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Transgenic Bt Technology: 5. Substantial Equivalence of Transgenics and their Isogenics
Prof. C. Kameswara Rao
Foundation for Biotechnology Awareness and Education,
Bangalore, India
krao@vsnl.com, www.fbae.org, www.fbaeblog.org

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. This criterion 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.  

PSE is now being applied to products from GEOs, in order to assure the consumer that the product is 'substantially equivalent'  (SE) to its conventional counterpart and so is safe for human consumption.   In the context of GEOs, PSE is frequently an issue for serious discussion (http://www.fao.org/biotech/logs/c9logs.htm, http://www.i-sis.org.uk/subst.php, http://en.wikipedia.org/wiki/Substantial_equivalence).

The FDA has long considered GE crops to be substantially equivalent to conventional varieties and required no other regulatory review.   However, using the ‘provision for voluntary consultation’, biotech companies in the US seek independent SE certification by FDA, of all GE varieties and their products that are marketed in the US.

The policy of the FDA did not result in any health concerns but invited criticism on account of, a) the FDA itself has a mandatory process for approving transgenic animals, and 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 transgenic plants. 

Products from transgenics of such crops as soybean, tomato, corn, cotton, etc., on the US markets have been tested extensively and judged substantially equivalent to their conventional counterparts.   Some products may contain miniscule quantities of one or two additional proteins, which are usually broken down during processing or digestion, or some others may contain some compounds not occurring in the counterparts but at below threshold levels. Such products are categorized as 'Generally Recognized As Safe' (GRAS).  

The presence in the GEOs, of new genes that would code for fats, proteins or carbohydrates, that may be toxic or may cause allergies or may change the nutritional value of the product  (http://www.fbae.org/Channels/Views/not_allergic.htm, http://www.fbae.org/Channels/Views/TOXICITY_OF_GM_food.htm), prevents certification as SE or GRAS, without appropriate and adequate testing.   

While in the US no labeling as SE or GRAS is mandatory, it is not so in several other parts of the world. This leads to considerable confusion and to needless controversies. Suggestions were made for the application of PSE to all products of genetic engineering, including livestock feed and GE crops, which raises certain questions.

In the application of PSE, the comparison is between the GE variety and its isogenic, which is the basic variety into which a transgene was inserted.   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 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 transgenic environment.   Such an assurance requires scientific evaluation of the crop variety first, and then of its products. This involves additional efforts, time and expense, raising consumer costs.    

All US agricultural biotechnology companies submit to the FDA, voluminous dossiers on the safety and risk analysis of the GEOs and their products developed by them, before the products are on the US markets. Such a voluntary mechanism should be global.  If such testing procedures in different countries were uniform, what is considered safe in one country would be so in other countries.   This will eliminate the need for repeating the same and every test in every country.

At no time, transgenics are substantially equivalent to their isogenics in their entire genotypes.   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 more in letter than in spirit, and a lot more strictly than in other countries.  

 The official European consensus is that SE should only be used to guide to inform safety assessments. Codex Alimentarius sees it (www.codexalimentarius.net, CXG045e) as a starting point in the regulatory process rather than an end point. However, in the US, SE still plays a significant role in the regulation and commercialization of GE foods (http://en.wikipedia.org/wiki/Substantial_equivalence).

Notwithstanding the importance given to PSE, it has been criticized as vague, ill defined, flexible, malleable, open to interpretation, unscientific and arbitrary (Ho, M.W. and Steinbrecher, R. (1998); http://www.i-sis.org.uk/subst.php).

On account of such concerns, PSE should be re-examined, and 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.   There is also a dire need for a uniform and harmonized international policy.   At the moment, SE does not adversely affect Bt transgenics or their products.

September 15, 2005