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ANIMAL CLONING AND GENETIC MODIFICATION: A PROSPECTIVE STUDY

Report 3 to

Institute for Prospective Technological Studies (IPTS)

Seville

October 2005

GM animals

Socio-economic issues

Anette Braun5

Ann Bruce1

Renate Gertz2

Cecilia Oram3

Jonathan Suk1

Joyce Tait1

Chris Warkup3

Bruce Whitelaw4

5 Future Technologies Division of VDI Technologiezentrym GmbH, Graf-Recke-Strasse 84 D-40239 Duesseldorf, Germany1 Innogen (ESRC Centre for Social and Economic Research on Innovation in Genomics), University of Edinburgh, High School Yards, Edinburgh, Scotland2 AHRC Centre for Studies in Intellectual Property and Technology Law, University of Edinburgh, Old College, Edinburgh, Scotland3 Genesis Faraday Partnership, Roslin BioCentre, Roslin, Midlothian, Scotland4 Roslin Institute, Roslin, Midlothian, Scotland

Acknowledgements

We would like to thank the participants of the one day hearing held at Innogen as part of this project and also Eileen Mothersole for contributing her secretarial expertise.

List of Contents

Executive Summary.....................................................................................................1

SECTION 1 INTRODUCTION......................................................................................4

1.1 Introduction.........................................................................................................4

SECTION 2 OVERVIEW OF THE LEGAL FRAMEWORK..........................................6

2.1 Overview of the legal frameworks......................................................................6

2.2 EU legislation......................................................................................................6

2.2.1 GMOs for deliberate release in the environment.........................................6

2.2.2 Traceability..................................................................................................7

2.2.3 GM foods.....................................................................................................7

2.2.4 Food Safety Legislation...............................................................................8

2.2.5 Pharmaceutical products.............................................................................8

2.2.6 Xenotransplantation.....................................................................................8

2.3 The regulation of GM animals worldwide.........................................................11

2.3.1 USA...........................................................................................................11

2.3.2 Canada......................................................................................................14

2.3.3 Australia.....................................................................................................14

2.3.4 New Zealand.............................................................................................15

2.3.5 Singapore..................................................................................................16

2.3.6 China.........................................................................................................16

2.3.7 Japan.........................................................................................................17

2.3.8 Korea.........................................................................................................17

2.3.9 Conclusions...............................................................................................17

2.4 International regulation.....................................................................................18

2.4.1 The Cartagena Protocol on Biosafety.......................................................18

2.5 Nutraceuticals and Functional Foods...............................................................18

2.5.1 EU..............................................................................................................19

2.5.2 USA...........................................................................................................19

2.5.3 Japan.........................................................................................................20

2.5.4 Conclusions...............................................................................................20

2.6 Patenting GM animals......................................................................................20

2.6.1 The regulation of patenting on an international level.................................20

2.6.2 Patenting legislation in the EU..................................................................22

2.6.3 Patenting legislation worldwide.................................................................23

SECTION 3 RISKS AND RISK ASSESSMENT.........................................................26

3.1 Risks from GM animals....................................................................................26

3.1.1 Food safety issues.....................................................................................26

3.1.2 Pharmaceutical safety issues....................................................................27

3.1.3 Xenotransplantation safety issues.............................................................27

3.1.4 Environmental risks from releases to the environment.............................27

3.1.5 Disease risk to current animals.................................................................28

3.2 Risk assessment..............................................................................................28

3.2.1 Risk and regulation of transgenic animals in the EU.................................28

3.2.2 Risk and regulation of transgenic animals in the USA..............................30

3.2.3 Risk and regulation of transgenic animals in New Zealand.......................37

3.2.4 Japan.........................................................................................................41

3.2.5 Conclusions...............................................................................................42

3.2.6 International risk assessment approaches................................................42

SECTION 4 INTERNATIONAL TRADE AND LABELLING ISSUES..........................51

4.1 International regulation of trade in GM animals and related products..............51

4.1.1 WTO – Sanitary and Phytosanitary Measures (SPS)................................51

4.1.2 WTO – Technical Barriers to Trade (TBT)................................................52

4.1.3 GATT 1994 and the product/process distinction.......................................53

4.1.4 Cartagena Biosafety Protocol and WTO – potential areas of dispute.......53

4.2 Additional potential trade issues.......................................................................58

4.2.1 Implications of international agreements for Developing Countries..........58

4.2.2 Unanticipated and illegal trade..................................................................58

4.3 Labelling...........................................................................................................59

4.3.1 The Codex Alimentarius............................................................................59

4.3.2 The WTO...................................................................................................60

4.3.3 Labelling in individual jurisdictions............................................................60

4.4 Traceability.......................................................................................................62

SECTION 5 ANIMAL WELFARE................................................................................64

5.1 Welfare of GM animals.....................................................................................64

5.1.1 Introduction................................................................................................64

5.1.2 Physiological issues..................................................................................64

5.1.3 Health issues.............................................................................................65

5.1.4 Behavioural issues....................................................................................65

5.1.5 Conclusions on comparison of GM and non-GM animals.........................65

5.2 Regulation on animal welfare...........................................................................65

SECTION 6 PUBLIC ATTITUDES.............................................................................66

6.1 Introduction.......................................................................................................66

6.2 Attitudes to GM animals...................................................................................66

6.2.1 Europe.......................................................................................................66

6.2.2 USA...........................................................................................................67

6.2.3 Japan.........................................................................................................67

6.2.4 Developing countries.................................................................................68

6.3 Ethical discussions around GM animals...........................................................68

6.4 Dilemma of human – animal relationships.......................................................69

SECTION 7 POLICY CONTEXT................................................................................71

7.1 Ethical Policy....................................................................................................71

7.2 EC Biotechnology Strategy..............................................................................71

7.3 Industry context: pharmaceutical and agricultural............................................72

7.4 Developing countries’ context..........................................................................73

SECTION 8 META-ANALYSIS OF GOVERNMENTAL TECHNOLOGY FORESIGHTS AND ASSESSMENTS.......................................................................75

8.1 Introduction.......................................................................................................75

8.2 Aim and objective.............................................................................................75

8.3 Findings: (inter)national technology assessments...........................................76

8.4 Findings: (inter)national technology foresight...................................................77

8.5 Outlook.............................................................................................................79

SECTION 9 CASE STUDIES.....................................................................................80

9.1 GM animals as bioreactors...............................................................................80

9.1.1 Aim............................................................................................................80

9.1.2 Markets......................................................................................................80

9.1.3 Technical aspects......................................................................................81

9.1.4 Drivers.......................................................................................................81

9.1.5 Regulation.................................................................................................81

9.1.6 Special issues............................................................................................81

9.1.7 Public attitudes..........................................................................................81

9.1.8 EU Competitiveness..................................................................................81

9.1.9 Alternative approaches..............................................................................82

9.2 Faster growth rate from GM animals................................................................84

9.2.1 Aim............................................................................................................84

9.2.2 Markets......................................................................................................84


9.2.4 Drivers.......................................................................................................84

9.2.5 Regulation.................................................................................................84

9.2.6 Special Issues...........................................................................................84




9.3 GM animals for food.........................................................................................87

9.3.1 Aim............................................................................................................87

9.3.2 Markets......................................................................................................87


9.3.4 Drivers.......................................................................................................87

9.3.5 Regulation.................................................................................................87

9.3.6 Special issues............................................................................................88




9.4 GM Pets............................................................................................................90

9.4.1 Aim............................................................................................................90

9.4.2 Markets......................................................................................................90


9.4.4 Drivers.......................................................................................................90

9.4.5 Regulation.................................................................................................90

9.4.6 Special issues............................................................................................90




9.5 Xenotransplantation.........................................................................................92

9.5.1 Aim............................................................................................................92

9.5.2 Markets......................................................................................................92


9.5.4 Drivers.......................................................................................................92

9.5.5 Regulation.................................................................................................92

9.5.6 Special issues............................................................................................92




SECTION 10 REFLECTIONS....................................................................................94

SECTION 11 REFERENCES.....................................................................................97

SECTION 12 APPENDICES....................................................................................101

Appendix 1 - Acronyms........................................................................................101

Appendix 2 - Selected Web sites.........................................................................102

Appendix 3 - ANNEX II of EU Directive 2001/18/EC: Environmental Risk Assessment..........................................................................................................103

Appendix 4 - Annex III of the Cartagena Biosafety Protocol: Risk Assessment (Available from: http://www.biodiv.org/biosafety/articles.asp?lg=0&a=bsp-43)....108

List of Tables

Table 1 Summary Table of US Regulatory System....................................................11

Table 2 Specific issues related to foods derived from animal biotechnology.............46

List of Figures

Figure 1 Roadmap demonstrating the drivers for GM animals as bioreactors...........83

Figure 2 Roadmap demonstrating drivers for products from faster growing GM fish becoming available in the EU..............................................................................86

Figure 3 Roadmap demonstrating the drivers for GM animal food products in the EU............................................................................................................................89

Figure 4 Roadmap demonstrating the drivers encouraging availability of pet GM fish in the EU.............................................................................................................91

Figure 5 Roadmap demonstrating the drivers to the availability of xenotransplants in the EU.................................................................................................................93

Executive SummaryThere are a large number of possible applications of GM animals, including:

Agricultural use for food production (including fish)

Production of pharmaceuticals in the milk, eggs and blood of animals

Production of organs for transplant into humans (xenotransplantation); and

Production of specific types of pets.

However, we identified relatively little activity within each area of application. Genetically modified animals were first created at the research level in 1985; but have not progressed to commercialisation in the way that has happened with GM crops. We have not identified any approved use of GM livestock in the food sector anywhere in the world. GM ornamental fish are on sale in the USA and pharmaceuticals produced in GM animals may be commercially available in the EU in the next few years.

Food Production

The lead product is probably genetically modified fish, including faster growing GM salmon developed in North America which are waiting regulatory approval for use in the food chain. Other applications are being considered at the experimental stage, but is seems unlikely that any will be in general use before 2010.

We have not identified any companies in the EU developing GM animals for food. GM foods are extensively regulated throughout the EU and elsewhere in the world but most of these regulatory systems have been developed for crops rather than livestock. It is not clear to what extent these regulatory requirements are compatible. Unlike crops, environmental risk is not perceived to be a major concern with food-producing animals, with the exception of fish. Risk issues are therefore more concentrated on risks to human health. Animal welfare is however an additional concern with GM animals.

The EU has clear regulatory requirements with respect to releases to the environment, labelling and traceability of GM and GM-derived foodstuffs, as well as safety assessment of GM foods. At the international level, the Cartagena Protocol on Biosafety to the Convention on Biodiversity applies to GM animals but compatibility of different international regulatory regimes is less clear, as is evident from the current dispute in the World Trade Organisation between USA and EU concerning GM crops. The outcome of this dispute may be influential in subsequent developments with regard to GM animals.

Although there is a legal requirement to label GM products in the EU (and many other jurisdictions), as there is currently no reliable method for detecting all GM animals, it may be difficult to prevent accidental mixing or deliberate illegal trade. The situation is likely to be even more difficult with respect to products derived from GM animals, such as milk.

The USA does, however, have different regulatory regimes for GM plants and GM animals. Following their practice of regulating according to the product rather than process, there are a number of different ways in which GM animals may be regulated depending on the intended use of the product. The Food and Drug Administration’s approach to GM plants and crops is based upon ‘substantial equivalence.’ GM crops are not normally subject to pre-market review since they are generally considered to be ‘substantially equivalent’ to conventional counterparts. With respect to animals, it seems likely that the most common approach will be to consider genetic constructs and their expression products as ‘animal drugs’. This will require a case-by-case pre-market assessment of products, with the onus on the producers to demonstrate

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safety. It is noteworthy, however, that an application of GM animals to improve the quality of the food product would be more likely to be evaluated under the ‘Generally Recognized as Safe’ procedures.

Production of pharmaceuticals

As stated in Report 1, one of the most likely applications to be available commercially within the next 5 years is pharmaceuticals produced by GM animals (so called ‘bioreactors’ or ‘pharming’). We identified a small number of companies in the EU active in this area. The major barrier to development appears to be meeting regulatory requirements. Whilst the regulatory system for pharmaceuticals generally is well co-ordinated in Europe under the auspices of the European Medicines Agency (EMEA), it is not clear that there is a specific regulatory route for biologics derived from ‘bioreactors’. Furthermore, EMEA’s focus is on safety and efficacy of the product and regulation of other factors such as releases to the environment and accidental (or deliberate) releases into the food chain are regulated by other bodies, as for GM crops.

Production of organs for transplant

The production of GM pigs to supply organs for human transplants has been the subject of considerable research effort. We have not identified any examples of xenotransplantation products from GM livestock that are currently on the market or available for treatments. Various degrees of optimism are expressed about the prospects for xenotransplantation but most proponents suggest that it will be 10 years or more before GM pig organ transplants become available. Several European countries have considered regulation of xenotransplantation and deemed it allowable only if certain ethical and safety considerations are met. There is currently no unified regulatory system for xenotransplantation in the EU.

Pets

GM ornamental fish have been available commercially in the USA since late 2003, and these are essentially unregulated. Research is reportedly also being conducted to produce GM cats with reduced allergenicity for humans. Import of such animals into the EU would be covered under existing GM regulation.

Welfare and ethical issues

One of the most contentious issues with regard to use of GM animals is the welfare and ethical issues which these raise. GM animal welfare may need a case-by-case assessment, both predictive and through monitoring of test GM populations for several generations. Relatively little information appears to be available on attitudes to particular applications for specific purposes, rather than GM animals in general. However, extensive ethical reflection has been carried out, particularly with respect to xenotransplants, although this does not necessarily mean that there is universal agreement on the ethical considerations.

Genetically modified and cloned animals

Somatic Cell Nuclear Transfer (cloning) is being used in conjunction with genetic modification, as a technique which enables genetic modification. Since there is little regulation specific to cloning, the main regulatory issues will be around genetic modification. Within Europe, there are a few exceptions. Denmark has recently enacted regulation which restricts the use of GM and cloning only to research purposes for health and environmental benefits. In Norway, legislation prohibits cloning and this is also likely to apply to animals which are GM and cloned.

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Technology assessment and foresight

Animal biotechnology presents many challenges and opportunities for government regulators and the public in all nations. The technology is often controversial even within one country. The complexities multiply when considering the regulation of animal biotechnology in several nations. This is reflected in the way in which different counties are assessing, validating and judging this technology in order to ensure that regulation is efficient and safety maintained.

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SECTION 1 INTRODUCTION1.1 IntroductionThe purpose of this report is to identify potential socio-economic impacts (benefits and risks) and new policy implications arising from the development of Genetically Modified (GM) animals to the EU and of the commercialisation of products from genetically modified animals. Furthermore the aim is to compare regulatory frameworks and visions world-wide.

GM animals are being developed for a number of different applications such as production of pharmaceuticals, organs for transplantation and meat and milk for human consumption. A full description of applications of GM animals is given in Report 1. GM animals may also be used as experimental tools to understand fundamental biology and model human diseases, but these applications were excluded from our remit. In some cases somatic cell nuclear transfer (SCNT) cloning is used in conjunction with genetic modification as the processes of SCNT enables GM to be carried out, as described in more detail in Report 1. Ethical questions and public concerns are only briefly considered in this report as they are the subject of a larger EC Specific Support Action on ‘Farm Animal Cloning and the Public’. Within this report the term ‘cloning’ should be understood to mean SCNT cloning unless otherwise stated and the term ‘animal’ should be understood to refer to non-human animals only. Genetic markers are also being applied to livestock by breeders (Marker Assisted Selection) and are the subject of considerable research effort to better understand genetics and gene function in farm livestock. These applications (broadly defined as farm animal genomics) were excluded from our remit. Issues raised by the development of cloned animals are covered separately in Report 2.

This report is in 12 sections.

Section 1 is an introduction.

Section 2 gives an overview of the regulatory frameworks.

Section 3 considers the risks from GM animals and the risk assessment methods adopted by regulatory bodies.

Section 4 considers issues around international trade in GM animals and the products from GM animals, including labelling issues

Section 5 considers the issues around physiological animal welfare

Section 6 considers public attitudes

Section 7 considers the policy contexts and visions around GM animals

Section 8 gives a meta-analysis of governmental technology foresights and assessments

Section 9 considers Case Studies of applications of GM animals.

