IFT Expert Report onBiotechnology and Foods

The report focuses on rDNA biotechnology-derived foods, food ingredients, and animal feed of plant origin, and on the use of rDNA biotechnology-derived microorganisms such as yeasts and

1 EXPERT REPORT ON BIOTECHNOLOGY AND FOODS

he use of modern biotechnology (recombinant DNA

technology) to produce foods and food ingredients is a

subject of heightened interest among consumers and

public policy makers, and within the scientific

com-munity As a result, the news media have extensively covered the

subject, seemingly with each development Eager to contribute

to a meaningful dialogue on scientific issues and consumer

concerns about rDNA biotechnology, the Institute of Food

Technologists (IFT), the 29,000-member nonprofit society for

food science and technology, implemented a new initiative

IFT’s leaders provided the impetus and strategies, including

es-tablishment of a Task Force, for the initiative The

Biotechnolo-gy Task Force identified the overall goal of providing

science-based information about this modern tool to multiple

audien-ces, e.g., its members, journalists, and the general public The

Task Force identified issues within three main topics—safety,

labeling, and benefits and concerns—and decided that each

would be addressed within a comprehensive, scientific report

IFT convened a panel of experts, comprising IFT members

and other prominent biotechnology authorities, to prepare

re-port sections on each of the three main topics Each panel

con-tributed to an Introduction section Thus, this scientific report

consists of four parts: Introduction, Safety, Labeling, and Benefits

and Concerns Members of the panels of experts are identified

within each report section IFT’s Office of Science,

Communica-tions, and Government Relations coordinated the development

of the report

The report focuses on rDNA biotechnology-derived foods,

food ingredients, and animal feed of plant origin, and on the

use of rDNA biotechnology-derived microorganisms such as

yeasts and enzymes in food production Milk from cows that

have received rDNA biotechnology-derived hormones is

dis-cussed; transgenic animals resulting from the application of

rDNA biotechnology techniques to animal production are not

addressed

The Introduction presents background information to help

readers understand rDNA biotechnology-derived foods and

fed-eral regulation and oversight of rDNA biotechnology The Safety

section discusses issues relevant to evaluation of rDNA

biotech-nology-derived foods, including the concept of substantial

equivalence, introduced genetic material and gene products,

un-intended effects, allergenicity, and products without

conven-tional counterparts The internaconven-tional scientific consensus

re-garding the safety of rDNA biotechnology-derived foods is also

IFT Expert Report on

Biotechnology and Foods

discussed The Labeling section provides an overview of the

rele-vant United States food labeling requirements, including consti-tutional limitations on the government’s authority to regulate food labeling and specific case studies relevant to labeling rDNA

biotechnology-derived foods The Labeling section also discusses

U.S and international labeling policies for rDNA biotechnology-derived foods and the impact of labeling distinctions on food distribution systems Consumer perceptions of various label

statements are also discussed The Benefits and Concerns section

considers in detail numerous specific benefits regarding plant at-tributes; food quantity, quality, and safety; food technology and bioprocessing; animals; the environment; economics; diet, nutri-tion, and health; and medical benefits Concerns addressed in-clude economic and access-related concerns, research incentives, environmental concerns, monitoring, allergenicity, antibiotic re-sistance transfer, and naturally occurring toxicants

The report sections were published in three issues of Food Technology The first page of each report section identifies the Food Technology publication volume, month, and page numbers.

IFT extends its deep gratitude to each of the panelists These experts traveled to full-day meetings in Chicago and devoted many other hours to drafting their respective sections of the re-port, participating in multiple conference calls to discuss drafts, and reviewing the other report sections IFT appreciates their in-valuable dedication to furthering the understanding of rDNA biotechnology—a tool that is vital to enhancing the world’s food supply

Founded in 1939, the Institute of Food Technologists is a nonprofit scientific society with 29,000 members working in food science, technology, and related professions in the food industry, academia, and government As the society for food science and technology, IFT brings sound science to the public discussion

of food issues.

Contents

Introduction 2

Safety 15

Labeling 24

Benefits and Concerns 37 Preface

T

he use of modern biotechnology to produce foods and food ingredients is a subject of significant public interest today, at the consumer, public policy, and scientific levels The popular press and media have reported a wide range of views on these foods and food ingredients.

To promote a meaningful public discussion

of these foods and food ingredients, IFT hascommissioned three expert panels to review theavailable scientific literature on three different,but related aspects, of these foods and food in-gredients: human food safety, benefits and con-cerns, and labeling The panels’ report will alsodiscuss some of the public policy implications ofthe underlying science

In keeping with the widespread usage in thepopular press and media, the report uses theterms “rDNA biotechnology” and “rDNA bio-technology-derived foods” to describe the appli-cation of recombinant DNA, or rDNA, technolo-

gy to the genetic alteration of plants and organisms, and foods made therefrom This tech-nology, commonly known as genetic modifica-tion or gene splicing, allows for the effective andefficient transfer of genetic material from one or-ganism to another Instead of cross-breedingplants for many generations or introducing mu-tations to introduce a desired trait—processesthat are imprecise and that sometimes introduceunwanted changes—scientists can identify andinsert one or more genes responsible for a partic-ular trait into a plant or microorganism withgreater precision and speed, although the currenttechnology produces gene insertions at randomlocations These transferred genes, or transgenes,

micro-do not have to come from a related species in der to be functional, and can be moved virtually

or-at will among different living organisms

IFT Expert Report on

Biotechnology and Foods

This report focuses on rDNA derived foods, food ingredients, and animal feed

biotechnology-of plant origin, and on the use biotechnology-of rDNA nology-derived microorganisms such as yeastsand enzymes in food production While milkfrom cows that have received rDNA biotechnolo-gy-derived hormones is discussed, transgenic ani-mals resulting from the application of rDNA bio-technology techniques to animal reproductionare beyond the scope of this report Health andmedical benefits associated with rDNA biotech-nology-derived plants are discussed briefly.This first section presents background infor-mation to assist the reader in understandingrDNA biotechnology-derived foods It will firstdiscuss biotechnology in the broad sense andhow rDNA biotechnology-derived foods are thelatest step in a 10,000-year sequence of humanintervention in the genetic improvement of food,then it will discuss federal regulation and over-sight of rDNA biotechnology

biotech-Overview of Biotechnology

Biotechnology in the broad sense is, in fact, not adiscrete technology It refers to a group of usefulenabling techniques, including but not limited togenetic modification, that have wide application

in research and commerce Over the past severaldecades, such techniques have become so inte-grated into the practice of plant breeding and mi-crobiology and so commingled with convention-

al techniques as to blur distinctions between

“old” and “new.” A useful working definition ofbiotechnology used by several United States gov-ernment agencies is the application of biologicalsystems and organisms to the production of use-ful goods and services These encompass advanc-

es in biology, genetics, and biochemistry to Introduction

tech-T

3EXPERT REPORT ON BIOTECHNOLOGY AND FOODS

nical and industrial processes as

differ-ent as drug developmdiffer-ent, fish farming,

forestry, crop development,

fermenta-tion, and oil spill clean-up (OTA, 1984)

Turning to food biotechnology, the

history of the development of modern

genetics and molecular biology, which

underpins much of this technology, has

been discussed and reviewed by a

num-ber of authors Two accounts accessible

to interested non-specialists are those by

Grace (1997), and Watson and Tooze

(1981) Historically, the key role played

by deoxyribonucleic acid (DNA) in

de-termining the mechanism of inheritance

in all living organisms was first

estab-lished by Avery et al (1944), who, using

S and R type pneumococci, showed that

DNA from one strain of bacteria can be

taken up by a different strain,

hereditar-ily altering that second strain This

piv-otal demonstration was the first

descrip-tion of transformadescrip-tion, a mechanism of

gene transfer that involves the uptake

and integration of isolated DNA by an

organism It is a phenomenon that is

central to an understanding of rDNA

biotechnology, and may even be said to

mark the beginning of the concept of

the new biotechnology

Geneticists had earlier recognized

that the chromosomes, linear structures

composed of DNA and protein, were the

vehicles of inheritance in the sense that

they carried genes determining

inherit-ed characteristics Genes were conceivinherit-ed

of as beads on a string Genes that

en-code similar functions in different

or-ganisms are called orthologs (also

loose-ly called homologs), and genes that have

the same structure in different

organ-isms are said to have synteny (also

loosely called homology) Many

organ-isms are diploid, that is, they have two

sets of chromosomes, one inherited

from each parent The pairs of

chromo-somes are present, in a constant and

characteristic number, in all the cells of

an organism

When the cells divide, the

chromo-somes also divide equally, by a process

called mitosis When a diploid organism

prepares for sexual reproduction by

forming gametes, a reduction division,

called meiosis, reduces the number of

chromosomes so that each egg or sperm

cell has exactly half the diploid number

At meiosis, there is a random

assort-ment of maternally and paternally

de-rived chromosomes, which is further

complicated by exchanges between

paired homologous chromosomes due

to “crossing over” that takes place tween chromosomes Thus, in a sense,the genetic constitution of each gameteresembles a hand of cards dealt from awell-shuffled deck In nature, gametes(germ cells) generally unite randomly atfertilization to restore the diploid condi-tion Plant breeders use this variation byselecting the best plants that result fromthese combinations and stabilizing them

be-by inbreeding or propagating them etatively Thus, sexual reproduction pro-duces “recombinant” organisms, in thesense that the organisms possess DNArearranged and combined from two sep-arate organisms

veg-The task of plant and animal ers is to select individuals that retain in

breed-a heritbreed-able wbreed-ay the desirbreed-able febreed-atures ofthe parent lines The segregation ofgenes with easily detected effects, such asround versus wrinkled seeds, was ob-served by Mendel, who first describedthe discrete nature of inheritance inpeas

Twentieth-century plant breeding,even before the advent of modern rDNAbiotechnology methods, sought ways totake advantage of useful genes and grad-ually has found a wider and wider range

of plant species and genera on which todraw Breeders have long used interspe-cies hybridization, transferring genes be-tween different, but related, species

Subsequently, plant geneticists foundways to perform even wider crosses be-tween members of different genera us-ing tissue culture techniques Crops re-sulting from such wide crosses are com-monly grown and marketed in the U.S

and elsewhere They include familiarand widely used varieties of tomato, po-tato, corn, oat, sugar beet, bread and du-rum wheat, rice, and pumpkin

Although DNA was known to play akey role in inheritance, it was not untilWatson and Crick (1953) described thestructure of the double-stranded DNAmolecule that scientists understood howthe exact replication of the DNA oc-curred at each cell division and how thesequence of nucleotides in the DNAmolecule determined the sequence ofnucleotides in messenger ribonucleicacid (mRNA) and in turn, through atriplet code, the sequence of amino ac-ids in a protein

When the DNA sequence of a gene isexpressed, it is transcribed to form a sin-gle-stranded mRNA molecule, which istranslated to make a protein It is nowknown that the instructions for pro-

gramming the development of a ized egg cell, or zygote, into an adult or-ganism composed of millions of cellscarrying identical sets of genes are en-coded in the nucleotide sequence of theDNA This is in the form of a code based

fertil-on the four nucleotides, adenine, ine, cytosine, and guanine, which form aseries of three-letter words, or codons,that specify the amino acid sequences ofthe many thousands of proteins thatcarry out the cellular functions

thym-Biochemists have established thatthe basic metabolic events in all organ-isms have far more in common than waspreviously suspected They found thatnot only is DNA the universal code used

by all living things, but that the centralfunctions of all organisms are nearlyidentical DNA and ribonucleic acid(RNA) replication, protein synthesis,photosynthesis, energy metabolism, and

a host of other functions were found tohave much in common throughout liv-ing systems Molecular biologists soonlearned to determine the sequences ofgenes that encoded these properties

As more and more genes were quenced and compared, scientists foundthat the products of the genes that en-code similar traits in very diverse organ-isms are often very similar in protein se-quence It also became apparent thatmost genes do not have characteristicsspecific to the organism in which theyare found In fact, it is impossible to de-termine the organism from which a genearises by inspection of the gene se-quence alone, although codon usagedoes vary among major groups of or-ganisms Put another way, there is noway to identify “fish genes,” “tomatogenes,” or “broccoli genes.” The unique-ness of organisms instead lies not only

se-in the DNA sequences of their genes, butalso the organization of the genes whichare present, and at what time and towhat extent they are expressed

Enormous quantities of DNA havenow been sequenced for a wide range oforganisms The genomes (the totality ofgenetic material) of several bacteria andsmall organisms have already been fullysequenced, and the genome sequences ofhigher organisms such as plants, insects,animals, and humans will soon be avail-able In fact, about 40 genomes are ex-pected to have been sequenced by theend of 2000 (Lander and Weinberg,2000) Even sequencing of the humangenome is now more than 90% com-plete One key observation is that, in the

course of determining DNA sequences,

identical genes are regularly found in

organisms that are only remotely

relat-ed This observation has provided

evi-dence that genetic transfer has occurred

in nature to produce natural

rDNA-con-taining organisms

A discovery important to modern

rDNA biotechnology techniques (Linn

and Arber, 1968) was the recognition

that a series of so-called “restriction

en-zymes,” thought to protect cells from

in-vading viral DNA, could be used to cut

the DNA at precise sites defined by the

sequence of four, five, or six nucleotides

at the site where the cut would be made

By using DNA ligases—enzymes that

fuse together two pieces of DNA—the

pieces of DNA formed by cutting DNA

with restriction enzymes could be

joined together into a single piece of

DNA The fragments or pieces of DNA

could also come from two different

or-ganisms Pieces of DNA from different

organisms are often called

“heterolo-gous DNA” and when heterolo“heterolo-gous

fragments of DNA are joined together

by a ligating enzyme, the fragment of

DNA is said to be a “recombinant”

mol-ecule; i.e., it recombines DNA from two

heterologous sources The word

“recom-binant” is used analogously to describe

the recombination of DNA of the

pa-rental chromosomes that takes place

during meiotic cell division

This ability to splice together pieces

of heterologous DNA means that it is

possible to clone fragments of DNA by

splicing them into a bacterial plasmid, a

circular self-replicating DNA molecule

that multiplies inside the bacterial cell

when it is introduced into the bacteria

by a process called transformation If

the heterologous DNA was spliced into a

site on the plasmid where the DNA

would have an opportunity to be

tran-scribed to mRNA, and then translated to

form a functional and active protein, its

action in the cell can be detected so that

the function of the cloned fragment can

be identified By this means, it is

possi-ble to produce very large numbers of

copies of a known DNA fragment that

can then be used to transform other

or-ganisms, such as plants and animals

Two methods of plant

transforma-tion are in use at the present time One

Expert Report

method, known as the ballistic or freeDNA method, uses a gun to shoot mi-croscopic particles of gold or tung-sten into cultured plant cells The parti-cles are first coated with the DNA carry-ing the gene of interest, isolated fromthe bacteria in which it has been cloned

Then, these particles are accelerated byreleasing a charge of helium under highpressure A small proportion of the par-ticles penetrate not only the plant cellwall but the nuclear membrane as well

The DNA carried by these particles can

be taken up and integrated into plantchromosomes

Although the entire nucleotide quence of the segment of DNA to be in-troduced is usually known with the freeDNA method, the site where the DNA isintegrated cannot be predicted Whilethe sequence of the starting DNA can bedetermined with precision, free DNAdelivery frequently leads to integration

se-of multiple copies or portions se-of thegene of interest Selectable markers, i.e.,genes whose expression can be detectedsoon after the cells have been treatedwith DNA, are used to recover the verysmall fraction of cells that are trans-formed For example, if the markersconfer resistance to a toxic agent, such as

an antibiotic or a herbicide added to theculture medium, then only those cellswhich carry and express the non-hostDNA are able to grow

Another method, more widely usedtoday, employs the bacterial plant

pathogen Agrobacterium tumefaciens In

nature, this bacterium infects wounds inbroad-leafed plants and induces the for-mation of tumors or galls The mecha-nism of tumor induction using the

Agrobacterium method involves the

movement of a part of the DNA of alarge plasmid carried by the bacteriuminto some of the host cells In some ofthe cells, a host cell chromosome takes

up a part of the plasmid DNA,

whereup-on the plasmid DNA directs the cell toundergo repeated divisions that result intumor formation This integrated tu-mor-inducing DNA also directs the syn-thesis of an uncommon group of aminoacid derivatives (opines) that only thebacterium can use as a source of carbonand nitrogen for further growth The tu-mor-inducing DNA can be made non-pathogenic by removing the elementsresponsible for releasing the controls ofcell division and for opine formation

