《生物技术与人类》课程教学资源（经典阅读）Assessment of the safety of foods derived from genetically modified（GM）crops

ELSEVIER Food and Chemical Toxicology 42(2004)1047-1088 Po www.elsevier.com/locate/foodchemtox Assessment of the safety of foods derived from genetically modified (GM)crops A.Koniga*,A.Cockburnb,R.W.R.Crevele,E.Debruyned,R.Grafstroeme, U.Hammerlingf,I.Kimber,I.Knudsen,H.A.Kuiper',A.A.C.M.Peijnenburg', A.H.Penninks',M.Poulsen,M.Schauzuk,J.M.Wal Harvard Center for Risk Analysis,Harvard School of Public Health,Harvard University,718 Huntington Avenue,Boston,MA 02115.USA PScientific Affairs,Agricultural Sector,Monsanto Service International.Avenue de Tervuren 270-272,B-1150 Brussels,Belgium SEAC Toxicology Department,Unilever Research Colworth,Colworth House,Sharnbrook,Bedford MK44 ILO,UK Regulatory Toxicology,Herbicides and Biotechnology,Bayer CropScience,355 rue Dostoievski-BP 153.F-06903 Sophia Antipolis Cedex,France Institute of Environmental Medicine,Karolinska Institutet,Nobelsvag 13.Box 210,SE-17177 Stockholm,Sweden Swedish National Food Administration,PO Box 622.SE-751 Uppsala,Sweden ECentral Toxicology Laboratory,Syngenta UK,Alderley Park Macclesfield,Cheshire SK10 4TJ,UK hInstitute of Food Safety and Toxicology.Danish Veterinary and Food Administration.19 Moerkhoej Bygade.DK-2860 Soborg.Denmark RIKILT-Institute of Food Safety,Wageningen University Research Centre,Bornsesteeg 45,PO Box 230, NL-6700 AE Wageningen.The Netherlands iTNO Nutrition and Food Research.Utrechtseweg 48.NL-3700 AJ Zeist.The Netherlands kCentre for Novel Foods and Genetic Engineering,Federal Institute for Risk Assessment,Thielallee 88-92,D-14195 Berlin,Germany Service de Pharmacologie et d'Immunologie,Laboratoire Associe INRA-CEA d'Immuno-Allergie Alimentaire.CEA-SACLAY Batiment 136. F-91191 Gif-sur-Yvette,France Received 15 November 2003;accepted 4 February 2004 Abstract This paper provides guidance on how to assess the safety of foods derived from genetically modified crops(GM crops);it sum- marises conclusions and recommendations of Working Group I of the ENTRANSFOOD project.The paper provides an approach for adapting the test strategy to the characteristics of the modified crop and the introduced trait,and assessing potential unintended effects from the genetic modification.The proposed approach to safety assessment starts with the comparison of the new GM crop with a traditional counterpart that is generally accepted as safe based on a history of human food use (the concept of substantial Abbreviations:ADI,Acceptable Daily Intake;ADME,absorption,distribution,metabolism,and excretion;ALLERGEST,EU-project on the effect of gastrointestinal digestion on the allergenicity of foods;APHIS,Animal and Plant Health Inspection Service;Bt,Bacillus thuringiensis;cDNA, DNA complementary to an RNA strand:CP4 EPSPS,Agrobacterium sp.CP4-derived enolpyruvylshikimate-3-phosphate synthase;DAFNE,Data Food Networking:DNA,deoxyribonucleic acid;EDI,estimated daily intake:EFG,Euro Food Group;EFSA,European Food Safety Authority: ENDB,European Nutrient Database:ENTRANSFOOD,European network safety assessment of genetically modified food crops;EPA,US Environmental Protection Agency:EPIC,European Prospective Investigation into Cancer and Nutrition:EPSPS.enolpyruvylshikimate-3-phos. phate synthase;EU,European Union:FAO,Food and Agriculture Organisation of the United Nations;FDA.US Food and Drug Administration; FOSIE,European Concerted Action Food Safety in Europe;FSANZ,Food Standards Australia New Zealand;GEMS/FOOD,Global Environ- ment Monitoring System/Food Contamination Monitoring and Assessment Programme;GM,genetically modified:GMO,genetically modified organism;IFBC,International Food Biotechnology Council;ILSI,International Life Sciences Institute;INFORMALL,EU-project about com- municating about food allergies and information for consumers,regulators,and industry;INVITTOX,databank of in vitro techniques in toxicol- ogy;MAFF,Japan Ministry of Agriculture,Food,and Fisheries;MHLW,Ministry of Health,Labour,and Welfare;MOS,margin of safety; NOAEL.No Observed Adverse Effect Level:ODE,US FDA Office of Device Evaluation;OECD,Organisation for Economic Co-operation and Development:PCR.polymerase chain reaction:Protall,EU-project on food allergens of plant origin and the relationship between allergenic potential and biological activity:RDA,recommended daily allowance:RNA,ribonucleic acid:SAFOTEST.EU-project on new methods for the safety testing of transgenic food:SGF,simulated gastric fluid:TMDI,theoretical maximum daily intake:UK.United Kingdom;UK ACRE,UK Advisory Committee on Releases into the Environment:US,United States;USA,United States of America;USDA,US Department of Agriculture; WHO.World Health Organisation of the United Nations Corresponding author.Tel.:+1-617-4324497;fax:+1-617-4320190. E-mail address:ariane_koenig@harvard.edu (A.Konig) 0278-6915/S-see front matter C 2004 Elsevier Ltd.All rights reserved. doi:10.1016j.fct.2004.02.019

Assessment of the safety of foods derived from genetically modified (GM) crops A. Ko¨niga,*, A. Cockburnb, R.W.R. Crevelc , E. Debruyned, R. Grafstroeme , U. Hammerlingf , I. Kimberg , I. Knudsenh, H.A. Kuiperi , A.A.C.M. Peijnenburgi , A.H. Penninksj , M. Poulsenh, M. Schauzuk, J.M. Wall a Harvard Center for Risk Analysis, Harvard School of Public Health, Harvard University, 718 Huntington Avenue, Boston, MA 02115, USA bScientific Affairs, Agricultural Sector, Monsanto Service International, Avenue de Tervuren 270-272, B-1150 Brussels, Belgium c SEAC Toxicology Department, Unilever Research Colworth, Colworth House, Sharnbrook, Bedford MK44 1LQ, UK dRegulatory Toxicology, Herbicides and Biotechnology, Bayer CropScience, 355 rue Dostoievski-BP 153, F-06903 Sophia Antipolis Cedex, France e Institute of Environmental Medicine, Karolinska Institutet, Nobelsva¨g 13, Box 210, SE-17177 Stockholm, Sweden f Swedish National Food Administration, PO Box 622, SE-751 Uppsala, Sweden g Central Toxicology Laboratory, Syngenta UK, Alderley Park Macclesfield, Cheshire SK10 4TJ, UK hInstitute of Food Safety and Toxicology, Danish Veterinary and Food Administration, 19 Moerkhoej Bygade, DK-2860 Søborg, Denmark i RIKILT- Institute of Food Safety, Wageningen University & Research Centre, Bornsesteeg 45, PO Box 230, NL-6700 AE Wageningen, The Netherlands j TNO Nutrition and Food Research, Utrechtseweg 48, NL-3700 AJ Zeist, The Netherlands kCentre for Novel Foods and Genetic Engineering, Federal Institute for Risk Assessment, Thielallee 88-92, D-14195 Berlin, Germany l Service de Pharmacologie et d’Immunologie, Laboratoire Associe´ INRA-CEA d’Immuno-Allergie Alimentaire, CEA-SACLAY Baˆtiment 136, F-91191 Gif-sur-Yvette, France Received 15 November 2003; accepted 4 February 2004 Abstract This paper provides guidance on how to assess the safety of foods derived from genetically modified crops (GM crops); it sum￾marises conclusions and recommendations of Working Group 1 of the ENTRANSFOOD project. The paper provides an