Substantial equivalence

The phrase substantial equivalence is given to a relatively new concept used in the regulation of new foods, especially genetically modified foods, also called [recombinant DNA] (rDNA) derived foods (hereafter GM foods).

The concept is used to determine whether a new food shares similar health and nutritional characteristics with an existing, familiar food with an established history of safe use.

Definition and Controversy
Reasoning about substantial equivalence is widely used by national and international agencies - including the Canadian Food Inspection Agency, Japan's Ministry of Health and Welfare and the U.S. Food and Drug Administration,  the United Nation’s Food and Agriculture Organization, the World Health Organization and the Organisation for Economic Cooperation and Development (hereafter OECD).

Some other new biochemical concepts that are important for understanding the substantial equivalence of a novel food or crop to an existing food or crop are metabolic profiling and protein profiling. These concepts refer, respectively, to the complete measured biochemical spectrum (total fingerprint) of compounds (metabolites) or of proteins present in a food or crop. Substantially equivalent foods have the same metabolic and protein profiles, or more precisely, biochemical profiles of a new food are deemed to be substantially equivalent to an existing food if they fall within the range of natural variation already exhibited by biochemical profiles of existing foods or crops.

Over the history of its usage the term substantial equivalence has been interpreted differently by the various participants in the debate about GM food safety.

The current state of the concept is clarified in several recent food science articles. International consensus has been reached on the principles regarding evaluation of the food safety of genetically modified plants. The concept of substantial equivalence has been developed as part of a safety evaluation framework, based on the idea that existing foods can serve as a basis for comparing the properties of genetically modified foods with the appropriate counterpart. Application of the concept is not a safety assessment per se, but helps to identify similarities and differences between the existing food and the new product, which are then subject to further toxicological investigation. Substantial equivalence is a starting point in the safety evaluation, rather than an endpoint of the assessment. (Kuiper and others, 2001)

The utility of the substantial equivalence concept is illustrated by the way certain food products - such as processed and purifed food components like soybean oil, starch or crystalline sugar - may be considered substantially equivalent even though the varieties from which they were obtained are different.

As a notion substantial equivalence was first articulated by the OECD, which hosted discussions that led to a key publication  'Safety Evaluation of Foods Derived by Modern Biotechnology: Concepts and Principles'  (OECD, 1993).

The concept has been criticised, for instance in 1999 by Erik Millstone (University of Sussex) Eric Brunner (UC London) and Sue Mayer (GeneWatch UK) who argued that the concept was pseudo-scientific, and that:

"[T]he 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."

But substantial equivalence recognises the fact that existing foods often contain toxic components ( usually called antinutrients) and are still able to be consumed safely - in practice there is some tolerable chemical risk taken with all foods, so a comparative method for assessing safety needs to be adopted. For instance, potatoes and tomatoes can contain toxic levels of respectively, solanine and alpha-tomatine alkaloids. .

It also recognised the well supported scientific argument that:

"While rDNA techniques may result in the production of organisms expressing a combination of traits that are not observed in nature, genetic changes from rDNA [recombinant DNA] techniques will often have inherently greater predictability compared to traditional techniques, because of the greater precision that the rDNA technique affords; (and) it is expected that any risks associated with applications of rDNA organisms may be assessed in generally the same way as those associated with non-rDNA organisms."

which was first voiced in 1986 by the OECD Recombinant DNA Safety Considerations. Paris: OECD, 1986, cited by Miller (1999), and has subsequently re-affirmed in numerous scientific deliberations , and by comprehensive chemical comparisons of recombinant DNA derived crops and their conventional crop counterparts discussed below.

It is for this reason legislators treat a new food food by comparison with its nearest existing known counterpart, taking into account natural ranges for variation in metabolic and proteins profiles, and particularly profiles of anti-nutrients. If a GM food was found to be substantially equivalent to its nearest existing counterpart by careful compositional analysis ( 'profiling'or 'fingerprinting' ) of the full set of chemical compounds in the food, it can be argued that it is at least as safe as that conventional counterpart.

For instance, the US FDA effectively uses substantial equivalence as part of their policy: The FDA's policy defines certain safety-related characteristics of new foods that, if present, require greater scrutiny by the agency. These include the presence of a substance that is completely new to the food supply, an allergen presented in an unusual or unexpected way (for example, a peanut protein transferred to a potato), changes in the levels of major dietary nutrients, and increased levels of toxins normally found in foods. Additional tests are performed when suggested by the product's composition, characteristics or history of use. For example, potatoes are generally tested for the glycoalkaloid solanine, because this natural toxin has been detected at harmful levels in some new potato varieties that were developed with conventional genetic techniques . A biotechnology company could establish substantial equivalence by comparing food biochemical profiles such as protein, carbohydrate, fatty acid levels, nutrients, antinutients and other plant metabolites between the novel food and its traditional counterpart.

Critics have argued that there were no clear and universal guidelines stipulating what to test and how similar the items in question should be. Thus Erik Millstone et al state:

"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."

But the response of the proponents to this criticism was that they were being misrepresented:

Substantial equivalence is not a substitute for a safety assessment. It is a guiding principle which is a useful tool for regulatory scientists engaged in safety assessments. It stresses that an assessment should show that a GM variety is as safe as its traditional counterparts. In this approach, differences may be identified for further scrutiny, which can involve nutritional, toxicological and immunological testing. The approach allows regulators to focus on the differences in a new variety and therefore on safety concerns of critical importance. Biochemical and toxicological tests are certainly not precluded. Peter Kearns (OECD) Paul Mayers (Health Canada)

The quandary of what to test has been resolved by the concept of testing everything and thus determine the biochemical profile of the food, as recently comprehensive biochemical profiling of metabolites and proteins in food have become technically possible. These provide an empirical route for determining if a food is in fact substantially equivalent to an existing food, and this approach, also called metabolomics (for metabolite profiling) or proteomics (protein profiling) has established the equivalence of one strain of GM potato and its conventional counterparts, and also the equivalence of a new GM tomato variety to its existing counterpart.

The range of biochemical profiles routinely seen in different conventional varieties of the same crop and under different growing condition provide a natural criterion for defining what constitutes an "equivalent composition". If a new GM food falls within the natural range of existing variation it is equivalent. Regulators are now placing emphasis on identifying the unintended consequences of genetic modification and comparing it with the many unexpected changes that are known to occur in conventional crop varieties. These studies are currently revealing that the extent of unexpected change in GM crop varieties is much less than seen with conventionally bred varieties: that is to say, from this aspect GM food is safer. Substantial equivalence is only the starting point of safety assessment. Better methods for testing composition, metabolic and protein profiles, metabolic activity, antinutrients, toxicity, and allergenicity continue to be developed.