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6-Regulation: On the Codex guidelines for GM foods

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TITLE:  Codex guidelines for GM foods include the analysis of unintended
SOURCE: Nature Biotechnology 21 (7): 739-741, by Alexander G Haslberger
DATE:   Jul 2003

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Codex guidelines for GM foods include the analysis of unintended effects

The author is at the University of Vienna and the World Health
Organization FOS Program for Food Safety, Geneva, Switzerland. e-mail:

In response to the increased delivery of genetically modified (GM) foods
to international markets, the Ad Hoc Intergovernmental Task Force on Food
Derived from Biotechnology of the Codex Alimentarius Commission (Rome)
agreed in March on principles for the human health risk analysis of GM
foods1. These principles dictate a case-by-case premarket assessment that
includes an evaluation of both direct and unintended effects. They state
that safety assessment of GM foods needs to investigate direct health
effects (toxicity), tendency to provoke allergic reactions
(allergenicity), specific components thought to have nutritional or toxic
properties, the stability of the inserted gene, nutritional effects
associated with genetic modification and any unintended effects that
could result from the gene insertion. Of particular note, the task force
broadens risk assessment to encompass not only health-related effects of
the food itself, but also the indirect effects of food on human health
(e.g., potential health risks derived from outcrossing).

Unintended effects of the product The Codex's aim is to anticipate not
only the direct risks, but also the indirect/unanticipated risks that the
products of modern agriculture might pose for human health. All of the
methods used for breeding or manipulating plant traits, including self-
and cross-pollination, the generation of hybrids or haploid breeding,
mutational breeding (including X-rays or chemicals) and advanced
biotechnologies (including protoplast fusion and/or recombinant DNA
technology), have the potential to generate unanticipated effects in plants.

In conventional breeding programs of spring barley, for example,
different degrees of a temporary breakdown of the resistance to powdery
mildew by a sudden relief of soil water-stress have been attributed to
the genetic background rather than the specific allele2. There have also
been reports that a traditionally bred squash caused food poisoning3, a
pest-resistant celery variety produced rashes in agricultural workers
(which was subsequently found to contain sevenfold more carcinogenic
psoralens than control celery4) and a potato variety Lenape contained
very high levels of toxic solanine5 (which was subsequently withdrawn
from cultivation).

The use of tissue culture in plant breeding has also often resulted in
somaclonal variation of plant lines and irregular phenotypes or field
performance. Somaclonal variations are mutational and chromosomal
instabilities of embryonic plants regenerated from tissue cultures. These
instabilities may result from activation of dormant transposons in the
chromosome6. The consequent genetic variability is known to persist for
many generations and is difficult to eliminate by backcrossing.

For plants generated by recombinant technology, unanticipated effects may
additionally arise from the process of introducing foreign genes or as a
result of the effects of environmental factors/genetic background on the
expression of the transgene(s)7.

Complex multicopy patterns of transgene integration at the same locus, as
well as position effects caused by random integration, are often
associated with instability in transgene expression8. Random insertion of
DNA sequences can cause modification, interruption or silencing of
existing genes as well as activation of silent genes9, 10. Safety aspects
have been discussed for a transgenic maize line following the observation
of integration of recombinant DNA into a retrotransposon11, 12.

Table 1 list examples of unanticipated phenotypes observed in transgenic
crops in the field. A comparison of data from documents prepared for
notification of GM rape, maize, tomato, soybean and potatoes (exhibiting
mainly pest resistances) suggested that environmental factors like heat
were more important than genetic modification in influencing variation in
the expression of antinutrients13. Epigenetic transcriptional silencing
has been reported for a complex transgene in rice14 and epigenetic
variations in Arabidopsis disease resistance have been attributed to DNA
methylation15. Environmental stress factors that influence methylation
patterns and/or chromatin conformations have been suggested as
explanations for gene silencing of transgenes in the field16. The
presence of a pathogen can induce host defense gene silencing
mechanisms17 also affecting transgenes. And environmental signals have
been shown to modulate mRNA stability and translation through modulation
of the phosphorylation of components of the mRNA 5'-cap-binding complex,
ribosomes and mRNA-binding proteins18.

