C Kameswara Rao

Foundation for Biotechnology Awareness and Education

Bangalore 560004, India


The US Food and Drug Administration (FDA) routinely and stringently used the ‘Principle of Substantial Equivalence’ (PSE) for decades to assure the public of the safety of foods and drugs marketed in the US. PSE refers only to the product and not the process of its production. On account of the high standards of FDA’s regulatory oversight, most other countries generally approve drugs and pharmaceuticals on the basis of FDA’s approval. 


In the context of modern agricultural biotechnology, antitech activists have repeatedly made PSE an issue of serious concern. 


Efforts are made in every country to demonstrate that a genetically engineered (GE) variety (transgenic) and its products are ‘substantially equivalent’ (SE) to its conventional variety (isogenic) and its products, but for the new genes (transgenes) in the transgenic variety and the consequent expected products of the transgenes.    Once SE is established, the FDA requires no further regulatory review.  


Under the ‘provision for voluntary consultation’, the US biotech companies seek SE certification by FDA, of all GE varieties and their products they intend to market.   The product developers submit to the FDA, voluminous dossiers on the safety and risk analysis of the GE varieties and their products developed by them.   These data are usually confined to the comparative study of proteins, carbohydrates and other components of nutritional significance.   The focus is on determining whether the new GE varieties and their products are toxic or allergenic.   If some GE products contain miniscule quantities of a few additional components that are a) broken down during food processing or digestion or b) if they occur below acceptable independently determined threshold levels, the products are regarded as 'Generally Recognized As Safe' (GRAS).  


The presence of new genes that would code for fats, proteins or carbohydrates in the GE products that may be toxic or may cause allergies or may adversely affect the nutritional value of the product, prevents certification as SE or GRAS, without additional appropriate and adequate testing.


Products from GE soybean, tomato, corn, cotton, etc., on the US markets have been tested extensively, much more than any conventional foods, and judged SE to their conventional counterparts and so are safe food and feed.  


The policy of the FDA did not result in any health concerns and over 350 million US citizens who have been consuming GE food products for about 13 years are a living testimony of their safety.  Nevertheless, the FDA policy has been criticized on account of, a) the FDA itself has a mandatory process for approving transgenic animals, b) the US Environment Protection Agency (EPA) and the US States Department of Agriculture (USDA) have a mandatory and open process for evaluating the biosafety of GE crops, and c) the data are provided by the product developers. 


Labelling GE products as SE or GRAS is not mandatory in the US, but there are persistent demands for labelling in several other parts of the world. This leads to considerable confusion and controversies, more so if PSE has to be applied to all products of GE, including livestock feed, and worse if SE has to be established for different transgenic varieties of the same crop with the same transgene, as demanded by some activist groups. 


In the application of PSE, the comparison should only be between the GE variety and its isogenic, which is the basic variety into which a new gene was inserted, but not any and every variety of the same crop.  The certification is to the effect that the GE crop variety is substantially equivalent to its isogenic, in genotype, marked characteristics and performance, but for the transgenes and their anticipated products and characteristics. If the isogenic were safe, the transgenic would be equally safe, provided that the newly introduced transgenes do not exercise any adverse effects by themselves or through altering the expression of any other genes of the isogenic in the new status which may happen very very rarely.  Such an assurance requires scientific evaluation of the crop variety and its products, which involves additional effort, time and expense, that escalate consumer costs.


The US practice of agricultural biotechnology companies voluntarily submitting detailed dossiers on the safety and risk analysis of the GEOs and their products, developed by them before they are marketed should be global, although the activists look down upon data provided by the product developers themselves, even when gathered by different recognized laboratories outside the companies. When testing standards and procedures in different countries were reasonably uniform, what is considered safe in one country should also be considered so in the other countries. This will eliminate the need for repeating the same and every test in every country, saving time and expense.


At no time, transgenics can be wholly SE to their isogenics in their entire genotypes and this is not related to transgenic technology. Even to start with, members of the same population are not entirely genetically identical. In addition, mutations occur naturally and randomly, involving different genes. Lethal mutations are naturally eliminated. Mutations of the genes of the desired characteristics are eliminated in the process of selection, but those that do not affect the desired characteristics escape attention and accumulate. After a certain number of generations, a critical genetic analysis will contravene SE, although SE can be established for the genes of the desired characteristics. Such a situation would cause problems in some countries, where the regulatory authorities apply the principle of SE more in letter than in spirit, and a lot more strictly than in other countries.


The official consensus of the European Union (EU) is that, SE should only be used to inform of basic safety assessments and so GE products require further confirmatory analysis by sophisticated methods. The EU safety regulations, based on this premise, are so stringent that they raised doubts whether any GE product will at all qualify to be considered safe.    


The Codex Alimentarius Commission (CAC) is the international organization established in 1963, jointly by the FAO and WHO, under the Food Standards Programme to set international guidelines for food standards and safety.   Comprised of 165 member countries, the CAC sees SE as a starting point in the regulatory process rather than as the end point.


Notwithstanding the importance given to PSE, it has been criticized as vague, ill defined, flexible, malleable, open to interpretation, unscientific and arbitrary. 


In the debate on SE it is often held that,

a)     the focus of SE has been well known nutritionally significant components, occurring in significant quantities,

b)     the studies employed routine food safety testing methods which are not sensitive enough to detect all components and are not detailed total critical analyses, 

c)      that more sophisticated and deep analytical approaches may reveal chemical compounds hither to unexpected and unknown, which may make the GE products unsafe for human consumption, and

d)     in the US, SE data were generated not by independent entities but by the product developers themselves (and so suspect) and largely remained in the private domain, not easy for others to access for evaluation.    

Metabolomics  is an area of sophisticated but complex ‘fingerprinting’ procedures that provide for a detailed profiling of all products of metabolism in a cell.  Metabolomic studies by  Catchpole Gareth and 11 others in 2005 demonstrated that, apart from targeted changes, field grown GE potatoes and their traditional cultivars were SE to each other.  The minor differences that were found between the GE and the non-GE varieties were of the same kind and magnitude of such differences among the non-GE varieties, that occur on account of natural variation in gene expression.  None of these differences are significant in the context of the safety of the GE potatoes for human consumption.  This study is safe from all reasonable criticism.  


Some activists groups demand sophisticated and complex procedures to establish SE, but such procedures entail time and money escalating consumer costs and so cannot be routine methods of establishing SE.  They should be used only if there was justification, perceived from standard analyses, to go for more intensive methods.


Invoking SE, which relates only to food and feed, in issues of non-target organisms such as the aquatic arthropod Daphnia magna with reference to MON 810 Bt corn, as was done last year, is tantamount to shifting goal posts.  There are other mandatory procedures to assess the impact of GE crops and products on non-target organisms and the environment.   


There is a dire need for a uniform and harmonized international policy on SE. On account of the concerns raised, the PSE should be re-examined, for re-defining its applicability to GE crop plants and their products, laying emphasis on a reasonable application of the principle, addressing only those genes and their products that are relevant to the objectives of developing a particular transgenic variety or product. 


At the moment, there is no evidence that SE is an issue that adversely affects the safety of GE crops or their products as food and feed.



July 7, 2009