approach for adapting the test strategy to the characteristics of the modified crop and the introduced trait, and assessing potential unintended effects from the genetic modification. The proposed approach to safety assessment starts with the comparison of the new GM crop with a traditional counterpart that is generally accepted as safe based on a history of human food use (the concept of substantial 0278-6915/$ - see front matter # 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.fct.2004.02.019 Food and Chemical Toxicology 42 (2004) 1047–1088 www.elsevier.com/locate/foodchemtox Abbreviations: ADI, Acceptable Daily Intake; ADME, absorption, distribution, metabolism, and excretion; ALLERGEST, EU-project on the effect of gastrointestinal digestion on the allergenicity of foods; APHIS, Animal and Plant Health Inspection Service; Bt, Bacillus thuringiensis; cDNA, DNA complementary to an RNA strand; CP4 EPSPS, Agrobacterium sp. CP4-derived enolpyruvylshikimate-3-phosphate synthase; DAFNE, Data Food Networking; DNA, deoxyribonucleic acid; EDI, estimated daily intake; EFG, Euro Food Group; EFSA, European Food Safety Authority; ENDB, European Nutrient Database; ENTRANSFOOD, European network safety assessment of genetically modified food crops; EPA, US Environmental Protection Agency; EPIC, European Prospective Investigation into Cancer and Nutrition; EPSPS, enolpyruvylshikimate-3-phos￾phate synthase; EU, European Union; FAO, Food and Agriculture Organisation of the United Nations; FDA, US Food and Drug Administration; FOSIE, European Concerted Action Food Safety in Europe; FSANZ, Food Standards Australia New Zealand; GEMS/FOOD, Global Environ￾ment Monitoring System/Food Contamination Monitoring and Assessment Programme; GM, genetically modified; GMO, genetically modified organism; IFBC, International Food Biotechnology Council; ILSI, International Life Sciences Institute; INFORMALL, EU-project about com￾municating about food allergies and information for consumers, regulators, and industry; INVITTOX, databank of in vitro techniques in toxicol￾ogy; MAFF, Japan Ministry of Agriculture, Food, and Fisheries; MHLW, Ministry of Health, Labour, and Welfare; MOS, margin of safety; NOAEL, No Observed Adverse Effect Level; ODE, US FDA Office of Device Evaluation; OECD, Organisation for Economic Co-operation and Development; PCR, polymerase chain reaction; Protall, EU-project on food allergens of plant origin and the relationship between allergenic potential and biological activity; RDA, recommended daily allowance; RNA, ribonucleic acid; SAFOTEST, EU-project on new methods for the safety testing of transgenic food; SGF, simulated gastric fluid; TMDI, theoretical maximum daily intake; UK, United Kingdom; UK ACRE, UK Advisory Committee on Releases into the Environment; US, United States; USA, United States of America; USDA, US Department of Agriculture; WHO, World Health Organisation of the United Nations. * Corresponding author. Tel.: +1-617-4324497; fax: +1-617-4320190. E-mail address: ariane_koenig@harvard.edu (A. Ko¨nig)

1048 A.Konig et al.Food and Chemical Toxicology 42 (2004)1047-1088 equivalence).This case-focused approach ensures that foods derived from GM crops that have passed this extensive test-regime are as safe and nutritious as currently consumed plant-derived foods.The approach is suitable for current and future GM crops with more complex modifications.First,the paper reviews test methods developed for the risk assessment of chemicals,including food additives and pesticides,discussing which of these methods are suitable for the assessment of recombinant proteins and whole foods.Second,the paper presents a systematic approach to combine test methods for the safety assessment of foods derived from a specific GM crop.Third,the paper provides an overview on developments in this area that may prove of use in the safety assess- ment of GM crops,and recommendations for research priorities.It is concluded that the combination of existing test methods provides a sound test-regime to assess the safety of GM crops.Advances in our understanding of molecular biology,biochemistry, and nutrition may in future allow further improvement of test methods that will over time render the safety assessment of foods even more effective and informative. C 2004 Elsevier Ltd.All rights reserved. Keywords:Food;Plant biotechnology;Genetic modification;Genetic engineering:Genetic manipulation;Transgenic crops;Novel foods;Recom- binant proteins;Plant metabolism;Regulation;Safety assessment;Risk analysis;Molecular characterisation;Toxicology;Allergy;Substantial equivalence;Unintended effects;Bioinformatics;In vitro test methods;In vivo test methods;Animal testing;Post market monitoring;Estimated consumption;Exposure assessment:Compositional analysis;Advanced analytical methods;Profiling 1.Introduction complex modifications.The remainder of this paper is divided into four sections.Section 2 provides an over- Approaches to the regulation and safety assessment of view of regulations and internationally agreed principles genetically modified(GM)crops have been developed in and guidelines for risk assessment of chemicals and a very proactive manner.The first international and foods derived from GM crops.Section 3 reviews exist- national provisions for the safety assessment and reg- ing test methods developed for chemicals and food ulation of genetically modified organisms (GMOs), additives,and examines their suitability for testing the including GM crops and derived foods were drawn up safety of foods and food constituents derived from GM by scientific experts in the mid-1980s (OECD,1986;US crops.Section 4 systematically sets out how to deter- OSTP,1986).This was nearly a decade before the first mine whether the GM crop is 'as safe as'a suitable regulatory approval of a genetically modified crop in comparator with a history of human consumption.It 1995.Since then,the global area of commercial cultiva- provides guidance on how to compile information on tion of such crops has risen to 58.7 million hectares in the parent crop and on the genetic modification.This 2002 (James,2002).Commercially cultivated GM crops information in turn guides the choice of test para- include soybean.maize,cotton.canola.potatoes,and meters and methods in the analysis of any introduced tomatoes.At present,the most widely grown GM crops substance and of the whole GM crop.Any significant contain new genes that confer herbicide tolerance or differences that are identified in this systematic compar- insect resistance.Other crops are being developed that ison of the GM crop and the comparator then are sub- have improved nutritional characteristics for their food ject to further investigation as to whether this difference or feed use;GM soybeans and oil seed rape with altered might have implications for human health.Section 5 fatty acid profiles,for example,have already undergone discusses implications of advances in molecular biology regulatory