Unintended effects mediated via the environment In addition to
investigating health risks directly associated with food products, the
broadening of the Codex risk assessment to include indirect effects now
encompass effects of novel foods on the environment that may have an
indirect impact on human health. This concept has a precedent in
agricultural practice (e.g., sustainability19) and embraces the view of
human "health as an integrating index of ecological and social
sustainability" outlined in a report from a joint World Health
Organization (Geneva, Switzerland) and the National Agency for the
Protection of the Environment (Rome, Italy) seminar in 2000 on potential
environmental hazards of GM crops20.

Several recent findings argue that such environmental effects could/
should be supported by evidence (e.g., the need to inhibit outcrossing
from plants containing biopharmaceuticals;
paper/05-Rainer%20Fischer.doc) in health risk assessment of GM crops. The
introgression of transgenic DNA into traditional landraces of maize in
Mexico (for review, see ref. 21), recently confirmed by the Mexican
government22, shows that gene flow may be commonplace for certain crops
in certain locations, and the effects of foreign genes in certain
backgrounds could pose health risks, although these concerns remain
speculative23. The risk of outcrossing and gene transfer could also
affect crop biodiversity, especially that of landraces, and may
compromise the planting of crops by farmers who wish to remain GM-free
(e.g., organic farmers). Indeed, the coexistence of GM crop agriculture
and organic agriculture (which does not tolerate GM use above specific
thresholds) is likely to be difficult for certain plants in specific
areas24. As a consequence, the wish for regions with restrictions on
planting of GM organisms (GMOs) and GMO-free foods has already been
expressed in different areas25, 26.

Conclusions Both conventional methods of breeding and recombinant
technology can affect the expression of genes and raise questions about
food safety. Phenotypic variability in a novel crop can also result from
environmental/epigenetic factors as well as the genetic background in
which a trait is expressed. Clearly, risk assessment must account for the
effects of transgene-specific factors, environmental signals and genetic
background on phenotype. The expression level of a gene, rather than the
sequence of the protein product, can often determine phenotypes that
contribute to natural variation27.

In any risk assessment, however, it is important to differentiate between
hypothetical and proven risks. And, to date, no food-derived health
problems have been identified with the use of GM plants. However, it must
be acknowledged that occasional pleiotropic, unintended safety relevant
effects in organisms produced with traditional or modern biotechnology
can occur and need to be addressed.

The decision by the Codex to include unintended effects (e.g.,
environmental health risks) in the risk assessment is an important new
development. The link between environment and human health operates
through the exposure of humans to environmental hazards, where such
hazards may take many forms, wholly natural in origin or derived from
human activities and interventions. There have been several attempts to
conceptualize environmental-human health interactions28, 29. Indicators
for environmental health and methods for the consideration of the burden
of disease from environmental risk factors are presently harmonized to
support and monitor policy on environment and health for many
developments30, 31. These concepts may be useful in the analyses of
effects of GM organisms for food production. Such assessments need to
compare different approaches to food production, such as conventional,
organic or GM technologies, and may also prove valuable in assessing
regional differences (health relevant decreases or increases of pesticide
use according to local agroecological situation) in the impacts of modern
methods of food production.

The Codex's approach to GM crops will be inherently linked to agreements
at the World Trade Organization (Geneva, Switzerland). Codex principles
do not have a binding effect on national legislation, but are referred to
specifically in the Sanitary and Phytosanitary Agreement of the World
Trade Organization (SPS Agreement), and can be used as a reference in
case of trade disputes. This has particular relevance in the light of the
recent complaint brought by the United States, Canada and Argentina to
the WTO against the EU de facto moratorium on GM crops.


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