Section 10 Reflections

Section 11 References

Section 12 Appendices

This study was conducted March-September 2005. The scientific aspects were investigated by staff at Roslin Institute, the commercialisation activities by staff at Genesis Faraday Partnership, legal aspects by staff at the Centre for Studies in Intellectual Property and Technology Law, technology foresights and assessments by VDI and the risk assessment, trade and socio-economic aspects by staff at the Innogen Centre. The methodology consisted primarily of literature and web surveys. A one-day ‘hearing’ was held at Innogen on Sept. 5th to bring a number of different

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types of expertise to bear on the subject, including experts in innovation processes. Additionally, useful interchange of information took place with the Specific Support Action “Farm animal cloning and the public” and in a 2-day workshop held in Seville in June 2005, co-organised by the IPTS and the above mentioned SSA.

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SECTION 2 OVERVIEW OF THE LEGAL FRAMEWORK2.1 Overview of the legal frameworksThere are a large number of possible areas where GM animals may be developed, including:

Agricultural use for food production

Production of organs for transplant into humans (xenotransplantation)

Production of pharmaceuticals in the milk, eggs and blood of animals; and

Production of specific types of companion animals (pets)

As stated in Report 1, the most likely applications to be available commercially within the next 5 years are pharmaceuticals produced by animals (so called ‘bioreactors’) where some products are in late clinical trials and companion animals (such as ornamental fish), which are already available commercially in the USA. Applications for xenotransplantation and food production appear to be further away from commercial reality.

Because of this extensive range of applications, the range of different regulations that must be considered is also extensive.

If cloned animals are also genetically modified, then, as there is a lack of legislation specific to animal cloning in Europe, the legislation regulating the genetic modification of animals will apply. Exceptions are Norway and Denmark as these countries have specific legislation regarding animal cloning, the details of which are given in Report 2.

2.2 EU legislationIn contrast to animal cloning, genetic modification of animals has been extensively regulated in the EU, largely due to the commercialisation of GM crops. Community legislation on GMOs designed to protect its citizens’ health and the environment while simultaneously creating a unified market for biotechnology has been in place since the early 1990s and throughout the decade, the regulatory framework has been further extended and refined.

2.2.1 GMOs for deliberate release in the environment

While the contained use of genetically modified micro-organisms, e.g. laboratory research (in a confined environment), is regulated by Directive 90/219/EC on the contained use of genetically modified micro-organisms, Directive 2001/18/EC provides the legislation governing the release of GMOs into the environment e.g. for cultivation, import or processing into industrial products, by putting in place a step-by-step approval process, based on a case-by-case assessment of the risks to human health and the environment before any GMO or product consisting of or containing GMOs can be released into the environment or placed on the market.

In order to market a GMO, the company must first submit an application to the competent national authority of the Member State where the product is to be first placed on the market. A full environmental risk assessment must accompany the application. If the national authority gives a favourable opinion, the Member State notifies the Commission, which then in turn informs the other Member States. If neither Commission nor Member States object, the competent authority that carried out the evaluation then consents to the product being placed on the market throughout the European Union subject to any conditions required in that consent.

In the case of objections, a decision will be taken at Community level. The Commission first obtains the opinion of its Scientific Committees and, if this opinion is favourable, proposes a draft Decision to the Regulatory Committee composed of

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representatives of Member States for opinion. If this opinion is also favourable, the Commission adopts the Decision. If any of the opinions is unfavourable, the draft Decision is submitted to the Council of Ministers for adoption by qualified majority or rejection. If the Council does not act within 3 months, the Commission can adopt the decision.

2.2.2 Traceability

Products consisting of or containing GMOs and food products obtained from GMOs which have been authorised on the basis of the procedure under Directive 2001/18/EC (Part C) or Regulation (EC) No 1829/2003 are also subject to traceability requirements according to Regulation (EC) No 1830/2003.

Traceability in this connection is the ability to track GMOs and food products obtained from GMOs at all stages, throughout the production and distribution chain. The traceability rules requires anyone who places a product on the market or receives a product placed on the market in the Community to be able to identify their supplier and the companies to which the products have been supplied. If products consist of or contain mixtures of GMOs to be used only and directly as food or feed or for processing, replacing this information by a declaration of use by the operator is permissible, if the declaration is accompanied by a list of the unique identifiers for all those GMOs that have been used to constitute the mixture.

2.2.3 GM foods

Until 18 April 2004, GM food was regulated as novel food with no specific legislation covering GM feed for animal consumption. Since then, the placing on the market of GMOs intended for food or feed and of food or feed products containing, consisting of or produced from GMOs is governed by Regulation 1829/2003 on genetically modified food and feed. It provides for a single Community procedure for the new authorisation of all food and feed derived from a GMO and, as the case may be, of the GMO itself as a food or as a feed and of food or feed containing the GMO. Where a food product contains or consists of GMOs, the applicant has a choice: either the application as a whole is subject solely to Regulation (EC) 1829/2003, in application of the principle of "one door, one key", in order to obtain authorisation for the deliberate release of a GMO into the environment - in accordance with the criteria laid down by Directive 2001/18/EC - and for the use of this GMO in food products - in accordance with the criteria laid down by Regulation (EC) 1829/2003; or the application - or part of it - is subject both to Directive 2001/18/EC and to Regulation (EC) 1829/2003.

To obtain this authorisation, an application must be sent to the competent authority of a Member State according to Regulation 641/2004. The European Food Safety Authority (EFSA) prepared further guidance to assist the applicants in the preparation of the application. Should the application concern food and feed containing or consisting of a GMO (rather than food and feed produced from a GMO) the applicant has the choice of either supplying an authorisation for the deliberate release into the environment already obtained under Part C of Directive 2001/18/EC, or of applying for the environmental risk assessment to be carried out at the same time as the safety assessment of the food and the feed. According to Article 9 of the directive, a member state must perform a public consultation before the release of any GMO. However, the way in which this consultation is performed is left up to each member state.

2.2.4 Food Safety Legislation

Food Safety Legislation regarding products derived from cloned animals is considered in greater detail in Report 2. The legislation applies to products derived from GM animals in the same way.

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2.2.5 Pharmaceutical products

Through Regulation (EC) No. 726/2004, the European Commission established the European Medicines Agency (EMEA). In operation since 1995, the EMEA has responsibility for co-ordinating and supervising the evaluation of medicinal products throughout the European Union. For the approval of drugs in the EU, there is both a mutual recognition procedure and a centralised procedure. In the latter, companies submit one marketing authorisation to the EMEA, which conducts an evaluation through its Committee for Medicinal Products for Human Use (CHMP) or Committee for Medicinal Products for Veterinary Use (CVMP).5

Products produced in transgenic animals would have to pass through the centralised procedure – Article 3.1 of Regulation 726/2004 gives the EMEA responsibility for all medicinal products produced via recombinant DNA technology.

i. Human medicinal products

The basic regulation of human medicinal products (HMPs) is found in Directive 2001/83/EC, amended by Directive 2004/83/EC. The Annex of Directive 2001/83/EC describes the requirements for testing of human medicinal products; recombinant DNA products are also subject to additional special requirements. Furthermore, products need to be developed in accordance with Directive 2001/20/EC which describes good clinical practice and Directive 2004/10/EC which describes good laboratory practice. All testing on animals must also be in accordance with Directive 86/609/EEC. It is likely that HMPs containing or derived from genetically modified organisms will also be considered in connection with relevant GM legislation such as Directive 2001/18/EC.

ii. Veterinary medicinal products

Veterinary medicinal products could also be produced from GM animals. The basic regulation of veterinary medicinal products (VMPs) can be found in Directive 2001/82/EC, modified by Directive 2004/28/EC. The annex to this Directive contains the requirements for tests to be performed in accordance with the provisions for good laboratory practice as prescribed by Directive 2004/10/EC. For VMPs containing genetically modified organisms this Directive needs to be considered in connection with the relevant GM legislation such as Directive 2001/18/EC.

2.2.6 Xenotransplantation

There is currently no implemented or asserted regulatory jurisdiction over Xenotransplantation in the EU. Rather, in 1997 the Council of Europe recommended Member States to establish regulatory systems that should focus on minimising the risks of transmission of disease.6 Meanwhile, a more comprehensive EU approach to xenotransplantation appears to be in development. As the UK’s Medicines and Healthcare Products Regulatory Agency (MHRA) declared in its business plan for 2005-2006:

The UK will hold the Presidency of the Council of the European Union between July and December 2005. Most of the legislation that underpins medicines and devices regulation in the UK comes from Europe. As a result there is a well developed infrastructure in the EU for co-ordinating Member States’ views and making decisions about regulation…

… We are also involved in two rather more specific areas: we are leading the development of European guidelines for the regulation of xenotransplantation and providing significant contributions to European

5 http://www.emea.eu.int/htms/aboutus/emeaoverview.htm site visited September 20056 http://www.coe.int/T/E/Social_Cohesion/Health/Recommendations/Rec(1997)15.asp

8

http://www.emea.eu.int/htms/aboutus/emeaoverview.htm

regulations for evaluating biological and biotechnology medicinal products.7

This may build on a report commissioned by the Council of Europe in 2003 (‘State of the Art Report in the Field of Xenotransplantation’8) that included a wide range of experts from member and non-member states.

A brief overview of legislation in some member states follows.

i. France

In 1995, the Etablissement Français des Greffes, the French national transplantation agency, formed an expert committee on xenotransplantation, which, in 1996, published a draft document on ‘Good Practice Guidelines for the Production of Pigs’. Ethical aspects of xenotransplantation are also considered by the French National Advisory Ethics Committee. On 14 January 1998, the French Parliament adopted a draft law on new ‘Health and Safety Regulations’, which contains regulation on xenotransplantation, stipulating that research on xenotransplantation will be regulated by existing biomedical research legislation. Applications for clinical trials require approval from the Health Safety Agency (Agence Française de Sécurité Sanitaire des Produits de Santé) and the Ministry of Health.

ii. Germany

In 1999, a statement from the Bundesaerztekammer (Federal Medical Association) was published in Germany. Accordingly, as for any treatment, the legal basis for a xenotransplantation is the contract between doctor and patient. In the current phase of clinical application, however, xenotransplantation must be considered as an experiment on human beings and falls under biomedical research according to paragraph 15 of the regulation of the medical profession and requires approval from the Ethics Commission. Thus, xenotransplantation will only be permitted if the proportionality principle is adhered to, i.e. if the proportion between benefit for the patient and risk of the procedure is balanced. Xenotransplantation itself is regulated through the Law Governing the Manufacture and Prescription of Drugs (Arzneimittelgesetz). Paragraph 13 requires permission for manufacturing and paragraph 67 requires proof of clinical trial. The Genetic Technology Law (Gentechnikgesetz) is applicable to the preparation of the donor animals. 9 This means in practice that all the necessary care must be taken as defined in great detail for four different degrees of safety according to the risk category involved. The law also regulates permits that need to be obtained for gene technology work.

iii. Netherlands

In the Netherlands, the Committee on Xenotransplantation of the Health Council presented a report on xenotransplantation to the Minister of Health, Welfare and Sport on 21 January 1998, concluding that xenotransplantation can be an alternative to transplantation of human organs, tissues or cells. However, clinical application is only considered ethically acceptable when the rejection problems are of approximately the same order as with human organs and the risk of pathogen transfer can be managed. Also, due consideration must be given to animal health and welfare and non-human primates should not be used as source animals.

7 http://www.mhra.gov.uk/publications/businessplan/engage&influence.htm?Open (site visited June 21, 2005)8 Available from:

http://www.coe.int/T/E/Legal_Affairs/Legal_co-operation/Bioethics/Activities/Xenotransplantation/INF_2003_12e%20xeno%20ER.pdf9 http://www.bundesaerztekammer.de/30/Richtlinien/Empfidx/Xenotrans1.html

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http://www.bundesaerztekammer.de/30/Richtlinien/Empfidx/Xenotrans1.html

http://www.mhra.gov.uk/publications/businessplan/engage&influence.htm?Open

The Committee also indicates the existence of legislative gaps and suggests the development of laws regulating the quality and control of medical products of living origin ("biologicals"). Source animals and transplant recipients will fall under the regulations concerning genetically modified organisms (GMOs), which may cause problems, as these regulations were not designed for medical applications. The report calls for international agreement on these and other regulatory measures. Finally, the Committee suggests giving the sole authority for approving xenotransplantation to the Central Committee on Medical Research, which will be formed within the framework of the Medical Research Involving Human Subjects Act.

iv. Spain

On 8 May 1997, the Permanent Committee on Transplantation of the Interterritorial Council of the Spanish National Health System approved a proposal to form a Subcommittee on Xenotransplantation formed of experts from different backgrounds.

The Subcommittee released a background document on xenotransplantation and the Spanish Guidelines on Xenotransplantation on 17 June 1998. These Guidelines require that before human trials, preclinical studies must demonstrate six-month survival and function of cells, tissues and organs as well as absence transmission of infectious agents.10

v. UK

The UK government established the Xenotransplantation Interim Regulatory Authority (XIRA) following the publication of a report by the Department of Health's Advisory Group on the Ethics of Xenotransplantation (the Kennedy Report) in January 1997. The Kennedy Report also confirmed the potential acceptability of using pig organs as a source for xenotransplants, thus concurring with the findings of a similar report published by the UK Nuffield Council on Bioethics in March 1996.

In governing xenotransplantation, XIRA evaluates applications for clinical trials or approvals on a case-by-case basis, considering evidence on safety, efficacy, animal welfare and infection surveillance. As of the publication of UK XIRA’s 5 th annual report, however, no applications have been approved. Further, XIRA has suggested xenotransplantation research “in other countries have similarly not advanced sufficiently to justify human studies to our knowledge.”11

2.3 The regulation of GM animals worldwideIt is impossible in this report to cover regulation in all the countries of the world, therefore special emphasis has been placed on countries which have developed/appear to be developing GM animals, and where regulatory information is available. It should be noted that we experienced considerable difficulty in ascertaining regulations in Asian countries in particular.

2.3.1 USA

i. Overview of US Regulatory System for Transgenic Animals

US regulation of biotechnology is covered by the 1986 Co-ordinated Framework for Regulation of Biotechnology, which deemed that no new laws are required to regulate the products of biotechnology because the products, not the process used to create them should be the focus of regulation. This is underpinned by the

10 Subcomisión de Xenotrasplante de la Comisión Permanente de Trasplantes del Consejo Interterritorial del Sistema Nacional de Salud11 UK XIRA, 5th Annual Report

(http://www.advisorybodies.doh.gov.uk/ukxira/fifthannualreport04.pdf)

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assumption that the process of biotechnology posed no special risks. Accordingly, the products of biotechnology are governed by the same laws that regulate health and safety of similar products derived by more traditional methods. Evidence of the FDA’s stance on transgenic animals for human food supply goes back as far as a 1996 publication and a USDA website from 1999.12

In the United States, the responsibility for regulating transgenic animals is shared between three federal agencies: the Food and Drug Administration (FDA), the Department of Agriculture (USDA) and the Environmental Protection Agency (EPA). The way in which these different agencies are involved is described in more detail in Report 2, and a summary is presented in Table 1. It is key to note that since transgenic animals are considered ‘animal drugs’, jurisdiction predominantly falls under the CVM and the FFDCA. However, this is not always the case and consideration must be paid to the role of the transgene.