The nonpathogenic DNA (T-DNA),which no longer induces tumor forma-

tion, can then be used to carry a ent organism’s gene into a host-cellchromosome As with the free DNAmethod, cells carrying T-DNA can bedetected by incorporating selectablemarkers such as antibiotic or herbicideresistance In this way, only cells carry-ing the resistance markers can grow onculture media in which the antibiotic orherbicide is incorporated; all untrans-formed cells are killed

differ-The use of A tumefaciens greatly

in-creases the precision of DNA insertion

Agrobacterium uses specific

DNA-signal-ing sequences (T-DNA borders) to termine the start and stop points ofDNA transfer to plant cells Althoughthere can still be substantial variation inthe transferred DNA, the endpoints ofDNA transfer are usually localized to asmall region, within 10–100 bases.Moreover, the number of copies of in-serted genes can usually be limited toone or a few Recent improvements intransformation procedures have permit-ted researchers to largely switch from

de-the free DNA techniques to

Agrobacteri-um In any case, the precision of rDNA

biotechnology permits accurate mination of the location and number ofcopies of the inserted DNA, even if thelocation of DNA insertion cannot becontrolled

deter-Scientific knowledge of the structure

of the plant genome has grown as a sult of research on the “laboratory

re-plant” Arabidopsis thaliana, a small

plant in the cabbage family that has onlyfive chromosomes and grows from seed

to seed in about seven weeks ing the entire genome of this plant isnow almost complete Because of thegreat similarities among plants in gener-

Sequenc-al, Arabidopsis can be used as a crop

plant analog, and DNA sequences from

Arabidopsis of known function can be

used to identify their homologs in nomic crops DNA markers can be used

eco-to identify chromosome regions thatcarry blocks of genes of individuallysmall effect, quantitative trait loci orQTLs, which contribute to characteris-tics such as yield, maturity, baking qual-ity, flavor, and aroma, making possiblemuch more sophisticated selection pro-cedures for plant breeding (McCouch,1998)

The opportunity to select and ply a gene of interest and then introduce

multi-it into a crop plant was of great interest

to most plant breeders because it alded the era of directed genetic change

her-5EXPERT REPORT ON BIOTECHNOLOGY AND FOODS

It was now possible to introduce a new

gene into an accepted and adapted

vari-ety in a single step This reduced the

long and tedious process of winnowing

out the many forms that are inferior to

the adapted varieties that are

character-istic products of most conventional

breeding programs which introduce

new characters from wild unadapted

material In practice, rDNA

biotech-nology-derived forms can be better

thought of as new forms of germplasm

to be incorporated into breeding

pro-grams, thereby extending the range of

characteristics available to a breeder

The breeder must still test the results to

ensure that the step of introducing the

non-host gene, or transgene, causes no

other changes that would be detrimental

to the farmer, the consumer, or the

envi-ronment As discussed in the Safety

sec-tion of the report, these tests include

de-tailed analyses of the composition of the

product harvested from the rDNA

bio-technology-derived form

The first rDNA

biotechnology-de-rived food plant marketed in the U.S

was the FlavrSavrTM tomato, introduced

in 1994 Produced using T-DNA, this

to-mato carried an antisense gene for the

enzyme polygalacturonase (PG), an

en-zyme formed as the fruit ripens and

which is responsible, in large part, for

fruit softening The gene encoding PG

was isolated, inverted in the cloning

vec-tor (producing an antisense form), and

then introduced into cells that also carry

the gene in the normal orientation In

the inverted DNA, the mRNA is

tran-scribed from the wrong DNA strand to

form an antisense message As a result,

much less of the enzyme is produced It

was expected that the fruits of the

toma-to would have an extended shelf life,

since they would not soften as rapidly as

normal fruit In fact, the FlavrSavr

to-mato was not a commercial success as a

retail product because of uncompetitive

agronomic characteristics; however, a

processing variety engineered with a

re-lated construct proved to be useful to

processors, since the ripe fruit has a

higher solids content, resulting in

eco-nomic and quality advantages

Following the introduction of the

rDNA biotechnology-derived tomato in

1994, other rDNA

biotechnology-de-rived crops that contained modified

ag-ronomic traits soon followed These

plants included squash that are resistant

to some strains of zucchini yellows and

watermelon mosaic viruses in 1994,

in-sect-resistant potato and cotton in 1995and corn in 1996, and herbicide-toler-ant soybean and canola in 1996 Al-though the consumer’s awareness islargely limited to these products, thereare many others under developmentthat are expected to appeal more direct-

ly to consumers These include fruits,root and leaf vegetables, and grains withenhanced nutritional and health-pro-moting properties

Recombinant DNA Biotechnology-Derived

Foods

Recombinant DNA rived foods are part of the continuingsequence of genetic improvement of thefood supply Although it is sometimesportrayed as fundamentally new, thenewness of rDNA biotechnology is bestconsidered from a historical perspective

biotechnology-de-The plants and animals that modernagriculture produces today to feed theworld’s people are the result of morethan 10,000 years of genetic modifica-tion and refinement For example, there

is the agricultural green revolution,which has contributed to increased hu-man longevity and improved quality oflife in developing countries The greenrevolution is viewed by many knowl-edgeable scientists as the latest majorachievement in a long quest begun byancient agriculturists who first cultivat-

ed and domesticated wild plants forfood and fiber

Genetic modification of plants gan approximately 10,000 years agowhen man first used what is referred to

be-as selective breeding This techniquesimply involved saving seeds from themost vigorous plants in an environmentfor replanting at a later time Over a pe-riod of many years, this selection result-

ed in higher-yielding varieties of thecrop It is this type of selection that, forexample, turned the wild precursor ofmodern maize, teosinte, into an impor-tant human food and animal feed crop

in America The same processes in theNear East—the Fertile Crescent—result-

ed in einkorn and emmer wheat, barley,lentil, pea, chickpea, and bitter vetch(Lev-Yadun et al., 2000) Likewise, theprogenitor of the modern tomato bearsalmost no resemblance to its modernrelatives, which are the result of centu-ries of selection and DNA recombina-tion at the organism level

Selective breeding relies principally

on sexually transmitted genetic diversity

in a starting population By picking thebest or most vigorous plants, breedersover time enrich the genetic makeup of

a plant for attributes such as higheryields, increased resistance to pests, andgreater compatibility with productionschemes It should be noted that thisprocess in itself runs counter to naturalselection Breeding involves selection foroptimal growth for human purposes orother characteristics in an agriculturalsetting and in many cases is inconsistentwith nature and the ability of the organ-ism to survive under evolutionary pres-sure Therefore, human intervention hasinvolved what can be called a primitivetype of genetic engineering from theoutset

An excellent example of breedingversus natural selection can be gleanedfrom the history of cultivated wheat.The seeds of wild wheat relatives are dis-persed by the shattering of brittle seedheads In the earliest stages of domesti-cation, 10,000 years ago, forms that donot shatter were selected, which enabledgatherers to collect the ripe seeds ratherthan pick them up from the ground.Such a mutation in nature would pre-vent seed dispersal and lead to rapid ex-tinction of those plants in the wild

As the available unused genetic versity of the species diminishes, the po-tential for improvement also decreases.Since crop improvement relies on genet-

di-ic diversity, i.e., new sources of genesand expression of existing genes, contin-ued improvement has required and willcontinue to require even greater diversi-

ty This need for diversity led to the nextdevelopments in plant breeding whenfarmers discovered that crosses betweencertain closely related species wouldproduce fertile offspring Cross-breed-ing (also known as interspecies or inter-generic breeding), either fortuitous orintentional, permitted recombinationand selection among genes at a wholenew level to provide new sources of ge-netic diversity and desirable traits.Interspecies or cross-breeding offerstwo possible outcomes First, new spe-cies that contain all of the genes frommultiple parents can be created Thus,triticale, a fertile wheat-rye hybrid, be-came a reality The first wheat-rye hy-brid plants, reported in 1876, were com-pletely sterile, but fifteen years later fer-tile sectors were reported on a spike thatresulted from spontaneous chromosome

doubling (Gregory, 1987) Second,

an-other alternative involves

recombina-tion, where a single genome is

main-tained in the offspring, but that genome

now consists of randomly chosen copies

of genes from either of the parent

spe-cies This latter type of breeding in a

sense is the precursor to modern rDNA

biotechnology; however, it is highly

im-precise Large segments of

chromo-somes containing thousands of

individ-ual genes have been introduced from

one species into another in this way

This type of technology is employed

to-day by breeders of many crops,

includ-ing tomato (discussed below), soybean,

canola, and cotton, which are all

prod-ucts of extensive genetic modification

and selection

The products of naturally occurring

interspecies crosses have been employed

for thousands of years, and many of the

foods eaten today are derived from such

crosses A good example is cultivated

hexaploid wheat, which has three

differ-ent genomes, each derived from a wild

ancestral species For thousands of

years, this technology has relied upon

the ability of a genetic cross to produce

fertile offspring Thus, it is considered

“natural.” Many interspecific hybrids

are infertile; for example, the original

wheat-rye hybrids were sterile, and seeds

could only be produced after

spontane-ous chromosome doubling had taken

place Thus, while interspecific crosses

opened up a vast new genetic resource

to plant breeders, the need for fertile

progeny limited the usefulness of this

diversity

Sometimes, a cross of two species

can produce a viable embryo, which

de-velops for a period of time, then

degen-erates and dies However, by using the

technique known as embryo rescue, the

embryo can be recovered shortly after

fertilization and placed in an in-vitro

tissue culture system In this artificial

setting, the embryo can develop into a

mature, fertile plant Tissue culture can

thus expand access to genetic diversity

by saving crosses that would not survive

outside a laboratory

Some attention has been paid to the

use of ionizing radiation and chemicals

to induce mutations and expand the

range of variation available to breeders,

but very few successful new forms ofcrop plants have been obtained in thisway The same is true of somaclonalvariation arising in tissue culture How-ever, spontaneous mutations have beenimportant in the development of somecultivated plants

All of these conventional techniquesfor crop improvement share the disad-vantage that they are, by nature, impre-cise and unpredictable and only occa-sionally useful Spontaneous and in-duced mutation can lead to one desir-able change and many undesirable col-lateral changes in an organism’s DNAmakeup, which must be selected out

Breeders cannot and do not attempt todefine in molecular terms the changesthat they make within a genome Rather,they employ standard selection proce-dures to screen for new plants with nov-

el alterations and incorporate theseplants into their breeding programs Inspite of the undefined nature of thesechanges, many years of experience haveaffirmed the safety and usefulness of ge-netically improved varieties Plantbreeders, farmers, food manufacturers,and consumers all have routine, fre-quent, and extensive exposure to thesegenetically improved varieties

An excellent example of how ers use all of the above techniques is the

breed-tomato The tomato, Lycopersicon lentum var cerasiforme, originates from

escu-central Mexico The original speciesbears little resemblance to current vari-eties, which are the result of much ge-netic manipulation The growth habits

of the plant, resistance to viruses,

diseas-es, and nematoddiseas-es, as well as fruit tasteand appearance are a consequence ofmutation, hybridization, and selection

For example, resistances to several eases, tobacco mosaic virus, and nema-todes were introduced from the distant-

dis-ly related species, Lycopersicon anum and Lycopersicon chilense Crosses between these two species and L escu- lentum required embryo rescue Each

peruvi-new resistance represents the tion of a large chromosome segment

introduc-from the distant relative into L lentum The typical introduced non-

escu-host DNA segment contains between

100 and 1,000 genes

A specific example illustrates theimprecision of traditional breeding In-troduction of resistance to the fungal

disease Fusarium crown rot involved a cross between an irradiated L escu- lentum variety and L peruvianum

(Rowe and Farley, 1981) From this

cross, a resistant plant was selected andused in subsequent breeding This resis-tance gene, along with its complement

of other genes, is present in many mercial varieties of tomato today As thetomato is a member of the nightshadefamily and many of its wild relativescontain high levels of toxicants in the

com-interspecific crosses with L esculentum,

breeders have selected for varieties withminimal toxicant content While there is

no requirement for toxicant screening intraditional tomato breeding programs, it

is widely practiced Moreover, toxicantscreening is an integral part of assessingthe safety of new rDNA biotechnology-derived varieties

It is against this experience base thatrDNA biotechnology must be examinedand compared Recombinant DNA tech-niques involve the introduction of one

or a few defined genes into a plant.While these introduced genes are oftenfrom other, non-host sources, the intro-duction of non-host DNA is not novel

In fact, remnants of an ancient terium transformation have been identi- fied in Nicotiana species (Furner et al,

Agrobac-1986) It is important to note that it is

the very same Agrobacterium that is now

used widely by researchers to introducegenes into plants

Similarly, microorganisms have beenused in food technology for thousands

of years As early as 6000 B.C., ans and Babylonians used yeast to brewbeer Although the ancients knew noth-ing about microorganisms and couldnot knowingly culture them, they never-theless systematically selected those withdesirable fermentation characteristics to

Sumeri-improve their food In modern times,

the increasingly powerful science of netics has been systematically applied toproduce many valuable variants of yeastand bacteria

ge-Recombinant DNA techniques haveprovided both an important new set oftools and access to a broader range ofmarkets They enable researchers seek-ing specific plant characteristics to pre-cisely identify, characterize, enhance,and transfer the appropriate individualgenes rather than uncontrolled and ran-domly assorted groups of genes, hopingthe desired ones were included Re-searchers can now readily move selectedand well-characterized genetic materialfrom virtually any source in nature,greatly increasing the diversity of usefulgenes available for crop and microbe

Expert Report

7EXPERT REPORT ON BIOTECHNOLOGY AND FOODS

improvement The long, continuous

search for improved plants and the

ben-efits of useful microorganisms is now

increasingly based on the use of rDNA

biotechnology techniques

Microorganisms are used in the

pro-duction of foods, beverages, industrial

detergents, antibiotics, organic solvents,

vitamins, amino acids, polysaccharides,

steroids, and vaccines Practical

applica-tions of pre-rDNA biotechnology

in-clude a variety of organisms used in pest

control (including many that are

them-selves often considered to be pests, in

other settings, e.g., preparations of the

bacterium Bacillus thuringiensis sold at

most garden supply stores) Biological

agents are also used as growth

promot-ers for plants Preparations containing

the bacterium Rhizobium, which fixes

atmospheric nitrogen, converting it into

nitrogen-containing ions that are

essen-tial plant nutrients, have been sold in

the U.S since the late 19th century As

early as the mid-1980s, these pre-rDNA

biotechnology products, together, had a

value in excess of $100 billion annually

(Anonymous, 1985) Since the

introduc-tion of rDNA biotechnology, many of

these microorganisms have been

im-proved, such as those used to produce

the enzyme chymosin necessary for

cheese production

Some critics of rDNA biotechnology

have taken the view that it represents a

fundamental change from traditional

techniques for the genetic modification

of plants and microorganisms In a 1989

report, the National Research Council

considered and rejected this argument:

However, no conceptual distinction

exists between genetic modification

of plants and microorganisms by

classical methods or by molecular

techniques that modify DNA and

transfer genes The same physical

and biological laws govern the

re-sponse of organisms modified by

modern molecular and cellular

methods and those produced by

classical methods

The NRC went on to characterize

rDNA biotechnology as part of a

se-quence of scientific advances that has

extended over a 10,000-year period

(NRC, 1989)

A 1991 joint Food and Agriculture

Organization/World Health

Organiza-tion consultaOrganiza-tion, addressing the

ques-tion of the safety of rDNA

biotechnolo-gy-derived foods, came to similar clusions (FAO/WHO, 1991):

con-Biotechnology has a long history ofuse in food production and process-ing It represents a continuum em-bracing both traditional breedingtechniques and the latest techniquesbased on molecular biology Thenewer biotechnological techniques,

in particular, open up very greatpossibilities of rapidly improvingthe quantity and quality of foodavailable The use of these tech-niques does not result in food which

is inherently less safe than that duced by conventional ones

pro-A timeline that shows the increasingpower of genetic modification over thepast 12,000 years appears in Fig 1

Even though food derived from technology in the broad sense is hardlynew, some critics nevertheless have beenconcerned that rDNA biotechnologymay result in different and dangerousorganisms Considering that there aretens of thousands of the host organism’sown genes, the introduction by precisetechniques of one or a few additional,well-characterized genes does not create

bio-an orgbio-anism that is more likely to bechanged in gross physical properties orwholesomeness than an organism de-rived through a traditional breedingprogram Indeed, because of the greaterprecision in selecting the desired trait,

an adverse result is unlikely A corn

plant with a newly inserted bacterialgene that confers increased resistance tothe European corn borer (a commercial-

ly important insect predator) is still acorn plant Likewise, a microorganismlong used for food production is not al-tered in any fundamental way by the in-sertion of additional copies of a gene-encoded rate-limiting enzyme Aided bythe recent voluminous data from theDNA sequencing of various genomesand other basic research on plants, suchquestions have been widely discussedand reported by an array of nationaland international scientific groups.Their conclusions are discussed in the

Safety section of the report.