review.Future advances in genomic sciences and the development of in vitro and in vivo test methods promise the discovery of new genes conferring desirable for the future refinement of food safety assessment characteristics to crops that may fundamentally alter a strategies. crop's metabolic functions,promising further nutri- The paper provides detailed guidance for anyone tional enhancement and resistance to abiotic stresses.It involved in risk assessment and regulation of GM crops. is important that we should continue to proactively The paper emphasises that this systematic approach to assess whether current approaches to safety assessment food safety assessment of GM crops offers a high level are appropriate also for future GM crop products with of safety assurance:this iterative and case-focused more complex traits. design of safety testing strategies ensures that all tested This paper presents a systematic approach for com- and approved foods derived from GM crops are as safe bining different test methods to assess the safety of and nutritious as currently consumed plant-derived foods derived from a specific GM crop.It provides foods.The paper also considers how our continuously guidance on how to tailor the test strategy to the improving understanding of molecular biology,bio- characteristics of the modified crop and the introduced chemistry,and nutrition will over time facilitate the trait and identifying potential unintended effects from development of new crop varieties and their safety the genetic modification.The approach builds on assessment.The conclusion provides recommendations internationally agreed guidelines and principles,and is on priorities for research and development of test suitable for current and future GM crops with more methods and strategies

equivalence). This case-focused approach ensures that foods derived from GM crops that have passed this extensive test-regime are as safe and nutritious as currently consumed plant-derived foods. The approach is suitable for current and future GM crops with more complex modifications. First, the paper reviews test methods developed for the risk assessment of chemicals, including food additives and pesticides, discussing which of these methods are suitable for the assessment of recombinant proteins and whole foods. Second, the paper presents a systematic approach to combine test methods for the safety assessment of foods derived from a specific GM crop. Third, the paper provides an overview on developments in this area that may prove of use in the safety assess￾ment of GM crops, and recommendations for research priorities. It is concluded that the combination of existing test methods provides a sound test-regime to assess the safety of GM crops. Advances in our understanding of molecular biology, biochemistry, and nutrition may in future allow further improvement of test methods that will over time render the safety assessment of foods even more effective and informative. # 2004 Elsevier Ltd. All rights reserved. Keywords: Food; Plant biotechnology; Genetic modification; Genetic engineering; Genetic manipulation; Transgenic crops; Novel foods; Recom￾binant proteins; Plant metabolism; Regulation; Safety assessment; Risk analysis; Molecular characterisation; Toxicology; Allergy; Substantial equivalence; Unintended effects; Bioinformatics; In vitro test methods; In vivo test methods; Animal testing; Post market monitoring; Estimated consumption; Exposure assessment; Compositional analysis; Advanced analytical methods; Profiling 1. Introduction Approaches to the regulation and safety assessment of genetically modified (GM) crops have been developed in a very proactive manner. The first international and national provisions for the safety assessment and reg￾ulation of genetically modified organisms (GMOs), including GM crops and derived foods were drawn up by scientific experts in the mid-1980s (OECD, 1986; US OSTP, 1986). This was nearly a decade before the first regulatory approval of a genetically modified crop in 1995. Since then, the global area of commercial cultiva￾tion of such crops has risen to 58.7 million hectares in 2002 (James, 2002). Commercially cultivated GM crops include soybean, maize, cotton, canola, potatoes, and tomatoes. At present, the most widely grown GM crops contain new genes that confer herbicide tolerance or insect resistance. Other crops are being developed that have improved nutritional characteristics for their food or feed use; GM soybeans and oil seed rape with altered fatty acid profiles, for example, have already undergone regulatory review. Future advances in genomic sciences promise the discovery of new genes conferring desirable characteristics to crops that may fundamentally alter a crop’s metabolic functions, promising further nutri￾tional enhancement and resistance to abiotic stresses. It is important that we should continue to proactively assess whether current approaches to safety assessment are appropriate also for future GM crop products with more complex traits. This paper presents a systematic approach for com￾bining different test methods to assess the safety of foods derived from a specific GM crop. It provides guidance on how to tailor the test strategy to the characteristics of the modified crop and the introduced trait and identifying potential unintended effects from the genetic modification. The approach builds on internationally agreed guidelines and principles, and is suitable for current and future GM crops with more complex modifications. The remainder of this paper is divided into four sections. Section 2 provides an over￾view of regulations and internationally agreed principles and guidelines for risk assessment of chemicals and foods derived from GM crops. Section 3 reviews exist￾ing test methods developed for chemicals and food additives, and examines their suitability for testing the safety of foods and food constituents derived from GM crops. Section 4 systematically sets out how to deter￾mine whether the GM crop is ‘as safe as’ a suitable comparator with a history of human consumption. It provides guidance on how to compile information on the parent crop and on the genetic modification. This information in turn guides the choice of test para￾meters and methods in the analysis of any introduced substance and of the whole GM crop. Any significant differences that are identified in this systematic compar￾ison of the GM crop and the comparator then are sub￾ject to further investigation as to whether this difference might have implications for human health. Section 5 discusses implications of advances in molecular biology and the development of in vitro and in vivo test methods for the future refinement of food safety assessment strategies. The paper provides detailed guidance for anyone involved in risk assessment and regulation of GM crops. The paper emphasises that this systematic approach to food safety assessment of GM crops offers a high level of safety assurance: this iterative and case-focused design of safety testing strategies ensures that all tested and approved foods derived from GM crops are as safe and nutritious as currently consumed plant-derived foods. The paper also considers how our continuously improving understanding of molecular biology, bio￾chemistry, and nutrition will over time facilitate the development of new crop varieties and their safety assessment. The conclusion provides recommendations on priorities for research and development of test methods and strategies. 1048 A. Ko¨nig et al. / Food and Chemical Toxicology 42 (2004) 1047–1088

