ISIS Reply to Questionnaire Codex Guideline GMOS

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Reply to Questionnaire Codex Guideline for the Conduct of

Food Safety Assessment of Foods Derived from Recombinant-DNA Plants

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Mon, 19 Dec 2005 16:09:04 +0000

 

 

 

 

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ISIS Press Release 19/12/05

 

Reply to Questionnaire Codex Guideline for the Conduct of

Food Safety Assessment of Foods Derived from Recombinant-DNA

Plants

 

 

Professor Joe Cummins

 

 

 

Dr. Mae-Wan Ho

 

 

 

For Independent Science Panel*

 

 

 

 

Question # 1: In your view, what would be important factors

in determining if a recombinant-DNA plant is to be

considered a A Recombinant-DNA Plant Modified for

Nutritional or Health Benefit@, and as such within the scope

of the proposed annex?

 

 

 

Answer: First, it is essential to exclude the evaluation of

pharmaceutical products such as oral vaccines, immune

modulating proteins, hormones, antimicrobials and growth

factors from the present considerations. Such products

should be considered separately and reviewed independently

from the current annex; they are inherently hazardous and

require special consideration under a separate annex.

 

 

 

Plants modified for nutritional or health benefit should

include only those with enhanced vitamins, minerals,

antioxidants (for example plant phenolics (flavonoids) known

to fight cancer) and enhanced primary metabolites such as

essential amino acids and health promoting reduced linolenic

fats. Recombinant genes derived from a plant used to modify

another plant species should not automatically be deemed

safe for humans. This is highlighted in a recent

investigation in which a protein from bean was found

immunogenic when expressed in pea [1]. Specifically,

immunological assessments carried out for the first time on

a transgenic protein revealed that post-translational

processing subsequent to gene transfer into an alien species

introduced new antigenicities that turned a previously

harmless protein into a strong immunogen. In addition, the

transgenic protein promoted immune reactions against

multiple other proteins in the diet.

 

 

 

As practically all the transgenic proteins involve cross-

species gene transfer, they will be subjected to different

post-translational processing, and hence they too, will have

the potential to become immunogenic. And yet, none of the

transgenic proteins that have been commercially approved has

been tested. This omission is a most serious public health

issue, and the Independent Science Panel has already called

for an immediate ban on all GM food and feed until proper

assessment on the immunogenicity of the transgenic proteins

has been carried out [2]. This should apply all the more so

to GM crops coming to the market that are meant for human

consumption.

 

 

 

Nutritional enhancement and traits for improved health may

be developed using conventional breeding or marker assisted

selection then those traits combined with recombinant traits

such as herbicide tolerance and/or insect resistance.

Monsanto's Vistive soybean, for example, combines natural

genes reducing the oil content of linolenic acid, but also

has transgenes conferring the Roundup Ready trait. The

transgene activity is known to affect the precursor pools

leading to formation of trans fatty acids [3]. The point is

that when nutritional or health traits are combined with

transgenic ones, the interaction of the two should be fully

evaluated. Interactions between transgenic nutrition and

health traits and other genetic modifications within a

cultivar should be carefully evaluated, as should

interactions between conventional nutritional or health

traits with transgenes in recombinant strains with which

they are combined.

 

 

 

A number of nutritional- and health-related transgenic

plants are being developed (see Box). We must ask if these

developments provide real benefits for people, and whether

there are safer, cheaper and more effective alternatives for

producing the nutritional/health benefit. More importantly,

in every single case, it is necessary to assess the GM

plant, the transgene and protein for toxicity and

immunogenicity, for reasons given above.

 

 

 

Nutritional and health-related GM crops under development

 

 

 

· Cassava is being genetically modified to enhance activity

of an enzyme that destroys the toxic cyanogenic glycosides

[4]. But these compounds, which release cyanide when eaten,

are normally destroyed if the cassava is adequately

processed.

 

 

 

· A sweet protein, brazzien, was produced in GM maize by

introducing a gene from an African plant. The sweetener was

proposed for use in the food industry [5].

 

 

 

· A synthetic gene for porcine alpha-lactalbumin was

introduced into maize along with a signal peptide from maize

for localizing the protein to the endoplasmic reticulum. The

pig-corn was supposed to provide a more digestible plant

protein for humans [6].

 

 

 

· Human milk proteins genes were used to modify maize,

supposed to improve human nutrition [7].

 

 

 

· Enhanced seed phytoesterol was achieved by transferring a

gene from the rubber tree to tobacco [8]. The compounds

would be used as cholesterol-lowering foods when food crops

are modified.

 

 

 

· Canola was modified as a source of omega-3 fatty acid

using fungal genes [9].