Consider whether genetic nation, itself, is of concern It has al-ready been established that people havelong engaged in the systematic improve-ment of domesticated microbes, plants,and animals But the impact and impor-tance of these changes are much smallerthan what occurs continuously in na-ture Innumerable recombinations be-tween related and unrelated organismshave occurred by several mechanisms.Sexual reproduction randomly com-bines genes from two parents in the off-spring, which then has a unique set ofgenes to pass along to the next genera-tion In the gut, decomposing tissue, andinfected wounds, bacteria take up nakedmammalian DNA, albeit inefficiently,when they encounter disintegratingcells, and some of this DNA may be in-

MOLECULAR GENETICS GENE TRANSFORMATION COMPUTERIZED DATA MANAGEMENT EMBRYO RESCUE CELL AND TISSUE CULTURE (Fusion and Somaclonal Variation) BROAD CROSSES

INDUCED MUTATION QUANTITATIVE GENETICS MENDELIAN GENETICS HYBRIDIZATION

SELECTION

TIME (YEARS)

POWER OF GENETIC MODIFICATIONFig 1—Increase in power of genetic modification over time Adapted from NRC (1989)

corporated into the bacterial genome,

but there is no established evidence that

this happens (Davis, 1986) Over the

past million years and longer,

mammali-an-bacterial genetic hybrids have

ap-peared, been tested by competition

within bacterial populations and by

en-vironmental stresses, and conserved or

discarded by natural selection Similar

genetic recombination and

hybridiza-tion also has been widespread among

fungi, viruses, and plants

Evolutionary biology provides data

relevant to the issue of the uniqueness

of chimeric genes (genes containing

modified or substituted control signals

joined to portions of the native genetic

information) created by rDNA

biotech-nology Does the transfer into a squash

of a viral gene to confer viral resistance

affect its “squashness” or transfer

“viral-ness” to the new hybrid? The sequencing

of various genomes during the past

de-cade has revealed that nature has been

remarkably conservative about

main-taining and using effective molecules as

they evolved Similar protein sequences

and biochemical pathways are found in

different species, across genera, and even

across phylogenetic kingdoms The

Es-cherichia coli genome, for example,

con-tains gene sequences that are closely

re-lated to those in a wide spectrum of

or-ganisms, ranging from other bacteria to

plants, insects, amphibia, birds, and

hu-mans

Another issue, conversion of a

non-pathogen into a non-pathogen through

lim-ited genetic recombination, is best

con-sidered within the context of the nature

of pathogenicity This process is both

complex and multifactorial

Pathogenic-ity usually is not a trait produced by a

single gene; however, the transfer of a

single gene to an organism that has all

the other necessary genes can make it

pathogenic Pathogenicity requires the

coordinated activity of a set of genes

that affect essential properties

A pathogen must possess three

gen-eral characteristics, each of which

in-volves multiple genes First, pathogens

must survive and be able to multiply or

produce toxin in or upon host tissues or

food sources This necessitates an

ap-propriate oxygen tension, pH,

tempera-ture, water activity, and nutritional

mi-lieu Pathogens must be able to adhere

to specific surfaces on or in the host

Second, the pathogen must be able toresist or avoid the host’s defense mecha-nisms for the period of time necessary

to multiply to sufficient levels to causedisease Third, the pathogen must beable to survive outside of the host andmust be disseminated to new host or-ganisms The organism must be meticu-lously adapted to this pathogenic life-style On the other hand, a mutationthat interferes with a gene essential toany one of the three characteristics of apathogen can eliminate pathogenicity It

is worth noting that severe

pathogenici-ty is even more dependent upon able conditions and is, therefore, muchrarer in nature than mild pathogenicity

favor-The probability of creating andcommercializing an organism inadvert-ently capable of producing a medical oragricultural problem is therefore quitesmall The expert panels are of the viewthat this probability is lower with rDNAbiotechnology than with the more ran-dom, less targeted, and less predictabletraditional methods of genetic modifi-cation In rDNA biotechnology-derivedorganisms, typically one, two, or threegenes are being inserted The genes, geneproducts, and their functions areknown This information guides scien-tists in determining which possible risksare relevant and need to be explored Incomparison, with traditional breeding, alarge number of genes with unknownfunctions are involved, making it muchmore difficult to sort through the proge-

ny and focus on the relevant risks volved

in-Adverse outcomes accompanyinggenetic change have always been possi-ble but are routinely intercepted duringthe usual, extensive testing that takesplace in growth chambers, greenhouses,and the field Whatever the techniqueused to craft a variety, it goes throughextensive testing before being used com-mercially, particularly if the developerchooses to enter it into formal seed reg-istration programs In practice, the test-ing is even more extensive in the case of

an rDNA biotechnology-derived variety

Therefore, the expert panels are of theview that rDNA biotechnology has thepotential to reduce still further thechance that any such mishap will occur

The field and chemical testing that company it—even more thorough than

ac-in traditional genetic modification—

make such an unfavorable outcome even

more unlikely As noted earlier, geneticchanges that make a plant more useful

to humans usually have made the plantless “fit” and less able to survive in thewild

Federal Regulation of rDNA Biotechnology

Regulatory oversight over rDNA technology spans three major federalagencies: the Food and Drug Adminis-tration (FDA), the Environmental Pro-tection Agency (EPA), and the U.S De-partment of Agriculture (USDA) Juris-diction over the varied rDNA biotech-nology products is determined by theiruse, as has been the case for productsmade by traditional means More thanone agency may be involved in regulat-ing different aspects of an rDNA bio-technology-derived product As the reg-ulatory mandate varies, so does the na-ture of the agencies’ risk assessment andmanagement protocols

bio-The “Coordinated Framework forRegulation of Biotechnology,” prepared

by the White House’s Office of Scienceand Technology Policy (OSTP) and

published in the Federal Register of June

26, 1986 (51 FR 23302), is the currentcomprehensive federal policy for ensur-ing the safety of rDNA biotechnologyresearch and products It established theprinciples and procedures for coordina-tion and jurisdiction among federalagencies for the oversight of rDNA bio-technology Subsequently, the OSTP

prepared and published in the Federal Register of February 24, 1992 (57 FR

6753) “Exercise of Federal Oversightwithin Scope of Statutory Authority:Planned Introductions of BiotechnologyProducts into the Environment.” Thisnotice described a risk-based, scientificapproach to the oversight of planned in-troductions of rDNA biotechnology-derived products into the environment,focusing on the characteristics of theproduct and the environment intowhich it is being introduced, not theprocess by which the product is created.The ultimate goal of the OSTP poli-

cy is to ensure the overall safety to mans and the environment of, in rele-vant part, foods, food ingredients, andfeeds produced using rDNA biotechnol-ogy In an April 2000 report, the Nation-

hu-al Research Council stated: “In generhu-al,the current U.S coordinated frameworkhas been operating effectively for over a

Expert Report

9EXPERT REPORT ON BIOTECHNOLOGY AND FOODS

decade” (NRC, 2000)

Although the approach outlined in

the 1986 and 1992 OSTP regulatory

pol-icy guidelines states that federal policies

should be risk-based—i.e., should focus

on the risk-related characteristics of

products, rather than on the process

used—that principle has not been

fol-lowed by regulatory agencies The

fun-damental approach by the federal

gov-ernment to the review and regulation of

rDNA biotechnology-derived products

has largely been through a

process-based trigger to oversight As discussed

below, crops and microbes produced

us-ing rDNA biotechnology have been

con-sistently subjected to higher

require-ments and standards than those applied

to similar products produced using

tra-ditional techniques (Miller, 1997, 2000)

At this time, there is less experience with

rDNA biotechnology-derived products,

but that experience base is increasing

substantially

Food and Drug Administration

FDA regulates different aspects of

rDNA biotechnology under the

authori-ty of the Federal Food, Drug, and

Cos-metic Act (FFDCA) and the Public

Health Service Act (PHSA) FDA has a

mandate to ensure the safety of all food

(except for meat and poultry products)

sold in the U.S., as well as the safety and

efficacy of pharmaceutical products To

date, FDA has conducted almost fifty

re-views of rDNA biotechnology-derived

plant products used for human food or

animal feed

• Human Food and Animal Feed.

Except for meat and poultry products

regulated by USDA, FDA is responsible

for ensuring the safety and proper

label-ing of food products for human

con-sumption FDA also regulates the safety

and labeling of animal feed, taking into

account both the safety to human

con-sumers of animal-derived food products

and the safety to the animal being fed

FDA’s statutory authority is provided by

the FFDCA FDA’s framework for the

regulation of food labeling is discussed

in the Labeling section of the report; the

framework for the regulation of food

safety is discussed below

FDA has very broad authority to

regulate the introduction of new food

crops, whether conventionally grown,

produced through hybridization or

cross-breeding, or produced using

rDNA biotechnology Every firm or

in-dividual that produces whole foods or

food ingredients is legally required toensure the safety of foods and food in-gredients introduced into commerce

FDA has a number of enforcement toolsthat can be used to ensure the safety offood Specifically, the FFDCA prohibitsthe adulteration of any food item thatmoves in interstate commerce (21 USC

§342) Of particular importance, foodsare deemed adulterated if they containcertain poisonous and deleterious sub-stances (21 USC §342(a)(1)) With cer-tain exceptions that are not relevant tothis discussion, the FFDCA defines a

“food additive” as any substance, not

“generally recognized as safe” (GRAS)

by qualified experts for its intended use,that becomes a component or otherwiseaffects the characteristics of food (21USC §321(s)) Food additives must bethe subject of a petition to FDA, fol-lowed by FDA premarket approval; theirmanufacturers have the burden of estab-lishing, through scientific testing, thesafety of the substances (21 USC §348)

In comparison, a food manufacturerthat believes its food ingredient is GRASmay market the ingredient withoutseeking FDA’s concurrence, subject tothe risk that FDA will disagree and takelegal action to remove the ingredientfrom the marketplace

In the U.S., whole foods such asfruits, vegetables, and grains are not reg-ulated as “food additives” and are notrequired to undergo premarket approv-al; nor are they commonly subjected toextensive safety testing Thus, new vari-eties of crop plants produced by tradi-tional breeding methods are not subject

to FDA premarket review Nevertheless,authority exists to ensure that suchfoods do not present a reasonable possi-bility that consumers might be injured

by consuming them With respect to allfoods, FDA can initiate legal action toremove a food from the market if it isjudged to present a health risk Whilethere is no evidence that such authorityhas ever needed to be exercised with re-spect to traditional breeding practices,plant breeders and food processors haveseveral times intercepted toxic foodplants before they reached the market

An example, mentioned in the Safety

sec-tion of the report, is the Lenape potato

On May 29, 1992, FDA published apolicy statement (57 FR 22983) onfoods and animal feed derived from newplant varieties developed by convention-

al and new breeding techniques, ing rDNA biotechnology techniques

includ-FDA stated:

This policy statement is a tion of FDA’s interpretation of theFederal Food, Drug, and CosmeticAct (the act) with respect to technol-ogies to produce foods, and reflectsFDA’s current judgement based onnew plant varieties now under de-velopment in agricultural research.This action is being taken to ensurethat relevant scientific, safety, andregulatory issues are resolved prior

clarifica-to the introduction of such productsinto the marketplace

FDA set forth its authority to trol food products derived by rDNAbiotechnology techniques and listed thesafety issues that need to be addressed inassessing the safety of whole foods thatcontain or use rDNA biotechnology-de-rived plants and microorganisms Onekey point is that under certain condi-tions, foods and food ingredients de-rived from rDNA biotechnology-derivedplants or microorganisms may be sub-ject to the provisions of existing require-ments governing food additives andGRAS substances FDA noted that in thecase of foods derived from new plantvarieties, it is the transferred geneticmaterial and intended expressionproduct(s) that could be subject to foodadditive requirements if these materialsare not GRAS FDA stated that if the in-tended expression product is a protein,carbohydrate, or other substance thatdiffers substantially from substancescurrently present in food, then that sub-stance might not be GRAS and may be afood additive requiring premarket ap-proval Another important point is that

con-if an rDNA biotechnology-derived plant

or microorganism is used to produce aGRAS substance or an approved foodadditive, the resulting material wouldcontinue to be regulated in a similarfashion to the way in which it has his-torically been regulated

FDA’s 1992 policy on new plant eties applies irrespective of whether theplant arose from rDNA biotechnology

vari-or “conventional” genetic modificationmethods FDA does not routinely sub-ject foods from new plant varieties to apremarket approval process or to exten-sive scientific safety tests FDA’s policydoes, however, define certain safety-re-lated characteristics of new foods—such

as transfer of an allergen or increasedlevels of a natural toxicant—that triggeradditional scrutiny FDA’s policy in-

cludes a flow chart (Fig 2) for guidance

that asks a series of questions directed to

scientific issues of safety and nutrition

of the foods derived from the new plant

variety The assessment focuses on the

following risk-based considerations:

- Toxicants known to be

characteris-tic of the host and donor species

- The potential that food allergens

will be transferred from one food source

to another

- The concentration and

bioavail-ability of important nutrients for which

a food crop is ordinarily consumed

- The safety and nutritional value of

newly introduced proteins

- The identity, composition, and

nu-tritional value of modified

carbohy-drates, fats, or oils

Fundamentally, FDA’s current

(1992) policy is that existing

require-ments mandate the same safety

stan-dards for foods, food ingredients, and

feeds, regardless of the techniques used

in their production and manufacture

Nevertheless, FDA has maintained a

“voluntary consultation procedure,” in

which producers of rDNA

biotechnolo-gy-derived foods are asked to consult

with the agency before marketing their

products, and without exception they

have done so (HHS, 2000) To date,

al-most 50 new rDNA

biotechnology-de-rived foods have been evaluated

success-fully in FDA’s voluntary consultation

process These evaluations are

summa-rized in Table 1 Each entry represents a

separate consultation, and each

consul-tation may represent more than one line

of the traits indicated Products are

grouped by the year in which their

con-sultations were completed The trait

in-troduced into the variety plus the origin

and identity of the introduced gene

re-sponsible for the trait are given (FDA,

2000)

FDA’s official policy may change

sig-nificantly, as the Clinton Administration

announced in May 2000 that FDA will

publish a proposed rule that would

re-quire producers to notify FDA 120 days

before marketing an rDNA

biotechnolo-gy-derived food and provide the agency

with data that affirm the new food’s

safety In practice, assuming that new

regulatory requirements are proposed

and finalized, FDA’s current voluntary

consultation procedure would becomemandatory

• Pharmaceuticals and Human cines FDA regulates rDNA biotechnolo-

Vac-gy-derived pharmaceutical products forhuman and animal use under theFFDCA and the PHSA FDA also regu-lates rDNA biotechnology-derived vac-cines for human use under the PHSA,while USDA regulates vaccines for ani-mal use Under both the FFDCA and thePHSA, new products must be the sub-ject of premarket approval, based onlaboratory and clinical testing to showthe safety and effectiveness of the prod-ucts for their intended uses (21 USC

• Foods The Food Safety and

In-spection Service (FSIS) is responsible forregulating the safety and labeling ofmeat and poultry products for humanconsumption FSIS consults with FDAregarding the safety of food ingredients

Because transgenic animals are beyondthe scope of this report, USDA’s regula-tion of meat and poultry products willnot be discussed further

The Animal and Plant Health spection Service (APHIS) is the agencywithin the USDA charged with protect-ing American agriculture against pestsand diseases Under the Plant Quaran-tine Act (PQA, 7 USC §151) and theFederal Plant Pest Act (FPPA, 7 USC

In-§150), APHIS can regulate the tion and interstate movement of plantsand plant products that may result inthe entry into the U.S of injurious plantdiseases or insect pests

importa-The field-testing and the cial sale of agricultural rDNA biotech-nology-derived crops are regulated byAPHIS through a permit and notifica-tion system USDA’s regulations (7 CFRPart 340) cover the introduction of or-ganisms and products altered or pro-duced through genetic engineeringwhich are plant pests or for which there

commer-is reason to believe are plant pests

“Plant pests” include agents that candirectly or indirectly injure or causedisease or damage in or to any plant A

“regulated article” includes any ism or any product, which has been al-tered or produced through rDNA bio-technology, which is a plant pest, or for

organ-which there is reason to believe is aplant pest The permit and notificationsystem does not apply to plants that aremodified through traditional breedingmethods Thus, USDA’s regulatory pro-tocol is process based

The introduction of a regulated ticle is prohibited unless a permit un-der 7 CFR Part 340 authorizes the in-troduction The regulation is intended

ar-to prevent the introduction, tion and establishment of plant pests inthe U.S APHIS will grant a permit only

dissemina-if it determines that the plant poses nosignificant risk to other plants in theenvironment and is as safe to use asmore traditional varieties APHIS canauthorize nonregulated status for anarticle through a petition for a “deter-mination of nonregulated status.”Nonregulated status allows a plant to

be treated like any other plant, i.e., lows for the plant to be widely grownand commercialized

al-• Animal Vaccines APHIS regulates

animal vaccines under the Toxin Act (21 USC §§151–159) In gen-eral, animal vaccines are subject to pre-market approval, based on testing toshow their safety and effectiveness

Virus-Serum-Environmental ProtectionAgency

EPA’s stated mission is to protect man health and to safeguard the naturalenvironment—air, water, and land—upon which life depends EPA’s responsi-bilities under the Federal Insecticide,Fungicide, and Rodenticide Act (FIFRA,

hu-7 USC §§136–136r) for registering cides, setting environmental tolerancesfor pesticides, and establishing exemp-tions for pesticide residues in and oncrops are relevant to rDNA biotechnolo-gy-derived foods A pesticide is any sub-stance or mixture of substances intendedfor preventing, destroying, repelling, ormitigating any pest

pesti-The Food Quality Protection Act(FQPA) of 1996 amended FIFRA andthe FFDCA by establishing a single,health-based standard for assessing therisks of pesticide residues in food orfeed The standard measures the aggre-gate risk from dietary exposure and oth-

er non-occupational sources of sure EPA must now focus explicitly onexposures and risks to infants and chil-dren, assuming when appropriate, anadditional safety factor to account foruncertainty in data

expo-If EPA determines that there is a

“rea-Expert Report

11EXPERT REPORT ON BIOTECHNOLOGY AND FOODS

Fig 2—Safety assessment of new varieties: summary From FDA (1992)

Unexpected orunintended effects

Are the

concentra-tion and

or oils in new variety

If food from thedonor is com-monly allergenic,can it be demon-strated that theallergenic determi-nant has not beentransferred to thenew variety?