Most transgenes affecting animal performance or function would fall under the authority of the FDA’s Center for Veterinary Medicine (CVM). Transgenes producing constitutive immunity would be considered veterinary biologics, the responsibility of the USDA Animal and Plant Health Inspection service (APHIS), Center for Veterinary Biologics. Transgene-mediated expression of a pesticide-like product is the responsibility of the EPA. Each of these agencies is responsible for interacting with food safety regulators, such as the FDA’s Center for Food Safety and Applied Nutrition [CFSAN], and the USDA’s Food Safety and Inspection Service [FSIS].13

Table 1 Summary Table of US Regulatory System

Genetically Modified Products Agency LawAnimals FDA FFDCA

Animals producing toxic substances EPA TSCA

GMO Derived Products

Meat, poultry, eggs USDA – FSIS MIA; PPIA; EPIA

Food additives FDA – CFSAN FFDCA

Dietary supplements FDA – CFSAN DSHEA

Human Drug FDA – CDER FFDCA

Human Biologic FDA – CBER PHSA

Animal Drug FDA – CVM FFDCA

Animal/Veterinary Biologic USDA – APHIS (CVB)

VSTA

ii. The ‘animal drug’ provision for food derived from transgenic animals

Relatively recent and prominent reports on animals in biotechnology, such as the report published by the National Academy of Sciences entitled Animal Biotechnology:

12 Miller& Matheson, 1996

www.aphis.usda.gov/vs/ceah/cei/EmergingMarketConditions_files/animal_pharming.htm13 Howard et al. 2001, E2

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Science-Based Concerns (Vanderbergh et al. 2002), envision three initial types of products derived from animal biotechnology in need of oversight:

modifications that affect the performance of the animal or attributes of products derived from the animal through the action of the expression product of an inserted gene;

animals modified to produce drugs, biologics, or other substances of commercial value; or

cloned animals.14

Likewise, there are three main types of regulatory oversight required:

standards are established for the care and treatment of animals used in biotechnology research and testing activities,

decisions are made about market access and conditions of use for the commercial products of animal biotechnology, and

government post-approval oversight is provided to verify that marketed products are in compliance with regulatory requirements.15

Concerning transgenic animals, regulation is based upon laws that largely preceded biotechnology. As earlier mentioned, following the 1986 Co-ordinated Framework for Regulation of Biotechnology, US federal policy has been that no new laws were required to regulate the products of biotechnology, since the products and not the process used to make products, are the focus of regulation. This approach has led the FDA to select ‘animal drug’ provisions to regulate transgenic animals.

It is important to note that the ‘animal drug’ approach is notably different from the FDA’s regulation of GM plants and crops, which is based upon ‘substantial equivalence.’ Under this system, GM crops are not normally subject to pre-market review since they are generally to be ‘substantially equivalent’ to conventional counterparts. The FDA would only take action if products were materially different such that they affected human or animal health.16

In the case of transgenic animals, however, the FDA deems genetic constructs, and their expression products, to be ‘new animal drugs’. The ‘new animal drug’ regulatory approach requires pre-market review, placing the onus on manufacturers to demonstrate via “adequate tests by all methods reasonably applicable” that the animal drug is “safe for use under the conditions prescribed” and with a “reasonable certainty of no harm”.17 The responsibility for evaluation lies with the FDA’s Centre for Veterinary Medicine (CVM). This centre advocates the ‘animal drug’ solution as capable of integrating environmental with animal and human safety concerns:

“One of the good things about regulating transgenics as animal drugs," says CVM director Stephen F. Sundlof, DVM, PhD, "is that we can make sure that the environmental controls and other safety measures are built right into the process." This process includes target animal safety, safety to the environment, and safety for consumers to eat foods derived from genetically engineered animals.18

14 Vanderbergh et al. 2002, 16115 Vanderbergh et al. 2002, 16116 Pew Initiative (2003)17 Pew Initiative (2003)18 Cited in Lewis (2001)

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However, these merits have been questioned since there appears to be considerable scope for interpretation within the FFDCA laws covering animal drugs, particularly concerning the focus of safety and environmental assessments:

In numerous cases, the many differences between a traditional new animal drug, which typically involves the administration of a chemical substance to an animal, and a transgenic animal, whose altered DNA affects the animal’s chemical functioning, raises many questions about the ‘fit’ of existing agency rules and practices for addressing transgenic issues.19

iii. Regulation of animal bioreactors

The products from ‘pharming’ are essentially considered as human biologics. Under the authority of the Public Health Service Act and the FFDCA, they are regulated by the FDA’s Centre for Biologics Evaluation and Research (CBER).

iv. Regulation of xenotransplantation

In January 2001, the United States Public Health Service, formed by representatives from the Food and Drug Administration (FDA), National Institutes of Health (NIH), the Centres for Disease Control and Prevention (CDC), the Health Resource Services Administration (HRSA), and staff from the Office of the Assistant Secretary for Planning and Evaluation (OASPE), published the Public Health Service (PHS) Guideline on Infectious Disease Issues in Xenotransplantation, recommending application of established procedures for infectious disease control to xenotransplantation. Risks to the public of human disease due to known and new diseases arising from xenotransplantation are to be minimised; and safety measures for the procurement, screening and use of xenotransplantation products as well as clinical care requirements for recipients are suggested. Also, the FDA position that non-human primates should not be used as source animals for xenotransplantation at the current time is reiterated. The FDA, in its position as the federal authority under the Public Health Service Act and the FDDCA to regulate xenotransplantation, has a Xenotransplantation Action Plan. Accordingly, xenotransplantation products are subject to FDA review and approval. Investigators wishing to use xenotransplantation products in clinical trials need to obtain FDA approval. In April 2003, the FDA published guidance for industry, clarifying the type of information required for product applications.

2.3.2 Canada

Together, the Canadian Food Inspection Agency (CFIA) and Health Canada are responsible for assessing the safety of GM agricultural and food products. Health Canada is responsible for conducting food safety assessments for novel foods, including those derived through biotechnology. Animal products developed using biotechnology are classified under the Novel Food Regulations section of the Food and Drugs Act and Regulations.20

Before a genetically modified agricultural or food product can be produced and marketed in Canada, it must undergo a number of scientific safety assessments. These assessments are designed to determine that the product is not dangerous for humans, animals, or the environment. Government of Canada evaluators conduct these safety assessments, taking into consideration expert advice from the global scientific community and the latest scientific literature.

The Animal Biotechnology Unit (ABU) of the Animal Health and Production Division, Canadian Food Inspection Agency (CFIA) is responsible for establishing animal 19 Pew Initiative (2003, p. 53)20 http://www.inspection.gc.ca/english/sci/biotech/gen/anibioe.shtml

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health standards and augmenting regulatory controls for the development of biotechnology-derived animals.21

In addition to fulfilling the Canadian Food Inspection Agency’s core responsibilities regarding animal health, the Animal Biotechnology Unit collaborates with other government departments and agencies to develop and implement appropriate risk-based regulatory controls for the assessment and control of biotechnology-derived animals.

The Biologics and Genetic Therapy Directorate of Health Canada, the Canadian Health Ministry, is the regulatory authority responsible for ensuring the safety, efficacy and quality of all biologics and radiopharmaceuticals for human use, marketed in Canada. These include, among others, genetic therapeutic products, tissues, organs and xenografts manufactured in Canada or elsewhere.22

Before a manufacturer/sponsor is eligible to receive a licence to market the product in Canada (called a Notice of Compliance), manufacturers must demonstrate the safety and effectiveness of their products. Once a product is approved for marketing in Canada, the Directorate continues to monitor its safety and effectiveness for the lifecycle of the product in Canada.

Xenotransplants are considered therapeutic products (drugs or medical devices) and are subject to the requirements of the Food and Drugs Act, and the Food and Drug Regulations or the Medical Devices Regulations. Pursuant to these regulations, sponsors of human clinical trials involving xenotransplants are required to submit an application to Health Canada for approval before a clinical trial may proceed.23

2.3.3 Australia

The Australian national regulatory scheme for GM animals was formally enacted by the Gene Technology Act 2000, which came into force in June 2001. This legislation replaced the former voluntary system, which had been in place since 1987. The purpose for introducing the legislation was to ensure that research into gene technology and the resulting products are regulated to identify and manage possible risks both to human safety and to the environment. An independent body, the Office of the Gene Technology Regulator (OGTR) oversees a science-based risk assessment process. The OGTR evaluates applications regarding the release of GMOs into the environment on a case-by-case basis, subject to a strict public safety and environmental risk assessment. During the process, members of the public have the opportunity to comment on the application, the risk assessment and the risk management proposals. If the application is approved, the OGTR may impose conditions and has the power to investigate and prosecute breaches of the conditions.

Foods derived from transgenic animals are subject to pre-market and safety assessment by the co-national Food Standards Australia New Zealand (FSANZ). The applicable Food Standards Code is 1.5.2. – Food produced using gene technology. Accordingly, a mandatory pre-market safety assessment is required.

The Gene and Related Therapies Research Advisory Panel (GTRAP) was established by the National Health and Medical Research Council (NHMRC) in 1994 and expanded to include xenotransplantation in 1999. GTRAP provides scientific advice to human research ethics committees in the institutions where the research

21 http://www.inspection.gc.ca/english/anima/vetbio/abu/abumainprine.shtml22 http://www.hc-sc.gc.ca/hpfb-dgpsa/bgtd-dpbtg/aboutus_e.html23 Health Canada, Biologics and Genetic Therapy Directorate, Factsheet Xenotransplantation, 1 March 2001

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would be carried out who decide whether to allow the research at that institution or not.

2.3.4 New Zealand

The Hazardous Substances and New Organisms (HSNO) Act 1996 and the Biosecurity Act 1993 are the two main pieces of legislation governing genetic modification and its application to living things in New Zealand. In 2003, the laws governing new organisms, including genetically modified organisms (GMOs), were amended in line with the Government’s overall policy of proceeding with caution with genetic modified organisms while preserving opportunities for research and innovation. The new laws came into force on 30 October 2003. The HSNO Act applies to anything that can potentially reproduce or grow; this includes fresh food (eg, GM potatoes) and any medicine containing a live GMO. The Biosecurity Act allows for the exclusion, eradication and management of pests and other unwanted organisms in New Zealand – including GM organisms. The HSNO Act seeks to protect the environment and the health and safety of people and communities by preventing the adverse effects of hazardous substances and new organisms. A ‘new organism’ in this connection is defined as a new species coming into New Zealand for the first time and includes any animal, fish, seed, plant or micro-organism. It also includes in its definition any plant, animal or micro-organism developed through genetic engineering. The Act includes a public consultation process which will allow interested parties to make submissions prior to the assessment and decision making process outlined in the Act.

Foods derived from transgenic animals are subject to pre-market and safety assessment by the co-national Food Standards Australia New Zealand (FSANZ). In its document ‘Guidelines for the Safety Assessment of Genetically Modified Foods’, last updated in March 2004, a rationale is provided for basing the regulatory approach on substantial equivalence. After these assessments, the New Zealand Food Safety Authority (NZFSA) is responsible for the enforcement of GM food labelling standards in New Zealand.

The Environmental Risk Management Authority (ERMA) is responsible for approving the release of transgenic animals. It makes its decisions under the HSNO Act, following detailed criteria set down in a formal Methodology developed in accordance with the HSNO Act, weighing up the risks, costs and benefits in each case. Some decisions for low risk GMOs are delegated to Institutional Biological Safety Committees (IBSC) in scientific institutions. These Committees also have to follow the Act and the Methodology.

Medsafe, part of the Ministry of Health, is the agency responsible for evaluating the quality and safety of all medicines approved in New Zealand under the Medicines Act 1981. Only then can they be distributed or sold as medicines.

The New Zealand Ministry of Health declined an application for a xenotransplantation clinical trial in 2001. It commented on the regulatory status of xenotransplantation in the country:

In the opinion of the Ministry of Health, xenotransplantation of cells can be regulated within the New Zealand Medicines Act 1981. Xenotransplantation must therefore meet the same requirements for safety as any other clinical trial. Due to the nature of xenotransplantation research, New Zealand needs guidance on policy and guidelines from organisations such as the Food and Drug Administration before we can even consider whether xenotransplantation can occur in this country.24

24 http://www.moh.govt.nz/moh.nsf/aa6c02e6249e7359cc256e7f0005521d/ff5646c096e846e7cc256a880003bdb4?OpenDocument

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Other agencies are involved in various aspects of GM regulation:

Medicines containing live organisms must also be approved by the Minister of Health.

The Ministry of Agriculture and Forestry carries out inspections to ensure that organisms approved for experimental or conditional release are done according to regulations

An Animal Ethics Committee must also approve all research involving animals under the Animal Welfare Act

The ERMA can also take findings from New Zealand’s Bioethics Council into account in decision making processes 25

The HSNO Act also requires the ERMA to take into account the relationship the Maori people and their “culture and traditions have with their ancestral lands, water, sites, wahi tapu, flora and fauna and other taonga.”26

2.3.5 Singapore

There are several guidelines in place with regards to research on and handling (including care and use) of transgenic animals, issued by the Genetic Modification Advisory Committee (GMAC) and the National Advisory Committee for Laboratory Animal Research (NACLAR) respectively.

2.3.6 China

The Chinese government enacted a framework Regulation on the Safety Control of Agricultural GMOs intended to protect human, animal and plant health and the environment. After this enaction, three implementing regulations were issued on Biosafety Evaluation, Import Safety and Labelling. The labelling regulation, however, only applies to five plant GMOs, namely soybean, corn seeds, rapeseeds, cotton seeds and tomato seeds as well as to the products thereof.

2.3.7 Japan

Further to ratification of the Cartagena Protocol, Japan established the ‘Law Concerning the Conservation and Sustainable Use of Biological Diversity through Regulations on the Use of Living Modified Organisms’ (LMOs). This law promulgates an approval system for using genetically modified organisms and also includes regulatory requirements for their export. It replaces the previous guidelines on experiments involving recombinant DNA techniques for the development of LMOs and the guidelines for using such LMOs for the development in agriculture, forestry, fisheries and food industry. The law provides that experiments involving recombinant DNA techniques for the development of LMOs are governed by the Ministry of Education, Culture, Science, Sports and Technology (MECSST), while the application of LMOs for veterinary purposes is governed by the Ministry of Agriculture, Forestry and Fisheries (MAFF). The field use of genetically modified animals is also controlled by the MAFF. An application must be made to the MAFF for approval, which the subgroup on animals in the Committee for Evaluation of Biological Diversity Effects (CEBDE) gives an opinion on. The required risk assessment is then discussed in the Agriculture, Forestry and Fisheries Research Council (AFFRC) of the MAFF.27

The MECSST is also responsible for regulating and overseeing experiments on xenotransplantation. The commercial application of transgenic pigs, however, is 25 Ministry for the Environment (2004)26 Ministry for the Environment (2004, p. 16)27 Yamanouchi, K., (2005)

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monitored by the MAFF. No regulation has yet been determined on the commercial use of cells, tissues or organs derived from transgenic animals for clinical trials.28

2.3.8 Korea

In 2001, the Korean Ministry of Commerce, Industry and Energy adopted the Law on Transboundary Movement of Living Modified Organisms. According to this law, each government agency is responsible for the safety assessment of both domestically developed and imported GMOs. The legislation includes government approval procedures for commercialisation of GMOs, safety assessment procedures, identification of GMOs, operation of Biosafety Committees, safety standards for research facilities involved in GMO research and the enforcement of the regulation.29

2.3.9 Conclusions

Although the countries analysed in this section all have fairly extensive regulatory systems governing transgenic animals and their use in the food chain, there appears to be little consistency of these approach between countries and much room for interpretation within countries. A notable issue is that several of the regulatory systems appear to be geared towards GM plants rather than animals.

Several countries have considered xenotransplantation and deemed it allowable if certain ethical and safety considerations are met. This appears to be an example of regulators anticipating innovation far in advance – as noted in Report 1, currently most xenotransplantation proponents estimate that GM pig organ transplantation is at least 10 years away. As the UK XIRA noted in its 3 rd annual report: ‘…the likelihood of whole organ xenotransplantation…being available within a clinically worthwhile timeframe may be starting to recede.’30

2.4 International regulation2.4.1 The Cartagena Protocol on Biosafety

The Cartagena Protocol on Biosafety regulates the transboundary movements of GMOs. As of 6 September 2005, it has been signed by 125 countries including the European Union. The US is not a party to the Biodiversity Convention and therefore has not signed the Biosafety Protocol. The Protocol came into force 11 September, 2003, 90 days after receipt of the 50th ratification. It is legally binding for the countries that will ratify it and countries that have signed it are expected, under international law, to act in good faith and not to take measures which could contradict its objectives.31

The Protocol establishes an Advanced Informed Agreement (AIA) procedure for ensuring that countries are provided with the information necessary to make informed decisions before agreeing to the import into their territory of GMOs intended for deliberate release into the environment (this includes all vegetative parts that are meant for planting such as seeds). However, the AIA procedure does not apply to GMOs which are for human consumption (food), for animal feeds or for processing. For these, relevant information has to be provided to the Parties through the Biosafety Clearing House (a mechanism set up by the Protocol to facilitate the exchange of information on GMOs, including national regulation pertaining to them, and to assist countries in the implementation of the Protocol). Moreover, these

28 Yamanouchi, K., (2005)29 See Kim, T., “Regulatory framework for GMOs in Korea: Environmental safety approval process”, International Symposium 2004 on Safety Assessment GM Crops and Foods, Korea30 UK XIRA, 3rd Annual Report (http://www.advisorybodies.doh.gov.uk/ukxira/ukxann3.htm), also cited in Turner (2002, p. 54)31 <http://www.biodiv.org/biosafety/>

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commodities, when exported, must be accompanied by documentation specifying that they ‘may contain’ GMOs and that they are not intended for intentional introduction into the environment. The Parties shall decide on the detailed requirements for this purpose, including specification of the identity of the GMOs and any unique identification.

