by Dr. M. Alewynse and Dr. W. D. Price

On May 29, 1992, the FDA published a Statement of Policy: Foods Derived from New Plant Varieties in the Federal Register. This statement laid out issues that individuals should consider during the development of new plant varieties which includes those developed using rDNA techniques. After publication of the policy, FDA's Center for Food Safety and Applied Nutrition (CFSAN) and Center for Veterinary Medicine (CVM) initiated a voluntary consultation process where the developer of a new plant variety consults with the Agency about safety and regulatory issues prior to marketing. In June 1996, these procedures were formalized. Included in the procedures are the CVM concerns published in the FDA Veterinarian by Price and Alewynse (September/October 1995). Typically, the developer submits summary information about the safety and nutritional assessment of the plant to FDA. The Agency may then conclude the consultation process by issuing a letter to the developer which indicates that there are no unresolved issues associated with that variety. The consultation procedures are described in more detail on CFSAN's WWW site (http://vm.cfsan.fda.gov/~lrd/consulpr.html).

Twenty-five consultations involving eight different crops, including both human foods, such as tomatoes, and traditional animal feedstuffs, like the soybean, have been completed. In 1994, the Agency and plant developers concluded eight consultations. During 1995, seven consultations were concluded; and by November, 1996, another ten had completed the process. Some of the consultations involved several different plant lines. In 1996, the first multiple trait plant, corn to be marketed for both its insect protection and herbicide tolerance qualities, completed the consultation process.

At the present time, five different consultations have been concluded for tomatoes which exhibit modified ripening or softening behavior. Several potatoes which contain the cryIIIA gene product to confer insect protection have also been examined. In addition, virus resistant squash has completed the process.

For crops such as corn and soybeans which have traditionally been used in animal feed, the primary focus of trait development has been to improve insect resistance and plant tolerance to herbicide application. Insect resistance has been accomplished by plant expression of insecticidal proteins. At the present time, genes obtained from Bacillus thuringiensis have been utilized to obtain the insecticidal trait. This characteristic has been incorporated into both cotton and corn. In corn, the desired effect, a reduction in European corn borer infestations, has been the subject of five consultations. These insecticidal proteins are classified as pesticides by the Environmental Protection Agency (EPA) which is responsible for licensing these genetically modified crops. However, FDA is still responsible for the wholesomeness of the plants.

Herbicide tolerance is also a trait of interest to plant breeders and has been the subject of nine consultations. Many herbicides can not be used on or have a limited time when they can be applied to crops. By engineering a gene into the plant which allows herbicide application without injury or yield reduction, firms hope to aid farmers in the control of field weeds. With herbicide tolerant crops, weeds can be treated anytime they become a problem which allows more freedom in the timing of herbicide application. Corn, cotton, canola, and soybeans have all been modified to be tolerant to different herbicides. FDA has the sole responsibility for the safety of these genetically modified crops, while EPA regulates the use of the herbicide.

In addition, several consultations have dealt with modifications to aid traditional plant breeding, such as male sterility in corn, and hybridization in oilseed rape. Plant composition has also been changed using rDNA techniques. Canola has been modified to produce oil containing an increased level of laurate, making its composition similar to coconut oil which is used in nondairy whipped toppings.

The use of antibiotic resistance marker genes in the development of biotech plants has been a concern. Plant breeders have indicated in the consultation process that kanamycin (kanr), ß lactam, chloramphenicol, and aminoglycoside resistance genes have been used in several modified plants released thus far. Only the kanr gene produces a product in the plant. Calgene Inc. filed a Food Additive Petition (FAP) for aminoglycoside 3' phosphotransferase II (NPT II) encoded by the kanr gene. This gene product appears in small quantities in the Flavr Savr™ tomato, and cotton, rape (canola) and potato varieties. The FAP was approved after a thorough review which substantiated that NPT II would not raise a safety concern. It was also concluded that NPT II would not significantly affect the stability of neomycin in animal feed.

Genes encoding resistance to kanamycin, ß lactam, chloramphenicol, and aminoglycoside antibiotics have been used in the development of other modified plant varieties, but these genes are not expressed in those plants. These genes have bacterial promoters to target expression in bacteria where the total gene construct to be inserted in the crop is cloned, and are used only as a gene detection tool. Convincing arguments have been made by the plant developers that it is highly unlikely that a functional copy of these genes would be transferred from the plant to rumen or gut microflora. However, the use of antibiotic resistance marker genes continues to be an issue on the international scene.