Are there anyunusual or toxiccomponents?

Are there anyalterations thatcould affectnutritional qualities

or digestibility in

a macroconstituent

of the diet?

Is there anyreported toxicity,

or does thebiological functionraise any safetyconcern?

Is the introducedprotein likely to be

a macroconstituent

in the human oranimal diet?

sonable certainty that no harm” to the

public will result from aggregate

expo-sure to a particular pesticide residue,then that residue level will be deemed

“safe.”

In the case of pesticides produced

by plants developed using rDNA technology, EPA’s November 23, 1994(59 FR 60519), proposed rule takes theview that its regulatory process is fo-

bio-cused on the pesticide and not on theplant; plants are subject to regulationonly if they produce plant pesticidalproteins as a result of modification withrDNA techniques Although EPA has notfinalized that proposed rule, EPA hasbeen implementing its essential elementssince 1995 (NRC, 2000) EPA’s evalua-

Expert Report

The barnase gene from Bacillus amyloliquefaciens.

S-adenosylmethionine hydrolase gene from Escherichia coli bacteriophage T3 The phytase gene from Aspergillus niger var van Tieghem.

The nitrilase gene from Klebsiella pneumoniae subsp ozaenae.

Phosphinothricin acetyltransferase gene from Streptomyces viridochromogenes Phosphinothricin acetyltransferase gene from S viridochromogenes.

The cry9C gene from Bacillus thuringiensis (Bt) subsp tolworthi and the bar gene from Streptomyces hygroscopicus.

The male-sterile canola contains the barnase gene, and the fertility-restorer canola contains the barstar gene from B amyloliquefaciens Both lines have the phosphinothricin acetyltransferase gene from S viridochromogenes.

Nitrilase gene from Klebsiella pneumoniae and the cryIA(c) gene from B thuringiensis subsp kurstaki.

The cryIA(c) gene from B thuringiensis subsp kurstaki.

A modified enolpyruvylshikimate-3-phosphate synthase gene from corn.

The cryIIIA gene from B thuringiensis sp tenebrionis and the Potato Leafroll Virus replicase gene.

The cryIIIA gene from B thuringiensis sp tenebrionis and the Potato Virus Y coat protein gene.

The enolpyruvylshikimate-3-phosphate synthase gene from Agrobacterium sp strain CP4, and a truncated glyphosate oxidoreductase gene from Ochrobactrum anthropi The DNA adenine methylase gene from E coli.

Acetolactate synthase gene from Arabidopsis.

Phosphinothricin acetyltransferase gene from S viridochromogenes.

The barnase gene from B amyloliquefaciens.

The cryIA(c) gene from B thuringiensis.

Sense suppression of the GmFad2-1 gene which encodes a delta-12 desaturase enzyme.

Coat protein genes of Cucumber Mosaic Virus, Zucchini Yellow Mosaic Virus, and Watermelon Mosaic Virus 2.

Coat protein gene of the Papaya Ringspot Virus.

Table 1

2000

Aventis Male-sterile corn

1999

Agritope Inc Modified fruit-ripening cantaloupe

BASF AG Phytaseed canola

Rhone-Poulenc Ag Co Bromoxynil-tolerant canola

1998

AgrEvo, Inc Glufosinate-tolerant soybean

Glufosinate-tolerant sugar beet Insect-protected and glufosinate-tolerant corn

Male-sterile or fertility-restorer and glufosinate-tolerant canola

Calgene Co Bromoxynil-tolerant/insect-protected

cotton Insect-protected tomato Monsanto Co Glyphosate-tolerant corn

Insect- and virus-protected potato Insect- and virus-protected potato Monsanto Co./Novartis Glyphosate-tolerant sugar beet

Pioneer Hi-Bred Male-sterile corn

University of Saskatchewan Sulfonylurea-tolerant flax

1997

AgrEvo, Inc Glufosinate-tolerant canola

Bejo Zaden BV Male-sterile radicchio rosso

Dekalb Genetics Corp Insect-protected corn

DuPont High-oleic-acid soybean

Seminis Vegetable Seeds Virus-resistant squash

University of Hawaii/ Virus-resistant papaya

Cornell University

Foods derived from new plant varieties derived through rDNA technology: final consultations under FDA’s

1992 policy From FDA (2000)

13EXPERT REPORT ON BIOTECHNOLOGY AND FOODS

tion of products of rDNA

biotechnolo-gy is distinct from the procedures used

to assess the safety of the products of

more conventional technology In April

2000, the NRC issued a report after

evaluating the science and regulation of

rDNA biotechnology-derived

pest-pro-tected plants The NRC panel accepted

without critical evaluation the EPA’sregulatory approach In contrast, elevenmajor scientific societies representingmore than 80,000 biologists and foodprofessionals published a report warn-ing that the EPA policy would discour-age the development of new pest-resis-tant crops and prolong and increase the

use of synthetic chemical pesticides; crease the regulatory burden for devel-opers of pest-resistant crops; limit theuse of biotechnology to larger develop-ers who can pay the inflated regulatorycosts; and handicap the U.S in competi-tion for international markets

in-Continued on next page

Table 1 continued

S-adenosylmethionine hydrolase gene from E coli bacteriophage T3.

Phosphinothricin acetyl transferase gene from S hygroscopicus.

Acetolactate synthase gene from tobacco, Nicotiana tabacum cv Xanthi.

The cryIIIA gene from B thuringiensis.

The cryIA(b) gene from B thuringiensis subsp kurstaki.

The cryIA(b) gene from B thuringiensis subsp kurstaki.

The enolpyruvylshikimate-3-phosphate synthase gene from Agrobacterium sp strain CP4 and the glyphosate oxidoreductase gene from O anthropi in the glyphosate tolerant lines The cryIA(b) gene from B thuringiensis subsp kurstaki in lines that are also insect protected.

The cryIA(b) gene from B thuringiensis subsp kurstaki.

The male-sterile oilseed rape contains the barnase gene from B amyloliquefaciens; the fertility restorer lines express the barstar gene from B amyloliquefaciens The barnase gene from B amyloliquefaciens.

Phosphinothricin acetyltransferase gene from S viridochromogenes.

Phosphinothricin acetyltransferase gene from S viridochromogenes.

The 12:0 acyl carrier protein thioesterase gene from California bay, Umbellularia californica.

The cry1A(b) gene from B thuringiensis subsp kurstaki.

Enolpyruvylshikimate-3-phosphate synthase gene from Agrobacterium sp strain CP4 Enolpyruvylshikimate-3-phosphate synthase gene from Agrobacterium sp strain CP4 The cryIA(c) gene from B thuringiensis subsp kurstaki.

Coat protein genes of Watermelon Mosaic Virus 2 and Zucchini Yellow Mosaic Virus Antisense polygalacturonase gene from tomato.

A nitrilase gene isolated from Klebsiella ozaenae.

A fragment of the aminocyclopropane carboxylic acid synthase gene from tomato Enolpyruvylshikimate-3-phosphate synthase gene from Agrobacterium sp strain CP4 Aminocyclopropane carboxylic acid deaminase gene from Pseudomonas chloraphis strain 6G5.

The cryIIIA gene from B thuringiensis sp tenebrionis.

A fragment of the polygalacturonase gene from tomato.

1996

Agritope Inc Modified fruit-ripening tomato

Dekalb Genetics Corp Glufosinate-tolerant corn

DuPont Sufonylurea-tolerant cotton

Monsanto Co Insect-protected potato

Insect-protected corn Insect-protected corn Glyphosate-tolerant/insect-protected corn

Northrup King Co Insect-protected corn

Plant Genetic Systems NV Male-sterile and fertility-restorer oilseed

rape Male-sterile corn

1995

AgrEvo Inc Glufosinate-tolerant canola

Glufosinate-tolerant corn Calgene Inc Laurate canola

Ciba-Geigy Corp Insect-protected corn

Monsanto Co Glyphosate-tolerant cotton

Glyphosate-tolerant canola Insect-protected cotton

1994

Asgrow Seed Co Virus-resistant squash

Calgene Inc FlavrSavr TM tomato

Bromoxynil-tolerant cotton DNA Plant Technology Corp Improved-ripening tomato

Monsanto Co Glyphosate-tolerant soybean

Improved-ripening tomato Insect-protected potato Zeneca Plant Science Delayed-softening tomato

In this section, the general concept of

biotechnology has been introduced and

the scope of the overall report has been

defined Further, extensive background

information has been provided to assist

the reader in understanding rDNA

bio-technology-derived foods

Biotechnolo-gy has been discussed in considerable

detail, and the point has been made that,

in the view of many knowledgeable

sci-entists, rDNA biotechnology-derived

foods are the latest major step in a

10,000-year process of genetic

improve-ment of food Finally, this section has

discussed federal regulation and

over-sight of rDNA biotechnology

This section has provided the

foun-dation for the three sections that follow

The sections are based on a review of

the scientific literature on three different

but related aspects of rDNA

biotechnol-ogy-derived foods—human food safety,

benefits and concerns, and labeling—

and the public policy implications of the

underlying science In developing this

state-of-the-science report, it is IFT’s

in-tent to promote a meaningful public

discussion of the subject that is based on

sound science

REFERENCES

Anonymous 1985 Health impact of biotechnology: Report

of a WHO Working Group Swiss Biotechnol 2: 7-16.

Avery, O.T., MacLeod, C.M., and McCarty, M 1944.

Studies on the chemical nature of the substance

induc-ing transformation of Pneumococcal types J.Exp.Med.

79: 137-158.

Davis, B.D 1986 Evolution, epidemiology, and

recombi-nant DNA In “Storm Over Biology,” pp 271-273.

Prometheus Books, Buffalo.

FAO/WHO 1991 Strategies for assessing the safety of

foods produced by biotechnology Report of a Joint

FAO/WHO Consultation Food and Agriculture Org./

World Health Org World Health Org., Geneva.

FDA 2000 “Foods Derived from New Plant Varieties

De-rived through Recombinant DNA Technology.” Food

and Drug Administration, Center for Food Safety and

Applied Nutrition, Washington, D.C (http://

vm.cfsan.fda.gov/~lrd/biocon.html).

Furner, I., Huffman, G., Amasino, R., Garfinkel, D.,

Gor-don, M., and Nester, E 1986 An Agrobacterium

trans-formation in the evolution of the genus Nicotiana

Na-ture 319: 422-427.

Grace, E.S 1997 “Biotechnology Unzipped: Promises

and Realities.” Joseph Henry Press, Washington, DC.

Gregory, R.S 1987 Triticale breeding In “Wheat

Breed-ing: Its Scientific Basis,” ed F.G.H Lupton, pp

269-286 Chapman & Hall, London.

HHS 2000 FDA to strengthen pre-market review of bioengineered foods Press release, U.S Dept of Health and Human Services, Washington, D.C., May 3.

Lander, E.S and Weinberg, R.A 2000 Genomics: ney to the center of biology Science, March 10, p.

pro-1300-1306.

McCouch, S 1998 Toward a plant genomics initiative:

Thoughts on the value of species and genera comparisons in the grasses Proc Natl Acad of Sciences 95: 1983-85.

cross-Miller, H.I 1997 Chpt 3 in “Policy Controversy in technology: an Insider’s View.” R.G Landes Co and Academic Press, Austin, Tex.

Bio-Miller, H.I 2000 Anti-biotech sentiment has its own risks.

Expert Report

Financial Times, March 22, p 10.

NRC 1989 “Field Testing Genetically Modified isms: Framework for Decisions.” Natl Res Council Na- tional Academy Press, Washington, D.C.

Organ-NRC 2000 “Genetically Modified Pest-Protected Plants: Science and Regulation.” Natl Res Council National Academy Press, Washington, D.C.

OTA 1984 Commercial biotechnology: An international analysis OTA-BA-218, p 3 U.S Congress, Office of Technology Assessment U.S Govt Printing Office, Washington, D.C.

Rowe, R.C and Farley, J.D 1981 Strategies for ling Fusarium crown and root rot in greenhouse toma- toes Plant Disease Repts 65: 107-108.

control-Watson, J.D and Crick, F.H.C 1953 Molecular structure

of nucleic acid A structure for deoxyribose nucleic acid Nature 171: 737-738.

Watson, J.D and Tooze, J 1981 “The DNA Story: A Documentary History of Gene Cloning.” W.H.Freeman, San Francisco ●

Key documents referenced in the report and other biotechnology resources

Food and Drug Administration (FDA) Center for Food Safety and Applied Nutrition

• Biotechnology main page: vm.cfsan.fda.gov/~lrd/biotechm.html

• 1992 policy statement: vm.cfsan.fda.gov/~acrobat/fr920529.pdf

• Guidance on current consultation procedures: vm.cfsan.fda.gov/~lrd/consulpr.html

U.S Department of Agriculture (USDA)

• Agency regulation of biotechnology: www.aphis.usda.gov/biotechnology/index.html

• Biotechnology resources from the National Agricultural Library (NAL): www.nal.usda.gov/bic

• NAL Internet resources and links: www.nal.usda.gov/bic/www.html

National Research Council (NRC)

• 2000 report on genetically modified pest-protected plants: books.nap.edu/catalog/9795.html

• 2000 report on transgenic plants and world agriculture: bob.nap.edu/html/transgenic/notice.html

• 1989 report on field testing of GMOs: www.nap.edu/books/0309040760/html

Food and Agriculture Organization of the United Nations (FAO)

• Statement on biotechnology: www.fao.org/biotech/state.htm

• Biotechnology resources: www.fao.org/waicent/faoinfo/agricult/guides/subject/b.htm

• 1996 joint FAO/WHO consultation, Biotechnology and Food Safety: www.fao.org/waicent/faoinfo/ economic/esn/biotech/tabconts.htm

World Health Organization (WHO)

• Genetically modified food main page, including information about Codex Alimentarius activities: www.who.int/fsf/gmfood/index.htm

• 2000 joint FAO/WHO consultation, Safety Aspects of Genetically Modified Foods of Plant Origin: www.who.int/fsf/gmfood/fao-who_consultation_report_2000.pdf

• 1990 FAO/WHO joint consultation, Strategies for Assessing the Safety of Foods Produced by Biotechnology: www.who.int/faf/gmfood/bio1991repo.pdf

Organization for Economic Co-operation and Development (OECD)

• Biotechnology and food safety main page: www.oecd.org/subject/biotech

• 1993 report on safety evaluation of biotech foods: www.oecd.org/dsti/sti/s_t/biotech/prod/

modern.htm

• Biotechnology publications main page: www.oecd.org//ehs/icgb/biopubs.htm

Institute of Food Technologists (IFT)

• Main page: www.ift.org

• Backgrounder on Genetically Modified Organisms: www.ift.org/resource/pdf_files/gmoback.pdf

American Dietetic Association (ADA)

• Position statement on food biotechnology: www.eatright.org/abiotechnology.htm

Council for Agricultural Science and Technology (CAST)

• Biotechnology communications: www.cast-science.org/biotechnology/index.html

International Food Information Council (IFIC)

• Main page: www.ificinfo.health.org

15EXPERT REPORT ON BIOTECHNOLOGY AND FOODS

his section begins with a discussion of issues relevant to safety evaluation of recombinant DNA biotechnology-derived foods, including the concept of substantial equivalence, safety of introduced genetic material and gene product, unintended effects, allergenicity, and products without conventional counterparts.

It is followed by the scientific consensus of international scientific groups regarding safety

of rDNA biotechnology-derived foods.