2.5 Nutraceuticals and Functional FoodsNutraceuticals and functional foods are a growing area of research and development and potentially problematic for regulators. As foods with complex traits and pharmaceutical attributes, they have the potential to ‘blur the boundary between foods and pharmaceuticals.’32

This might be particularly worrisome if indeed transgenic animal products begin to comprise a large proportion of the nutraceutical products offered, as Turner (2002), for example, has suggested.

Generally, there appear to be two critical issues surrounding nutraceuticals/functional foods. The first is whether or not they will be governed as foods or as drugs, which in many regulatory systems have different implications. Second, regulatory agencies around the globe are attempting to establish science-based systems to determine what health and safety claims nutraceutical/functional foods manufacturers might make without misleading consumers.

2.5.1 EU

The European Commission ran a programme called FUFOSE (Functional Food Science in Europe), which focused on developing a science-based approach to the evidence needed to evaluate functional foods, which include foods altered via biotechnology.33

The FUFOSE project called for the creation of a committee to execute its findings, which has taken the form of the PASSCLAIM project.34

It should be noted that these two projects focus on functional foods generally and not specifically on biotechnology-derived foods. Currently, nutraceutical/functional food products do not have any specific EU legislation. Decision-making is at the national level, however existing EU regulations, such as those related to safety aspects or labelling of GMOs, would apply. In 2003 the Commission submitted a final proposal for a new regulation on nutrition and health claims made on foods, (COM2003/424) thus setting a new framework which will allow health claims under strict conditions and following and independent scientific assessment.

2.5.2 USA

A recent court case in the United States decided that the FDA should govern ephedra, a nutraceutical product, as a food and not a drug, thus placing the onus on the FDA to demonstrate a product is harmful. With drugs, the manufacturer must demonstrate the product is safe.35

Concerning any biotechnology-derived nutraceutical, regulation would likely fall under the jurisdiction of the FDA’s Center for Food Safety & Nutrition:

A third grouping of transgenic animals are those modified in a manner to affect their quality as food for humans. Examples might include cattle

32 Turner (2002, p. 51)33 http://www.eufic.org/gb/what/what.htm (site visited August 10, 2005)34 http://passclaim.ilsi.org/ (site visited August 10, 2005)35 Thiessen (2005)

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producing more nutritionally complete milk, fish that produce more omega-3 fatty acids, and farm-raised trout whose flesh is pinker. It is anticipated that CFSAN, rather than CVM, will evaluate these types of modifications under the food additive, color additive or Generally Recognized As Safe (GRAS) provisions of the FFD&C Act.36

This would appear to create a demarcation between transgenic animals modified to affect growth, behavioural or disease-resistance characteristics, which would be regulated under the animal drug provisions, and transgenic animals modified so as to affect the quality of food. Thus, it may be concluded that the regulation of nutraceuticals, let alone biotechnology-derived nutraceuticals, is not clearly delineated and needs further clarification, since:

The Food and Drug Administration’s (FDA) involvement with functional foods has expanded in recent years; however, the regulation of functional foods remains confusing…Under current regulations, functional foods or components can be placed into a number of existing regulatory categories, including conventional foods, food additives, dietary supplements, medical foods, or foods for special dietary use37

2.5.3 Japan

According to the European Food Information Council, Japan is a world leader in the regulation of functional foods, however no information is provided about the Japanese approach to biotechnology-derived nutraceuticals.

2.5.4 Conclusions

Nutraceuticals represent a broad range of food types and present new challenges to regulatory agencies. These principally relate to food safety as well as to the claims that manufacturers are allowed to make concerning the health benefits of these foods. Regulators have not yet given much attention instances where biotechnology is used to produce nutraceuticals. A plausible scenario is that such products will fall under existing legislation governing GM foods as well as legislation governing nutraceuticals.

2.6 Patenting GM animalsIntellectual property, and patenting in particular, of life forms has caused considerable discussion worldwide. These discussions ranged from the question whether life forms could be patented at all to the extent of whether a living creature or only parts of DNA were patentable.

2.6.1 The regulation of patenting on an international level

Although intellectual property law normally only protects rights at a national level, patent law can probably be considered as the most harmonised area of law worldwide. The reason for this is the many international efforts to provide a uniform approach to the substance of intellectual property law throughout the world, efforts beginning with the Paris Convention for the Protection of Industrial Property as early as 1883. At that time, eleven countries signed the Convention. The Convention now has 169 country members, including all EU Member States, which makes it one of the most widely adopted treaties worldwide and has led to the establishment of the World Intellectual Property Organisation (WIPO). The Paris Convention was the first major international treaty designed to help the people of one country obtain

36 Miller & Matheson (1996)37 American Diabetic Association (2004)

(http://www.webdietitians.org/Public/GovernmentAffairs/92_adap1099.cfm, visited August 10, 2005)

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http://www.webdietitians.org/Public/GovernmentAffairs/92_adap1099.cfm

protection in other countries for their intellectual creations in the form of industrial property right; it entered into force in 1884 with 14 signatory states. An International Bureau was set up to carry out administrative tasks, such as organizing meetings of the signatory states. In 1974, WIPO became a specialised agency of the United Nations system of organizations, with a mandate to administer intellectual property matters recognised by the member states of the UN.

The Patent Cooperation Treaty of 1970 simplifies and reduces the cost of obtaining international patent protection and facilitates public access to a wealth of technical information relating to inventions. By filing one international patent application under the Patent Cooperation Treaty applicants can simultaneously seek protection for an invention in over one hundred countries, including developing countries, throughout the world.

An international harmonisation treaty on patent formalities, the Patent Law Treaty was adopted in June 2000, to standardise divergent formal requirements applied in national and regional patent systems to patent applications and patents. The Patent Law Treaty will allow users of the patent system to rely upon predictable and simple procedures for filing national and regional patent applications and for the maintaining of patents in all contracting parties. The Patent Law Treaty entered into force on April 28, 2005.

The Budapest Treaty on the International Recognition of the Deposit of Micro-organisms for the Purposes of Patent Procedure from 1977 enables a patentee of a contracting state who wishes to patent an invention internationally to deposit one sample of a micro-organism to his national patent office instead of being required to deposit in each country in which protection of the patent is sought. This treaty was ratified by around 30 countries and for nearly 25 years was the only intellectual law treaty dealing exclusively with patenting life forms.

The Agreement on Trade-Related Aspects of Intellectual Property Rights 1994 (TRIPS) was included in the Accord finalising the Uruguay Round of the General Agreement on Tariffs and Trade (GATT) in 1994, touching all major forms of intellectual property right. TRIPS is administered by the World Trade Organisation (WTO). Signatory countries that do not comply with the provisions of TRIPS may face proceedings before the GATT dispute settlement panel. Article 27 of TRIPS obliges signatory states to provide patent protection ‘in all fields of technology’, with Article 27 (2) and (3) providing exemptions:

1. Subject to the provisions of paragraphs 2 and 3, patents shall be available for any inventions, whether products or processes, in all fields of technology, provided that they are new, involve an inventive step and are capable of industrial application. Subject to paragraph 4 of Article 65, paragraph 8 of Article 70 and paragraph 3 of this Article, patents shall be available and patent rights enjoyable without discrimination as to the place of invention, the field of technology and whether products are imported or locally produced.

2. Members may exclude from patentability inventions, the prevention within their territory of the commercial exploitation of which is necessary to protect ordre public or morality, including to protect human, animal or plant life or health or to avoid serious prejudice to the environment, provided that such exclusion is not made merely because the exploitation is prohibited by their law.

3. Members may also exclude from patentability:

(a) diagnostic, therapeutic and surgical methods for the treatment of humans or animals;

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http://www.wipo.int/pct/en/basic_facts/index.htm

(b) plants and animals other than micro-organisms, and essentially biological processes for the production of plants or animals other than non-biological and microbiological processes. However, Members shall provide for the protection of plant varieties either by patents or by an effective sui generis system or by any combination thereof. The provisions of this subparagraph shall be reviewed four years after the date of entry into force of the WTO Agreement.

These exemptions are possible for inventions that are contrary to public order and morality, which includes inventions the sale of which must be prevented to protect human, animal, plant life and health or to avoid serious harm to the environment. Furthermore, inventions relating to the diagnostic, therapeutic and surgical treatment of humans and animals are excluded in Article 27.3 (a). Article 27.3 (b) excludes the essentially biological processes for the production of plants and animals, but grants the patentability of micro-organisms as well as microbiological and non-biological processes for the production of plants and animals. These exemptions, however, are not mandatory. Rather, signatory states may invoke them if they wish to.

Due to this harmonisation, the requirements for patenting of biotechnological inventions do not vary significantly between countries and will only be described for Europe with any important differences flagged up.

2.6.2 Patenting legislation in the EU

The Convention on the Grant of European Patents of 5 October 1973, commonly known as the European Patent Convention (EPC), is a multilateral treaty instituting the European Patent Organisation. The Convention provides an autonomous legal system according to which European patents are granted. There is currently no single European Union-wide patent, however, since the 1970s, there has been concurrent discussion towards the creation of a Community Patent in the European Union. In May 2004 however, this led to a stalemate and the prospect of a single EU-wide patent is receding. The EPC is separate from the European Union, and its membership is different, but includes all current EU member states. A single patent application may be filed at the European Patent Office at Munich, at its branches at The Hague or Berlin or at a national patent office of a Contracting State, if the national law of the state so permits.

The substantive law of the Convention includes provisions on patentability, provisions related to the right to a European patent and more. One of its most important articles is Article 52(1), entitled “Patentable inventions”. This article states that “European patents shall be granted for any inventions which are susceptible of industrial application, which are new and which involve an inventive step”, the basic patentability provision under the EPC. However, the EPC also provides exceptions to patentability, such as exceptions by virtue of the nature of the patent system (Article 52(2) and (3)) and exceptions by virtue of policy (Articles 52(4) and 53). Other exceptions include methods for treatment of the human body by surgery, inventions contrary to ordre public or morality and plant or animal varieties (exceptions by virtue of policy). Article 53 (b) states that plant or animal varieties or essentially biological processes for the production of plants or animals are not patentable, but elaborates further that this provision does not apply to microbiological processes or the products thereof.

Differences in interpretation of Articles 53 (a) – ordre public – and 53 (b) – the exclusion of plants and animals – have led to confusion. The European Patent Office as well as several member states of the European Patent Convention have applied the two Articles in an inconsistent manner when considering whether to grant patents regarding transgenic plants and animals. An example of this is the ‘Oncomouse’ patent. Having successfully applied for a patent in the USA, Harvard University filed a

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http://en.wikipedia.org/wiki/Invention

http://en.wikipedia.org/wiki/Patentability

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http://en.wikipedia.org/wiki/European_Union

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http://en.wikipedia.org/wiki/Treaty

http://en.wikipedia.org/wiki/1973

http://en.wikipedia.org/wiki/October_5

patent application with the European Patent Office in June 1985. It was initially refused in 1989 by an examination division of the European Patent Office among other things on the grounds that the European Patent Convention excludes the patentability of animals per se. The decision was appealed with the result that the Board of Appeal held that animal varieties were excluded of patentability by the EPC (and especially its Article 53(b)), while animals (as such) were not excluded from patentability. Thus, the term “animal variety” was applied to mean animal species, while “animal” was the individual animal. The examination division then granted the patent in 1992.

In 2000, EC Biotechnology Directive (98/44/EC) finally came into force. Article 3 states that inventions are patentable if they are new, involve an inventive step and are likely to have industrial application.38 Article 4 provides that animal varieties and biological processes for the production of animals are not patentable, however, inventions concerning animals are patentable if the invention is not confined to one particular animal variety. The Directives include a non-exclusive list of unpatentable processes, for example, human cloning, germ-line modifications, embryo processes, transgenic processes, etc.

The Directive allows for the patenting of plants and animals provided that the application of the invention is not technically confined to a single plant or animal variety. This means that a patent for a novel gene sequence that confers a benefit to a plant will extend to any plant in which the gene has been artificially inserted.

According to Article 3, inventions which are new, which involve an inventive step and which are susceptible of industrial application are patentable. The requirement that an invention display ‘novelty’ is measured against state of the art. State of the art, however, has a different meaning in Europe and the USA. While in Europe, state of the art is defined as the sum total of human knowledge available by any means anywhere in the world, in the USA, this human knowledge is seen to extend only throughout the USA.

In 1999, the Administrative Council of the European Patent Office (EPO) amended its Guidelines in 1999 to reflect several of the Directive’s provisions, as well as to avoid a conflict between the Biotechnology Directive and the European Patent Convention.

2.6.3 Patenting legislation worldwide

i. USA

The patentability of inventions under U.S. law is determined by the Patent and Trademark Office (USPTO) in the Department of Commerce. A patent application is judged on four criteria. The invention must be useful in a practical sense, novel, and non-obvious. The invention also must be described in sufficient detail to enable one skilled in the field to use it for the stated purpose (sometimes called the "enablement" criterion).

In general, raw products of nature are not patentable. DNA products usually become patentable when they have been isolated, purified, or modified to produce a unique form not found in nature.

In the United States, patent priority is based on the “first to invent” principle: whoever made the invention first (and can prove it) is awarded property rights for the 20-year period. Inventors have a one-year grace period to file after they publish. All other countries except the Philippines, however, follow a “first inventor to file” rule in establishing priority when granting patents.

When a biotechnology patent involving an altered product of nature is issued, the patent holder is required to deposit a sample of the new invention into one of the 26 38 De Simone, F. and Serratosa, J., 2005

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worldwide culture depositories. Most DNA-related patents are issued by the USPTO, the European Patent Office, or the Japanese Patent Office.