A.Konig et al.Food and Chemical Toxicology 42 (2004)1047-1088 1049 2.Food safety of GM crops:regulation,principles,and into force on 17 October 2002,introduces mandatory guidelines labelling and traceability requirements.It also limits approvals to a period of 10 years;furthermore,appli- 2.1.Regulatory frameworks for GM crops and derived cants have to provide post-market monitoring plans for foods some categories of products. Since 1997 a separate approval procedure for foods Food safety systems,comprising institutions,policies, derived from genetically modiifed organisms exists. laws,and guidelines for assessments,continually evolve Regulation EC No 258/97 concerning novel foods and over time.The evolution of food safety systems in indi- food ingredients in 1997 (hence forth Novel Foods vidual jurisdictions is affected both by science and Regulation)(European Commission,1997a)covers all society:Scientific advances improve our understanding foods that have not hitherto been used for human con- of health implications of foods and lead to adoption of sumption to a significant degree within the European new agri-food production technologies,some of which Community.The European Commission has published require regulatory oversight.Changing societal values guidelines for data and information to be included in can lead to shifts in emphasis in consumer protection applications by petitioners (European Commission, policies and regulatory and institutional change.Reg- 1997b).The Novel Foods Regulation requires the risk ulation in turn can affect both innovation and risk per- assessment and pre-market approval of novel foods, ception.The Organisation for Economic Co-operation and also specifies labelling requirements for certain and Development (OECD)recently compiled descrip- categories of novel foods.The Novel Foods Regulation tions of national food safety systems of its twenty-nine gave the European Commission a clear role in the gov- Member States;these descriptions also specifically ernance of food safety in the European Union. address national approaches to the regulation and This role was strengthened with the publication of the assessment of foods derived from GM crops(OECD, Regulation EC No 178/2002 on the general principles of 2000.2003). food law and the establishment of the European Food Two types of regulatory frameworks for foods derived Safety Authority (hence forth the General Food Law) from GM crops can be distinguished.Some jurisdictions (European Commission,2002;see also European Com- enacted specific 'process-based'legislation for the reg- mission,2000a).The General Food Law provides the ulation of all genetically modified organisms,these legal basis for the establishment of a fully integrated include the European Union (EU)and Australia.In system for food safety legislation and controls covering contrast,other regulatory systems are 'product-based', all aspects of food production and the establishment of focusing on the resulting product characteristics and an independent European Food Safety Authority use,and not on the process of genetic modification,as (EFSA).The General Food Law provides an integrated for instance those in the United States of America approach to ensuring food safety across the EU Mem- (USA)and Canada. ber States and across the food and feed sectors.General In the European Union(EU)the regulation of foods principles of EU food law state that risk analysis is derived from genetically modified organisms has under- based on scientific risk assessment conducted by the gone two significant changes since it first was instituted recently instituted European Food Safety Authority and in the early 1990s.These changes occurred in tandem establish an EU-level authorisation procedure.Other with more fundamental changes in the governance of general principles include the protection and informing food safety in the EU.First,a horizontal,process-based of consumers through comprehensive labelling schemes; law regulating all genetically modified organisms to be provisions for traceability-that is the ability to trace released into the environment came into force in 1990. back to the origin and to understand the distribution of Directive 90/220/EEC governed experimental releases foods and food ingredients;and the application of the and marketing authorisation of all genetically modified precautionary principle in instances of significant organisms(European Commission,1990).The Directive uncertainty in the risk assessment.Furthermore,the set out an approval process requiring the case-by-case new law clarifies accountability of all legal entities assessment of the potential risks to human and animal involved in food production and regulation in the EU health and the environment of all genetically modified by describing general food safety requirements that are organisms or products consisting of or containing a imposed on both the Member States and business GMO (except for pharmaceuticals,which are regulated operators. separately).Partly in response to the public debate on The General Food Law provides for one decision- GM crops,the Directive was revised to strengthen the making procedure for all products that require EU- existing requirements for risk assessment and the deci- level approvals,such as food additives,pesticide resi- sion-making process (European Commission,2001). dues in food,novel foods,and genetically modified The revised Directive 2001/18/EC on the deliberate organisms.The procedure is as follows:The European release of genetically modified organisms,which entered Commission Directorate for Health and Consumer