CFSAN and CVM in cooperation with USDA's Foreign Agricultural Service have participated in several international meetings, including those with Japan and the European Union (EU) in an attempt to harmonize preclearance requirements. CVM has worked with Canada, Japan, and the EU on guidance for animal feed use of Novel (biotech) Foods. Labeling of food and feed derived from new plant varieties appears to be an issue within the EU. In the U.S., labeling has only been suggested for high laurate canola oil because of the compositional changes. Feed or food labeling would be required in the U.S. if there is a safety issue, such as the presence of an allergen or a significantly higher level of a toxic factor, such as gossypol in cottonseed, or if the product would be misbranded, due to changes in composition, such as occurred in high laurate canola.

The following table lists plant varieties which have completed the consultation process as of December 6, 1996. The table includes the name of the developer, the crop, the trait, and the source of the genetic material conferring the trait. An updated version of the table is maintained at the CFSAN WWW site (http://vm.cfsan.fda.gov/~lrd/biocon.html).

Firm Crop and Trait Responsible Gene Gene Source


Agritope Inc. Modified fruit S- hydrolase gene E. coli

ripening tomato adenosylmethionine bacteriophage T3


Dekalb Genetics Glufosinate Phosphinothricin Streptomyces

Corp. tolerant corn acetyl transferase hygroscopicus

gene


Dupont Sulfonylurea Acetolactate tobacco

tolerant cotton synthase gene


Monsanto Co. Insect protected CryIIIA gene Bacillus

potato thuringiensis


Monsanto Co. Insect protected CryIA(b) gene Bacillus

corn thuringiensis

subsp. kurstaki


Monsanto Co. Insect protected CryIA(b) gene Bacillus

corn thuringiensis

subsp. kurstaki


Monsanto Co. Glyphosate Enolpyruvylshikimate Agrobacterium sp.

tolerant/insect -3-phosphate strain CP4

protected corn synthase gene and

glyphosate Ochrobactrum

oxidoreductase anthropi

gene in the

glyphosate tolerant

lines



Bacillus

CryIA(b) gene thuringiensis

in lines that are subsp. kurstaki

insect protected



Northrup King Insect protected CryIA(b) gene Bacillus

corn thuringiensis

subsp. kurstaki


Plant Genetic Male Male sterile oilseed Bacillus

Systems sterile/fertility rape contains the amyloliquefaciens

restorer oilseed barnase gene

rape





Fertility restorer Bacillus

lines express the amyloliquefaciens

barstar gene


Plant Genetic Male sterile corn Barnase gene Bacillus

Systems amyloliquefaciens



AgrEvo Inc. Glufosinate Phosphinothricin Streptomyces

tolerant canola acetyltransferase viridochromogenes

gene



AgrEvo Inc. Glufosinate Phosphinothricin Streptomyces

tolerant corn acetyltransferase viridochromogenes

gene



Calgene Inc. Laurate canola 12:0 acyl carrier California bay,

protein thioesterase Umbellularia

gene californica



Ciba-Geigy Corp Insect protected CryIA(b) gene Bacillus

corn thuringiensis

kurstaki


Monsanto Co. Glyphosate Enolpyruvylshikimate Agrobacterium sp.

tolerant cotton -3-phosphate strain CP4

synthase gene



Monsanto Co. Glyphosate Enolpyruvylshikimate Agrobacterium sp.

tolerant canola -3-phosphate strain CP4

synthase gene



Monsanto Co. Insect protected CryIA(c) Bacillus

cotton thuringiensis

subsp. kurstaki


Asgrow Seed Virus resistant Coat protein genes watermelon

Co. squash mosaic virus 2 and

zucchini yellow

mosaic virus



Calgene Inc. Flavr Savr™ Antisense tomato

tomato polygalacturonase

gene



Calgene Inc. Bromoxynil Nitrilase gene Klebsiella
ozaenae

tolerant cotton



DNA Plant Improved ripening Fragment of the tomato

Technology tomato aminocyclopropane

carboxylic acid

synthase gene



Monsanto Co. Glyphosate Enolpyruvylshikimate Agrobacterium sp.

tolerant soybean -3-phosphate strain CP4

synthase gene form



Monsanto Co. Improved ripening Aminocyclopropane Pseudomonas

tomato carboxylic acid chloraphis strain

deaminase gene 6G5



Monsanto Co. Insect protected CryIIIA gene Bacillus

potato thuringiensis sp.

tenebrionis


Zeneca Plant Delayed softening Fragment of the tomato

Science tomato polygalacturonase

gene