been transfer of genomic regions which have perhaps been only partly
characterised" (p. 11) This gives the impression that such
are hypothetical cases that might arise in future,
But that is not so. The report has failed to point out that at least one
such transgenic organism already exists: Tracy, a sheep engineered with a
large segment of a human genome-most of which contains unknown sequence
with unknown functions--to produce huge quantities of alpha-antitrypsin in
her milk (Colman, l996). Tracy and her clones may he walking incubators
for cross-species viruses to arise by recombination between human and
sheep viral sequences. All genomes contain endogenous proviral sequences,
and recombination between endogenous and erogenous viral sequences are
already implicated in several kinds of animal cancers (.5ce Ho, 1997a).
One might think that the report would treat such cases with extra caution.
Not so.
We are assured that even if a food or food component is considered to be
not substantially equivalent, producers need not despair, for "it
does not necessarily mean it is unsafe and not all such products will
necessarily require extensive testing" (Joint FAO/WHO Biotechnology
and Food Safety Report, 1996, p. 12). The-report seems to prepare
the grounds for slipping those products through a regulatory framework
that is already worse than toothless.
Further on, in Section 6.6 on "Food organisms expressing
pharmaceuticals or industrial chemicals" (Joint FAO/WHO Biotechnology
and Food Safety Report, 1996, p. 19), there is the telling statement, "The
Consultation recognised that, generally, the genetically modified organism
would not he used as food without prior removal of the pharmaceutical or
industrial chemical" (p. 19). That is a prelude to serving up
the rest of Tracy and the "elite herd' cloned from her, or,
more likely, superannuated "pharm" animals and any failed
transgenic experiment, whatever, as meat for our dinner tables. Transgenic
technology is very inefficient and generates a lot of transgenic
wastes--the large numbers of failed experiments. Such "foods"
from transgenic wastes may be sources of exotic, cross-species foodborne
viruses, as mentioned earlier. Furthermore, they will be exempt from
safety assessment if the report is to be taken seriously. A similar
category of transgenic waste could be the leftover carcasses of pigs
engineered for xenotransplantation. All the signs are that the producers
are handed carte blanche to do as they please for maximum profitability,
with the regulatory body acting to allay legitimate public fears and
opposition.
Insufficiency of Background Information for Assessing
Substantial Equivalence
The procedure for establishing substantial equivalence, described in
less than three pages in the 27-page report (pp. 6, 7, and 8), comes under
two headings: 'background information an the characterisation of the
modified organism, and actual determination of substantial equivalence, or
characterisation of the food product itself.
One glaring omission in the background information is the propensity of
the transgenic organism for gene-rating pathogenic viruses by
recombination (and whether experiments have been carried out to
investigate this propensity). This information is highly relevant for
assessing impacts an biodiversity as well as food safety, in view of our
current knowledge that superinfecting viruses may he generated from many
transgenic plants at much higher frequencies than previously thought and
that insecticidal recombinant viruses may attack human liver cells. There
is also disturbing new evidence that viral DNA can survive digestion in
the gastrointestinal tract of mice, with large fragments getting into the
blood stream and into many kinds of cells (Schubbert et al., 1994, 1997).
Likewise, information on the stability of transgenes, and potential for
mobility of introduced genes, which are mentioned on page 6 of the report,
ought to 'be based on data collected over a number of generations,
documenting the stability of the insert as well as expression of the
transgenes and the transgenic line in successive generations, so that both
consumers and farmers can have confidence in quality control. In a paper
presented at a World Health Organisation (WHO) workshop, Conner stated, "The
main difficulty associated with the biosafety assessment of transgenic
crops is the unpredictable nature of transformation. This unpredictability
raises the concern that transgenic plants will behave in an inconsistent
manner when grown commercially" (Conner, 1995) In general, the
inheritance of genetically engineered traits is non-Mendelian in
subsequent generations (Schuh et al., 1993) necessitating clonal
propagation.
Earlier this year, 60,000 bags of genetically engineered canola seeds,
enough for planting 600,000 acres, had to be recalled after they were sold
in western Canada, because unexpectedly a gene, not yet approved for
market, turned up in the seeds. The seeds were bred and sold by Limagrain,
under licence from Monsanto (reported in Mani- toba co-operator, 24/4/97,
and in The Ram's Horn, No. 147, April 1997). If the transgenic
plants had been monitored for genetic stability of both the transgenes and
the transgenic line in successive generations, as they should have been,
and careful records kept, those seeds would never have reached the market.
This incident also indicates the necessity for product segregation, clear
labelling, and postmarket monitoring as part of the condition for market
approval.