2. Food safety of GM crops: regulation, principles, and guidelines 2.1. Regulatory frameworks for GMcrops and derived foods Food safety systems, comprising institutions, policies, laws, and guidelines for assessments, continually evolve over time. The evolution of food safety systems in indi￾vidual jurisdictions is affected both by science and society: Scientific advances improve our understanding of health implications of foods and lead to adoption of new agri-food production technologies, some of which require regulatory oversight. Changing societal values can lead to shifts in emphasis in consumer protection policies and regulatory and institutional change. Reg￾ulation in turn can affect both innovation and risk per￾ception. The Organisation for Economic Co-operation and Development (OECD) recently compiled descrip￾tions of national food safety systems of its twenty-nine Member States; these descriptions also specifically address national approaches to the regulation and assessment of foods derived from GM crops (OECD, 2000, 2003). Two types of regulatory frameworks for foods derived from GM crops can be distinguished. Some jurisdictions enacted specific ‘process-based’ legislation for the reg￾ulation of all genetically modified organisms, these include the European Union (EU) and Australia. In contrast, other regulatory systems are ‘product-based’, focusing on the resulting product characteristics and use, and not on the process of genetic modification, as for instance those in the United States of America (USA) and Canada. In the European Union (EU) the regulation of foods derived from genetically modified organisms has under￾gone two significant changes since it first was instituted in the early 1990s. These changes occurred in tandem with more fundamental changes in the governance of food safety in the EU. First, a horizontal, process-based law regulating all genetically modified organisms to be released into the environment came into force in 1990. Directive 90/220/EEC governed experimental releases and marketing authorisation of all genetically modified organisms (European Commission, 1990). The Directive set out an approval process requiring the case-by-case assessment of the potential risks to human and animal health and the environment of all genetically modified organisms or products consisting of or containing a GMO (except for pharmaceuticals, which are regulated separately). Partly in response to the public debate on GM crops, the Directive was revised to strengthen the existing requirements for risk assessment and the deci￾sion-making process (European Commission, 2001). The revised Directive 2001/18/EC on the deliberate release of genetically modified organisms, which entered into force on 17 October 2002, introduces mandatory labelling and traceability requirements. It also limits approvals to a period of 10 years; furthermore, appli￾cants have to provide post-market monitoring plans for some categories of products. Since 1997 a separate approval procedure for foods derived from genetically modiifed organisms exists. Regulation EC No 258/97 concerning novel foods and food ingredients in 1997 (hence forth Novel Foods Regulation) (European Commission, 1997a) covers all foods that have not hitherto been used for human con￾sumption to a significant degree within the European Community. The European Commission has published guidelines for data and information to be included in applications by petitioners (European Commission, 1997b). The Novel Foods Regulation requires the risk assessment and pre-market approval of novel foods, and also specifies labelling requirements for certain categories of novel foods. The Novel Foods Regulation gave the European Commission a clear role in the gov￾ernance of food safety in the European Union. This role was strengthened with the publication of the Regulation EC No 178/2002 on the general principles of food law and the establishment of the European Food Safety Authority (hence forth the General Food Law) (European Commission, 2002; see also European Com￾mission, 2000a). The General Food Law provides the legal basis for the establishment of a fully integrated system for food safety legislation and controls covering all aspects of food production and the establishment of an independent European Food Safety Authority (EFSA). The General Food Law provides an integrated approach to ensuring food safety across the EU Mem￾ber States and across the food and feed sectors. General principles of EU food law state that risk analysis is based on scientific risk assessment conducted by the recently instituted European Food Safety Authority and establish an EU-level authorisation procedure. Other general principles include the protection and informing of consumers through comprehensive labelling schemes; provisions for traceability-that is the ability to trace back to the origin and to understand the distribution of foods and food ingredients; and the application of the precautionary principle in instances of significant uncertainty in the risk assessment. Furthermore, the new law clarifies accountability of all legal entities involved in food production and regulation in the EU by describing general food safety requirements that are imposed on both the Member States and business operators. The General Food Law provides for one decision￾making procedure for all products that require EU￾level approvals, such as food additives, pesticide resi￾dues in food, novel foods, and genetically modified organisms. The procedure is as follows: The European Commission Directorate for Health and Consumer A. Ko¨nig et al. / Food and Chemical Toxicology 42 (2004) 1047–1088 1049

1050 A.Konig et al.Food and Chemical Toxicology 42 (2004)1047-1088 Protection administers the review process.The Eur- The USDA regulates the import,interstate movement, opean Food Safety Authority reviews the risk assess- field trial release,and commercial release of GM crops ment submitted by applicants intending to place a under the Federal Plant Pest Act and the Plant Novel Food on the European market.It is up to the Quarantine Act,which are administered by the Animal administrators in the European Commission Directo- and Plant Health Inspection Service (APHIS).Prior to rate General for Health and Consumer Protection to approval for unrestricted release,as in commercialisa- draft proposals based on the risk assessment and other tion,the USDA/APHIS must determine that the GM broader considerations that may affect choice of policy crop is not a plant pest.There is no Federal regulation options.A regulatory committee of representatives of requiring the registration of new plant varieties.The Member States competent authorities then decides EPA has regulatory oversight for all GM crops that whether to accept the Commission proposal through a produce a plant pesticide.Plant-integrated pesticides are weighted voting system.If the regulatory committee's regulated according to the same procedures as other opinion is not in accordance with the proposed pesticides. measure or if no opinion is delivered,the question is The FDA has authority over human food and animal referred to the Council of Ministers.The Council of feed safety and the wholesomeness of all plant products, Ministers can approve or reject a Commission proposal including those produced via genetic modification, given a qualified majority of member States support under the Federal Food Drug and Cosmetic Act.The the position.If rejected,the European Commission has FDA has concluded that food and feed derived from to prepare a new proposal.If the Council of Ministers GM crops pose no unique safety concerns and,there- takes no decision within three