 

 

 

· Very long fatty acids were produced in Arabidopsis using

genes from a tiny alga, a protozoa and a fungus [10].

 

 

 

· Soybean naturally deficient in methionine is being

engineering to remedy the amino acid deficiency in free

amino acids and in storage proteins [11].

 

 

 

· Soybean was modified with a gene from maize, delta-zein,

which is rich in methionine [12].

 

 

 

· Maize was modified with a bacterial gene that provided

increased free lysine in cellular pools [13].

 

 

 

· A grape stilbene synthetase was used to modify tomato to

reduce lipid peroxidation [14].

 

 

 

· Maize modified with prentyltransferase from barley seeds

resulted in a large increase in vitamin E [15].

 

 

 

· Golden rice expresses a daffodil gene to increase beta-

carotene, which is then converted to vitamin A. This

modification has now been extended to Indica rice [16]. The

golden rice cultivars do not produce sufficient beta-

carotene to fulfill the human requirement for vitamin A,

however.

 

 

 

· Fructans are considered important functional foods because

they promote the growth of beneficial intestinal bacteria.

Fructans enhance mineral re-sorption, decrease cholesterol

and hence may help prevent cardiovascular disease, colon

cancer and osteoporosis. Onion fructosyl transferase was

used to modify sugar beet, a crop that does not normally

produce fructans [17].

 

 

 

· Deficiencies of iron and zinc in food crops are

widespread, and approaches to increasing trace element

uptake or increasing trace element absorption were reviewed

including genetic modification [18]. A technique called ion

genomics has been developed to elucidate all of the genes

involved in mineral nutrition in plants [19]. Iron was

fortified in rice seeds by modifying the iron in the seeds

using soybean ferritin gene expressed in the seed endosperm

[20]. Some plant species can utilize zinc from zinc

deficient soils, this ability has been studied to find out

whether or not it can be transferred food crops suffering

from deficiency [21]. A polyhistidine sequence was fused to

a rubisco sub-unit by plastid transformation of tobacco. The

polyhistidine sequence specifically binds zinc, which

accumulates at low zinc levels in the culture medium [22].

The approach may be applied to food crops.

 

 

 

 

Question #2: In order to assist with the identification of

additional safety and nutritional considerations that the

assessment of recombinant-DNA plants modified for

nutritional or health benefit may warrant, please consider

the elements listed below and for each of them provide

comments on the need, added value and relevance of

addressing such items given the intent of the modification

introduced in such recombinant-DNA plants.

 

 

 

a) Estimation of potential exposure distribution patterns -

how to go about determining potential exposure distribution

patterns in both target and non-target populations of a

country and evaluate the safety of such exposure in

vulnerable groups. Techniques are available using

population dietary intake data that permit modelling of

usual intakes through simulated inclusion of the modified

food in exchange for foods reported to be used the dietary

survey. In this regard, lessons can be learned from

modeling of potential intakes resulting from vitamin and

mineral addition to foods;

 

 

 

Answer: Modeling is appropriate but there is no substitute

for controlled trials and investigations, first in animals,

and then in consenting, informed humans. It is essential

that the GM foods be clearly labelled in the marketplace to

provide a means of identifying the GM foods in

epidemiological studies as part of post-release monitoring

and risk management.

 

 

 

b) Bioavailability - when bioavailability testing would be

advisable and some considerations of the techniques

available for determining bioavailability of various types

of substances;

 

 

 

Answer: Bioavailability should be incorporated into

regulatory reviews of all of the modified plants purporting

to enhance nutrition or health. Bioavailability can be

studied using radioactively labeled tracers of the compounds

or elements being studied. Gut cell cultures have been

employed in such studies; approaches to studying

bioavailability of nutrients have been reviewed [23].

 

 

 

c) Upper limits of safe intake - the need to determine upper

limits of safe intake for the nutrient or bioactive

substance, if they are not already defined, and how to

assess the level of exposure according to population sub-

group of the substance or substances in question against

those upper limits;

 

 

 

Answer: Upper limits of elements such as iron are essential

because iron overload in males leads to a condition called

hemochromatosis, resulting in liver dysfunction and cancer.

Vitamin A toxicity is linked to birth defects and toxic side

effects in adults. Genetic modification to provide for

deficiency in some geographic areas may therefore create

toxic side effects in areas where the diet for the nutrients

is adequate. The supplemented crops must be clearly

identified and efforts taken to prevent their use without

informed consent.

 

 

 

Upper limits for novel supplements such as human milk

protein in maize or pig lactalbumin in maize clearly require

full testing. Full tests for immunogenicity and toxicity

must be carried out on all novel proteins, as stated above.

