Prestigious Scientific Journal Attacks Notion of "Substantial Equivalence"
and Safety of GE and Conventional Foods

Oct. 7, 1999
by Erik Millstone, Eric Brunner and Sue Mayer
Showing that a genetically modified food is chemically similar to its
natural counterpart is not adequate evidence that it is safe for human
Whenever official approval for the introduction of genetically modified
(GM) foods has been given in Europe or the United States, regulatory
committees have invoked the concept of 'substantial equivalence'. This
means that if a GM food can be characterized as substantially equivalent
to its 'natural' antecedent, it can be assumed to pose no new health
risks and hence to be acceptable for commercial use. At first sight, the
approach might seem plausible and attractively simple, but we believe
that it is misguided, and should be abandoned in favour of one that
includes biological, toxicological and immunological tests rather than
merely chemical ones.
The concept of substantial equivalence has never been properly defined;
the degree of difference between a natural food and its GM alternative
before its 'substance' ceases to be acceptably 'equivalent' is not
defined anywhere, nor has an exact definition been agreed by
legislators. It is exactly this vagueness which makes the concept useful
to industry but unacceptable to the consumer. Moreover, the reliance by
policymakers on the concept of substantial equivalence acts as a barrier
to further research into the possible risks of eating GM foods.
Acceptable daily intake
The concept of substantial equivalence emerged in response to the
challenge confronting regulatory authorities in the early 1990s.
Biotechnology companies had developed several GM foods and, to reassure
their customers, wanted official approval for their introduction. But
government statutes did not cover GM foods, nor provide the authority to
regulate these innovations. Legislation could be amended, but that would
not address the core problem of how to assess the risks. One obvious
solution at that time would have been for legislators to have treated GM
foods in the same way as novel chemical compounds, such as
pharmaceuticals, pesticides and food additives, and to have required
companies to conduct a range of toxicological tests, the evidence from
which could be used to set 'acceptable daily intakes' (ADIs).
Regulations could then have been introduced to ensure that ADIs are
never, or rarely, exceeded.
>From the point of view of the biotechnology industry, this approach
would have had two main drawbacks. First, companies did not want to have
to conduct toxicological experiments, which would delay access to the
marketplace by at least five years, and would add approximately $25
million per product to R&D costs. Second, by definition, using ADIs
would have restricted the use of GM foods to a marginal role in the
diet. An ADI is usually defined as one-hundredth of the highest dose
shown to be harmless for laboratory animals. Thus, even if laboratory
animals show no adverse effects on a diet consisting exclusively of a
test material, human intake would still be restricted to 1% of the human
diet. The biotechnology companies want to market GM staples, such as
grains, beans and potatoes, which individually might account for as much
as 10% of the human diet, and collectively might provide more than half
of a person's food intake.
The adoption of the concept of substantial equivalence by the
governments of the industrialized countries signalled to the GM food
industry that as long as companies did not try to market GM foods that
had a grossly different chemical composition from those of foods already
on the market, their new GM products would be permitted without any
safety or toxicology tests. The substantial-equivalence concept was also
intended to reassure consumers, but it is not clear that it has served,
or can serve, that purpose. Although toxicological and biochemical
tests, and their interpretation, are notoriously problematic and
contested, and are slow and expensive, they can provide information
vital to consumer protection.1
Trying to have it both ways
The challenge of how to deal with the issue of risk from consuming GM
foods was first confronted in 1990 at an international meeting,
consisting of officials and industrialists but no consumer
representatives, of the UN Food and Agriculture Organisation (FAO) and
the World Health Organisation (WHO).2 The FAO/WHO panel report makes
intriguing reading, because what it fails to mention is as important as
what is discussed. It does not use the term 'substantial equivalence' or
mention ADIs. It implies that GM foods are in some important respects
novel, but it then argues that they are not really novel at all ? just
marginal extensions of traditional techniques. These inconsistencies are
inevitable, given that the industry wanted to argue both that GM foods
were sufficiently novel to require new legislation and a major overhaul
of the rules governing intellectual property rights to allow them to be
patented, yet not so novel that they could introduce new risks to public
or environmental health.
The biotechnology companies wanted government regulators to help
persuade consumers that their products were safe, yet they also wanted
the regulatory hurdles to be set as low as possible. Governments wanted
an approach to the regulation of GM foods that could be agreed
internationally, and that would not inhibit the development of their
domestic biotechnology companies. The FAO/WHO committee recommended,
therefore, that GM foods should be treated by analogy with their non-GM
antecedents, and evaluated primarily by comparing their compositional
data with those from their natural antecedents, so that they could be
presumed to be similarly acceptable. Only if there were glaring and
important compositional differences might it be appropriate to require
further tests, to be decided on a case-by-case basis.
Unfortunately, scientists are not yet able reliably to predict the
biochemical or toxicological effects of a GM food from a knowledge of
its chemical composition. For example, recent work on the genetics of
commercial grape varieties shows that, despite detailed knowledge going
back for centuries of the chemistry and flavour of grapes and wines, the
relationship between the genetics of grapes and their flavour is not yet
understood3. Similarly, the relationship between genetics, chemical
composition and toxicological risk remains unknown. Relying on the
concept of 'substantial equivalence' is therefore just wishful thinking:
it is tantamount to pretending to have adequate grounds to judge whether
or not products are safe.