U.S. patent applications are confidential until a patent is issued, so determining which sequences are the subject of patent applications is impossible. This is different from the European regulation, where a patent application is made public 18 months after filing. One problem this fact raises is that if a European researcher applies unsuccessfully for a patent, the information is then released into the public domain without the protection of a patent, and this may seriously affect any work in progress. In the USA, if a patent is not granted, the information has never been made public and the research can continue being developed until a more robust invention is produced.

ii. Canada

In Canada, the patenting of life forms has evolved chiefly as a result of court or patent office rulings rather than through amendments of the Patent Act, in particular through the so-called ‘Oncomouse’ decision. In 1988, the Oncomouse, a mouse carrying a human cancer gene, had already been patented in the USA and also has patent protection in Australia, Japan and several European countries. From this patent, Harvard derives the exclusive right to create the mice and to charge licensing fees for their use. In 1993, Harvard had obtained a patent on the oncogene and the related process claims, but not on the mouse itself or its progeny carrying the gene, from the Canadian Intellectual Property Office. In 1995, the decision was upheld by the Commissioner of Patents and an appeal was dismissed by the Trial Division of the Federal Court in 1998. In 2000, however, the Trial Court’s decision was overturned by the Federal Court of Appeal granting patenting rights over both process and mouse. In December 2002, the Supreme Court of Canada delivered a landmark decision. In the case of Commissioner of Patents v. President and Fellows of Harvard College39, the Court decided that ‘invention’ under the Canadian Patent Act excluded the patenting of mammals. An invention under the Patent Act is defined as “any new and useful art, process, machine, manufacture or composition of matter, or any new and useful improvement in any art, process machine, manufacture or composition of matter.” The Court held that “just as ‘machine’ and ‘manufacture’ do not imply a living creature, words ‘composition of matter’ are best read as not including higher life forms.” The patenting of other multicellular organisms, plants or invertebrates for example, is, since not touched upon in the decision, still possible. The same applies to single cell organisms, cell cultures, modified genes, vectors for transferring genes into cells, cells containing the genes as well as methods of modifying and using genes. Justice Bastarache expressed the Court’s opinion by stating that the patenting of higher life forms should only be considered under clear direction of the Parliament.40

In 2004, the Supreme Court of Canada delivered another important decision on biotechnology, Monsanto Canada Inc. v. Percy Schmeiser.41 This decision, sadly, adds to the confusion rather than clarifying matters regarding the patenting of life forms further. In this case, a 5-4 majority of the Court gave the ruling that there could be infringing use of a patented gene and cell no matter what their container, that a patent on a plant cell or on a modified gene within a cell can give the patent holder a right of control over what others are allowed to do with the plants, as each single cell in the plant contains this modified gene. While the Court stressed that there was no intention to revisit the Oncomouse conclusion, the Monsanto ruling makes the 2002 39 2002 SCC 76. File No.:2815540 Canadian Biotechnology Advisory Committee, “Advisory Memorandum: higher life forms and the Patent Act”, February 24, 200341 2004 SCC 34

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ruling meaningless in practice. The ruling provides the possibility that any higher life form that contains a patented gene or cell may be subject to some exercise of power by the patent holder.

iii. Australia

Australia has one of the most liberal approaches to the patenting of biotechnology with the protection of intellectual property rights exceeding the current requirements of TRIPs (Trade-related Aspects of Intellectual Property Rights). As early as 1976, the Australian Patent Office (APO), in Rank Hovis McDougall Ltd’s Application, held that living organisms are patentable, thus implying that they can be invented. Then, in 1989 during the parliamentary debate regarding the Patent Act, the issue of whether genes and life forms should be excluded from the patent system resulted in the single exclusion of human beings and the biological processes for their generation. Under the Australian Patent Act, a patent can cover the methods for creating new life forms, the life forms themselves as well as substances using the new life forms. 42 Accordingly, the APO considers all living organisms excluding human beings as potentially patentable subject matter. Section 18 of Australia's Patents Act 1990 provides that an invention is a patentable invention if the invention is a manner of manufacture within the meaning of Section 6 of the Statute of Monopolies, is novel and involves an inventive or, respectively, an innovative step when compared to the prior art, is useful, and has not been secretly used in Australia before the priority date. In addition to these usual requirements a criterion is necessary, which is not compulsory for non-biological invention, namely that a biological invention has to be repeatable. Traditional methods of creating new life forms such as hybridisation or selective breeding are thus excluded from patenting. 43

iv. New Zealand

Patents in New Zealand was previously considered in Report 2 (2.6.5).

42 “IPR protection of biological innovations”, Trade Related Aspects of Intellectual Property Rights, Staff Research Paper, Productivity Commission43 “IPR protection of biological innovations”, Trade Related Aspects of Intellectual Property Rights, Staff Research Paper, Productivity Commission

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SECTION 3 RISKS AND RISK ASSESSMENT3.1 Risks from GM animalsA GM animal has had new DNA experimentally introduced into its genetic material. Often this genetic material is termed a transgene.

The new genetic material can be:

A range of different sizes, from a large piece of DNA, potentially harbouring many genes, to single base mutations (although the later has not been achieved yet in species other than the mouse).

Derived from a different species or from the same species as the GM animal.

To-date, the transferred DNA has been in a non-mobile form. This means that once integrated, the DNA can not excise itself from the host DNA and move to another part of the genome. This includes DNA introduced using viral vectors, as in this case the viral vector has been altered in such a way that it is non-mobile.

The transferred DNA is expected to confer an activity not normally associated with the host, e.g. the production of human pharmaceutical protein in the milk of sheep. The activity of the transferred DNA can be largely anticipated through our (increasing) understanding of gene function. Depending on this activity, varying risk issues may exist.

The transferred DNA may integrate into the proximity of a host gene and induce an unexpected activity. This cannot be predicted and may carry potential risk; most likely to the well-being of the animal, and less likely to the environment or humans. The use of SCNT and cloning allows the integration event to be targeted to a given, predetermined site with the genome and therefore overcome this issue.

Three basic GM events are possible:

normal gene activity can be removed (or reduced)

normal gene activity can be increased

novel gene activity can be introduced.

The engineered alteration of activity of a gene can be expected to cause associated changes in many other genes. These changes can be dramatic or subtle. In addition, combinations of events or multiples events can be engineered.

The following description of risk from GM animals is divided into food safety issue, pharmaceutical safety issues, xenotransplantation safety issues, environmental risks from release to the environment and disease risk to current animals.

Generic issues will be discussed since the specific risk issues associated with a given GM event will require a case-by-case assessment. Two basic risks are envisaged. The risk associated with products from GM animals and the risk associated with the GM animal itself.

3.1.1 Food safety issues

The risk in this use is associated with products obtained from GM animals. Products from GM animals that are to be eaten may deliberately contain the transgene product or the GM event may be targeted at another aspect of the animal phenotype, e.g. a transgene product expressed in the skin of an animal should not contribute to muscle composition. These products may be for human or animal consumption.

Any risk will be solely dependent on the biological activity associated with the transgene encoded protein. It is anticipated that most examples will involve altered composition of host proteins through engineered enzymatic activity or

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addition/removal of specific gene products. The risk associated with these GM events is predicted to be low given that analogous changes are already accomplished through normal breeding regimes of during food processing stages. Risks arising from random insertion would require case-by-case evaluation and are also likely to be related to the function of the introduced gene. Any risks arising are more likely to be related to animal welfare than toxicity or allergenicity.

3.1.2 Pharmaceutical safety issues

The risk in this use is associated with products obtained from GM animals. In most cases the harvested product will be derived from the transgene. For most products some form of enrichment or isolation procedure will have been performed.

Given that the desired product would be destined for medical application it is unlikely to carry any risk above that associated with the biology of the, most probably, protein pharmaceutical. This is probably known or easily anticipated due to knowledge of that protein, perhaps through previous use of the protein isolated from an alternative source, e.g. a blood protein isolated from pooled human donated blood.

There may be risk associated with any co-harvested or co-isolated host animal proteins. In this case the proteins are not GM derived but will be normal animal proteins. Alternatively, there is the potential to co-isolate an animal pathogen, which will constitute a risk if the pathogen has the ability to infect humans. Again considerable knowledge of this risk can be estimated from previous use of (non-GM) animal products.

3.1.3 Xenotransplantation safety issues

In this use the GM animal is generated to provide donor tissue or organs for advanced surgical treatments. There are three relevant risk issues; the transgene product, host proteins and the host DNA present within the transplanted tissue.

It is unlikely that the transgene product will carry any significant risk as it is likely to have enzymatic activity or form an inactive protein. The risk associated with host proteins will be similar, but greater than, that encountered for a transgene encoded pharmaceutical product.

There is a theoretical risk associated with the host DNA present within the transplanted tissue. More specifically from endogenous retroviruses present in this host DNA; in the case of pigs these are termed porcine endogenous retroviruses (PERV) and are considered as the main infectious barrier in xenotransplantation. PERV has been shown to infect, but not to cause symptomatic disease in mice after islet transplantation.

Even though there is no evidence to shown that activation of endogenous virus poses a real risk, this issue has led to many countries restricting research in this application.

3.1.4 Environmental risks from releases to the environment

Two aspects are considered to pose potential risk. The first relates to survival and interbreeding of the GM animal with wild populations. In this aspect species differences in the likelihood of the risk should be considered. The second aspect relates to the risk of the GM animal being eaten by wild animals.

The first issue is dependent on the nature of the transgene and the host species. If the transgene confers some form of growth or survival advantage then an escaped animal could integrate into wild populations. This is unlikely for most commercially reared or companion animal species as there is no ‘equivalent wild population’ to integrate into (as discussed in Report 2). The exception is with GM fish and there is currently an active debate about the consequence of risk in this species.

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The second issue is unlikely to raise any additional risk beyond that associated with use of products from GM animals as food, which is predicted to carry a low risk.

At present definitive scientific scrutiny of likelihood and consequence of release is limited and usually restricted to mathematical predictive modelling. It is hard to see how such models could be tested without performing a deliberate release. Rather as our models become more predictive, then our predictions will become more reliable. This makes the assumption that we have detailed knowledge of gene activity with respect to the transgene, and each transgene will confer a different activity. Thus, risk with respect to environment will require a case-by-case evaluation.

3.1.5 Disease risk to current animals

Either deliberately, if trying to investigate a disease state, or unintentionally there is a risk that the transferred DNA will directly impact on the health and welfare of the animal. A detailed knowledge of the transgene will enable an assessment of the risk in many, but not all cases.

Again this will require a case-by-case assessment in conjunction to extensive monitoring of the animal to detect unpredicted consequences.

3.2 Risk assessmentIt is noteworthy that in a recent survey conducted by the World Organization for Animal Health (OIE), only 40% of delegates of OIE member countries indicated that their animal health regulatory agencies had appropriate capability to conduct risk assessments on biotechnology-derived animals or products. Further, “20% of respondents did not consider the guidelines for risk analysis helpful for carrying out an import risk analysis on biotechnology-derived animals or products.”44

3.2.1 Risk and regulation of transgenic animals in the EU

i. EU legislation/regulation over GM food

Directive 2001/18/EC is the principal EU legislation governing the deliberate release of GMOs into the environment as described earlier.

Applications for approval must be submitted to competent authorities of Member States. For food coming directly from a transgenic animal, both an environmental and food safety assessment must be conducted.45

Thereafter, applications for authorization are referred to European Food Safety Authority (EFSA), which makes a summary of the application dossier available to the public. EFSA carries a risk assessment and makes its opinion public for 30 days. Following this, the EFSA makes a final opinion and submits it to the European Commission, which drafts a proposal to grant or refuse the authorization. To be approved, there must be a qualified majority in the Section on GM food and feed of the ‘Standing Committee on the Food Chain and Animal Health.’46 Approved products are subject to the labelling and traceability requirements of Regulation EC 1829/2003 and EC 1830/2003.47

As of 21 June 2005, no food consisting of or produced by a GM animal has been approved by the EU.48 Furthermore, the Standing Committee on the Food Chain and Animal Health and its section on Genetically Modified Food and Environmental Risk

44 OIE (2005) 73rd General Session: Final Report (Paris: OIE). A list of the 167 OIE Member States can be found at: http://www.oie.int/eng/OIE/PM/en_PM.htm.45 http://europa.eu.int/comm/food/food/biotechnology/authorisation/environ_assess_en.htm46 http://europa.eu.int/comm/food/food/biotechnology/authorisation/decision_comm_en.htm47 http://europa.eu.int/comm/food/food/biotechnology/authorisation/decision_comm_en.htm

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as well as its section on Animal Health and Animal Welfare does not appear to have considered Food from Transgenic Livestock in any detail.49

It therefore seems as though the EU regulatory system is much more geared towards GM plants than GM animals. This perspective is supported by the UK’s AEBC (2002) report Animals and Biotechnology, which commented on the Defra public consultation relating to EC/2001/18:

“We have not come across any specific new issues for these regulations in looking at prospective applications of GM to farm (or other) animals. But we have noted that the present regulations and associated risk assessments are focussed on plants rather than animals. Were greater numbers of GM animals to enter experimental use outside the laboratory, the terms of the regulations and the nature of the risk assessments should be reviewed to check that they adequately cover all the necessary areas.”50

The EFSA’s remit is to provide independent scientific advice on issues related to food and feed safety, including animal health and welfare. This scientific advice is designed to inform legislative and regulatory measures designed to ensure consumer protection.51

Thus the EFSA is responsible for scientific risk assessment covering environmental risk and human health and animal health safety assessments. Environmental assessments must follow the methodology outlined in Appendix II of Directive 2001/18/EC (see Appendix 3). This methodology lays out general principles for environmental risk assessments. It does not explicitly deal with GM animals, however under the heading ‘GMOs other than higher plants’, it highlights which type of information should be assessed, which include the chance of gene transfer, the selective advantage/disadvantage of released species, and the possible impacts of the organism on both the environment and human health.52

There are two panels operational within the EFSA relevant to the safety evaluation of foods from transgenic animals. The Panel on genetically modified organisms is specifically focused on the deliberate release and food/feed from transgenic organisms, while the Animal Health and Welfare Panel focuses on all aspects of animal health and welfare related to food producing organisms, including fish.53

As of 2 June, 2005, neither of these two panels have published statements or guidance related to food from transgenic animals, suggesting that the EFSA has yet to consider the safety evaluation of products derived from GM animals in any great detail. Further indication of this is that searches on the EFSA website for terms ‘transgenic animal’, ‘genetically modified animal’ did not yield any relevant documents or notes.54

48 No products are listed on the Community Register of GM Food and Feed; http://europa.eu.int/comm/food/food/biotechnology/authorisation/commun_register_en.htm49 As not found on websites linked to http://europa.eu.int/comm/food/animal/index_en.htm (site visited June 21, 2005).50 AEBC (2002, para. 114)51 http://www.efsa.eu.int/about_efsa/catindex_en.html52 Appendix II, Directive 2001/18/EC53 http://www.efsa.eu.int/science/gmo/catindex_en.html, http://www.efsa.eu.int/science/ahaw/catindex_en.html54 Websites visited: http://www.efsa.eu.int/science/gmo/statements/catindex_en.html; http://www.efsa.eu.int/science/gmo/gmo_opinions/catindex_en.html;

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http://www.efsa.eu.int/science/gmo/catindex_en.html

http://europa.eu.int/comm/food/animal/index_en.htm

ii. EU risk regulation of molecular pharming

As discussed in 2.2.4, the responsible agency for medicinal products produced from recombinant DNA techniques, the European Medicines Evaluation Agency (EMEA) oversees product applications on a case-by-case basis. It has been reported that the EMEA may decide upon the approval of a human antithrombin product. ATryn, produced in goat’s milk to treat a hereditary disorder.55 The producer of ATryn expects the EMEA’s opinion to be announced in February 2006.56 However, there is little evidence to suggest that there is a European risk assessment framework specifically designed for products derived from transgenic animals.

Annex II of Directive 2001/83/EC describes the requirements for testing of biological products, but does not specifically address biologic products produced in transgenic animals. It is unclear which agency would be responsible for an environmental risk assessment, although in the language of Article 6.1 of Directive 2001/18/EC, this would be the “competent authority of the Member State within whose territory the release is to take place.” Furthermore, as has been noted elsewhere in this report, although the European Food Safety Authority (EFSA) is technically responsible for transgenic animals entering the food supply, it has yet to consider transgenic animals in great detail and does not appear to have made recommendations on drug-producing transgenic animals entering the human food supply.

3.2.2 Risk and regulation of transgenic animals in the USA

i. US risk assessment and regulation of transgenic animals for food consumption

a) Introduction

The FDA has considered the risks from transgenic animals more carefully than the EFSA of the EU. It has commissioned experts, such as a panel from the National Academy of Sciences, to study the risks of animal biotechnologies, namely genetic engineering and cloning. These findings influenced FDA regulation of cloned animals (see Report 2) as well as on transgenic animals (as earlier discussed in section 2.3.1). As the Pew Initiative reported, the two safety concerns noted in the study were toxicity, of less concern to the FDA because of its expertise in preventing them from entering food supplies, and the potential allergenicity of proteins accidentally introduced because of genetic modification. This was viewed of as more problematic, and the panel recommended that animals used as bioreactors should never enter food supplies.57

As of 6 September 2005, the FDA had not approved any transgenic animal to enter the food supply.58

b) The FDA’s Center for Veterinary Medicine (CVM)

The FDA’s Center for Veterinary Medicine (CVM), as of September 29, 2003, had “not permitted genetically engineered animals to be placed into the human food supply.” This was stated by the FDA in a warning letter sent to an investigator at the

http://www.efsa.eu.int/science/gmo/gmo_consultations/catindex_en.html;

http://www.efsa.eu.int/science/gmo/gmo_guidance/catindex_en.html; http://www.efsa.eu.int/science/ahaw/ahaw_opinions/catindex_en.html; http://www.efsa.eu.int/science/ahaw/ahaw_scientific_documents/catindex_en.html55 Stix (2005)56 http://www.transgenics.com/pressreleases/pr091605.html57 http://pewagbiotech.org/buzz/display.php3?StoryID=8258 http://www.fda.gov/cvm/transgen.htm (site visited 6 September 2005)

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http://www.fda.gov/cvm/transgen.htm

http://www.efsa.eu.int/science/ahaw/ahaw_opinions/catindex_en.html

http://www.efsa.eu.int/science/gmo/gmo_guidance/catindex_en.html

University of Illinois that had, without seeking FDA approval, released experimental animals for slaughter.59

Aside from this letter and evidence that the FDA will govern transgenic animals under the ‘animal drug provisions’ (section 2.3.1; ii), there is little information about how the FDA’s approach to governing transgenic animals will evolve. For example, there is negligible information about how risk assessments related to products coming from transgenic animals will be conducted; on the FDA’s website there is little mention of the CVM’s stance on the regulation of products derived from genetically modified animals.