Under background information, it is also crucial to include the upstream
and downstream effects of transgenic promoter and enhancer sequences, as
well as any possible regulatory elements contained in the coding
sequences. Furthermore, the need identification and recently the presence
of genetic elements in the host that might compromise the stability of the
transgenes. A further serious omission in the background information is
the lack of an explicit requirement to disclose the presence of marker
genes, especially antibiotic marker genes, which are considered in a later
section.
There Is No Specification of Tests for Establishing
Substantial Equivalence
We are told in the report that "characterisation of the food
product" entails "molecular characterisation," "phenotypic
characterisation," and "compositional analysis." While the
latter two categories are elaborated subsequently, "molecular
characterisation" has mysteriously disappeared. Nowhere is it
specified which methods of molecular characterisation are required, nor
what molecular information should be established. Though this would be
crucial for identifying unintended effects. A previous document that
reports on a WHO Workshop on the principle of substantial equivalence,
Applications of the Principle of Substantial Equivalence to the Safety
Evaluation of Foods or Food Components From Plants Derived by Modern
Biotechnology (WHO/FNU/FOS/95.1, p. 7), leaves molecular
characterisation very vague. It refers to "the inserted DNA,"
and to "the level and mechanism of expression of the protein,"
which is considered to 'be "more important than knowing the gene copy
number." It appears the inserted DNA sequence need not be well
characterised at all. The report then mentions "the level and
function of the introduced gene product in the plant may be useful in
judging substantial equivalence," again implying that the
function of the gene product need not be known as a condition for safety
approval. If the gene(s) and gene product(s) transferred are well
understood, however, the safety evaluation can then "focus on the
safety of the expression product and/or changes "brought about by the
expression product." This is an open endorsement of a totally
inadequate, reductionist safety assessment that ignores effects on the
system as a whole, especially in the longer term
In effect, a thorough molecular characterisation of the product is not
required. Not even the level of expression of the introduced transgene(s)
or marker gene(s) needs to be ascertained, much less the effects of
promoters and enhancers on neighbouring genes, as judged by the samples of
papers presented in the WHO workshop on substantial equivalence (see
Health Aspects of Marker Genes in Genetically Modified Plants, Report of a
WHO Workshop, WHO/FNU/FOS.93.6, 1993). If one happens to know what has
been transferred, then safety assessment can focus only on the gene
product and its effects- So the two main categories of characterisation of
the food product are simply the phenotypic characteristics-agronomic,
morphological, and physiological-and the compositional comparison-key
nutrients and toxicants that are known to be inherently present in the
species.
There Is No Requirement to Test for Unintended Effects;
Current Tests Are Undiscerning and May Even Serve to Conceal Unintended
Effects
Although the report recognises the possibility of "indirect
consequences" (p. 4) and that "assessment of the safety of
genetically modified organisms must address both intentional and
unintentional effects that may result as a consequence of the
genetic modification of the food source" (p. 5), these are
limited to phenotypic changes that are readily apparent, and alterations
in the concentrations of major nutrients or increases in the level of
natural (known) toxicants. There is thus no specific requirement to test
for unintended effects per se.
Similarly, while it is stated that "attention must be paid
to the impact of growth conditions on level of nutrients and toxicants"
and "attention must be paid to the impact of different sails and
climatic conditions" (p. 5), these are not elaborated
further, and certainly are not required for safety assessment recommended
in the report.
The range of tests that are actually carried out, as exemplified by
WHO's Workshop Report on applying the principle of substantial
equivalence, are not sufficiently discerning to pick out unintended
effects Unless there are gross morphological or phenotypic changes, there
is no need to lock for them. And even when there are gross abnormalities,
the product can still be assessed to be "substantially equivalent."
One paper presented in the WHO workshop reported, "Field trials on
the transgenic lines used in these studies showed marked deformities in
shoot morphology and poor tuber yield involving a low number of small,
malformed tubers during field trials.... These changes were attributed to
somaclonal variation during the tissue culture phase of transformations.
Despite these marked morphological abnormalities, virtually no changes in
tuber quality attributes were detected" (Conner, 1995). So much for
the discerning power of the tests carried out.
There were no metabolic profiles done by routine analytical techniques
such as high-pressure liquid chromatography (HPLC), or two-dimensional gel
electrophoresis to scan for unintended expression of genes. The
compositional analyses reported are limited to uninformative amino acid
profiles, or to known components present at levels greater than 0.1%, or
0.01% at best. And, as mentioned earlier, the arbitrariness of the
comparison will already hide any changes due to the transferred gene(s)
per se, which should alert researchers to unintended effects.