months,or does not fore,that the food and feed products derived from these reach a qualified majority indicating that it opposes the plants should be regulated no differently than compar- proposal,the European Commission shall adopt the able products derived from traditional plant breeding or proposal. any other genetic modification approach (US FDA, In June 2003 the European Council of Ministers 1992).Labelling is only mandated for foods that present adopted two new Regulations specific for foods and a health risk to subgroups of the population,such as feeds derived from genetically modified organisms. allergenic foods:the FDA does not mandate process- Regulation (EC)No 1829/2003 on genetically modified based labelling informing consumers for instance on a food and feed provides the legal basis for the approval food's content of genetically modified organisms.Partly procedure for genetically modified organisms as speci- in response to demonstrations by activists against GM fied in the General Food Law.The safety of foods crops in Seattle,Washington in 1999,and to three pub- derived from genetically modified organisms is assessed lic hearings,the FDA decided to adopt measures to by the European Food Safety Authority's Scientific strengthen the scientific basis and transparency of its Panel on genetically modified organisms (European decision-making process.The FDA proposed to modify Commission,2003a).[The panel assesses the food its voluntary process so as to establish mandatory pre- safety,environmental and animal health aspects of market notification and to make its decision process genetically modified organisms ('one-door-one-key' more transparent.The agency also developed draft gui- principle.)]Regulation (EC)No 1830/2003 concerning dance for food manufacturers who wish to label their the traceability and labelling of genetically modified foods voluntarily. organisms and the traceability of food and feed pro- Other systems that present variations of either the US ducts produced from genetically modified organisms or the EU approach are Canada,Australia,and Japan. requires traceability and labelling of genetically mod- In Canada all plants with novel traits are regulated, ified organisms and derived products (European Com- regardless of whether a plant with novel traits was pro- mission,2003b);this regulation also provides a legal duced by conventional breeding,mutagenesis,or basis for case-by-case decisions on post market mon- recombinant DNA techniques (Health Canada,1994; itoring requirements where deemed necessary. CFIA,1998).Foods derived from GM crops are con- The US regulatory framework for GM crops was laid sidered novel foods under the Food and Drugs Act out in the 1986 'Coordinated Framework for Regula- (CFIA,1998).The Canadian Biotechnology Advisory tion of Biotechnology'(US OSTP,1986).Existing laws Committee recently reviewed the Canadian regulations for the regulation of plant pests,pesticides and foods of GM foods;its recommendations include that were amended,resulting in a vertical,product-based research be carried out in order to monitor for hypo- regulatory framework for GM crops and derived foods. thetical long-term health effects(CBAC,2002). Three principal regulatory agencies conduct science- In Japan,the Ministry of Agriculture,Food,and based assessments of risks to human health and the Fisheries (MAFF)and the Ministry of Health,Labour, environment:the United States Department of Agri- and Welfare (MHLW)administer the regulation of food culture (USDA),the Environmental Protection Agency safety of GMOs,including GM crops and other foods (EPA),and the Food and Drug Administration(FDA). and food additives that contain organisms or have been

Protection administers the review process. The Eur￾opean Food Safety Authority reviews the risk assess￾ment submitted by applicants intending to place a Novel Food on the European market. It is up to the administrators in the European Commission Directo￾rate General for Health and Consumer Protection to draft proposals based on the risk assessment and other broader considerations that may affect choice of policy options. A regulatory committee of representatives of Member States competent authorities then decides whether to accept the Commission proposal through a weighted voting system. If the regulatory committee’s opinion is not in accordance with the proposed measure or if no opinion is delivered, the question is referred to the Council of Ministers. The Council of Ministers can approve or reject a Commission proposal given a qualified majority of member States support the position. If rejected, the European Commission has to prepare a new proposal. If the Council of Ministers takes no decision within three months, or does not reach a qualified majority indicating that it opposes the proposal, the European Commission shall adopt the proposal. In June 2003 the European Council of Ministers adopted two new Regulations specific for foods and feeds derived from genetically modified organisms. Regulation (EC) No 1829/2003 on genetically modified food and feed provides the legal basis for the approval procedure for genetically modified organisms as speci- fied in the General Food Law. The safety of foods derived from genetically modified organisms is assessed by the European Food Safety Authority’s Scientific Panel on genetically modified organisms (European Commission, 2003a). [The panel assesses the food safety, environmental and animal health aspects of genetically modified organisms (‘one-door-one-key’ principle.)] Regulation (EC) No 1830/2003 concerning the traceability and labelling of genetically modified organisms and the traceability of food and feed pro￾ducts produced from genetically modified organisms requires traceability and labelling of genetically mod￾ified organisms and derived products (European Com￾mission, 2003b); this regulation also provides a legal basis for case-by-case decisions on post market mon￾itoring requirements where deemed necessary. The US regulatory framework for GM crops was laid out in the 1986 ‘Coordinated Framework for Regula￾tion of Biotechnology’ (US OSTP, 1986). Existing laws for the regulation of plant pests, pesticides and foods were amended, resulting in a vertical, product-based regulatory framework for GM crops and derived foods. Three principal regulatory agencies conduct science￾based assessments of risks to human health and the environment: the United States Department of Agri￾culture (USDA), the Environmental Protection Agency (EPA), and the Food and Drug Administration (FDA). The USDA regulates the import, interstate movement, field trial release, and commercial release of GM crops under the Federal Plant Pest Act and the Plant Quarantine Act, which are administered by the Animal and Plant Health Inspection Service (APHIS). Prior to approval for unrestricted release, as in commercialisa￾tion, the USDA/APHIS must determine that the GM crop is not a plant pest. There is no