Issues Relevant to Safety Evaluation

Food manufacturers are required by law to sure the safety and quality of their products regard-less of the source or identity of the ingredients Tra-ditional foods are viewed by the Food and Drug Ad-ministration as “safe” based on a long history of use

en-The consuming public also views traditional foods assafe However, many traditional foods contain natu-rally occurring toxins that can present hazards toconsumers under some circumstances of exposure

Fortunately, in most circumstances, these naturallyoccurring toxins are present in concentrations thatare not hazardous to consumers ingesting typicalquantities of the food prepared under typical condi-tions Also, some traditional foods are allergenic tosome consumers, even though they are safe for thevast majority of consumers

IFT Expert Report on

Biotechnology and Foods

New foods produced through conventionalbreeding or introduced into the marketplace fromother parts of the world are not required to under-

go any type of safety assessment They are assumed

to be safe because they are comparable to other rieties (if newly introduced through conventionalbreeding) or because they have been safely con-sumed in other parts of the world In fact, thesenewly introduced foods may contain numerousunique components that are not individually orcollectively assessed for safety

va-In contrast, products derived through rDNAbiotechnology are assessed for safety before theirintroduction into the food marketplace Foodmanufacturers also must ensure the safety andquality of products that contain ingredients de-rived from rDNA biotechnology In 1992, FDAprovided a general outline for the safety assess-ment of rDNA biotechnology-derived food prod-ucts based on risk analysis related to the character-istics of the products (FDA 1992) All of the exist-ing foods produced using rDNA biotechnologyhave undergone a rigorous science-based safety as-sessment focusing on the characteristics of theproducts, especially the unique components.While this practice has been voluntary in the Unit-

ed States, FDA announced in May 2000 that it tends to propose a premarket notification systemfor rDNA biotechnology-derived foods that wouldmake this unofficial policy into a regulatory re-quirement (HHS, 2000) Thus, in practice, thesafety assessment of foods derived using rDNAbiotechnology has been more stringent than forconventionally derived products

in-Human Food Safety Evaluation of rDNA Biotechnology-Derived Foods T

This section is reprinted from Food Technology, vol 54, no 9, September 2000

Report: Safety

Substantial Equivalence

In the safety assessment of rDNA

biotechnology-derived foods, it is helpful

to compare the new plant variety to its

traditional counterpart because the

counterpart has a history of safe use as a

food The concept of substantial

equiva-lence effectively focuses the scientific

as-sessment on potential differences that

might present safety or nutritional

con-cerns

Substantial equivalence is not an

ab-solute determinant of safety per se, since

compositional changes in an rDNA

bio-technology-derived food may have no

impact on the safety of the food

Howev-er, substantial equivalence provides a

process to establish that the composition

of the plant has not been changed in such

a way as to introduce any new hazards

into the food, increase the concentration

of inherent toxic constituents, or

de-crease the customary content of

nutri-ents For example, high-oleic-acid

soy-bean oil from rDNA

biotechnology-de-rived soybeans has an oleic acid

concen-tration that falls outside the range

typi-cally found in soy oils From a scientific

perspective, this food is nevertheless

con-sidered safe, based on scientific

knowl-edge about the safety of oleic acid, a

com-mon fatty acid in foods

A determination of substantial

equiv-alence considers the intentional and

un-intentional effects of genetic

modifica-tion, and includes an evaluation of

phe-notypic and compositional

characteris-tics With respect to food safety,

substan-tial equivalence involves the quantitative

assessment of the concentration of

inher-ent constituinher-ents in the modified food,

compared to the often wide range

typi-cally found in its traditional counterpart,

under similar food production

condi-tions

Most food sources (e.g., soybeans,

corn) are exceedingly complex mixtures

that vary widely in composition, so it is

necessary to consider all of the factors

that determine the normal range of

vari-ation (IFBC, 1990) Key constituents

measured include nutrients, such as

pro-teins, fats, carbohydrates, vitamins, and

minerals, as well as inherent

antinutri-tional factors, toxins, and allergens

(Mi-raglia et al., 1998) The breadth of nology used to measure these constitu-ents is evolving rapidly, with new meth-ods available to assess the integrity ofmetabolic pathways and to measure sec-ondary metabolites, functional proteins,and gene expression at the molecular lev-el

tech-A recent report (Ftech-AO/WHO, 2000) ofthe Food and Agriculture Organization

of the United Nations (FAO) and theWorld Health Organization (WHO) con-sidered the concept of substantial equiva-lence:

A comparative approach focusing

on the determination of similaritiesand differences between the geneti-cally modified food and its conven-tional counterpart aids in the identi-fication of potential safety and nu-tritional issues and is considered themost appropriate strategy for thesafety and nutritional assessment ofgenetically modified foods

The Consultation was of the viewthat there were presently no alterna-tive strategies that would provide abetter assurance of safety for geneti-cally modified foods than the appro-priate use of the concept of substan-tial equivalence Nevertheless, it wasagreed that some aspects of the steps

in safety assessment process could berefined to keep abreast of develop-ments in genetic modification tech-nology The concept of substantialequivalence was developed as a prac-tical approach to the safety assess-ment of genetically modified foods

It should be seen as a key step in thesafety assessment process although it

is not a safety assessment in itself; itdoes not characterize hazard, rather

it is used to structure the safety sessment of a genetically modifiedfood relative to a conventionalcounterpart The Consultation con-cluded that the application of theconcept of substantial equivalencecontributes to a robust safety assess-ment framework The Consultationwas satisfied with the approach used

as-to assess the safety of the geneticallymodified foods that have been ap-proved for commercial use

Similarly, in a May 2000 report, theOrganization for Economic Cooperationand Development (OECD) examined thesafety of novel foods and feeds It con-cluded that:

Safety assessment based on tial equivalence is the most practicalapproach to address the safety offood and food components derivedthrough modern biotechnology

substan-In its 1992 policy on foods derivedfrom new plant varieties (FDA 1992),FDA employs the concept of substantialequivalence by focusing on the character-istics of the food product Foremost, thispolicy on food products from new plantvarieties is intended to be applied regard-less of the derivation of the plant, i.e.,through conventional breeding or rDNAbiotechnology methods FDA has identi-fied certain characteristics of these foodsthat would dictate the need for furtherscrutiny to establish safety These include

a substance that is completely new to thefood supply, an allergen expressed in anunusual or unexpected circumstance,changes in the concentrations of majordietary nutrients, and increased concen-trations of antinutritional factors andtoxins inherent to the food Although theFDA policy does not specifically use theterm substantial equivalence, the absence

of the characteristics mentioned abovewould lead to the conclusion that a foodfrom a new plant variety is substantiallyequivalent to its traditional counterpart

Safety of Introduced GeneticMaterial and Gene Product

Under FDA’s current (1992) policy, as

a starting point, the characteristics of theproduct are assessed, including the nucle-otide sequence of the DNA of the geneticmaterial that is used for plant transfor-mation This procedure provides impor-tant information on the encodedprotein(s), regulatory elements control-ling expression, and the presence or ab-sence of additional potential coding se-quences within the DNA Although allextraneous non-coding DNA may not beidentified, it can be minimized to verysmall segments This level of detail can-not ordinarily be determined for newplant varieties produced in conventionalways such as hybridization

Thus, the FDA policy contemplatesthat the structure and function of pro-teins encoded by the gene(s) introducedinto plants will be understood in consid-erable detail This information is used toassess the level of any potential risk, both

of the introduced protein and of otherproducts that may be produced or altered

by the presence of the introduced tein An additional factor is the source of

pro-the gene The FDA policy contemplates

that the following questions be addressed:

Does the source organism have a history of

safe use? and Does the source of the gene

produce any endogenous toxins or

aller-gens, that would need to be assessed in the

genetically modified plant?

Any potential safety concerns

associat-ed with the source organism would serve

to focus the safety assessment of the rDNA

biotechnology-derived plant and the

prod-ucts derived from that plant For example,

if a gene were obtained from a source that

produced a known allergen, the proteins

encoded by the introduced DNA would

have to be assessed to demonstrate that

this DNA did not encode an allergen

• Safety of Introduced Genetic

Materi-al The initial step in a safety assessment is

full characterization of the genetic

con-struct being inserted This step includes

identifying the source of the genetic

mate-rial to establish whether it originates from

a pathogenic, toxin-producing, or

allergen-ic source Parameters measured include the

size of the genetic construct that is inserted

into the plant genome, the number of

con-structs inserted, the location of insertion,

and the identification of genetic sequences

within the construct that allow for its

de-tection (marker sequences) and expression

(promoter sequences) in the plant

The genetic material transferred is

composed of DNA All food, rDNA

bio-technology-derived or otherwise, contains

DNA Individuals consume large quantities

of DNA when eating conventional foods

(Beever and Kemp, 2000) The DNA

intro-duced using rDNA biotechnology

repre-sents only a tiny fraction of the total DNA

consumed when the food is eaten, and

transfer of genes from rDNA

biotechnolo-gy-derived plants to mammalian cells is

extremely unlikely

Since DNA occurs in all foods, it is not

subject to a safety evaluation (IFBC, 1990;

Miraglia et al., 1998) It is well-established

that DNA is rapidly digested in the

gas-trointestinal tract, and there is no evidence

of DNA transfer from foods to human

in-testinal cells or gut microorganisms

(Donaldson and May, 1999) Any plant

DNA that might be found in human

tis-sues is likely to be a small, non-functional

fragment resulting from centuries of

con-sumption and does not imply that plant

foods are unsafe Moreover, the likelihood

of transfer of rDNA segments from foods

produced using rDNA biotechnology is far

less than for DNA from conventional foods

simply because the novel DNA is less than

1/250,000 of the overall amount consumed

(FAO/WHO, 2000)

Earlier rDNA biotechnology-derivedfoods were based on the use of selectablemarker genes that confer resistance to anantibiotic A workshop convened by theWHO concluded that the presence ofmarker genes per se in food would notconstitute a safety concern (WHO, 1993)

FAO/WHO (2000) recently reconsideredthe issue of antibiotic resistance markergenes and again found there is no evidencethat the markers currently in use pose ahealth risk to humans or domestic ani-mals Still, genes that confer resistance todrugs with specific medical use or limitedalternative therapies should not be used inwidely disseminated rDNA biotechnolo-gy-derived foods

Following extensive examination, FDAdecided to permit the use of kanamycin-resistance genes in the development ofrDNA biotechnology-derived tomatoes,oilseed rape, and cotton for food and feeduse and permitted these crops in food andfeed (FDA, 1994) FDA concluded that theDNA for kanamycin resistance was notdifferent from other rDNA in its digest-ibility and does not pose a food safetyconcern

The marker gene used to confer mycin resistance was the neomycin phos-photransferase, type II gene (NPTII) TheNPTII protein is rapidly degraded, likeother dietary proteins, when subjected toconditions which simulate mammalian di-gestion This protein has also been tested

kana-in acute toxicology studies at levels morethan one million times the level thatwould be consumed by people eating foodfrom rDNA biotechnology-derived plants

Finally, the transformation of intestinalbacteria by kanamycin resistance fromplants is negligible, with a calculated theo-retical maximum of less than 1 in 100,000compared to bacterial transfers of resis-tance (WHO, 1993) Thus, this proteinposes no food safety concerns FDA con-cluded that there is no inherent dangerpresented by the presence of the antibioticresistance markers used in earlier rDNAbiotechnology-derived foods These mark-

er genes, such as the NPTII gene, do notpresent a food or feed safety concern andare not considered to be either toxic or al-lergenic

The risk that the use of antibiotic sistance genes could lead to a transfer ofantibiotic resistance and reduced efficacy

re-of antibiotics is extremely small, because itwould require a series of events, each ofwhich is highly unlikely Moreover, if such

a move did occur, antibiotic selection

would be needed to make the newly tant strain a common one (Salyers, 2000)

resis-These concerns are addressed in additional

detail in the Benefits and Concerns section.

• Safety of Gene Product FDA’s 1992

policy also contemplates that, once the netic construct has been fully character-ized, an assessment of the safety of thegene product will be conducted [The geneproduct is the protein, often an enzyme,that is produced by the newly introducedgene(s) and is present in the rDNA bio-technology-derived food or food ingredi-ent, e.g., the protein expressed in Bt corn,

ge-encoded by genes from Bacillus sis (Bt), that confers pesticidal specificity

thuringien-for lepidopteran insects.] Safety tions typically include identification of thecomposition and structure of the geneproduct; a quantification of the amount ofgene product expressed in the edible por-tion of the food; a search for similarity toknown toxins and antinutritional factors,allergens, and other functional proteins; adetermination of the thermal and digestivestability of the gene product; and the re-sults of both in-vivo and in-vitro toxico-logical assays to demonstrate lack of ap-parent allergenicity or toxicity (Donaldsonand May, 1999)

evalua-Unintended Effects

From a safety perspective, unintendedeffects of genetic modification have beenspeculated to manifest as the unintendedexpression of some unknown or unexpect-

ed toxic or antinutrient factor, or the erwise unintended enhanced production

oth-of known toxic constituents (Royal ety, 1998)

Soci-However, based on the knowledgegained to date from the multitude of foodsderived from rDNA biotechnology, there is

no scientific evidence of the occurrence ofsuch unintended effects Given the moreprecise and predictable nature of geneticchange accomplished through rDNA tech-niques as compared to the random geneticchanges observed in conventional breed-ing, such unintended effects would be con-sidered less likely in foods derived fromrDNA biotechnology Furthermore, theseeffects have been observed infrequently inthe many thousands of crosses involvingconventional crop breeding In such cases,the source of the toxic constituent can typ-ically be traced back to a related speciesused in conventional cross-breeding ma-nipulations For example, high glycoalka-loid concentrations were found in the con-ventionally bred Lenape potato, and thevariety was subsequently withdrawn by the

17EXPERT REPORT ON BIOTECHNOLOGY AND FOODS

Report: Safety

U.S Department of Agriculture (Zitnak

and Johnston, 1970) These toxins are

present in all potatoes, and new potato

cultivars are routinely screened for

gly-coalkaloid content The unusually high

glycoalkaloid content in Lenape was

at-tributed to the use of the wild,

non-tuber-bearing Solanum chacoense in its

parentage Interestingly, Lenape is a parent

of Atlantic, a current potato variety with a

glycoalkaloid content typical of the range

for edible potatoes

Allergenicity

Food allergies involve abnormal

im-munological responses to substances in

foods, usually naturally occurring proteins

found in commonly allergenic foods such

as peanuts, milk, and seafood Allergic

re-actions can be manifested by symptoms

ranging from mild cutaneous or

gas-trointestinal symptoms to life-threatening

anaphylactic shock reactions Virtually all

food allergens are proteins, although only

a small fraction of the proteins found in

nature (and in foods) are allergenic Since

genetic modifications involve the

intro-duction of new genes into the recipient

plant and since these genes would produce

new proteins in the improved variety, the

potential allergenicity of the newly

intro-duced protein should be a key component

of the safety assessment process

An assessment of the potential

allerge-nicity of rDNA biotechnology-derived

foods typically follows the decision-tree

process outlined by the International Food

Biotechnology Council (IFBC) and the

Al-lergy and Immunology Institute of the

In-ternational Life Sciences Institute (ILSI)

(Metcalfe et al., 1996) This strategy

focus-es on specific scientific criteria, including

the source of the gene(s), the sequence

ho-mology of the newly introduced

protein(s) to known allergens, the

immu-nochemical reactivity of the newly

intro-duced protein(s) with immunoglobulin E

(IgE) antibodies from the blood serum of

individuals with known allergies to the

source from which the genetic material

was obtained, and the physicochemical

properties, e.g., digestive stability, of the

introduced protein

At the recently concluded expert

con-sultation (FAO/WHO, 2000), several other

criteria, including the level of expression ofthe newly introduced protein(s) in the edi-ble portions of the improved variety andthe evaluation of the functional categoryfor the introduced protein (some function-

al categories of proteins, e.g., ionine 2S albumins, are known to containseveral allergens from different sources),were suggested for addition to the IFBC-ILSI allergenicity assessment strategy

high-meth-The first step of the allergenicity ment (Fig 1) involves the classification ofthe source of the genetic material as eithercommonly allergenic, less commonly aller-genic, or of unknown allergenic potential

assess-Eight foods or food groups, including milk,eggs, fish, crustacean shellfish, peanuts,soybeans, tree nuts, and wheat, are well ac-cepted as commonly allergenic; these eightfoods or food groups account for morethan 90% of all food allergies in the world(FAO, 1995) More than 160 other foodshave been described to cause allergic reac-tions (Hefle et al., 1996), and would beclassified as less commonly allergenic

However, many of the genes that have beenand will be used to produce rDNA biotech-nology-derived foods are obtained fromsources with no history of allergenicity asfoods Certainly, if the source contains wellknown environmental allergens, e.g., rag-weed that contains common ragweed pol-len allergens, then the allergenicity of new-

ly introduced protein(s) from such sourcesmust be carefully evaluated

The approaches to allergenicity ment vary according to the nature of thesource of the transferred genetic material

assess-If the genetic material is obtained from aknown allergenic source, either commonly

or less commonly allergenic, and the coded protein is expressed in the edibleportion of the rDNA biotechnology-de-rived food, then the protein must be con-sidered to be an allergen unless proven oth-erwise

en-In such situations, the next step in theallergenicity assessment is a determination

of the immunoreactivity of the newly troduced protein with IgE antibodies fromthe sera of individuals allergic to the donororganism The blood serum can be testedfor reactivity with the purified protein orextracts of the genetically modified foodusing immunoassays (Yunginger andAdolphson, 1992; Taylor and Lehrer, 1996)

in-If a sufficient number of test sera are used

as advocated in the decision tree approach(Metcalfe et al., 1996), the allergenicity ofthe introduced protein can be determinedwith a high degree of confidence However,

if negative results are obtained in the

im-munoassays, the rDNA derived food or extracts of that foodshould be tested further using in-vivoskin-prick tests (Bock et al., 1977; Taylorand Lehrer, 1996), double-blind, placebo-controlled food challenges (Bock et al.,1988; Taylor and Lehrer, 1996), or diges-tive stability assessments (Astwood et al.,1996) as advocated by the IFBC-ILSI deci-

biotechnology-sion tree If the immunoassays and these

other tests, as appropriate, are negative,then the likelihood that the rDNA bio-technology-derived food contains an aller-gen would be quite small