Instead, the tests are aimed specifically at intended effects only, and,
if anything, at concealing secondary, unintended effects as much as
possible.
The hazard of unintended effects is already well
attested to by the U.S. epidemic of eosinophilia-myalgia syndrome in the
U.S. in 1990, resulting in more than 1500 affected and 37 deaths, which is
linked to the consumption of L-tryptophan produced by a genetically
modified strain of Bacillus amyloliquefaciens (Mayeno & Glich,
1994). Several trace contaminants identified by HPLC have been implicated
in pathogenesis of this syndrome.
A metabolite, mothylglyoxal, was found to accumulate at
toxic, mutagenic levels in yeasts engineered with multiple copies of one
of several yeast glycolytic enzymes to increase the rate of fermentation
(Inose & Murata, 1995). Recently, tobacco plants genetically
engineered to produce the gamma-linoleic acid also unexpectedly produced
actodecatetraenoic acid, a substance previously unknown in natural tobacco
plants (Reddy & Thomas, 1996). In the absence of a metabolic profile
on the product, unintended toxic metabolites might have easily escaped
notice in safety assessment.
It is equally important to cheek for unintended gene
products being produced, which will not be revealed by routine amino acid
analyses of total lysates, as is done by Calgene for canola meal
(Redenbaugh et al., 1995). A minimum requirement should be a two-
dimensional gel electrephoretogram of the total proteins. Even then, minor
modifications in a proportion of the proteins may not be detect- able,
which may change the properties of the proteins involved. For example, a
proportion of the recombinant porcine and bovine somatotropins synthesised
in Escherichia coli were found to contain the abnormal amino acid
e-N-acetyllysine in place of the normal lysine only when reversed-phase
HPLC analyses were carried out (Voland et al., 1994).
Key questions on the allergenic potential of transgenic foods are raised
by the recent identification of a brazil-nut allergen in soybean
genetically engineered with a brazil-nut gene (Nordlee et al.,
1996). It is possible to test for known allergens, as in the case of the
brazil-nut soybean, but not for allergenicity to proteins completely new
to the foods involved, as acknowledged in the report (Joint FAO/WHO
Biotechnology and Food Safety Report, 1996, p. 14). It is significant that
allergenicity in plants is thought to be linked to proteins involved in
defence against pests and diseases (Franck & Keller, 1995). Therefore,
transgenic plants engineered for resistance to diseases and pests may have
a higher allergenic potential than the unmodified plants. Furthermore, it
has been shown that common food allergens are invariably proteins that
have been glycosylated. The whole area of glycosylation and, in fact any
posttranslational modification of GE proteins, needs urgent attention with
regard to allergenicity. One major novel protein is the insecticide
produced by the gene from Bacillus thuringiensis (Bt), now
incorporated into a range of transgenic crop plants that had never
contained them before. Nevertheless, the producers were able to claim
substantial equivalence by pointing to its "comparability" (not
identity!) "to one of the proteins contained in the commercial
microbial formulations that have been used commercially since 1988"
(Fuchs et al., 1995). In fact, the genetically engineered Bt loxin
is a truncated, immediately active form of the protein produced by the
bacteria itself and is thus entirely new to our diet. One important
characteristic of an allergen is that it resists digestion in the stomach
(gastric digestion). According to a recent publication (Astwood et al.,
1996), known allergens wore stable for 60min, whereas nonallergens were
fully digested within 15 s. While one study claimed the Bt protein was
readily digestible (Fuchs et al., 1995), another report showed
that it failed to he completely digested under gastric conditions after 2
h (Noteborn & Kuiper, 1995). In both cases, we are assured that the
protein is safe. In view of the recent discoveries that predators eating
pests that have ingested the Bt toxin in transgenic crop plants are also
harmed (Bigler & Keller, 1997; Hawkes, 1997), it is irresponsible to
assume that the toxin is safe for human, especially [in the] long term.
We accept that no safety assessment system is foolproof. A case in point
is the rigorous testing that goes on with pharmacological products. It is
estimated that despite such rigorous testing, 3% of the products approved
for market turned out to have such harmful effects that they have to be
withdrawn, while an additional 10% have sufficiently harmful side effects
that limited use has to be recommended (Suurkula, 1997). This underlines
the importance of segregation, clear labelling, and postmarket monitoring
of the health and other impacts of genetic engineered foods. Labeling is a
matter of traceability, especially for the case of potential
allergenicity, and should be a scientific requirement, not only a consumer
option.
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