One exception is a 1996 article on the CVM website, which stated that the CVM did not intend to offer a standard set of guidelines for how the food safety determination of transgenic animals would be conducted. Rather, it suggested that the human food safety assessment would resemble those for recombinant protein products. Sponsors would need to demonstrate the safety of:

“1) the transgene, including the promoter and other unexpressed regions; 2) the expression products and 3) in some cases, pleiotrophic effects, in edible animal products. Information on the biology of the genetic modification from the scientific literature, data on the biochemical characterization of the transgene and the expression products, information on the mode of action, data on the quantity of transgenes and expression products, and studies investigating oral bioavailability of the expressed protein will be useful in performing the food safety assessment.”60

The 1996 CVM article also commented on the potential that animals used in pharming end up in the human food supply:

“Safety evaluation of food derived from biopharm animals would include, in addition to the factors addressed above, an evaluation of effect of the management of the animals on their residue profile. Animal management would be examined for the potential for unsafe residues of drugs and other chemicals that were used during the utilization of the animal as a protein factory.”61

This would seem to contradict the recommendation of the panel from the National Academy of Sciences that such animals should never enter the food supply. The CVM suggested it might also consider the entry of animals used in xenotransplantation into the human food supply.62

Curiously, as pointed out in 2.5.2, where genetic modifications might impact the quality of the food product generated by transgenic animals, the CVM delegates authority to the FDA’s Centre for Food Safety and Nutrition (CFSAN).This raises serious questions around the extent to which transgenic animals modified to affect the animals’ characteristics will be regulated differently than transgenic animals modified to affect only the food’s characteristics.

c) CFSAN (Centre for Food Safety & Nutrition)

As discussed above, CFSAN has regulatory jurisdiction over genetically modified food additives and dietary supplements.63 However, there is very little published by CFSAN concerning risk assessment approaches for foods coming from transgenic

59 http://www.fda.gov/cvm/FOI/UIUCLetter.htm60 Miller & Matheson (1996)61 Miller & Matheson (1996)62 FDA (2003)

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animals modified such to affect the properties of human foods.64 A scan of approved products also suggests that the majority if not all of CFSAN’s regulatory activities concerning biotechnology has been focused on GM plants/crops.

d) USDA – FSIS (Food Safety Inspection Service)

The Food Safety Inspection Service (FSIS) has jurisdiction over meat and poultry derived from genetically modified animals to ensure general safety, wholesomeness and accurate labelling of all meat and poultry products.65

As a result, the FSIS has published guidance for industry on requirements for transgenic animals, entitled ‘Points to consider in the food safety evaluation of transgenic animals from transgenic animal research’.

Importantly and consistent with the general US regulatory approach to transgenic animals, the points to consider document stated its “intention to regulate foods produced by new methods, such as recombinant DNA techniques, within the existing regulations.”66

Likely key to FSIS regulatory activities concerning risk and transgenic livestock will centre around a definition of ‘adulterated’ and whether genetic modification (or perhaps also cloning) are a form of adulteration. As the Pew Initiative explains:

“This is because, under the Meat Inspection Act, USDA has authority to prohibit in commerce meat and meat food products that are adulterated (21 U.S.C. 601 et seq.; 9 CFR Part 301)…

Therefore, the Meat Inspection Act appears to give FSIS the discretion to declare a construct an adulterant if there is some element of risk from the construct or its expression product(s).”67

Additional information about FSIS activities in this area – including the original Points to Consider document - were not found through searching the web site http://www.fsis.usda.gov/.

e) EPA

According to the Pew Initiative, the EPA only has authority for GM Animals producing toxic substances. This authority would be under the Toxic Substances Control Act. It is predominantly the FDA that has an environmental assessment incorporated into required data files.

ii. US risk assessment and regulation of transgenic animals used in pharming

a) The FDA’s Center for Biologics Evaluation and Research (CBER)

The Center for Biologics Evaluation and Research (CBER) is the lead FDA Center responsible for the risk assessment of biopharming, with the CVM acting as a consulting group. A 1995 document, ‘Points to Consider in the Manufacture and Testing of Therapeutic Products for Human Use Derived from Transgenic Animals’ appears to be the CBER’s most substantial contribution to risk assessment of biopharming. This document outlines aspects such as characterisation of transgene constructs, characterizing and establishing stable transgenic founder animals and maintenance and animal welfare of transgenic animals.

63 Pew Initiative (2001)64 http://www.cfsan.fda.gov/~lrd/biotechm.html#pres65 Vanderbergh et al. (2002)66 http://www.neavs.org/programs/papers/birdsreasearch_7_conclusion_kdavis.htm67 Pew Initiative (2001, p.22)

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Generally, so long as the transgenic animal is cared for under Animal Welfare and other related regulations, the products from ‘pharming’ are essentially considered as biologics.68 These guidelines should be followed by manufacturers in order to prepare IND (investigational new drug) and NDA (new drug application) submissions. Risk assessment – safety evaluation as phrased in the report – focuses on testing for endogenous or adventitious agents, analysing product identify and purity. Adventitious agents are a particular concern with drugs produced via transgenic animals:

“The lack of experience with many of these hosts raises potential safety concerns about adventitious agents which will be considered on a case-by-case basis as submissions are received by the FDA.”69

The FDA states that this is generally the case with most biological products. Consequently, manufacturers should have a wide range of analytical tests and assays and purification processes in order to avoid contamination. Likewise, infection control in the animals themselves is expected to be rigorous.70

One important aspect is the ability to trace products to source animals, which in turn necessitates strong records about an animal’s history. As one study argued:

“Reliable animal history, identification, and chain of custody are intrinsic in the capability needed to trace pharmaceutical ingredients back to the animals that produced them and to retrieve the animals’ complete health and production histories”.71

This is in part because genetically modified animals producing drugs are considered as production facilities or bioreactors for regulatory purposes.

Concerning the disposal of transgenic animals, if manufacturers wish to slaughter them for human or pet food, they must seek approval with the CVM, as discussed in 3.2.2:i.

b) United States Department of Agriculture (USDA) & the Animal and Plant Health Inspection Service (APHIS)

Within APHIS, the Centre for Veterinary Biologics (CVB) is the responsible for assuring that veterinary biologicals are pure, safe and potent.72 Given this focus on biologics, there is some speculation that the definition of ‘biologics’ given in 9 CFR 101.2 covers transgenics.73 Clearly, transgenic animals producing animal vaccines do, as asserted by APHIS:

“Animal vaccines produced by transgenics will fall under APHIS regulation, just as transgenic plants and arthropods are already overseen by APHIS”.74

68 Biological products, including cellular therapies, are regulated by CBER under authority of the Public Health Service Act (42 U.S.C., Sec.201 et seq.) and the Federal Food, Drug, and Cosmetic Act (21U.S.C., Sec. 301 et seq.).69 FDA (1995)70 FDA (1995)71 Howard et al .(2001)72 http://www.aphis.usda.gov/vs/cvb/mission.htm73 CFR is the Code of Federal Regulations74 http://www.aphis.usda.gov/vs/ceah/cei/EmergingMarketConditions_files/animal_pharming.htm (site visited 21 June 2005).

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http://www.aphis.usda.gov/vs/ceah/cei/EmergingMarketConditions_files/animal_pharming.htm

http://www.aphis.usda.gov/vs/ceah/cei/EmergingMarketConditions_files/animal_pharming.htm

Transgenes producing constitutive immunity would also fall under APHIS jurisdiction.75 There is little published on the APHIS or CVB websites concerning risk assessment procedures. This is clearly a relatively new area for CVB, as its website states:

“The Animal and Plant Health Inspection Service (APHIS) of the USDA has also begun to explore implications of increased production of transgenic animals. As commercial use of transgenic food animals increases, APHIS will encounter new questions concerning animal health and disease control”.76

iii. US risk assessment and regulation of transgenic fish

a) Center for Veterinary Medicine (CVM) and transgenic fish for human food

The CVM has posted comments on its website dated from February 2000. Consistent with other FDA regulations (e.g. as in 2.3.1), it is argued that for most products, their regulation will fall under provisions for ‘new animal drugs’ until/unless new types of products directly affect the characteristics of the human food:

“The animal drug provisions of the Federal Food, Drug, and Cosmetic Act best fit transgenic animals that have agronomic traits now being investigated and developed. Other transgenics will no doubt come along that could be viewed as containing food additives, color additives, and vaccines. Development of site-specific gene insertion techniques and animal genome projects could change the scope of potential genetic modifications to yield a wider variety of products than are currently being investigated”.77

As regards the release of transgenic fish, the CVM/APHIS asserts its authority over the pre-market assessment:

“No transgenic fish have been approved for producing food in the U.S., although a variety of transgenic fish species can be found in laboratories around the world. As there is active investigation of transgenic fish abroad, as well as in the U.S., the public and the research community are occasionally exposed to predictions of the imminent commercial release of transgenic fish into the food supply. This should not occur without the pre-market approval from CVM, for those fish that have an added gene-based animal drug”.78

b) Critique of US environmental regulation of transgenic fish

Under the FFDCA, the FDA has asserted regulatory authority over transgenic fish. It should be noted that this also includes environmental assessment, albeit loosely: the FFDCA contains no explicit provisions for dealing with environmental risks – the language is focused on safety as related to ‘health of man or animal’. The FDA, in turn, interprets this risk broadly so as to include direct or indirect harms to the health of humans or animals. However, as it has been observed:

“The ‘animal’ referenced in the statute, however, typically means the animal on which the drug will be used. But in the case of transgenic fish, the key issue is not the health of the transgenic fish itself, but the effects

75 Howard et al.(2001, p.E2)76 http://www.aphis.usda.gov/vs/ceah/cei/EmergingMarketConditions_files/animal_pharming.htm77 http://www.fda.gov/cvm/transgen.htm78 http://www.fda.gov/cvm/transgen.htm (site visited 6 September 2005)

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http://www.fda.gov/cvm/transgen.htm

of the release of transgenic fish on wild fish populations. The FDA agrees that it cannot consider environmental impacts that have no health risk, such as an environmental impact that would detract from scenic beauty…Some of the potential environmental impacts of transgenic fish – including harm to centers of species origin and other genetic resources or a decline in fish community resilience – would appear to fall into that category. It is uncertain whether the FDA could exercise its authority to prevent, reduce, or mitigate such consequences”.79

Partly for the reasons surrounding environmental regulation, as well as the difficulties of post-approval monitoring and the general critique that the FDA might not be the agency with suitable expertise to regulate the environmental issues surrounding the release of GM fish, the US approach to regulation of GM fish has been critiqued by the Pew Initiative on Food and Biotechnology:

“…the FDA is only one of several agencies that could lead the regulatory review process of transgenic fish. The fact that it has stepped forward first and asserted its authority does not necessarily mean it is the most appropriate agency to do so. The FFDCA does not comfortably cover all the key issues that must be addressed when evaluating the safety of transgenic fish. Unlike conventional animal drugs, genetically modified fish carry the ‘drug’ from generation to generation. The ‘drug’ cannot stop being administered if the modified fish escape into an uncontrolled environment. As a result, environmental issues from gene flow – issues not associated with conventional animal drugs – must also be considered. The new animal drug approval authority seems least appropriate here. The FDA’s legal authority to consider environmental risks beyond harm to the modified animal itself is uncertain at best. The agency also lacks the expertise to consider ecological risks, such as those that might be posed by the escape of transgenic fish”.80

iv. US risk assessment and regulation of transgenic animals used in xenotransplantation

a) USA – FDA regulation of xenotransplants

The FDA has a Xenotransplantation Action Plan81 and, according to the website of the Centre for Biologics Evaluation and Research (CBER) of the FDA, the FDA has regulatory jurisdiction over xenotransplants.82

For regulatory and risk assessment purposes, the FDA classifies xenotransplantation products under the category ‘biologics’.

As is the case with most FDA regulation, responsibility for compiling safety assessments rests with the sponsors of research. In the case of xenotransplantation, the FDA published a ‘Guidance for Industry’ on April 3, 2003.83 This document clarifies the type of information required for product applications, which includes a wide range of information concerning the characterization of animals and xenotransplantation products (for safety, identify, purity and potency), microbial testing, manufacturing standards, as well as instructions on the collection and

79 Pew Initiative (2003, p.48)80 Pew Initiative (2003, p. 59)81 http://www.fda.gov/cber/xap/xap.htm82 http://www.fda.gov/cber/xap/comp.htm83 FDA (2003)

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presentation of preclinical and clinical data. For example, with regards to preclinical study design, the FDA states:

“Specific considerations in the design of preclinical studies that are intended to support the safety of xenotransplantation products should include:

the animal source for the xenotransplantation product;

the tissue’s anatomic and physiologic similarity to its human homologue;

the determination of function of the xenotransplantation product;

the animal model system;

the integrity of the device components (if a device is used);

the dose levels (based on tissue mass, as well as pharmacologic/metabolic activity or release kinetics of bioactive molecules);

the route of administration (site of implantation/injection, extracorporeal or ex vivo use);

the study duration (as related to potential human exposure);

reactions between source animal and host immune systems;

interspecies extrapolation (i.e., cross-species activity of secreted proteins/hormones at receptors); and

device biocompatibility”.84

Concerning instructions for clinical studies include guidelines for risk/benefit assessments, the risk of transmission of infectious disease (e.g. microbial infections, latent viruses, zoonotic diseases); the risk to patient’s immune systems (e.g. graft versus host disease) and potential public health consequences are highlighted as areas that require consideration.85

Sponsors of xenotransplantation research must also ensure that animal welfare and husbandry concerns are in-line with US legislation (e.g. Animal Welfare Act (7 U.S.C. 2131, et seq.). Finally, as mentioned in 3.2.2: i, the CBER defers to the CVM issues surrounding the potential entry of animals used in xenotransplantation into the human food supply.

In an ongoing attempt to mitigate potential public health risks from xenotransplantation, the FDA / CBER has also recently published a Draft Guidance entitled ‘Precautionary Measures to Reduce the Possible Risk of Transmission of Zoonosis by Blood and Blood Products from Xenotransplantation Product Recipients and Their Contacts’.86

3.2.3 Risk and regulation of transgenic animals in New Zealand

i. Background

A primary legislation in New Zealand is the Hazardous Substances and New Organisms Act 1996 (HSNO Act 1996) which asserts that before importing, developing, field testing or releasing any new organism, including genetically modified organisms, applicants must get the approval of the Environmental Risk Management Authority (ERMA).87

84 FDA (2003)85 FDA (2003)86 FDA (2005), published in March, 2005.87 Ministry for the Environment (2004, p. 7)

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In New Zealand, products are assessed on a case-by-case basis. Foods must also be tested for safety by the co-national Food Standards Australia New Zealand (FSANZ), and foods must comply with labelling laws which require labelling of genetically modified foods. As of June, 2004, “none of the fresh meat, fruit and vegetables currently sold in New Zealand have been genetically modified.”88

ii. Safety assessment of food from transgenic animals in New Zealand – FSANZ

According to FSANZ, all foods produced using gene technology (including animals themselves) are subject to both pre-market safety assessments (based upon data supplied by manufacturers) and labelling requirements.89

FSANZ has published a document, ‘Guidelines for the Safety Assessment of Genetically Modified Foods’, which further describes its approach to risk assessment. This document, last updated March 2004, draws upon international initiatives in risk assessment such as the Codex Ad Hoc Inter-Governmental Task Force on Foods Derived from Biotechnology, the OECD Task Force for the Safety of Novel Foods and Feeds, and the Joint FAO/WHO Expert Consultations on Foods Derived from Biotechnology.

