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