The results of Arpad Pusztai's experiments with GM potatoes and their
interpretation remain a matter of controversy (see Nature 398, 98;1999),
but his starting hypothesis was that GM potatoes would be substantially
equivalent to non-GM potatoes. Pusztai interpreted his still unpublished
results as indicating that the GM potatoes exerted adverse biochemical
and immunological effects, which could not have been predicted from what
was known of their chemical composition. The kinds of experiments which
he conducted are not legally required and are therefore not routinely
conducted before GM foods are introduced into the food chain.
Failure to define 'substantial equivalence'
The concept of 'substantial equivalence' was first introduced in 1993 by
the OECD4, and was subsequently endorsed in 1996 by the FAO and WHO.
Given the weight the concept has been required to carry, it is
remarkable how ill-defined it remains, and how little attention has been
devoted to it. The OECD document states:
"For foods and food components from organisms developed by the
application of modern biotechnology, the most practical approach to the
determination is to consider whether they are substantially equivalent
to analogous food product(s) if such exist....The concept of substantial
equivalence embodies the idea that existing organisms used as foods, or
as a source of food, can be used as the basis for comparison when
assessing the safety of human consumption of a food or food component
that has been modified or is new."
That is the closest there has been to an official definition of
substantial equivalence, but the definition is too vague to serve as a
benchmark for public health policy.
GM glyphosate-tolerant soya beans (GTSBs) illustrate how the concept has
been used in practice. The chemical composition of GTSBs is, of course,
different from all antecedent varieties, otherwise they would not be
patentable, and would not withstand the application of glyphosate. It is
quite straightforward to distinguish, in a laboratory, the particular
biochemical characteristics which make them different. GTSBs have,
nonetheless, been deemed to be substantially equivalent to non-GM soya
beans by assuming that the known genetic and biochemical differences are
toxicologically insignificant, and by focusing instead on a restricted
set of compositional variables, such as the amounts of protein,
carbohydrate, vitamins and minerals, amino acids, fatty acids, fibre,
ash, isoflavones and lecithins. GTSBs have been deemed to be
substantially equivalent because sufficient similarities appear for
those selected variables.
But this judgement is unreliable. Although we have known for about 10
years that the application of glyphosate to soya beans significantly
changes their chemical composition (for example the level of phenolic
compounds such as isoflavones5), the GTSBs on which the compositional
tests were conducted were grown without the application of glyphosate6.
This is despite the fact that commercial GTSB crops would always be
treated with glyphosate to destroy surrounding weeds. The beans which
were tested were, therefore, of a type which would never be consumed,
while those which are being consumed were not evaluated. If the GTSBs
had been treated with glyphosate before their composition was analysed
it would have been harder to sustain their claim to substantial
equivalence. There is a debate in the research community on whether such
changes to the chemical composition are desirable or undesirable, but it
is an issue which remains unresolved, and which has been neglected by
those who have deemed GTSBs and non-GM soyabeans to be substantially
Acknowledged limitations
Only one official organization has recognized some of the limitations of
the concept of substantial equivalence. A Dutch government team has
acknowledged that "compositional a screening method for
unintended effects...of the genetic modification has its particular regarding unknown anti-nutrients and natural
toxins", and it has given a lead by trying to explore some
alternatives7. The Dutch team accepts that comparisons of relative
crude compositional data provide a very weak screen against the
introduction of novel genetic, biochemical, immunological or
toxicological hazards, and they have suggested a finer-grained screen to
test for differences in some of the relevant biological variables, such
as DNA analysis, messenger-RNA fingerprinting, protein fingerprinting,
secondary metabolite profiling and in vitro toxicity testing. If the
use of such a finer screen revealed that a GM food contained a relevant
novelty then the case for further studies would be far stronger, and
those studies might benefit from having some clues as to which
end-points might be most worthy of investigation.
Substantial equivalence is a pseudo-scientific concept because it is a
commercial and political judgement masquerading as if it were
scientific. It is, moreover, inherently anti-scientific because it was
created primarily to provide an excuse for not requiring biochemical or
toxicological tests. It therefore serves to discourage and inhibit
potentially informative scientific research. The case of GTSBs shows,
moreover, that the concept of substantial equivalence is being
misapplied, even on its own terms, within the regulatory process. If
policymakers are therefore to provide consumers with adequate
protection, and genuinely to reassure them, then the concept of
substantial equivalence will need to be abandoned, rather than merely
supplemented. It should be replaced with a practical approach which
would actively investigate the safety and toxicity of GM foods rather
than merely taking them for granted, and which could give due
consideration to public health principles as well as to industrial
Erik Millstone, SPRU ? Science and Technology Policy Research, Mantell
Building, Sussex University, Brighton BN1 9RF (E-mail; Eric Brunner, Department of Epidemiology
and Public Health, University College, 1-19 Torrington Place, London
WC1E 6BT; and Sue Mayer, GeneWatch UK, The Courtyard, Whitecross Road,
Tideswell, Buxton, Derbyshire SK17 8NY
1 'The ADI Debate', Appendix I of Food additives and the consumer',
European Commission, 1980, pp. 41-3;
2. Strategies for assessing the safety of foods produced by
biotechnology, WHO, Geneva, 1991
3. Bowers, J. et al. Science 285, 1562-1565 (1999)
4. Safety Evaluation of Foods Derived by modern biotechnology OECD,
Paris, 1993.
5. Lydon, J. & Duke, S.O. Pesticide Science 25, 361-374 (1989)
6. Padgette, S. R. et al. Journal of Nutrition 126, 702-716 (1996).
7. Kuiper, H. A. et al. Food Safety Evaluation of Genetically Modified
Foods as a Basis for Market Introduction (Ministry of Economic Affairs,
The Hague, 1998).