Federal regulation requiring the registration of new plant varieties. The EPA has regulatory oversight for all GM crops that produce a plant pesticide. Plant-integrated pesticides are regulated according to the same procedures as other pesticides. The FDA has authority over human food and animal feed safety and the wholesomeness of all plant products, including those produced via genetic modification, under the Federal Food Drug and Cosmetic Act. The FDA has concluded that food and feed derived from GM crops pose no unique safety concerns and, there￾fore, that the food and feed products derived from these plants should be regulated no differently than compar￾able products derived from traditional plant breeding or any other genetic modification approach (US FDA, 1992). Labelling is only mandated for foods that present a health risk to subgroups of the population, such as allergenic foods; the FDA does not mandate process￾based labelling informing consumers for instance on a food’s content of genetically modified organisms. Partly in response to demonstrations by activists against GM crops in Seattle, Washington in 1999, and to three pub￾lic hearings, the FDA decided to adopt measures to strengthen the scientific basis and transparency of its decision-making process. The FDA proposed to modify its voluntary process so as to establish mandatory pre￾market notification and to make its decision process more transparent. The agency also developed draft gui￾dance for food manufacturers who wish to label their foods voluntarily. Other systems that present variations of either the US or the EU approach are Canada, Australia, and Japan. In Canada all plants with novel traits are regulated, regardless of whether a plant with novel traits was pro￾duced by conventional breeding, mutagenesis, or recombinant DNA techniques (Health Canada, 1994; CFIA, 1998). Foods derived from GM crops are con￾sidered novel foods under the Food and Drugs Act (CFIA, 1998). The Canadian Biotechnology Advisory Committee recently reviewed the Canadian regulations of GM foods; its recommendations include that research be carried out in order to monitor for hypo￾thetical long-term health effects (CBAC, 2002). In Japan, the Ministry of Agriculture, Food, and Fisheries (MAFF) and the Ministry of Health, Labour, and Welfare (MHLW) administer the regulation of food safety of GMOs, including GM crops and other foods and food additives that contain organisms or have been 1050 A. Ko¨nig et al. / Food and Chemical Toxicology 42 (2004) 1047–1088

A.Konig et al.Food and Chemical Toxicology 42 (2004)1047-1088 1051 obtained through recombinant DNA techniques.The risk.Examples of risk management for conditional food safety assessment of genetically modified organ- approvals include labelling requirements to inform the isms is mandatory under the Specifications and Stan- target group at risk,as done for food products that dards for Food and Food Additives and Other Related contain major allergens.Risk communication is defined Products and is conducted according to guidelines pub- as the exchange of information and opinion on risk lished by the Ministry of Health and Welfare (Japan between risk assessors,risk managers,other interested MHLW,2000).The definition of recombinant DNA parties,and the general public (FAO/WHO,1995, pertains to the introduction of foreign DNA from 1997). sources other than the host;"self cloning"is exempt Some critics voice concerns that the separation of risk from the assessment (Japan MAFF,1995). assessment and risk management neglects that risks are In Australia and New Zealand,the Food Standards also a product of societal circumstances:the salience of Australia New Zealand (FSANZ)has regulatory over- expert advice to concerns of policy makers and the sight over food safety,including the safety of foods public is thus potentially reduced (Jasanoff,1990:NRC. derived from genetically modified organisms.Food 1994,1996;Presidential/Congressional Commission on Standard 1.5.2 specifically regulates the marketing of Risk Assessment and Risk Management,1997;James et foods derived using recombinant DNA techniques al,1999). (FSANZ,2000).The standard also provides for the The focus of this paper is on risk assessment,defined possible post-market monitoring requirements for foods as the evaluation of the probability of known or poten- derived from genetically modified organisms on a case- tial adverse health effects arising from human or animal by-case basis,in particular for foods derived from GM exposure to the identified hazards (FAO/WHO,1995, crops the nutritional characteristics of which were 1997).Such evaluation will always be a central part in modified (FSANZ,2001). the regulation of health risks,regardless of who frames Whilst regulatory frameworks differ across jurisdic- the questions and how broad the assessment is.Risk tions,the approaches to the safety assessment of foods assessment involves combining information on severity derived from GM crops are similar in most countries,as of the consequences of exposure to a hazard and expec- they are based on general principles for risk analysis ted degree of exposure.The first stage in risk assessment and international guidelines for the safety assessment of is to identify the hazards posed by a substance,by foods derived from genetically modified organisms establishing a cause-effect relationship between the hazard and the product or process using toxicological 2.2.General principles of risk analysis experiments,modelling and/or epidemiological meth- ods.It establishes the intrinsic potential of a substance, The general principles for risk analysis were first such as a chemical,protein,or food,to cause adverse established for evaluation of health effects from poten- health effects. tially toxic chemicals.Risk is defined as the likelihood Hazard characterisation aims to evaluate in qualita- that,under particular conditions of exposure,an intrin- tive and quantitative terms the nature of the identified sic hazard will represent a threat to human health.Risk intrinsic hazard.This usually involves an analysis of the is thus a function of hazard and exposure.Hazard is dose-response relationship of harmful effects in the tar- defined as the intrinsic potential of a material to cause get organism or an appropriate surrogate species and adverse health effects:implicit in the definition is the characterisation of the severity of the effect.In routine concept of severity and adversity of the effect.This toxicological studies animals are usually administered definition is consistent with internationally accepted three different doses,including very small doses and principles(FAO/WHO,1995;FAO/WHO,1997;Codex doses that exceed anticipated human exposures by sev- Alimentarius Commission,2003a). eral orders of magnitude.The purpose of these studies is The international principles and guidelines,as well as the establishment of the highest dose level at which no most European policy documents on risk analysis and adverse effect occurs-the No Observed Adverse Effect food safety (see for example European Commission, Level (NOAEL).Animal-based toxicological methods 2000b),draw a distinction between science-based risk for hazard identification and characterisation have assessment usually conducted by experts,risk manage- recently been reviewed by Barlow et al.