The safety assessment process described by FSANZ is applied to the food derived from a GM organism, and is not applied directly to the organism itself, except in so far that the organism is itself the food. The safety assessment is essentially based upon the substantial equivalence approach, since the objective is to determine whether GM food is as safe as its conventional counterpart. The safety evaluation has three key approaches: a pre-market, case-by-case evaluation; a consideration of intended and unintended effects of the genetic modification; comparisons with conventionally produced foods having acceptable standards of safety.90

More specific considerations that the FSANZ guidance document describes include:

Safety assessments of novel proteins (e.g. toxicity, allergenicity)

Nutritional considerations (e.g. intended and non-intended nutritional changes)

Unintended effects of genetic modifications (comparing GM and non-GM for key nutrients, toxicants and anti-nutrients)

Horizontal gene transfer

Post-market surveillance

Finally, it is important to highlight that FSANZ, following international initiatives, believes that the comparative risk assessment approach is also applicable for food from GM animals. FSANZ argues that foods derived from new strains of animals bred conventionally are not evaluated for safety and wholesomeness prior to human consumption. Nonetheless:

“An important concept in relation to the safety of foods from GM animals, particularly mammals, is the ‘healthy animal’ concept. Namely, mammals are important indicators of their own safety, since adverse consequences of introduced genetic material will generally be reflected in the growth, development and reproductive capacity of the animal (WHO 1991). It is recognised that this concept does not however apply to aquatic food organisms because many such species may contain compounds that are toxic to humans (OECD 1993). However, if the notion of healthy appearance is applied in conjunction with other attributes to assess

88 Ministry for the Environment (2004, p. 13)89 http://www.foodstandards.gov.au/_srcfiles/Standard_1_5_2_GM_v70.doc90 FSANZ (2004)

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safety, then it is still considered to have utility when applied to foods from aquatic animals (OECD 1994).

As with other GM food, the production of new, more efficient, food animals must be monitored for any changes in nutritional quality or composition of the resulting food”.91

iii. Environmental safety assessment of transgenic animals in New Zealand – ERMA

a) ERMA risk assessment of GM animals

The ERMA is responsible for approving the release – contained, conditional or unconditional – of GMOs. As the ERMA states, applications must be approved before a new organism – including GM animals – can be: imported or released into the environment; imported into containment; developed in containment; field tested in containment; or used in an emergency92

Generally, GMOs count as ‘new organisms’ under the HSNO Act but in some cases GM animals would be considered as ‘low-risk’ for purposes of the rapid assessment applications, as was the case for an approved application for the development of transgenic cattle with potential use in pharming.93

ERMA safety assessments are based upon applications submitted from sponsors. These must generally take into account:

“The sustainability of all native and valued introduced flora and fauna

The intrinsic value of ecosystems

Public health

The relationship of Maori culture and traditions with their ancestral land, water, sites, etc.

The economic and related benefits and costs to be derived from the organism

New Zealand’s international obligations”94

Some additional insight into the ERMA risk assessment approach is given by a 1999 document entitled ‘Identifying Risks for applications under the HSNO Act 1996’.95

Under the heading genetically modified new organism, the ERMA listed two primary sources of risk:

Organism habitat and nature

Escape from containment (if application is for containment) or release of the organism (if the application is for release)

Approval for applications is only given if, “in the opinion of EMRA New Zealand, the benefits of GMOs outweighs the risks or adverse effects of the GMO.”96 Further insight on ERMA risk assessment approaches can be gained by examining where the institute has evaluated a specific GM case, as the following section will do.

b) EMRA safety assessments of GM animals

91 FSANZ (2004)92 http://www.ermanz.govt.nz/resources/publications/pdfs/ER-QG-18-3.pdf93 The following link describes the rapid assessment rules. http://www.ermanz.govt.nz/resources/publications/policy/no/lrgmo.html94 ERMA (2003)95 ERMA (1999)96 ERMA (2003)

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http://www.ermanz.govt.nz/resources/publications/policy/no/lrgmo.html

In October 2002, the ERMA approved, for limited and conditional release, an application from a company to develop transgenic cattle for pharming. Following the initial data submission by the company, the application was open for public comment before the final decision was made. In making the decision, the ERMA:

“…especially considered risks to animal welfare, the development of new diseases, the potential for the transfer of existing diseases to the cattle, risks arising from HGT[horizontal gene transfer], and Maori spiritual concerns. These risks are all related to the nature of the genetic modifications. There were considered to be negligible risks to public health and the environment associated with the possible escape of genetically modified animals from containment”.97

However, the ERMA put a wide range of constraints on the application, which met the requirements of the HSNO (Low Risk Genetic Modification) Regulations 1998. These included some specifications on indoor and outdoor containment facilities be managed, a stipulation that cattle were managed in accordance with the Animal Welfare Act 1999, and the requirement that animal husbandry be overseen by an experienced veterinarian. In addition, it was clearly specified that no part or product of genetically modified cows should enter the food chain, and that all animals had to be individually identified by ear tags and subcutaneous microchips. Finally, the applicant was required to facilitate the operation of monitoring by Ngati Wairere representatives.98

A different EMRA assessment concerns the approval of a field test of GM sheep that had been modified for research purposes. The EMRA decision, announced October 31, 2000, approved the application based upon the assessment that the containment facility was adequate and that no genetically modified material would enter the food chain. The EMRA statement indicated a further description of the risks considered:

“In terms of potential risks, the Committee noted the concerns raised by submitters about horizontal gene transfer but considered this to be negligible. It noted that there is no intention for the meat, milk or offal from the sheep to enter the human food chain - but if products from the GM sheep were ingested, it was extremely unlikely to present any ill effects and that the neomycin resistance and puromycin resistance gene products involved do not pose any allergenic concerns”.99

Finally, it is interesting to note that the agency must consider Maori values – which in this application argued against its approval:

“The Minority decision was that the application should be declined on the grounds of the cumulative adverse effects on the local hapu, Ngati Wairere; that it is inappropriate for the applicant themselves to conduct the assessment of cultural effects; and that the proposed benefits of scientific information do not outweigh the possible adverse effects on the health and well being of the animals involved in the research programme…

The Committee acknowledged the seriousness of the issues raised on behalf of Ngati Wairere and weighed them carefully. But the Majority decision did not consider that these matters were such to justify declining the application”.100

97 http://www.ermanz.govt.nz/news-events/archives/media-releases/2002/mr-20021001.asp98 http://www.ermanz.govt.nz/news-events/archives/media-releases/2002/mr-20021001.asp99 http://www.ermanz.govt.nz/news-events/archives/media-releases/2000/mr-20001031.asp100 http://www.ermanz.govt.nz/news-events/archives/media-releases/2000/mr-20001031.asp

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c) EMRA safety assessment of GM salmon

One company in New Zealand had been developing genetically modified salmon before the introduction of the HSNO Act and the EMRA decided that there were grounds for a reassessment of the application. The majority of the reassessment decision, released in February 2000, approved the application but focused on ensuring more stringent containment measures: such as reducing the size of wire mesh screens, disposing biological Chinook salmon by burial under specified conditions, and mandating a contingency plan in the case of events like flooding that might render the containment system ineffective.101

d) Note on taste-testing of GM animals

It is interesting to note that the EMRA has put controls on the taste-testing of GM Animals, including GM salmon. In the case of GM salmon, this was because “the Authority wished to cover the possibility that such tests would fall outside the scope of the Australia New Zealand Food Authority (ANZFA) and would therefore be unregulated.”102 It was thought that because taste-testing did not involve the sale of GM products, there might have been a regulatory loop-hole through which the FSANZ did not have jurisdiction over taste-testing.

iv. Risk regulation of medicines derived from GM animals – Medsafe

Medsafe is the agency responsible for evaluating the quality and safety of all medicines approved in New Zealand.

It appears as though Medsafe would only review the protein product derived from a transgenic animal, however little is published on Medsafe’s website concerning genetic modification. Where a medicine consists of a live organism (e.g. a live vaccine) Medsafe and the EMRA must approve of the product.

v. New Zealand risk/regulation of xenotransplantation

The New Zealand Ministry of Health has cited the risk of rejection and the risk of transmission of animal diseases to humans (zoonosis) as two prominent issues surrounding xenotransplantation.103 The Ministry of Health has stated that the current regulatory framework for human tissue research is “not comprehensive” and “out of date” and (as of June 2005) is in the process of conducting a review of xenotransplantation in the broader context of tissue-based therapies.104 The review will cover a broad range of topics including current controls of xenotransplantation. Following the completion of the review, which will include a public consultation, a new legislative framework for human tissue will be proposed.105

3.2.4 Japan

i. Safety assessment of foods derived from biotechnology

In Japan, the Ministry of Health, Labor, and Welfare (MHLW) introduced requirements for the safety assessment of foods derived from biotechnology in May, 2000. This is for any food and food additive produced by DNA technologies, and

101 http://www.ermanz.govt.nz/news-events/focus/gm-salmon.asp#media102 http://www.ermanz.govt.nz/news-events/focus/gm-salmon.asp#taste103 http://www.moh.govt.nz/moh.nsf/aa6c02e6249e7359cc256e7f0005521d/ff5646c096e846e7cc256a880003bdb4?OpenDocument104 http://www.moh.govt.nz/moh.nsf/aa6c02e6249e7359cc256e7f0005521d/ff5646c096e846e7cc256a880003bdb4?OpenDocument105 http://www.moh.govt.nz/moh.nsf/aa6c02e6249e7359cc256e7f0005521d/ff5646c096e846e7cc256a880003bdb4?OpenDocument

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calls for case-by-case analysis.106 Applicants for approvals must submit a safety examination in consultation with the Food Safety Examination Council. The safety examination must include a range of technical details on topics including the DNA construct, the vector, the host, the potential toxicity of the food, history of consumption and records of approval in other countries, and descriptions of the production process.107

Japan’s MHLW also released standards for the manufacturing of foods and food additives produced through recombinant DNA techniques. It should be noted that although these standards are general, they appear to be more focused on plants and micro-organisms than animals. A perusal of the products approved for safety suggests that only biotechnology-derived plants and food additives had been assessed for safety as of September, 2001.108

ii. Japanese Ministry for Agriculture, Forestry and Fisheries

The Japanese Ministry for Agriculture, Forestry and Fisheries has also produced guidelines on for the use of biotechnology. However, these guidelines, according to the MAFF website, were last revised in 1995. They explicitly consider plants, micro-organisms and small laboratory animals but do not contemplate GM fish or livestock.109The guidelines are technical and in general seek to ensure that safety assessments are carried out to assure the safe use of rDNA organisms.110.

3.2.5 Conclusions

So far, this chapter has reviewed the regulatory approaches of the EU, USA, New Zealand and Japan. It would appear as though the transgenic animal application most carefully considered from the perspective of risk regulation is xenotransplantation, where much emphasis has been placed on the public health risks of zoonosis and the individual risks of transplant rejection.

It is noteworthy that, insofar as it is possible to know, no GM animal-derived foods have been granted regulatory approvals. There appears to be little global consistency in the regulatory approaches to GM animals, other than the observation that previous work on GM plants is highly (and potentially problematically) influential. In many instances, it would seem that the potential utility of risk assessments are compromised by either the relative lack of existing regulatory/legislative structures (or regulatory structures focused rather more on plants than animals) in the country/region.

New Zealand, following international initiatives on risk regulation (to be discussed further below), has established a comparative approach generally based upon ‘substantial equivalence’ and equally focused on protecting the environment through containment of GMOs. New Zealand’s medical authority appears set to regulate pharmed proteins as normal biologics.

The USA, meanwhile, has continued to fit new biotechnologies into regulations that preceded them. Thus the FDA has decided that GM animals will be governed by ‘new animal drug’ provisions, necessitating pre-market authorisation. However, one potential loophole in this is that if the modification strictly relates to the food products, manufacturers may be able to have their products regulated as food additives under the ‘generally recognized as safe’ system. Either way, some controversy over the

106 http://www.mhlw.go.jp/english/topics/food/3-3.html107 http://www.mhlw.go.jp/english/topics/food/3-3.html108 http://www.mhlw.go.jp/english/topics/qa/dna/index.html109 http://www.s.affrc.go.jp/docs/sentan/eguide/eguide.htm110 http://www.s.affrc.go.jp/docs/sentan/eguide/eguide.htm

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USA’s environmental regulation of transgenic animals, particularly fish, exists. Concerning pharmed pharmaceuticals, the FDA’s CBER will likely continue to regulate these as it would normal biologics.

The European Union, having implemented Directive 2001/18/EC which covers GMOs and having established the European Food Safety Authority, theoretically has a coherent system for the regulation of food from transgenic animals. However, this system was largely designed for GM plants and there is little evidence to suggest that the EU has considered in detail the unique issues surrounding transgenic animals. Concerning pharmed proteins, the EMEA would have responsibility for assessing the products of the product, but other aspects of the transgenic animal would likely be governed through the provisions of Directive 2001/18/EC.

A cursory examination of Japan, meanwhile, identifies a system that has largely been considered in the context of GM plants.

3.2.6 International risk assessment approaches

Several ongoing and sometimes contradictory approaches to the risk assessment of biotechnology generally and animal biotechnology more specifically exist. It is hoped that attempts at standardisation and harmonisation of risk assessment approaches might positively influence trade, since in the lack of harmonisation trade is hampered:

“Difficulty in reaching international agreement on food safety standards and scientific uncertainty about how to evaluate safety, coupled with the lack of a clear, ‘one-window’ approach for regulation in developing countries, means that developed and developing countries lack a clear, uniformly accepted path to regulatory approval of GM foods”.111

Prominent risk assessment initiatives have been the product of organisations such as the OECD, WTO, WHO, FAO, OIE and prominent treaties/initiatives include the Codex Alimentarius, the WTO (specifically the SPS and TBT agreements), ICH, Cartagena Biosafety Protocol.

i. Codex Alimentarius

The Codex Alimentarius has based risk assessment approach on consultations from the FAO and WHO. In the 26th session of the Codex Alimentarius Commission, 2003, it adopted ‘Principles for the risk analysis of foods derived from biotechnology.’112

Generally, the FAO/WHO consultation suggested that substantial equivalence should be a starting point for safety assessments. The principles for risk assessment, which were not explicitly developed for foods derived from GM or cloned animals, address food safety and use the same definition of biotechnology employed by the Cartagena Biosafety Protocol.

The WHO states that the Principles advocate case-by-case premarket assessment. Safety evaluations require details on toxicity, allergenicity, stability of the inserted gene, nutritional or toxic properties of components of the food, and unintended effects of the gene insertion.113 There are six key principles, which are:

Risk assessment includes a safety assessment, which includes comparison with a conventional counterpart…If a new or altered hazard, nutritional or other safety concern is identified by the safety assessment, the risk associated with it should be characterized to determine its relevance to human health

111 Cohen et al. (2003)112 Available from: ftp://ftp.fao.org/es/esn/food/princ_gmfoods_en.pdf (site visited July 28, 2005)113 WHO (2005, p. 12)

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ftp://ftp.fao.org/es/esn/food/princ_gmfoods_en.pdf

A safety assessment is an assessment of a whole food or component thereof relative to the appropriate conventional counterpart, taking into account intended and unintended effects, identifying new or altered hazards and identifying changes, relevant to human health, in key nutrients

A pre-market safety assessment should be conducted on a case-by-case basis and based on sound science

Risk assessments apply to all relevant aspects of foods derived from biotechnology and are based on a consideration of science-based multidisciplinary data

Scientific data for risk assessments are generally obtained from a variety of sources, such as developer of the product, scientific literature, independent scientists, regulatory agencies, etc.

Risk assessments should take into account all available scientific data and information114

Finally, it is important to note that the Codex Alimentarius is a reference point for the WTO’s SPS Agreement – it is recognized as a competent, standard-setting body.

ii. FAO/WHO

The Food and Agriculture Organization (FAO) and the World Health Organization (WHO) conducted a series of expert consultations to assist the Codex Alimentarius Commission’s Inter-governmental Task Force on Foods Derived from Biotechnology. These consultations, studying the issue from a scientific perspective, informed the Codex Alimentarius 2003 document, ‘Principles for the risk analysis of foods derived from biotechnology,’115 as discussed above.

