Where does the concept of Substantial Equivalence fit within the framework for evaluation of the safety of genetically enhanced crops?

Regulatory Framework in the United States

In the United States, three agencies assure genetically enhanced crops are safe. In general, the (USDA) makes sure these crops are safe to grow, the Environmental Protection Agency (EPA) makes sure they are safe for our environment, and the United States Department of Agriculture and the Food and Drug Administration (FDA) makes sure they are safe for feed and food.

United States Department of Agriculture (USDA)

The USDA is a regulatory agency that monitors and regulates the use of biotechnology for agricultural purposes. They have the responsibility to determine whether a product or crop has the potential to become a plant pest or cause any detrimental effects on the environment.

Environmental Protection Agency (EPA)

The mission of the EPA is to protect the quality and health of our environment. With respect to protection of the environment from genetically enhanced crops, the focus is on regulation of pest management products. There are three categories of pesticides the EPA reviews for registration:

• Antimicrobials
• Bio-pesticides
• Conventional pesticides

Genetically enhanced plants with Plant-Incorporated Protectants (PIPs) are considered Bio-pesticides. EPA regulates the new protein that is manufactured by the plant and its genetic material, not the plant itself.

Genetically enhanced varieties with PIP undergo seven to ten years of extremely thorough testing before they finally arrive in the farmer’s field. The EPA evaluation includes where and how the protein is produced in the plant and evaluates:

• risks to humans;
• risks to non-target organisms and the environment;
• gene flow potential; and
• insect resistance management plans.

The following tests are examples of requirements to identify possible risks to humans or their environment:

• Identification of new genetic material and all new proteins
• Mammalian toxicity testing of all new proteins
• Comparison of new proteins to known toxins and allergens
• Toxicity testing on birds, fish, earthworms, and insects such as: bees, ladybird beetles, and lacewings
• Toxicity testing on insects related to target insect pests
• Length of time required for the new proteins to degrade in the environment

Food and Drug Administration (FDA) – Concept of Substantial Equivalence

The primary focus of FDA’s assessment is the concept of “Substantial Equivalence”, (SE). This concept was published by the Organization for Economic Cooperation and Development (OECD) and has been validated by the United Nations (UN) Food and Agriculture Organization (FAO), the World Health Organization (WHO) and the International Life Science Institute (ILSI).

Substantial equivalence simply means that food or feed derived from genetic enhancement is as safe as an existing food with the same compositional and nutritional value and a history of safe use. Primarily, the issues regarding substantial equivalence focus on:

• allergenicity;
• toxicity;
• nutrient composition and level including natural toxins and anti-nutrients;
• unintended effects; and
• the safety of antibiotic-resistant marker-encoded proteins included with the transgene.

To evaluate these concerns, the FDA reviews data generated from research on the genetic enhancement and the protein that is produced by the genetic enhancement to assure it:

• has no history of toxicity or allergy;
• doesn’t chemically resemble known toxins or allergens;
• has a well understood function;
• is expressed in very low levels;
• is rapidly degraded in the stomach;
• demonstrates no adverse effects in mice at high levels of consumption;
• demonstrates no adverse effects in animal feeding studies at normal levels of consumption; and
• is well characterized with respect to the specific genetic modifications including markers.

Note: Some of this data overlaps with data required for both USDA and EPA reviews.

At the heart of the FDA substantial equivalence review is a comparison of nutrient compositional data from genetically enhanced crops with non enhanced varieties including:

• protein, crude fiber, oil, carbohydrate, ash;
• amino acid composition;
• fatty acid composition;
• isoflavones;
• minerals;
• vitamins;
• anti-nutritional factors such as phytic acid, trypsin inhibitor, stachyose, raffinose, sucrose; and
• naturally occurring toxins.

Validity of these assessments is based on comparison to historical data for non-enhanced varieties. This historical data is found in databases from a variety of sources for example, http://www.cropcomposition.org/ and summarized in the OECD's Task Force for the Safety of Novel Foods and Feeds consensus documents. These consensus documents contain information for use during the regulatory assessment of a particular food/feed product and are science-based documents, which are mutually acceptable among member countries. Consensus documents include information regarding:

• nutrients;
• anti-nutrients;
• naturally occurring toxins;
• information regarding the product's use as a food/feed; and
• other relevant information.

All genetically enhanced crops potentially fit into three FDA categories:

• Generally Recognized as Safe Substances (GRAS) – must demonstrate that the substances generally appear in nature, have been consumed for long periods without recorded hazards, and are scientifically found to have no undesirable effects on humans.
• Whole Foods – must demonstrate there are no changes in nutritional profile and no introduction of foreign substances that might present health hazards.
• Food Additives – must receive pre-market approval of substances intentionally added to foods that are significantly different in structure, function, or amount than in current food substances.

Substantial equivalence evaluation is simply the first step in the food and feed safety review. The results of these analyses can yield three conclusions. The new food may be found: 1) substantially equivalent to a conventional counterpart; 2) substantially equivalent except for a few clearly defined differences; and 3) not substantially equivalent. Any significant differences between the biotech food and its conventional counterpart would trigger additional tests and possible mandatory labeling under the food additive provision mentioned above.

So far, based on the Substantial Equivalence evaluations, foods derived from genetically enhanced crops have fallen into the Whole Foods and GRAS substance categories. This will certainly change as new products with improved qualities reach the next level in the process. Functional foods, bio-pharmaceuticals and new input traits will require continued review in the regulatory process to protect food and feed safety and our environment.

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