 

 

 

Safe upper limits of ingestion should be established using

pure nutrients or enzymes and the final foodstuffs, first in

animals then in human volunteers.

 

 

 

d) Stability - what is involved in stability testing, and

why that is a component of risk assessment;

 

 

 

Answer: Stability of primary nutrients such as vitamins and

minerals are well established, however the stability of

novel proteins such as the enzymes introduced into the

modified crop should be undertaken because the novel

products may create unexpected toxic by-products. The

behavior of these products during food processing and

storage must be studied, and altered products should be

subject to toxicity testing.

 

 

 

e) Risk/benefit consideration - what consideration should be

given to the benefit intended to be provided by the modified

food in drawing conclusions from the risk assessment.

Benefits may accrue to certain target groups while at the

same time, health risks may be a concern for others, but

also there may be benefits at lower intakes and adverse

effects at higher intakes. Additionally, how strong the

evidence is for the benefits compared to potential adverse

effects may need to be assessed in these circumstances;

 

 

 

Answer: The precautionary principle must prevail in every

case. Consideration must be given as to whether the benefit

really exists, and whether cheaper, safer alternatives

exist, given the known risks of genetic modification.

 

 

 

f) Animal feeding studies - when should animal feeding

studies be considered and what types of studies might be

useful depending on the question;

 

 

 

Answer: Animal studies should be undertaken with every

modified crop or in crosses between modified crops and

crops bearing genes for nutrients or health products that

have been enhanced using conventional breeding or marker

assisted breeding. It has become common practice to used

crude measures of size to evaluate the outcome of feeding

experiments. That is not acceptable. Full tissue and organ

necropsy is required in every case to detect cell damage and

to identify pre-cancerous lesions. In addition, immunogenic

and toxicity tests must also be carried out.

 

 

 

g) Study Design - the design and conduct of studies to

obtain reliable, repeatable data on composition of the

modified food with respect to the intended and potential

unintended changes, at the appropriate stages of crop and

food production. In particular, whereas in evaluating

unintended effects comparative data in the raw product is

usually quite acceptable, where an intended change has been

introduced, there will need to be data on the variation in

tissue concentration relevant to the parts of the plant that

will be used for food production and data to show that the

content of the substance remains stable with time,

processing and storage. The impact of factors known to

affect crop composition from year to year and by

geographical location, soil type and fertility, etc. may

need special attention in the case of intended changes.

 

 

 

Answer: Common stress factors in crops such as water

deprivation or water logging, nitrogen deprivation or over

use and temperature stress all contribute markedly to

nutritional value and health related products. We understand

that Codex has pointed to the need for evaluation of stress

in the approval of GM crops. Codex should work to formalize

the most significant stressors and to insure that those

significant stressors are evaluated correctly in the

approval of GM crops slated for the global market. It is

certainly clear that GM crops approved under optimum

environmental conditions cannot presume to be substantially

equivalent to GM crops produced under conditions of extreme

stress.

 

 

 

h) Any other considerations? Please specify.

 

 

 

Answer: Two major flaws are present in the regulation of GM

crops in North America. The first of these is secretive

field tests of GM crops prior to their commercialization.

Bystanders and residents near the test areas are provided

little or no information as to the nature of the crops being

tested. These individuals are exposed to pollen, plant

debris from broken and decayed plant material in dust and

from transgenic products in surface and ground water. The

other major flaw is that the GM food products are not

labelled in the marketplace and those suffering ill effects

from consuming the novel materials have no way of knowing

what has injured them. Proper epidemiology of human

exposures is impossible without labelling. GM nutrition and

health products must be labelled and details on field tests

must be revealed to the public in full.

 

 

 

 

*The Independent Science Panel, launched 10 May 2003 at a

public conference in London, UK, consists of dozens of

prominent scientists from 11 countries spanning the

disciplines of agroecology, agronomy, biomathematics,

botany, chemical medicine, ecology, epidemiology,

histopathology, microbial ecology, molecular genetics,

nutritional biochemistry, physiology, toxicology and

virology (http://www.indsp.org/ISPMembers.php)

 

 

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Foster PS, Higgins TJ and Hogan SP. Transgenic expression

of bean alpha-amylase inhibitor in peas results in altered

structure and immunogenicity. J Agric Food Chem. 2005 Nov

16, 53(23):9023-9030.

 

Ho MW. Transgenic pea that made mice ill. ISIS/ISP report,

27 November 2005.

 

Cummins J. Beware Monsanto's Vistive soybeans. ISIS Press

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Siritunga,D,Arias-Garzon,D,White,W. and Sayre,T. Over-

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Yang SH, Moran DL, Jia HW, Bicar EH, Lee M and Scott MP.

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