The most difficult assessment occurswhen genes are obtained from sourceswith no history of allergenicity, such as vi-ruses, bacteria, or non-food plants Thelikelihood that the proteins derived fromsuch sources of DNA will be allergens isnot very high, since most proteins in na-ture are not allergens (Taylor, 1997) Addi-tionally, many of these proteins will be ex-pressed in the rDNA biotechnology-de-rived food at very low levels, while allergicsensitization is more likely to occur to themajor proteins that exist in foods (Taylor,1997) The key features of the allergenicityassessment for such foods involve a com-parison of the amino acid sequence of theintroduced protein with the amino acidsequences of known allergens and the di-gestive stability of the introduced protein.While the combination of these two crite-ria provides reasonable assurance that theintroduced protein has limited allergenicpotential, the ideal approaches to the ap-plication of these two criteria have beendebated, and the desirability of addingother criteria for the allergenicity assess-ment of such products has been advocated(Wal, 1998)

The criterion of amino acid sequencehomology to known allergens is a logicaland increasingly powerful approach Theamino acid sequences of more than 300known allergens are available for compar-ative purposes The IFBC-ILSI strategy de-fines significant sequence similarity as amatch of at least eight contiguous, identi-cal amino acids based on the minimalpeptide length needed for T-cell binding,which is a necessary prelude to allergicsensitization; this approach is clearly limit-

ed in that it cannot identify discontinuous

or conformational epitopes that are pendent on the tertiary structure of the

de-protein (Metcalfe et al., 1996) Others have

suggested that the definition of significantsequence homology be modified to a min-imal peptide length of less than eight con-tiguous, identical amino acids (Consumer

19EXPERT REPORT ON BIOTECHNOLOGY AND FOODS

and Biotechnology Foundation, 1999)

While this criterion (amino acid sequence

homology to known allergens) is clearly

useful, international agreement must be

sought on its application

Known food allergens tend to be quite

stable to digestive proteases (Astwood et

al., 1996) with the exception of the

pollen-related food proteins that cause oral

aller-gy syndrome (Taylor and Lehrer, 1996)

Thus, digestive stability can be used as a

criterion for the assessment of the

aller-genic potential of the introduced proteins

Both simulated gastric and intestinal

mod-els of mammalian digestion are advocated

for such assessments (Astwood et al., 1996;

Metcalfe et al., 1996) While the usefulness

of this criterion is apparent, consensus isneeded on the ideal protocols for assess-ment of digestive stability It is recognizedthat novel proteins may exist that are sta-ble to digestion but will not become aller-gens Additional testing is needed to assessthe allergenic potential of such proteins(FAO/WHO, 2000)

The development of additional criteriaand additional tests to use in the assess-ment of the allergenicity of rDNA biotech-nology-derived foods would be advanta-geous in cases where the gene is obtained

from sources with no history of ity As mentioned, the level of expression

allergenic-of the introduced protein and the tional category of the introduced proteincould be used as additional criteria (FAO/WHO, 2000) In addition, the development

func-of suitable animal models for the tion of the allergenic potential of the intro-duced proteins is anticipated in the future.While several animal models appear to bepromising (Knippels et al., 1998), none hasbeen sufficiently validated for its routineuse in the assessment of the allergenicity ofrDNA biotechnology-derived foods.The existing decision-tree approach

predic-Fig 1—Assessment of the allergenic potential of foods derived from genetically

modified crop plantsa

Source of gene(allergenic)

Solid phase immunoassay

Commonly

allergenic Less commonlyallergenic

Skin prick test

c Any positive results obtained in tests involving allergic human subjects or blood serum from such subjects would provide a high level of confidence that the novel protein was a potential allergen Foods containing such novel proteins would need to be labeled to protect allergic consumers.

d A novel protein with either no sequence similarity to known allergens or derived from a less commonly allergenic source with no evidence of binding to IgE from the blood serum of a few allergic individuals (<5) but that is stable to digestion and processing should be considered a possible allergen Further evaluation would

be necessary to address this uncertainty The nature of the tests would be determined on a case-by-case basis.

e A novel protein with no sequence similarity to known allergens and that was not stable to digestion and processing would have no evidence of allergenicity Similarly, a novel protein expressed by a gene obtained from a less commonly allergenic source and demonstrated to have no binding with IgE from the blood serum of a small number of allergic individuals (>5 but <14) provides no evidence of allergenicity Stability testing may be included in these cases However, the level of confidence based on only two decision criteria is modest The FAO/WHO Expert Consultation suggested that other criteria should also be considered, such

as the level of expression of the novel protein.

f Double-blind placebo-controlled food challenge (institutional review board).

Report: Safety

has already been applied in the assessment

of the allergenicity of rDNA

biotechnolo-gy-derived foods The enzyme introduced

into glyphosate-tolerant soybeans has no

sequence homology to known allergens

and is rapidly digested in simulated

mam-malian digestion systems (Harrison et al.,

1996) Similarly, several of the Bt proteins

used in insect-resistant crops and the

pro-teins produced by common marker genes

are rapidly digested in simulated

mamma-lian digestion systems (Astwood et al.,

1996) A high-methionine protein

intro-duced into soybeans by the transfer of a

gene from Brazil nuts to correct the

inher-ent methionine deficiency in soybeans was

shown to bind to IgE from the sera of

Bra-zil nut–allergic individuals and to elicit

positive skin-prick tests in some of these

patients (Nordlee et al., 1996) This

pro-tein was thus identified as the major

aller-gen from Brazil nuts that had not

previ-ously been characterized As a result,

com-mercial development of this particular

soybean variety was discontinued

Clearly, the assessment of the

allerge-nicity of rDNA biotechnology-derived

foods should be a key component of the

overall safety assessment process in all

cases A useful strategy has been developed

for such assessments, although this

strate-gy should be viewed as dynamic and new

approaches and criteria should be added

once they are validated and accepted

Products without

Conventional Counterparts

Recombinant DNA-derived

biotech-nology foods without conventional

coun-terparts need to be evaluated on a

case-by-case basis and would be subject to some

types of toxicity assessments, depending

on the nature of the modification (IFBC,

1990) This situation has not yet arisen

with rDNA biotechnology derived foods,

although at some point it undoubtedly

will When it does, the situation will raise a

variety of issues that will need to be

ad-dressed in a scientifically based, flexible

manner

Whole foods are complex mixtures of

chemical components characterized by

wide variations in composition and

nutri-tional qualities, and are not well suited for

traditional toxicological studies designed

to assess individual chemical entities Thetesting of whole foods—rDNA biotech-nology-derived or conventional—in ani-mal feeding studies, for example, is limited

by factors such as the animal’s qualitativeand quantitative feeding preferences andthe levels of nutritional and antinutrition-

al factors and other substances that arepresent When one researcher attempted

to ascertain the toxic threshold for anrDNA biotechnology-derived tomato byfeeding rats freeze-dried tomato extract,the experiments were limited to the hu-man equivalent of 13 tomatoes a day bynegative effects of inorganic compounds,such as potassium, that are present inrDNA biotechnology-derived and conven-tional tomatoes alike But, as noted byMacKenzie (1999), “Toxicologists still said

we hadn’t fed them enough to get a ingful result.”

Another limitation is that animal icity tests are seldom sufficiently sensitive

to distinguish differences between the icity of a new variety and its conventionalcounterparts Indeed, most foods will pro-duce adverse effects in long-term animalfeeding studies when fed in high propor-tions of the diet, regardless of the nature

tox-of production The results tox-of such studiesare not easily interpreted, and apparentadverse effects are often the indirect effects

of related nutritional dietary imbalance,rather than any specific compound inquestion OECD (2000) recognized thatthere is no scientific justification for re-

quiring long-term feeding studies forrDNA biotechnology-derived foods, andthat such studies would be unlikely to pro-vide meaningful information in the greatmajority of cases FAO/WHO (2000) con-curred, finding that the practical difficul-ties in the application of conventional toxi-cology studies to whole foods precludetheir use as a routine safety assessmenttechnique

The key differences between the testing

of whole foods and the testing of

individu-al chemicindividu-al substances in animindividu-al feedingstudies are indicated in Table 1

Thus, given a hypothetical rDNA technology-derived food without a con-ventionally derived counterpart, animalstudies would need to be designed to ad-dress specific nutritional or toxicologicalconcerns However, these studies wouldneed to be carefully designed to avoid orminimize the limitations discussed abovethat are associated with the testing ofwhole foods or major food constituents(Munro et al., 1996) For example, toxico-logical studies could be used to examinethe potential for acute, chronic, carcino-genic, genotoxic, reproductive, and terato-genic effects of components or fractions ofconcern in a food derived from a newplant variety A complete assessmentwould also include pharmacokinetic dataregarding absorption, distribution, metab-olism, and excretion of the new product or

bio-a novel component thereof By focusingtoxicological examination on carefully se-

Table 1

Typically a single, chemically identified substance A complex mixture of many substances, most

unidentified Highest dose level should produce an adverse Highest dose that does not cause rejection of effect attributable only to the chemical the diet, or nutritional imbalance, very unlikely to

produce any toxic effect Low doses, usually <1% of the diet High doses, usually >10% of the diet Easy to give a dose high enough to assure an Difficult or impossible to achieve doses more adequate safety factor (>100× normal than a few multiples of human intake; therefore,

Acute effects obvious Acute effects, other than nutritional imbalance,

nearly always absent Nutritional effects generally absent Nutritional effects typically present Specific routes of metabolism capable of Complex metabolism of many ingredients, most being studied and ascertained unidentified; therefore, impossible to determine Cause/effect relatively clear Effects usually absent or, if observed, confused

by multiple possible causes

a Based on Munro et al (1986) and Hall (1981)

Differences between animal testing of individual chemicals and whole foodsa

21EXPERT REPORT ON BIOTECHNOLOGY AND FOODS

lected fractions or components of a food

derived from a new plant variety, and

ex-cluding major components of no concern,

it may be possible to reduce or eliminate

the difficulties associated with testing

whole foods

The assessment of macronutrient

sub-stitutes or other major food constituents

should follow a tiered approach (Munro et

al., 1996), whereby the physical and

chemi-cal properties of the constituent are

deter-mined, in addition to its potential to

dis-rupt or alter nutrient uptake Initial

pre-dictive effect studies would dictate the

physiologically relevant endpoint

determi-nants of subsequent in-vitro and in-vivo

studies (Munro et al., 1996) Further, the

choice of animal model for any such

in-vivo studies would have to be carefully

considered for relevance when applying

re-sults to humans (Battershill et al., 1999)

Without precedence, the above

discus-sion outlines a proposal which seems best

calculated to provide the data needed for a

persuasive showing of safety Clearly, such

novel foods without conventional

counter-parts, when they do become available, will

need careful testing, evaluation, and

regu-latory scrutiny using a flexible process that

contains case-by-case adaptation based on

the novel nature of the issues presented

Scientific Consensus

About Safety

The Human Food Safety Panel

re-viewed available information about the

safety of rDNA biotechnology-derived

foods and found that there is striking

con-gruence in the conclusions and

recom-mendations of various international

scien-tific groups that have considered the issue

The National Academy of Sciences

published a white paper (NAS, 1987) on

the planned introduction of organisms

de-rived using rDNA biotechnology into the

environment This white paper has had

wide-ranging impacts in the United States

and other countries Its most significant

conclusions and recommendations include

(1) there is no evidence of the existence of

unique hazards, either in the use of rDNA

biotechnology techniques or in the

move-ment of genes between unrelated

organ-isms, and (2) the risks associated with the

introduction of rDNA

biotechnology-de-rived organisms are the same in kind as

those associated with the introduction of

unmodified organisms and organisms

modified by other methods

In a 1989 extension of this white paper,

the National Research Council (NRC), theresearch arm of the NAS, concluded that

“no conceptual distinction exists betweengenetic modification of plants and micro-organisms by classical methods or by mo-lecular techniques that modify DNA andtransfer genes” (NRC, 1989) The NRC re-port supported this statement with exten-sive observations of past experience withplant breeding, introduction of rDNA bio-technology-derived plants, and introduc-tion of rDNA biotechnology-derived mi-croorganisms:

The committees [of experts sioned by NRC] were guided by the

commis-conclusion (NAS, 1987) that the uct of genetic modification and selec-

prod-tion should be the primary focus formaking decisions about the environ-mental introduction of a plant or mi-

croorganism and not the process by

which the products were obtained

Information about the process used

to produce a genetically modified ganism is important in understandingthe characteristics of the product

or-However, the nature of the process isnot a useful criterion for determiningwhether the product requires less ormore oversight

The same physical and biological lawsgovern the response of organismsmodified by modern molecular andcellular methods and those produced

to predict the phenotypic expression

Crops modified by molecular and lular methods should pose risks nodifferent from those modified by clas-sical genetic methods for similartraits As the molecular methods are

cel-more specific, users of these methodswill be more certain about the traitsthey introduce into the plants

The types of modifications that havebeen seen or anticipated with molecu-lar techniques are similar to those thathave been produced with classicaltechniques No new or inherently dif-ferent hazards are associated with themolecular techniques

The same principles were emphasized

in a comprehensive report (NIH, 1992) by

the U.S National Biotechnology Policy

Board, which was established by Congressand composed of representatives from thepublic and private sectors:

The risks associated with

biotechnolo-gy are not unique, and tend to be sociated with particular products andtheir applications, not with the pro-duction process or the technology per

as-se In fact biotechnology processestend to reduce risks because they aremore precise and predictable Thehealth and environmental risks of notpursuing biotechnology-based solu-tions to the nation’s problems are like-

ly to be greater than the risks of goingforward

These findings are consistent with theobservations and recommendations of theUnited Kingdom’s House of Lords SelectCommittee on Science and Technology(UK,1993), which was very critical of thatnation’s policy of subjecting rDNA bio-technology-derived products to additionalregulatory requirements:

As a matter of principle, rived products [i.e., those from genet-

GMO-de-ically manipulated organisms, or

re-combinant organisms] should be ulated according to the same criteria

reg-as any other product U.K tion of the new biotechnology of ge-netic modification is excessively pre-cautionary, obsolescent, and unscien-tific The resulting bureaucracy, cost,and delay impose an unnecessary bur-den to academic researchers and in-dustry alike

regula-Three joint FAO/WHO consultations,addressing specifically the question of thesafety of rDNA biotechnology-derivedfoods, came to similar conclusions Thefirst of these expert consultations (FAO/WHO, 1991) concluded:

Report: Safety

Biotechnology has a long history of

use in food production and

process-ing It represents a continuum

em-bracing both traditional breeding

techniques and the latest techniques

based on molecular biology The

new-er biotechnological techniques, in

par-ticular, open up very great possibilities

of rapidly improving the quantity and

quality of food available The use of

these techniques does not result in

food which is inherently less safe than

that produced by conventional ones

The second consultation (FAO/WHO,

1996) reaffirmed the conclusions and

rec-ommendations of the first FAO/WHO

con-sultation:

Food safety considerations regarding

organisms produced by techniques that

change the heritable traits of an

organ-ism, such as rDNA technology, are

basi-cally of the same nature as those that

might arise from other ways of altering

the genome of an organism, such as

conventional breeding While there

may be limitations to the application of

the substantial equivalence approach to

safety assessment, this approach

pro-vides equal or increased assurance of

the safety of food products derived

from genetically modified organisms as

compared to foods or food

compo-nents derived by conventional

meth-ods

The most recent consultation (FAO/

WHO 2000) examined the evidence to date

and concluded:

A comparative approach focusing on

the determination of similarities and

differences between the genetically

modified food and its conventional

counterpart aids in the identification

of potential safety and nutritional

is-sues and is considered the most

ap-propriate strategy The

Consulta-tion was of the view that there were

presently no alternative strategies that

would provide better assurance of

safety for genetically modified foods

than the appropriate use of the

con-cept of substantial equivalence

OECD (1993) offered several sions and recommendations that are whol-

conclu-ly consistent with the NAS, NRC, andFAO/WHO findings:

In principle, food has been presumed

to be safe unless a significant hazardwas identified

Modern biotechnology broadens thescope of the genetic changes that can

be made in food organisms andbroadens the scope of possible sources

of foods This does not inherently lead

to foods that are less safe than thosedeveloped by conventional tech-niques

Therefore, evaluation of foods andfood components obtained from or-ganisms developed by the application

of the newer techniques does not cessitate a fundamental change in es-tablished principles, nor does it re-quire a different standard of safety

ne-For foods and food components fromorganisms developed by the applica-tion of modern biotechnology, themost practical approach to the deter-mination of safety is to consider

whether they are substantially lent to analogous conventional food

equiva-product(s), if such exist

OECD (1998) reaffirmed the

conclu-sions and recommendations of previousconsultations of both FAO/WHO andOECD Regarding the specific question ofpotential allergenicity of novel proteins in-troduced in rDNA biotechnology-derivedfoods, the report stated:

While no specific methods can beused for proteins derived from sourceswith no history of allergy, a combina-tion of genetic and physicochemicalcomparisons exist which can be used

as a screen The application of such astrategy can provide appropriate as-surance that foods derived from ge-netically modified products can be in-troduced with confidence comparable

to other new plant varieties

In 2000, OECD acknowledged thepublic concerns about the safety assess-ment of rDNA technology (OECD 2000),stating:

Although [the] food safety assessment

is based on sound science, there is a

clear need for increased transparencyand for safety assessors to communi-cate better with the public Muchprogress has already been made inthis regard However, more could

be done in this area

The NRC’s Committee on GeneticallyModified Pest-Protected Plants published

a report (NRC, 2000) that reaffirmed theprinciples set forth in the 1987 NAS whitepaper Specifically, the committee foundthat “there is no strict dichotomy between,

or new categories of, the health and ronmental risks that might be posed bytransgenic and conventional pest-protect-

envi-ed plants” and that the “properties of a netically modified organism should be thefocus of risk assessments, not the process

ge-by which it was produced.” The tee concluded that “[w]ith careful plan-ning and appropriate regulatory oversight,commercial cultivation of transgenic pest-protected plants is not generally expected

commit-to pose higher risks and may pose less riskthan other commonly used chemical andbiological pest-management techniques.”(While the report focused on rDNA bio-technology-derived pest-protected plants,the committee stated that many of its con-clusions are also applicable to rDNA bio-technology-derived plants generally.)

