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Gene technology offers enormous potential benefits for world agriculture, including the possibility of producing higher yields of more nutritious food in more environmentally sustainable ways. It offers a powerful new tool to assist plant breeders to introduce resistance to insects and diseases, as well as traits for higher quality and nutritive value. Moreover, the next generation of genetically modified (GM) crop plants promises a significant impact on human health (eg, rice has been engineered with enhanced levels of vitamin A and iron to correct nutrient deficiencies common in the developing world, although more research is needed for a practical outcome).

The first commercial applications of gene technology in crop plants have involved modifying the plant for greater disease or insect resistance or a more efficient production system. Introduction of these GM crops has been extremely rapid, particularly in the United States. In 1996, transgenic crops covered 1.7 million hectares worldwide. By 1998, that area had increased 15-fold to almost 28 million hectares.³ In that year, the most common transgenic crops in the world were soybean and corn, with significant areas of cotton, canola and potato. There are now over 50 individual transgenic products, involving 13 separate crops. It has been predicted that, within 20 years, gene technology will touch every type of agricultural crop in the world, although this will depend on a high level of consumer acceptance.

In Australia, only one GM crop is currently grown commercially -- insect-resistant (INGARD) cotton. This is now entering its fourth commercial year and currently accounts for 30% of the Australian cotton crop. In the past three years, GM cotton has been sprayed with less than 50% of the insecticides used on the conventional crop -- a reduction of 1.5 million litres of spray per year.⁴

Although cotton is the only GM crop in Australia, the ready acceptance of GM crops by farmers in the US has resulted in about 50% of the soybean crop and 30% of the corn crop being genetically modified. This has relevance for Australia, as significant quantities of soybean are imported and used in processed food.

In dealing with the issue of safety of food and food products from GM plants, regulatory authorities in many parts of the world have relied on the principle of substantial equivalence. Substantial equivalence is established if food products are essentially the same in composition, nutritive value, functional characteristics and organoleptic properties (taste, smell, mouthfeel).

When it has been established that the food derived from a GM plant is substantially equivalent to that produced by the conventional crop, then the focus of testing becomes the introduced genes and their specific products. Alternatively, if a food derived from a GM plant differs from that produced by the conventional crop, then it must be assessed for food safety on a case-by-case basis. For example, transgenic rice with enhanced vitamin A would be considered a "new" food and assessed for safety accordingly.

The safety implications of new characteristics introduced into GM plants have been evaluated in much the same way as new food additive or agrochemical products such as pesticides (eg, in-vitro and animal-feeding trials). The company or institution applying for registration for use must provide a dossier describing safety tests performed in compliance with the protocols set by regulatory authorities. These data are rigorously assessed before regulatory approval is given. Examples include antibiotic-resistance genes, used as selectable "markers" during the development of the GM plant (Box 1). Herbicide-resistance genes can also be used as markers and give the plant an agronomic advantage. Both these introduced traits have caused considerable controversy, albeit for different reasons, and illustrate the type of assessment undertaken to establish confidence in their safety.

A concern about use of antibiotic resistance as a selectable marker is its potential to compromise the therapeutic use of antibiotics in humans and animals. The presence of the gene product in food or feed has been considered, as has the possible transfer of this resistance to gut and potentially hazardous microorganisms. Dröge et al clearly demonstrated that such transfer occurs, if at all, at extremely low frequency.⁶ Most, if not all, of the NPTII gene ingested will be degraded in the human stomach and small intestine. Moreover, the probability of gut microorganisms integrating this exogenous DNA and producing the NPTII protein is extremely low, particularly as the latter would require the bacterial DNA to be rearranged, with replacement of the plant promoter (the DNA sequence that allows RNA polymerase to bind) by a bacterial promoter. Even if the NPTII protein was produced, it would be expected to rapidly degrade, as shown by experiments under simulated gastric conditions.^7-9

Therefore, Kärenlampi, in his 1996 report to the Nordic Council (responsible for directing food policy issues in the five Nordic countries), concluded that the overall risk is effectively zero, and that the therapeutic use of antibiotics in humans or animals will not be affected by commercialisation of transgenic crops containing antibiotic-resistance selectable marker genes.⁵ Nevertheless, the Royal Society's report on GM plants, while conceding that risks were minimal, recommended that antibiotic-resistance marker genes no longer be used in GM food crops.¹⁰ Alternative systems to select for genetic modification are now available, and it is possible to delete the marker gene altogether in regeneration of some crops.

By far the largest area is planted to crops tolerant of the herbicide glyphosate (Roundup; Monsanto, St Louis, Mo), which is relatively non-toxic and readily deactivated and degraded in the soil. These crops contain a version of the herbicide target enzyme that was derived from bacteria and is naturally tolerant of the herbicide (Box 2). The target enzyme is present in all plant, microbial and fungal food sources and is therefore not novel to the food supply. A comprehensive series of scientific evaluations showed that the genetically modified version of the enzyme behaves like other versions and has no adverse safety effects.^4,11 Detailed analysis of nutrients and antinutrients, including fatty acids, amino acids, protein and micronutrients, in glyphosate-tolerant GM soybeans confirmed that they are substantially equivalent to conventional soybeans currently in commercial use.¹¹ Extensive testing of the bacteria-derived enzyme from GM soybeans established that, in simulated gastric and intestinal fluids, it is not toxic or allergenic and is rapidly digested.^4,12

Pusztai's experiments set out to investigate whether GM potatoes that contained a gene encoding snowdrop lectin (a plant protein with potential to increase insect and nematode resistance) affected the health and growth of rats to which they were fed. He concluded that the GM potatoes significantly affected the immune system of the rats, as a result of the genetic modification itself rather than of the particular gene that had been inserted. These claims were so serious and caused such public concern that the Royal Society set up a review of their implications for food safety. After examining all available information on the experiments, six independent reviewers with expertise in statistics, clinical trials, physiology, nutrition, quantitative genetics, growth and development, and immunology, prepared a report.¹³ This found that the Pusztai experiments were flawed in many aspects of design, execution and analysis, and that no conclusions could be drawn from them. The expert review group found no credible evidence of adverse effects from GM potatoes.