(2002).The ment,and risk communication.Risk management is NOAEL in the most sensitive animal species in which defined as "the process of weighing policy alternatives tests were conducted is the basis for establishing best to mitigate risks in the light of risk assessment and,if estimates of a safe exposure level for humans.This esti- required,selecting and implementing appropriate con- mation takes into account variations in susceptibility trol options,including regulatory measures"(FAO/ between animal species,and between individuals within WHO,1995;FAO/WHO,1997).Risk management the human population.The observed NOAEL is divi- strategies include authorisation,and implementation of ded by uncertainty factors to establish a margin of risk management measures to minimise or prevent the safety:the default uncertainty factors to account for

obtained through recombinant DNA techniques. The food safety assessment of genetically modified organ￾isms is mandatory under the Specifications and Stan￾dards for Food and Food Additives and Other Related Products and is conducted according to guidelines pub￾lished by the Ministry of Health and Welfare (Japan MHLW, 2000). The definition of recombinant DNA pertains to the introduction of foreign DNA from sources other than the host; ‘‘self cloning’’ is exempt from the assessment (Japan MAFF, 1995). In Australia and New Zealand, the Food Standards Australia New Zealand (FSANZ) has regulatory over￾sight over food safety, including the safety of foods derived from genetically modified organisms. Food Standard 1.5.2 specifically regulates the marketing of foods derived using recombinant DNA techniques (FSANZ, 2000). The standard also provides for the possible post-market monitoring requirements for foods derived from genetically modified organisms on a case￾by-case basis, in particular for foods derived from GM crops the nutritional characteristics of which were modified (FSANZ, 2001). Whilst regulatory frameworks differ across jurisdic￾tions, the approaches to the safety assessment of foods derived from GM crops are similar in most countries, as they are based on general principles for risk analysis and international guidelines for the safety assessment of foods derived from genetically modified organisms. 2.2. General principles of risk analysis The general principles for risk analysis were first established for evaluation of health effects from poten￾tially toxic chemicals. Risk is defined as the likelihood that, under particular conditions of exposure, an intrin￾sic hazard will represent a threat to human health. Risk is thus a function of hazard and exposure. Hazard is defined as the intrinsic potential of a material to cause adverse health effects; implicit in the definition is the concept of severity and adversity of the effect. This definition is consistent with internationally accepted principles (FAO/WHO, 1995; FAO/WHO, 1997; Codex Alimentarius Commission, 2003a). The international principles and guidelines, as well as most European policy documents on risk analysis and food safety (see for example European Commission, 2000b), draw a distinction between science-based risk assessment usually conducted by experts, risk manage￾ment, and risk communication. Risk management is defined as ‘‘the process of weighing policy alternatives to mitigate risks in the light of risk assessment and, if required, selecting and implementing appropriate con￾trol options, including regulatory measures’’ (FAO/ WHO, 1995; FAO/WHO, 1997). Risk management strategies include authorisation, and implementation of risk management measures to minimise or prevent the risk. Examples of risk management for conditional approvals include labelling requirements to inform the target group at risk, as done for food products that contain major allergens. Risk communication is defined as the exchange of information and opinion on risk between risk assessors, risk managers, other interested parties, and the general public (FAO/WHO, 1995, 1997). Some critics voice concerns that the separation of risk assessment and risk management neglects that risks are also a product of societal circumstances; the salience of expert advice to concerns of policy makers and the public is thus potentially reduced (Jasanoff, 1990; NRC, 1994, 1996; Presidential/Congressional Commission on Risk Assessment and Risk Management, 1997; James et al., 1999). The focus of this paper is on risk assessment, defined as the evaluation of the probability of known or poten￾tial adverse health effects arising from human or animal exposure to the identified hazards (FAO/WHO, 1995, 1997). Such evaluation will always be a central part in the regulation of health risks, regardless of who frames the questions and how broad the assessment is. Risk assessment involves combining information on severity of the consequences of exposure to a hazard and expec￾ted degree of exposure. The first stage in risk assessment is to identify the hazards posed by a substance, by establishing a cause-effect relationship between the hazard and the product or process using toxicological experiments, modelling and/or epidemiological meth￾ods. It establishes the intrinsic potential of a substance, such as a chemical, protein, or food, to cause adverse health effects. Hazard characterisation aims to evaluate in qualita￾tive and quantitative terms the nature of the identified intrinsic hazard. This usually involves an analysis of the dose-response relationship of harmful effects in the tar￾get organism or an appropriate surrogate species and characterisation of the severity of the effect. In routine toxicological studies animals are usually administered three different doses, including very small doses and doses that exceed anticipated human exposures by sev￾eral orders of magnitude. The purpose of these studies is the establishment of the highest dose level at which no adverse effect occurs—the No Observed Adverse Effect Level (NOAEL). Animal-based toxicological methods for hazard identification and characterisation have recently been reviewed by Barlow et al. (2002). The NOAEL in the most sensitive animal species in which tests were conducted is the basis for establishing best estimates of a safe exposure level for humans. This esti￾mation takes into account variations in susceptibility between animal species, and between individuals within the human population. The observed NOAEL is divi￾ded by uncertainty factors to establish a margin of safety; the default uncertainty factors to account for A. Ko¨nig et al. / Food and Chemical Toxicology 42 (2004) 1047–1088 1051