In summary, the safety of rDNA technology-derived foods has been exten-sively reviewed by a number of scientificorganizations, at the national and interna-tional level The use of rDNA biotechnolo-

bio-gy in itself has no impact on the safety ofsuch foods Foods derived using rDNAbiotechnology are subject to rigorous andsystematic scientific evaluations under ex-isting principles of food safety—far morethan are routinely applied to the products

of traditional breeding Thus, the level offield testing and premarket review forfood safety provide assurance that foodsderived from plants and microorganismsthrough rDNA biotechnology are at least

as safe as existing foods, and are consistentwith all existing standards of food safety

23EXPERT REPORT ON BIOTECHNOLOGY AND FOODS

al breeding techniques and the latest

tech-niques based on molecular modification of

genetic material, which are a major step

forward by virtue of their precision and

reach The newer rDNA biotechnology

techniques, in particular, offer the potential

to rapidly and precisely improve the

quan-tity and quality of food available

• Crops modified by modern molecular

and cellular methods pose risks no

differ-ent from those modified by earlier genetic

methods for similar traits Because the

mo-lecular methods are more specific, users of

these methods will be more certain about

the traits they introduce into the plants

• The evaluation of food, food

ingredi-ents, and animal feed obtained from

organ-isms developed with the newer rDNA

bio-technology techniques of genetic

manipu-lation does not require a fundamental

change in established principles of food

safety; nor does it require a different

stan-dard of safety, even though, in fact, more

information and a higher standard of

safe-ty are being required

• The science that underlies rDNA

bio-technology-derived foods does not support

more stringent safety standards than those

that apply to conventional foods

• The use of rDNA biotechnology and

molecular techniques of genetic

manipula-tion significantly broadens the scope of the

genetic changes that can be made in food

organisms and broadens the scope of

possi-ble sources of foods, but this does not

in-herently lead to foods that are less safe than

those developed by conventional

tech-niques By virtue of their greater precision,

such products can be expected to be better

characterized, leading to more

predictabili-ty and a more reliable safepredictabili-ty assessment

process

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Astwood, J.D., Leach, J.N., and Fuchs, R.L 1996 Stability of

food allergens to digestion in vitro Nature Biotechnol 14:

1269-1273.

Battershill, J., Hattersley, S.J., and Sanderson, M 1999 Critical

issues for the safety assessment of novel foods when no

con-ventional counterpart exists: Discussion meeting, Dept of

Health, London, UK, 12 February 1998 Food Additives and

Bock, S.A., Sampson, H.A., Atkins, F.M., Zeiger, R.S., Lehrer, S., Sachs, M., Bush, R.K., and Metcalfe, D.D 1988 Double- blind, placebo-controlled food challenges (DBPCFC) as an office procedure: A manual J Allergy Clin Immunol 82:

FAO/WHO 1991 Strategies for assessing the safety of foods produced by biotechnology Report of a Joint FAO/WHO Ex- pert Consultation Food and Agriculture Organization of the United Nations and World Health Organization WHO, Geneva, Switzerland.

FAO/WHO 1996 Biotechnology and Food Safety Report of a Joint FAO/WHO Expert Consultation Food and Agriculture Or- ganization of the United Nations and World Health Organiza- tion WHO, Geneva, Switzerland.

FAO/WHO 2000 Safety aspects of genetically modified foods

of plant origin Report of a Joint FAO/WHO Expert tion on Foods Derived from Biotechnology Food and Agricul- ture Organization of the United Nations and World Health Or- ganization WHO, Geneva, Switzerland.

Consulta-FDA 1992 Statement of policy: Foods derived from new plant varieties Food and Drug Admin., Fed Reg 57: 22984.

FDA 1994 Secondary direct food additives permitted in food for human consumption; Food additives permitted in feed and drinking water of animals; Aminoglycoside 3'-Phospho- transferase II; Final rule Food and Drug Admin., Fed Reg.

59: 26700.

Hall, R.L 1981 Evaluating the toxicity and health hazards of etary adjuvants (spices, herbs, etc.) In Proceedings of the Toxicology Forum, July 20–24, 1981, pp 404 Toxicology Forum, Washington, D.C.

di-Harrison, L.A., Bailey, M.R., Naylor, M.W., Ream, J.E., mond, B.G., Nida, D.L., Burnette, B., Nickson, T.E., Mitsky, T.A., Taylor, M.L., Fuchs, R.L., and Padgette, S.R 1996 The expressed protein in glyphosate-tolerant soybean, 5- enolpyruvylshikimate-3-phosphate synthase from Agrobacte- rium sp Strain CP4, is rapidly digested in vitro and is not toxic

Ham-to acutely gavaged mice J Nutr 126: 728-740.

Hefle, S.L., Nordlee, J.A., and Taylor, S.L 1996 Allergenic foods Crit Rev Food Sci Nutr 36: S69-S89.

HHS 2000 FDA to strengthen premarket review of neered foods Press release May 3 U.S Dept of Health and Human Services, Washington, D.C.

bioengi-IFBC 1990 Biotechnologies and Food: Assuring the Safety of Food Produced by Genetic Modification Intl Food Biotech- nology Council Regulatory Toxicol Pharmacol 12(3): Part 2.

Knippels, L.M.J., Pennicks A.H., Spanhaak S., and Houben G.F.

1998 Oral sensitization to food proteins: A Brown Norway rat model Clin Exp Allergy 28: 368-375.

MacKenzie, D 1999 Unpalatable truths New Scientist, April 17,

pp 18-19.

Metcalfe, D.D., Astwood, J.D., Townsend, R., Sampson, H.A., Taylor, S.L., and Fuchs, R.L 1996 Assessment of the aller- genic potential of food derived from genetically engineered crop plants Crit Rev Food Sci Nutr 36: S165-S186 Miraglia, M., Onori, R., Brera, C., and Cava, E 1998 Safety as- sessment of genetically modified food products: An evaluation

of developed approaches and methodologies Microchem J 59: 154-159.

Munro, I.C., McGirr, L.G., Nestmann, E.R., and Kille, J.W 1996 Alternative approaches to the safety assessment of macronu- trient substitutes Regulatory Toxicol Pharmacol 23: S6-S14 NAS 1987 Introduction of recombinant DNA-engineered or- ganisms into the environment: Key issues Natl Acad of Sci- ences National Academy Press, Washington, D.C NIH 1992 National Biotechnology Policy Board report Natl Insts of Health, Bethesda, Md.

Nordlee, J.A., Taylor, S.L., Townsend, J.A., Thomas, L.A., and Bush, R.K 1996 Identification of a Brazil nut allergen in transgenic soybeans New Eng J Med 334: 688-694 NRC 1989 “Field Testing Genetically Modified Organisms: Framework for Decisions.” Natl Res Council National Acade-

my Press, Washington, D.C.

NRC 2000 “Genetically Modified Pest-Protected Plants: ence and Regulation.” Natl Res Council National Academy Press, Washington, D.C.

Sci-OECD 1993 “Safety Evaluation of Foods Derived by Modern Biotechnology: Concepts and Principles.” Org for Economic Cooperation and Development, Paris.

OECD 1998 Report of the OECD Workshop on Toxicological and Nutritional Testing of Novel Foods Org for Economic Cooperation and Development, Paris.

OECD 2000 Report of the Task Force for the Safety of Novel Foods and Feeds Org for Economic Cooperation and Devel- opment, Paris 86/ADDI, May 17.

Royal Society 1998 Genetically modified plants for food use www.royalsoc.ac.uk/files/statfiles/document-56.pdf Salyers, A 2000 Genetically engineered foods: Safety issues associated with antibiotic resistance genes Reservoirs of Anti- biotic Resistance Network www.healthsci.tufts.edu/apua/ salyersreport.htm.

Taylor, S.L 1997 Food from genetically modified organisms and potential for food allergy Environ Toxicol Pharmacol 4: 121-126.

Taylor, S.L and Lehrer, S.B 1996 Principles and characteristics

of food allergens Crit Rev Food Sci Nutr 36:S91-S118.

UK 1993 Regulation of the United Kingdom biotechnology dustry and global competitiveness October United Kingdom’s House of Lords Select Committee on Science and Technology Wal, J.M 1998 Strategies for assessment and identification of allergenicity in (novel) foods Intl Dairy J 8: 413-423 WHO 1993 Health aspects of marker genes in genetically modified plants Report of WHO Workshop WHO/FNU/FOS/ 93.6 World Health Org., Geneva.

in-Yunginger, J.W., Adolphson, C.R 1992 Standardization of gens In “Manual of Clinical Immunology,” 4th ed., pp 678-

aller-684 Am Soc of Microbiology, Washington D.C.

Zitnak, A., and Johnston, G.R 1970 Glycoalkaloid content of B5141-6 potatoes Am Potato J 47: 256-260 ●

Human Food Safety Panel

Dallas Hoover, Ph.D., Professor, Dept of Animal and Food Science, University of

Delaware, Newark

Bruce M Chassy, Ph.D., Executive Associate Director, Biotechnology Center,

Assistant Dean for Biotechnology Outreach, Office of Research, College of

Agricul-tural, Consumer and Environmental Sciences, University of Illinois, Urbana

Richard L Hall, Ph.D., Consultant, Franklin, Maine; Towson, Md.

Harry J Klee, Ph.D., Eminent Scholar, Horticultural Sciences Dept., University of

Florida, Gainesville

John B Luchansky, Ph.D., Research Leader, Eastern Regional Research Center, U.S.

Dept of Agriculture, Agricultural Research Service, Wyndmoor, Pa.

Henry I Miller, Ph.D., Robert Wesson Fellow, Stanford University, Stanford, Calif Ian Munro, Ph.D., President, Cantox Health Sciences International, Mississauga,

Ontario, Canada

Ronald Weiss, Ph.D., Research Program Manager, Food Research Institute,

University of Wisconsin, Madison

Susan L Hefle, Ph.D., Assistant Professor, Food Allergy Research and Resource

Program, University of Nebraska, Lincoln

Calvin O Qualset, Ph.D., Director, Genetic Resources Conservation Program,

University of California, Davis

his section begins with an overview of the United States food labeling requirements directly relevant to the labeling of recombinant DNA biotechnology- derived foods, including constitutional limitations on the government’s authority to regulate food labeling and specific case studies relevant to labeling rDNA biotechnol- ogy-derived foods Next, the report discusses labeling policies for rDNA biotechnology- derived foods in the U.S and internationally and the impact of labeling distinctions on food product distribution systems Finally, consumer perceptions of various label statements are discussed.

U.S Food Labeling in General

Current Requirements, Policies,and Constraints

· Food and Drug Administration

Require-ments and Policies Generally speaking, the

Food and Drug Administration (FDA) has thority over food labeling, and the FederalTrade Commission (FTC) has authority overfood advertising A detailed analysis of FTCand its responsibilities regarding food advertis-

au-IFT Expert Report on

Biotechnology and Foods

ing is beyond the scope of this paper; however,

a brief overview follows later in this section.Except for meat and poultry products regu-lated by the U.S Department of Agriculture(USDA), the federal law governing the labeling

of food generally is the Federal Food, Drug,and Cosmetic Act (FFDCA) [21 USC §§301–397] The FFDCA is administered by FDA Un-der this statute, FDA regulates food labelingthrough a series of requirements that are in-tended to assure that information of signifi-cance about a food product is provided andthat food labeling is truthful and not mislead-ing

“Labeling” is defined in the FFDCA as

“written, printed, or graphic matter (1) uponany article or any of its containers or wrappers,

or (2) accompanying such article” [21 USC

§321(m)] Thus, “labeling” includes—but isnot limited to—the “label” that is physically at-tached to the immediate container of foods inpackage form [21 USC §321(k)] Physical at-tachment or proximity of the material to theproduct is not required for the material to beconsidered “labeling” for purposes of the stat-ute In 1948, the Supreme Court found that abooklet containing information about a prod-uct that was sold separately from the productwas nevertheless “labeling” for purposes of thestatute because the product and the booklet

“were parts of an integrated distribution

scheme” [Kordel v United States, 335 US 345 (1948)] The court in Kordel also pointed out

Labeling of rDNA Biotechnology-Derived Foods

T

25EXPERT REPORT ON BIOTECHNOLOGY AND FOODS

that material that is not regulated as

labeling by FDA will be regulated as

advertising by FTC

At the most basic level, the FFDCA

and its implementing regulations

specify that certain information is

re-quired on the labels of almost all

foods These label requirements are

intended to assure provision of

infor-mation that is fundamental to the

de-scription of the food or the operation

of the food safety regulatory system

Examples of these label requirements

are the common or usual name (or

other name) of the food; net contents

statement; an ingredient listing for

food products made from more than

one ingredient; name and place of

business of the manufacturer, packer,

or distributor; and nutrition labeling

· Constitutional Constraints In

the American legal system, the U.S

Constitution is paramount Therefore,

all statutory labeling requirements,

their implementing regulations, and

FDA labeling policies must satisfy

constitutional requirements The

prin-cipal constitutional consideration in

food labeling matters is First

Amend-ment constraint of governAmend-ment

label-ing regulation The First Amendment

of the U.S Constitution states:

“Con-gress shall make no law abridging

the freedom of speech.” This right has

recently been extended to include

“commercial speech,” which is

com-monly defined to be speech in any

form that advertises a product or

ser-vice for profit or for any business

pur-pose, or as speech that proposes a

le-gitimate business or commercial

transaction [Virginia State Bd of

Phar-macy v Virginia Citizens Consumer

Council, 425 US 748 (1976)].

Until the 1970s, advertising or

la-beling restrictions were viewed as

purely economic regulations that did

not implicate the First Amendment

Indeed, until the late 1970s, the

Su-preme Court had excluded

commer-cial speech from the coverage of the

First Amendment [Valentine v

Chrest-ensen, 316 US 52 (1942)] Today,

com-mercial speech is protected under the

First Amendment, but can be subject

to more stringent government

regula-tion than other kinds of speech, such

as political commentary

For food labeling purposes, the

most important modern commercial

speech case is Central Hudson v Public

Service Com’n of N.Y [447 US 557

(1980)] In Central Hudson, the

Su-preme Court held that commercialspeech is protected by the FirstAmendment, and set forth a four-pronged test for determining permis-sible regulation of commercial speech

Under Central Hudson, the

govern-ment may restrict commercial speech

if (1) the speech is either misleading

or concerns an unlawful activity, or if(2) the asserted governmental interest

in support of the restriction is stantial, (3) the restriction directly ad-vances the government’s substantialinterest, and (4) the regulation is notmore extensive than is necessary toserve that interest

sub-The First Amendment protectsboth the right to speak and the rightnot to speak The constitutionally pro-tected right not to speak, the com-pelled speech doctrine, is clearly es-tablished in Supreme Court precedent

[Harper & Row, Publishers, Inc v tional Enter., 471 US 539 (1985);

Na-Wooley v Maynard, 430 US 705

(1977)] Indeed, the Supreme Courthas suggested that compelling some-one to speak involuntarily is an evenmore serious constitutional matter

than preventing speech [West Virginia State Bd of Ed v Barnette, 319 US 624

(1943)]

The regulation of food labeling volves both the commercial speechand the compelled speech doctrines

in-The courts have not articulated a

“compelled commercial speech” trine Therefore, in assessing the con-stitutionality of government restric-tions on commercial speech, thecourts have applied the four-pronged

doc-Central Hudson commercial speech

analysis It should also be noted thatthe courts have been at least as skepti-cal about government requirementsthat compel speech as about limita-tions on speech

· False or Misleading Statements.

Beyond these fundamental label quirements and constitutional con-straints discussed above, the food pro-cessor is generally at liberty to makeuse of label or labeling space in themanner it deems fit, provided that thelabel or labeling is not false or mis-leading The FFDCA deems a food to

re-be misbranded if “its lare-beling is false

or misleading in any particular” [21USC §343(a)(1)] As noted above, theprohibition on misleading commercialspeech is specifically reinforced by the

Supreme Court’s decision in Central Hudson Under that case, government

restrictions on misleading commercialspeech are not subject to the rigors ofthe second, third, and fourth prongs

of the Central Hudson test The

prohi-bition of misleading labeling is the jective of many of the specific labelingrequirements of the FFDCA, as well asthe basis for most FDA regulation ofvoluntary labeling statements

ob-If a statement, picture, or otherrepresentation on the label or labeling

of any food product is false or leading, the food is misbranded re-gardless of the importance of the rep-resentation to the consumer The Su-preme Court has held that it is notnecessary to show that anyone was ac-tually misled or deceived, or that therewas any intent to deceive, in order tofind that a product is misbranded un-

mis-der the FFDCA [United States v 95 Barrels-Cider Vinegar, 265 US 438

(1924)] Other courts have stated thatthe test is not the effect of the label on

a “reasonable consumer” but on “theignorant, the unthinking, and the cred-

ulous” consumer [United States v An Article of Food ‘Manischewitz Diet Thins’, 377 F.Supp 746 (1974)].