Recently, despite the objections of several referees,¹⁴ The Lancet published some of Pusztai and colleagues' experiments.¹⁵ While The Lancet undoubtedly felt this was justified to promote critical discussion of the data, no definitive conclusion can reasonably be drawn from the published results.

Perhaps because of the unfortunate circumstances surrounding the Pusztai experiments, doubts continue to be raised about the longer-term safety of GM foods. As pointed out above, the principle of substantial equivalence relies on comprehensive testing of the introduced new trait in terms of the gene construct and its product -- not testing the whole food which contains that product. As a general rule, food is not tested for safety, other than for contaminants. For example, a new wheat variety containing new genes for disease resistance produced by conventional breeding is considered identical -- substantially equivalent -- to its parent cultivars. Providing the flour produced from this new wheat variety is acceptable to millers and bakers and similar to flour produced from other wheat, it is accepted into the food chain without further food safety evaluation. Therefore, the products of GM crop plants currently in the food chain have been tested far more thoroughly than any conventional food.

While the present protocol through GMAC provides a satisfactory avenue for planned release of GM organisms to the "proof of concept" (precommercialisation) stage, the pathway to commercialisation is far less clear. To correct this deficiency, the Australian government recently allocated funding for the establishment of an Office of the Gene Technology Regulator (OGTR) to ensure an effective, enforceable system of regulation for the biotechnology industry. This office, currently known as the Interim OGTR, will develop an appropriate regulatory regime to cover the development, clearance and labelling of foods and food products derived from the new gene technologies. As such, it needs to meet the dual imperatives of providing consumers with confidence in the safety and regulation of gene technology products and of fostering an environment conducive to industry innovation and commercialisation. The Interim OGTR is currently seeking community views and comment on the Draft Gene Technology Bill 2000 (dated December 1999), which covers the regulation of all aspects of the research, development and use of GM organisms and their products, where no other body has responsibility.

The Government has also established a Senior Ministerial Council to manage biotechnology issues across the relevant portfolios of Health, Industry, Environment, Education and Agriculture, as well as a Commonwealth agency within the Department of Industry, Science and Resources, to be known as Biotechnology Australia, to coordinate the Commonwealth's activities in biotechnology.

It is clear that the new regulatory system must provide consumers with confidence that the necessary checks and balances are in place to ensure food derived from the new technology is safe and beneficial. Consumer education will remain a major factor in determining the acceptance of the new technology, and it is important that balanced information on the science of the risk and safety assessment of food derived from gene technology is made freely available to the community.

1. Larkin P, editor. Genes at work: biotechnology. Canberra: CSIRO, 1994.
2. Commonwealth Scientific and Industrial Research Organisation. <http://genetech.csiro.au>
3. James C. Global review of commercialised transgenic crops. ISAAA Brief No 8. Ithaca, NY: ISAAA, 1998.
4. Fitt GP, Wilson LJ. Genetic engineering in integrated pest management: case study -- Bt plants. In: Emerging technologies in integrated pest management. Sutton T, Kennedy GG, editors. St Paul, Minn: American Phytopathological Society Press. In press.
5. Kärenlampi S. Health effects of marker genes in genetically engineered food plants. Report to the Nordic Council Copenhagen: TemaNord, 1996: 530.
6. Dröge M, Pühler A, Selbitschka W. Horizontal gene transfer as a biosafety issue: A natural phenomenon of public concern. J Biotechnol 1998; 64: 75-90.
7. Redenbaugh K, Hialt W, Martineau B, et al. Aminoglycoside 3'-phosphotransferase II (APH (39) II or NPTII): Review of its safety and use in the production of gentically engineered plants. Food Biotechnol 1994; 8: 137-165.
8. Nap JP, Bijvoet J, Strikena WJ. Biosafety of kanamycin-resistant transgenic plants: an overview. Transgenic Crops 1992; 1: 239-249.
9. Fuchs RL, Ream JE, Hammond BG, et al. Safety assessment of the neomycin phosphotransferase II (NPTII) protein. Bio/Technology 1993; 11: 1543-1547.
10. The Royal Society. Statement 1998: genetically modified plants for food use. London: The Royal Society, 1998.
11. Padgette SR, Taylor NB, Nida DL, et al. The composition of glyphosate-tolerant soybean seeds is equivalent to conventional soybeans. J Nutr 1996; 126: 702-716.
12. Fuchs RL, Re DB, Rogers SG, et al. Safety evaluation of glyphosate-tolerant soybeans. In: Food safety evaluation. Paris: OECD, 1996: 61-70.
13. The Royal Society. Statement 1999: review of data on possible toxicity of GM potatoes. London: The Royal Society, 1999.
14. Horton R. Genetically modified foods: "absurd" concern or welcome dialogue [editorial]? Lancet 1999; 354: 1314-1315.
15. Ewen SWB, Pusztai A. Effect of diets containing genetically modified potatoes expressing Galanthus nivalis lectin on rat small intestine. Lancet 1999; 354: 1353-1354.

Reprints will not be available from the authors.
Correspondence: Ms P A Fitzgerald, CSIRO Plant Industry, GPO Box 1600, Canberra, ACT 2601.

©MJA 2000
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