Sir

The Commentary by Erik Millstone et al.1 on the role of substantial equivalence in the safety evaluation of genetically modified (GM) food draws attention to important issues, but it gives an inaccurate and misleading account of the work of regulatory committees and the current role of substantial equivalence in safety evaluation.

The authors imply that regulatory committees depend on substantial equivalence as the sole basis for the safety evaluation of GM foods. They suggest that only chemical tests are used, and that biological, toxicological and immunological methods are ignored. This seriously misrepresents the work of independent expert committees that give careful and wide-ranging consideration to the safety of GM foods on a case-by-case basis, and do not rely solely on substantial equivalence.

From the standpoint of safety evaluation, substantial equivalence is a useful tool to address a major limitation in traditional toxicology approaches to whole GM foods. The feeding of excess quantities of individual chemical components to experimental animals can easily be distinguished from overall nutrition. This approach can be used to set acceptable daily intakes for non-nutrient chemical components of the diet. In contrast, whole GM foods are complex, contribute to nutrition and are limited in the quantity that can be consumed. So the interpretation of data from animal feeding experiments is far from simple.

The safety evaluation of GM food is far more rigorous than is applied to its conventional counterpart, and aims to establish that the accepted safety of the conventional counterpart has not been compromised. In Europe, the safety evaluation of GM foods is covered by European Commission (EC) regulation 258/97. The work of the UK Advisory Committee on Novel Foods and Processes (ACNFP) now falls within its framework2. According to the EC, “substantial equivalence is not a safety or nutritional assessment in itself, but an approach to compare a potential new food with its conventional counterpart”3.

In most instances GM technology is applied to a crop plant to introduce a new trait, so the GM plant cannot be substantially equivalent to its conventional parent. An example that illustrates the fact that much more than substantial equivalence is involved is the safety evaluation of GM soya4. Safety evaluation focused on four issues: intentional changes; unintentional changes; stability; and gene transfer. GM soya contains a single introduced bacterial gene that confers tolerance to the herbicide glyphosate. This gene produces a glyphosate-insensitive homologue of the natural plant enzyme, 5-enolpyruvylshikimate-3-phosphate synthase (EPSPS), that is involved in aromatic amino-acid biosynthesis. Detailed molecular analysis authenticated the genetic modification and demonstrated that it was stable through several generations of conventional plant breeding. An acute toxicity study in mice showed that the introduced EPSPS protein was non-toxic, and it was demonstrated that this protein is rapidly degraded under conditions encountered following consumption. Furthermore, the conventional processing of soya was shown to destroy the protein. So EPSPS, which in any event is inactivated in marketed GM food, is safe.

The possibility that unintended changes had taken place was evaluated by comparing compositional data and nutritional studies for GM and conventional soya. It is known that unprocessed soya beans can cause food allergy, and the levels of known allergenic proteins were unchanged in GM soya. The possibility of gene transfer from GM soya was eliminated by DNA degradation during processing. On the basis of this evaluation, ACNFP concluded that GM soya was as safe as its conventional counterpart.

Substantial equivalence has recently been re-evaluated by the Organization for Economic Cooperation and Development5. A useful aspect of this evaluation is the recommendation of a consensus on appropriate components for compositional analysis so as to standardize safety evaluation. Key nutrients and known toxins, antinutrients and allergens would be included in this consensus.

The expression of previously unknown toxins, antinutrients or allergens in GM foods so as to cause previously unrecognized harm is unlikely, given that conventional foods have been subject to massive changes in genetic make-up by established plant-breeding methods. The use of chemical fingerprinting, messenger RNA analysis, DNA arrays and proteomics to investigate unintended effects are recognized possibilities for the future, but the practical value of these techniques has not been established. Changes to gene expression and to the levels of individual proteins and metabolites are a normal feature of plant development and response to environmental change. Any such detailed holistic analysis needs to be considered in the context of a dynamic situation in which flux in gene expression is the norm.