The prohibition on false or leading labeling statements reaches farbeyond patently false claims State-ments that, while not false, are mis-leading are also prohibited For exam-ple, a “cholesterol-free” claim forbroccoli suggests that particular broc-coli is cholesterol-free, while ordinarybroccoli is not cholesterol-free Thus,the claim is misleading, since ordinarybroccoli does not contain cholesterol

mis-To reinforce this interpretation, theFFDCA explicitly prohibits a claimthat states the absence of a nutrientunless the nutrient is usually present

in the food [21 USC §343(r)(2)(A)(ii)(I)] To avoid being misleading,FDA permits the claim “broccoli, acholesterol-free food,” but not “choles-terol-free broccoli” [21 CFR §101.13(e)(2)]

Just as labeling statements may bemisleading because of what they say orimply, they may be misleading by vir-tue of what they do not say In deter-mining whether a food labeling state-ment is misleading, FDA and thecourts take into account the extent towhich the labeling fails to reveal anymaterial facts [21 USC §321(n)].There is neither a statutory nor a reg-

ulatory definition of “material fact,”

and the term has not been elaborately

defined by the courts Instead,

deter-minations of whether or not a fact is

material are made on a case-by-case

basis, with an extensive body of

prece-dents

Generally, if a new or modified

food is significantly different from its

conventional counterpart in

composi-tion, nutritional value, or safety, the

difference in the food would be

con-sidered a material fact For example, if

a new processing technique resulted in

a significant decrease in the nutrient

content or change in flavor, color, or

other valued characteristic of a food, a

label statement would be required to

inform consumers of that material

fact Absent a label statement

disclos-ing a material fact about a food, the

presentation of the food would be

misleading So the FFDCA prohibition

on false or misleading labeling may

ef-fectively require that a label include a

disclosure of the material fact

While some FDA disclosure

re-quirements are imposed to provide for

safe use of food ingredients [e.g., 21

CFR §172.804, “Phenylketonurics:

contains phenylalanine,” and 21 USC

§343(o) regarding saccharin

ings] or to provide consumer

warn-ings, many disclosure requirements

are imposed to clarify or explain an

otherwise misleading label statement

For example, FDA decided that a

state-ment of the percent reduction is

nec-essary to clarify a claim like “reduced

fat” [21 CFR §101.13(j)(2)] The

agen-cy determined that consumers would

likely be confused unless the

magni-tude of the reduction was specified

· Federal Trade Commission

Re-quirements FTC regulates food

adver-tising under the Federal Trade

Com-mission Act (FTCA) [15 USC

§§41-58], which is similar in structure to

the FFDCA The FTCA generally

pro-hibits “deceptive acts or practices in

commerce” [15 USC §45(a)(1)] It

prohibits false advertising that is likely

to induce the purchase of foods, and

declares such false advertising to be

prohibited as “deceptive acts or

be substantiated, and whether there is

a reasonable basis for the claims made

in the advertising

In the past, FTC has issued forcement policy statements statingthat it will defer to FDA regarding theenforcement of certain kinds of foodadvertising, e.g., the use of healthclaims and nutrient content claims(FTC, 1994) FTC has not yet elaborat-

en-ed on how it plans to enforce ing regarding rDNA biotechnology-derived foods, so it is not clear wheth-

advertis-er and to what extent FTC might low any FDA policy that is issued withrespect to rDNA biotechnology-de-rived foods

fol-Labeling Case Studies

In evaluating the labeling work for rDNA biotechnology-derivedfoods, consideration should be given

frame-to at least three analogous situations:

irradiated foods, milk from treated cows, and organic foods

rBST-· Food Irradiation Irradiation is

defined by statute as a food additive,the only process that is so defined Itentails the treatment of a food with anFDA-approved energy source that killsbacteria or pests, prevents sprouting

of root vegetables, or extends shelf life

in some foods

Irradiation is an example of a cess that triggers a label disclosure re-quirement because FDA determinedthat irradiation can render food mate-rially different organoleptically, e.g.,taste, smell, and texture (Althoughthe scientific information available to-day might support a different agencyconclusion, that view is not relevant inthe context of this case study.) There-fore, FDA determined by regulationthat the fact that a food is irradiated ismaterial, justifying the labeling re-quirement of a logo and a phrase such

pro-as “treated with irradiation” [21 CFR

§179.26(c); FDA (1986)]

Despite some limited studies cating good consumer acceptance ofirradiated food, food processors gen-

indi-erally took a conservative position inadoption of the technology They con-cluded that irradiated products withthe mandatory labeling would beavoided by consumers and could re-sult in loss of sales, bad publicity, andloss of investment Other factors thatmay have inhibited use of irradiationare opposition by some activistgroups, low-volume demand, overallcost of operation, high capital invest-ment, technical expertise needed byworkers, limited availability of suit-able packaging, slow equipment devel-opment, and large sums of money al-ready invested in alternative technolo-gies Nonetheless, there is considerableevidence that the irradiation labelingrequirement slowed the food indus-try’s adoption of this technology.Today, there are several recent ex-amples where consumers have pre-ferred an irradiated product to thetraditional nonirradiated product.One example is strawberries, where ir-radiation extends the shelf life of theraw fruit Recent concerns about mi-crobiological safety of foods havedrawn the public’s attention to the po-tential benefits of irradiation process-ing As a result, some food processorsare again considering further utiliza-tion of this technology

In summary, FDA determined thatthe process of irradiation caused food

to differ significantly from its tional counterpart, thus making irra-diation of food a material fact thatmust be disclosed The irradiation la-bel disclosure requirements have beencited as at least one significant factorinhibiting the use of this pathogen-re-ducing technology

conven-· Milk from rBST-Treated Cows In

the early 1990s, FDA approved ment of dairy cows with recombinantbovine somatotropin (rBST), an rDNAbiotechnology-derived version of anaturally occurring hormone that in-creases a cow’s milk production FDAdetermined that milk produced bycows treated with rBST was not signif-icantly different from conventionalmilk Nonetheless, significant contro-versy accompanied the introduction ofrBST into the marketplace Somemanufacturers attempted to addressconsumer interest in avoiding milkfrom rBST-treated cows by labelingmilk products as “rBST-free.” FDA dis-couraged “rBST-free” claims becausethey implied that there is some com-

treat-27EXPERT REPORT ON BIOTECHNOLOGY AND FOODS

positional difference, such as the

pres-ence of rBST, between milk from

treated and untreated cows Rather,

FDA encouraged the use of claims that

address the production procedure

rather than the product So FDA

an-nounced that an appropriate way to

phrase such an acceptable claim would

be, “from cows not treated with rBST,”

as long as the statement also provided

a context that did not imply a

differ-ence between the milks FDA’s example

was to include with the claim the

statement, “No significant difference

has been shown between milk derived

from rBST-treated and

non-rBST-treated cows” (FDA, 1994)

The controversy over introduction

of rBST was most pronounced in New

England states where it was seen as a

threat to the economic viability of the

region’s small dairies The state of

Ver-mont enacted a law requiring that

milk from cows treated with rBST bear

a mandatory label disclosure The

constitutionality of this state labeling

requirement was challenged in

Inter-national Dairy Foods Association v.

Amestoy [92 F.3d 67 (2d Cir 1996)].

Vermont sought to justify its law on

the basis of the consumer’s right to

know, not on health or safety

con-cerns However, the U.S Court of

Ap-peals for the Second Circuit stated

that Vermont’s limited justification

was understandable, as “the already

extensive record in the case contains

no scientific evidence from which an

objective observer could conclude that

rBST has any impact on dairy

prod-ucts.” The Second Circuit applied the

Central Hudson test for permissible

commercial speech regulation,

con-cluding that “consumer curiosity

alone is not a strong enough state

in-terest to sustain the compulsion of

even an accurate, factual statement.”

Thus, without a material fact that

distinguishes the characteristics of

milk from rBST-treated cows from

other milk, there was not a

“substan-tial government interest” to justify the

labeling requirement As a result,

Ver-mont’s disclosure requirement was

unconstitutional Voluntary label

statements are required to meet the

FFDCA’s “truthful and

nonmislead-ing” standard So voluntary label

statements could only be made in a

manner that did not mislead

consum-ers about the milk product on which

the claim appeared or the

convention-ally produced milk to which it was ing compared

be-· Organic Foods The term

“organ-ic” has been used to describe foodsgrown without certain modern farm-ing practices that some consumersfind objectionable The organic foodmovement began using statementsconcerning the production of foodswithout the use of certain types ofcommercial pesticides and fertilizers

The focus of the organic movementhas expanded and centered on the so-cietal goals of some citizens, including

a reduction in the usage of

agricultur-al chemicagricultur-als, a heagricultur-althier environment,more humane treatment of animals,greater worker safety, and enhancedfood safety The movement establishedproduction criteria that not only per-tained to conditions for growing cropsbut also for labeling and distribution

of such foods The organic movementoriginally enlisted several state gov-ernments to recognize or adopt docu-mentation and inspection programsdesigned to demonstrate compliancewith these criteria In some cases, ithas become necessary to provide sepa-rate production and distribution sys-tems for organic and non-organicfoods

To date, scientific evidence doesnot demonstrate that organic foodshave superior nutritional or food safe-

ty benefits over non-organic foods

Therefore, FDA has deemed someclaims on organic foods misleadingwhen the term “organic” has been used

in a manner that implied that the ganic food is somehow superior to asimilar non-organic food

or-In 1990, with the vigorous support

of the organic food movement, gress passed the Organic Food Pro-duction Act [7 USC §§6501-6522]

Con-which required USDA to develop tional organic standards and establish

na-an orgna-anic certification programbased on recommendations from anexpert panel On March 13, 2000,USDA announced its National Organ-

ic Program (NOP), a comprehensiveproposed rule that would set uniformnational standards (USDA, 2000) US-DA’s goal is to issue a final NOP rule

by the end of 2000 These regulationsare intended to further establish amarket for a niche category of “organ-ic” foods desired by consumers Underthe proposed rule, every farm or otherorganic operation would have to de-

velop and carry out an “organic plan”that would be approved and certified

by a USDA-accredited agent The NOPwould include a “National List” thatsets forth which chemical substancesare permitted for use in organic pro-duction

The NOP also would create threecategories of permissible label claims,each with its own criteria: “100 per-cent organic”; “organic”; and “madewith organic (specified ingredients).”Products labeled “100 percent organ-ic” would have to be all organic prod-uct; products bearing the “organic” la-bel would have to contain not lessthan 95% organically produced prod-uct; and products labeled “made withorganic (specified ingredients)” wouldhave to contain at least 50% organicingredients Any of the three labelclaims could be used, in accordancewith requirements set forth in the reg-ulations; e.g., all would have to bearthe seal or logo of the certifying agent,anywhere on the package and on anyother labeling or market informationabout the product

With the exception of products beled “100 percent organic,” the listingfor each organic ingredient wouldhave to be qualified with the term “or-ganic” in the ingredients statement.Products labeled “made with organic(specified ingredients)” would be sub-ject to labeling limitations (e.g., maxi-mum type size, no more than three or-ganic ingredients may be listed), and,unlike products labeled “100 percentorganic” or “organic,” would not be al-lowed to bear the USDA Organic Seal

la-In addition to the above categories,

in order for products containing lessthan 50% organic ingredients to usethe term “organic,” the label wouldhave to declare the total percentage oforganic ingredients on the informa-tion panel (the label panel that typi-cally includes nutrition information,the ingredients statement, and similarinformation) and qualify each organicingredient with the term “organic” inthe ingredients statement The prod-uct would not be allowed to use “or-ganic” anywhere else on the label or tobear the USDA Organic Seal or theseal or logo of any certifying agent.The proposed NOP rule is clearthat rDNA biotechnology-derived andirradiated foods are not considered

“organic.” Any product made withwhat the proposed rule terms “exclud-

ed methods” (which include the use of

rDNA biotechnology) could not be

la-beled as “organic.” USDA made this

decision based on “overwhelming

public opposition” to the use of rDNA

biotechnology in organic production

systems, even though the agency

ad-mitted “there is no current scientific

evidence that use of excluded methods

presents unacceptable risks to the

en-vironment or human health” (USDA,

2000)

Thus, it may be possible for

con-sumers wishing to avoid rDNA

bio-technology-derived foods to purchase

foods bearing one of the three

“organ-ic” label claims on the principal

dis-play panel With organic products a

rapidly growing percentage of the

market—organic food sales in the U.S

have risen dramatically, from $78

mil-lion in 1980 to an estimated $6 bilmil-lion

in 2000, and projected annual growth

is approximately 20%—organic foods

appear to be a readily available option

for consumers who wish to avoid

rDNA biotechnology-derived foods

The labeling of organic foods is an

example of a voluntary program that

focuses on production differences that

are of significant consumer interest,

even though they do not render foods

materially different from their

conven-tional counterparts Under the

consti-tutional restrictions described above,

such distinctions may not be

ad-dressed through

government-mandat-ed disclosures, but may be freely

de-scribed through voluntary label

state-ments To avoid confusion regarding

the meaning of terms and to clarify

rules in a manner that helps organic

food processors and marketers avoid

making misleading claims, Congress

actively monitored USDA’s

develop-ment of standards Improved clarity of

labeling terms and greater efficiency

associated with higher product

vol-umes appear to be facilitating growth

in organic foods

Summary

In summary, the FFDCA works

within the constitutional framework

to address the so-called “consumer’s

right to know” or, more accurately,right to be informed of significant ormaterial facts about their foods Thisright is addressed through a corre-sponding duty for food marketers tolabel foods in a truthful, nonmislead-ing manner, including the disclosure

of fundamental descriptive tion about the food The correspond-ing right to be informed and duty todisclose concerns all material facts re-garding the food product, such as thefact that a food has been irradiated(because of FDA’s conclusion thatthere are organoleptic changes in foodtreated by irradiation) However, notall facts are material As the VermontrBST labeling litigation demonstrates,

informa-a finforma-act thinforma-at does not render informa-a food nificantly different from its conven-tional counterpart is not material andtherefore is insufficient to give rise toinformational rights and duties

sig-Nonetheless, there may be sive consumer interest in such infor-mation As the organic foods experi-ence demonstrates, when marketplaceinterest is sufficient, consumer infor-mation desires are served by the estab-lishment of voluntary disclosure pro-grams where necessary, with certainlimitations and authorized label state-ments These voluntary programs andlabeling provisions have been used toachieve advantage in a competitivemarketplace Thus, the food labelingregulatory regime provides a graduat-

exten-ed series of requirements to addressconsumer information rights and de-sires in a truthful, nonmisleadingmanner

Labeling of rDNA Biotechnology-Derived

Foods

U.S Policies

FDA has not established special beling requirements for foods derivedusing rDNA biotechnology Yet, thegeneral framework of food labelingregulation provides a series of food la-beling requirements for rDNA bio-technology-derived foods

la-· Mandatory Disclosures As

ex-plained above, constitutional

re-strictions specified in Central son and the FFDCA prohibition of

Hud-labeling that is misleading by virtue

of omission of a material fact areimportant factors regarding manda-

tory label disclosures

Labeling requirements that apply

to foods in general also apply to foodsderived using rDNA biotechnology Aspreviously noted, to avoid a mislead-ing presentation of the food, the labelmust reveal all material facts In devel-oping its labeling policy for rDNAbiotechnology-derived foods, FDAconsidered public comments and sci-entific evidence regarding the presence

of material facts about such foods.FDA concluded that rDNA biotech-nology-derived foods do not differmaterially as a class of food from con-ventional foods On the other hand,individual rDNA biotechnology-de-rived foods may or may not be signifi-cantly different from their conven-tional counterparts

FDA requires labeling of specificrDNA biotechnology-derived foodsthat differ significantly in composi-tion, nutritional value, or safety fromtheir conventional counterparts (FDA,1992) Thus, if a food derived usingrDNA biotechnology differs from itsconventional counterpart such thatthe common or usual name no longeradequately describes the new food, thename must be changed or qualified todescribe the difference If a safety orusage issue exists for the new food, astatement must be made on the label

to describe the issue For example, if afood derived using rDNA biotechnolo-

gy has significantly different tional properties, its name must reflectthe difference (e.g., “high oil corn”).Likewise, if a new food includes an al-lergen that consumers would not ex-pect based on the name of the food,the presence of that allergen must bestated on the label (e.g., the hypotheti-cal use of a peanut protein in a toma-to)

nutri-Some have advocated that themandatory labeling requirementsreach beyond disclosure of materialfacts regarding the food They haveurged a blanket requirement for dis-closure when a food is derived usingrDNA biotechnology In developing its

1992 labeling policy (FDA, 1992), FDAconsidered public comments and allavailable scientific evidence in connec-tion with a possible blanket rDNAbiotechnology disclosure requirement.FDA rejected such a blanket require-ment because it was “not aware of anyinformation showing that [rDNA bio-technology-derived foods] differ from

Biotechnology

Report: Labeling