Following this document and earlier FAO/WHO work on the safety assessment of GM animal-derived foods, the FAO/WHO held an expert consultation on this specific topic in November 2003 in order to provide more detailed guidelines. The report’s scope included GM fish but did not consider cloned animals from SCNT. It also does not explicitly state whether progeny from transgenic animals were included, however this may be the case, as the report noted that ‘transgenic individuals can…be identified and bred to develop a transgenic line.’116

The consultation held the view that for such risk assessment processes, integrated toxicological and nutritional evaluations could be performed.117 The risk assessment approach described by the consultation follows the approach developed for GM plants and is based upon using substantial equivalence as a starting point in developing a comparative, case-by-case approach:

“The food safety assessment of GM animals and derived products can largely be performed along the lines that have already been established for the evaluation of GM plants and derived products for the consumer... This means that the initial step of the food safety assessment will be a comparative safety assessment of the GM animal with its appropriate comparator, including a food intake assessment, followed by a full risk characterization”.118

114 Codex Alimentarius (2003)115 Available from: ftp://ftp.fao.org/es/esn/food/princ_gmfoods_en.pdf (visited July 28, 2005)116 FAO/WHO (2003, p. 4)117 WHO (2005, p, 12)118 FAO/WHO (2003, p. 10)

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The FAO/WHO report notes that there have been suggestions to replace the substantial equivalence approach with a broader Comparative Safety Assessment concept, which is two-tiered, the first stage comparing a product with a conventional counterpart (through comparing phenotypic characteristics as well as compositional analysis). The second stage comprises toxicological and nutritional evaluation of any identified differences between the GM animal and its conventional counterpart. This approach means that risks are fully characterized through hazard identification and clarification and food intake assessments.119

The following describes the core aspects of the risk assessment approach described by the FAO/WHO:

a) Hazard Identification and characterization (comparative)

Molecular characterization of inserted genetic construct

Safety of the gene product

Allergenicity

Gene transfer

Unintended effects, through phenotypic and compositional analysis

b) Food Intake Assessment

Addresses complex foods and not individual compounds

Objective is to assess the amount of food or food ingredient an individual or population group may consume

Some approaches attempt to track animal-derived food and determine post-market consumption data to feed into models

c) Integrated toxicological evaluation (Following 1 and 2)

Combine all information from 1and 2

Needs to identify food safety issues that may require additional investigation

Approaches in this stage adopted in case by case basis

d) Integrated nutritional evaluation

In addition to integrated toxicological evaluation, combining all information on nutritional aspects of complex GM animal-derived product

Should focus on the potential replacement of nutritionally important food products by the novel GM animal-derived food products

Largely derived from initial CSA including compositional analysis and estimated consumption rates

e) Risk characterization

Integrating outcomes from full toxicological and nutritional evaluations to reach an overall conclusion about the safety of the food

The baseline for the safety of novel food products derived from GMOs, including GM animals, in all cases will have to be the assessment that the novel GM animal-derived food products are at least as safe as the conventional counterpart.

If any questions remain, additional tests may be required

119 FAO/WHO (2003, p. 11)

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If the safety standard cannot be satisfied, the GM animal-derived product should not be approved for marketing

The document also mentions post-market surveillance as a risk management tool. Of note are tracing and labelling:

“In order to enable consumers to related potential adverse, e.g. allergenic, effects to a GM animal-derived food product, it may be necessary not only to label the product as GM animal-derived, but also to provide information on the specific GM animal source, for instance by including on the label the unique identifier code specific for a single integration event”.120

The document then focuses on specific food safety issues related to foods derived from animal biotechnology. These principally relate to phenotypic analysis, used in hazard identification and characterization. It is observed that the selection process for initial founders will be much limited compared to plants, where thousands of GM plants are screened for incorporation of the transgenic insert. As a result, there will be limited information on the variation between animals with the same genetic modification, necessitating more background data (e.g. variation in animal tissue constituents such as key nutrients and possible compounds with adverse effects). Another key difference is that there are very few cases of natural toxins found in animals compared to plants. However, this is offset by the potential for zoonotic diseases and human pathogens of animal origin in the consideration of GM animal-derived foods. Table 2 summarises some of the key differences between the risk assessment of foods derived from GM plants and GM animals.

Table 2 Specific issues related to foods derived from animal biotechnology

Issue NotesPhenotypic analysis Phenotypic analysis relate to compositional analysis

but also to general performance parameters of the animal (growth rate, feed conversion efficiency, reproduction), disease resistance

Sampling Must be made statistically significant since much smaller sample size compared with plants

Compositional Analysis Same basic approach as for GM plants - key constituents of the tissue have to be established (key nutrients as well as compounds with potential adverse effects)

Background data on natural variation for individual constituents in different tissues needs to be generated and current data needs to be evaluated for suitability in comparative compositional analysis

Post-market surveillance Compared to the plant sector, the food animal sector has a comparable advantage since product tracking systems already exist, they will only need to be adjusted and elaborated

iii. Cartagena Biosafety Protocol

Whereas the Codex Alimentarius, FAO and WHO approaches address food safety, the Cartagena Biosafety Protocol, which governs the transboundary movement of

120 FAO/WHO (2003, p.16)

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genetically modified foods, is primarily focused on environmental safety. It is the only international regulatory instrument that specifically deals with the impact of GMOs on the environment.121

Article 15 of the Protocol requires nations to decide upon imports of LMOs based upon scientifically sound risk assessment. Article 16 requires nations to manage and control risks identified under the risk assessments prescribed by Article 15. Annex III of the Protocol specifically sets out general principles, methodological steps, and points to consider in the conduct of risk assessment122 which would be required for any LMOs introduced into the environment or traded as commodities for food, feed or processing.123 Annex III (see Appendix 3) offers a minimal set of risk assessment principles and calls for scientifically sound, case-by-case analyses. Where possible, it states that risk assessments should “take into account expert advice of, and guidelines developed by, relevant international organizations.”124 It has been noted that the 1995 UNEP ‘International Technical Guidelines for Safety in Biotechnology’ were recommended as a “valuable source of guidance” during negotiations on the risk assessment principles of the Cartagena Protocol.125

It should be noted that these principles are general and do not specifically refer to either GM plants, micro-organisms or animals. Since Annex III refers to other relevant risk assessment documents, it is probable that, concerning food from transgenic animals, the FAO/WHO ‘Expert Consultation on Foods Derived from GM Animals’ would be referred to.

iv. World Organization for Animal Health (OIE)

The OIE is recognized as a competent, standard-setting body under the WTO SPS Agreement. It is responsible, under its mandate in the WTO SPS Agreement, for standards relating to animal health and zoonoses, meaning that OIE standards apply to globally traded animal products.126

Concerning risk assessment techniques, there is evidence to suggest, consistent with the SPS Agreement’s encouragement of standards harmonisation, the OIE would follow risk assessment Codex Alimentarius initiative ‘Principles on Risk Assessment of Foods from Modern Biotechnology’. For example, the OIE stated in February, 2005:

“It has become apparent that the new global concept of implementing sanitary controls "from the stable to the table", aimed at improving the level of consumer protection, requires the OIE and the Codex Alimentarius Commission to work more closely together and collaborate on a permanent basis. This will ensure that the standards issued by the two Organisations cover all potential hazards throughout the food chain and those standards on topics of common interest do not prove to be contradictory for want of coordination”.127

121 WHO (2005, p. 19)122 http://www.biodiv.org/biosafety/issues/risk.aspx# (Site visited July 28, 2005)123 Andren & Parish (2002)124 http://www.biodiv.org/biosafety/articles.asp?lg=0&a=bsp-43 (Site visited July 28, 2005)125 Secretariat for the Convention on Biological Diversity (2003). As Andren and Parish (2002, p. 332) note, negotiations on whether Annex III was even necessary were tense. However, ‘because so much ground-breaking work had been carried out in developing and agreeing a final text for the [UNEP] Guidelines…it actually paved the way for and facilitated the biosafety protocol negotiations on risk assessment.’126 http://www.oie.int/eng/Edito/en_edito_feb05.htm

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http://www.biodiv.org/biosafety/articles.asp?lg=0&a=bsp-43

http://www.biodiv.org/biosafety/issues/risk.aspx#

There are also signs that the OIE is beginning to consider trade of genetically modified animals in more detail, as it recently established an Ad hoc group on Biotechnology, to focus on topics such as the:

“…research and use of vaccines for animals produced through biotechnology; animal health risks linked to cloning; exclusion of unapproved animals and products from the livestock population and segregation from the feed and food supply; and animals that have been genetically engineered to produce medicines or chemicals”.128

This work will likely build upon work published a recent special edition of the OIE’s ‘Scientific and Technical Review’ which was focused on ‘Biotechnology applications in animal health and production.’ Further demonstrating the OIE’s increased interest in collaboration authors of one paper (employees of the OIE and the Secretariat of the Convention on Biological Diversity) argued that the OIE and Cartagena Protocol would benefit from collaboration in a range of areas, including risk assessment, given its significant expertise in assessing animal health risks.129

v. Organization for Economic Cooperation and Development (OECD)

It is often noted that the origins of the term ‘substantial equivalence’ originated at the OECD, whose prominent reports on biotechnology have included ‘Safety Evaluation of Foods Derived by Modern Biotechnology’, released in 1993. Further, since 1995, the OECD has had a Working Group for Harmonization in Biotechnology.

The 1993 document considered a case study with transgenic animals (pigs transgenic for porcine somatotropin). This case study was used to demonstrate the substantial equivalence approach. It appears, however, that subsequent OECD reports or consensus documents on risk assessment have not specifically addressed products from transgenic animals. There is one exception, a recent workshop on the biology of Atlantic salmon “was the first occasion for the Working Group [for Harmonization in Biotechnology] to address environmental safety issues related to a transgenic animal.”130 The OECD states that a report on this workshop will be published, likely following a second workshop on the same topic.

vi. International Conference on Harmonization (ICH)

The International Conference on Harmonization (ICH) has the main focus of making recommendations for the coordination the regulatory approval of new drugs within the EU, USA and Japan. It consists of 6 members, including the EMEA, FDA, the Japanese Ministry of Health, Labor and Welfare and three pharmaceutical industry associations representing the EU, US and Japan. ICH Project Q6B is on ‘Test Procedures and Acceptance Criteria for Biotechnological/Biological Products’, however this is rather more focused on procedures for characterising biological products than it is on risk assessments. To this end, it also does not appear to focus specifically on biopharming.131

127 http://www.oie.int/eng/Edito/en_edito_feb05.htm128 http://www.ictsd.org/biores/05-06-10/story3.htm (Site visited August 5, 2005)129 Sendashonga et al. (2005)130 OECD (2005b)131 Information based on the programme document released 10 March, 1999 (http://www.ich.org/cache/compo/MediaServer.jser?@_ID=432&@_TYPE=MULTIMEDIA&@_TEMPLATE=616&@_MODE=GLB, visited July 29, 2005)

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http://www.ich.org/cache/compo/MediaServer.jser?@_ID=432&@_TYPE=MULTIMEDIA&@_TEMPLATE=616&@_MODE=GLB

http://www.ich.org/cache/compo/MediaServer.jser?@_ID=432&@_TYPE=MULTIMEDIA&@_TEMPLATE=616&@_MODE=GLB

http://www.ictsd.org/biores/05-06-10/story3.htm

vii. Note on harmonization and consistency between international risk assessment approaches

It has been generally noted that international protocols implicitly promote the harmonization of regulatory systems.132 For example, the WTO SPS Agreement encourages members to harmonize SPS measures by basing them on international standards. Thus it is notable that the Codex Alimentarius principles for risk assessment “form the basis for harmonization under the [WTO] SPS Agreement.”133

The expectation is that when dealing with GMO-derived products, the SPS Agreement will make reference to the Codex Principles. 134

It should also be remembered that the FAO/WHO has advised and influenced the development of ‘Codex Principles for the Risk Analysis of Foods Derived from Modern Biotechnology’.135 Furthermore, the definitions used in Codex (2003) are intentionally the same as those in the Cartagena Protocol on Biosafety, “so that the Codex texts on food safety and the CPB text on biosafety and environmental protection are mutually compatible and supportive.”136 Similarly, 3.2.6:iii noted that the CBP risk assessment was based on the 1996 UNEP ‘International Technical Guidelines for Safety in Biotechnology’. In another example, as discussed in 3.2.3:ii, the FSANZ has based its assessments of GM animals on the principles established by initiatives such as the FAO/WHO expert consultations.

Meanwhile, numerous other initiatives have explored harmonization of various aspects of biotechnology. This has the advantage of reducing infrastructure (e.g. regulatory) costs and improving access to export markets. As the OECD has stated:

“The benefits of harmonisation are clear. It increases mutual understanding among member countries, which avoids duplication, saves on scarce resources and increases the efficiency of the risk/ safety assessment process. This in turn improves safety, while reducing unnecessary barriers to trade (OECD 2000). Many delegates have said that the process of working towards harmonisation, and the resulting discussions among member countries, is almost as important as the products produced”.137

Several regional organizations have considered, to varying degrees, risk, regulation and biotechnology:

The Association of South-East Asian Nations has explored harmonization of legislation for products from biotechnology as well as a regional approach to biosafety, although the individual nations concede that “implementation might not be possible in the near future due to a lack of human resources.”138

132 E.g. WHO (2005)133 WHO (2005, p. 30). The report cites article 3.4 of the SPS agreement (available from http://www.wto.org/english/docs_e/legal_e/15-sps.pdf.)134 WHO (2005, p. 45)135 As already noted, the FAO/WHO has influenced the Codex Alimentarius principles on risk assessment, which include:

Pre-market, science-based safety assessment on a case-by-case basis; Assessment is based on comparative analysis with ‘conventional counterpart’ to ensure biotechnology-derived food is no less safe than foods normally consumed (substantial equivalence); Risk management measures should be proportional to the risks identified in the safety assessment and may include labelling, tracing.136 FAO/WHO (2003, p. 19)137 OECD (2005a)

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The Southern African Development Community has established a committee to “develop a common position on biotechnology and harmonize biosafety legislation in the region.”139

The TransAtlantic Economic Partnership, which has not been overly successful with regards to finding a common approach to the EU-US risk regulation of biotechnology.

Asia-Pacific Economic Cooperation has held ‘High Level Policy Dialogues’ on numerous topics related to agricultural biotechnology, including the ‘harmonization of regulatory frameworks.’140

138 WHO (2005, p. 31)139 WHO (2005, p. 31)140 http://www.apec.org/apec/apec_groups/other_apec_groups/agricultural_biotechnology.html

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SECTION 4 INTERNATIONAL TRADE AND LABELLING ISSUES4.1 International regulation of trade in GM animals and related productsWith an abundance of regulatory approaches, both domestic and international, to assess and manage the risks that GMOs and their products pose, complications and barriers to trade can be expected.

Some analysts have divided national regulatory schemes into three categories – those that base risk assessments on concepts of equivalence, those that employ the precautionary principle, and those that either don’t have or are only just establishing regulatory regimes (e.g. Zarrilli, 2005). The conflict between these approaches, in the context of international agreements that are not universally ratified (i.e. Cartagena Protocol), are likely to lead to trade issues:

“The legislation of GMOs and GM products enacted in some regions, and especially in the European Union, is hampering international trade in those products, and it is also claimed to be having indirect negative implications on the transboundary movement of conventional agricultural products.”141

In other words, the lack of consensus and the diversity of international and national organizations involved in safety assessments of biotechnology-derived products is likely to complicate the resolution of trade issues. Although written about GM crops, the following may prove to be true for GM animals also:

“The adoption of biotechnology and the introduction of GM foods into the international marketplace has exacerbated an already difficult area of trade policy. As biotechnology increases productive capacity in various products, it also increases the need to trade. But diverging national regulations are increasingly impeding trade in these products”.142

Currently, international trade in GMOs and products thereof take place under WTO rules established in the Uruguay Round, particularly under the Sanitary and Phytosanitary Measures (SPS), the Agreement on Technical Barriers to Trade (TBT), the General Agreement on Tariffs and Trade (GATT) 1994 and TRIPS. Outside of WTO rules, the Cartagena Protocol on Biosafety is particularly relevant.143

Before introducing specific trade issues that might arise, it will be useful to briefly introduce the aspects of these agreements most relevant to potential trade disputes surrounding GMOs. It is also useful to keep in mind that this is a very new area of international law: “In the event of trade disputes, it is rather uncertain which legal arguments might prevail.”144

4.1.1 WTO – Sanitary and Phytosanitary Measures (SPS)

This agreement, as discussed in Report 2, is designed to prevent domestic sanitary and phytosanitary standards to protect plant, animal and human life and/or health. Articles 2.2 and 5.1 are particularly relevant, as they effectively state that “measures that fall within the ambit of the SPS Agreement must be based on an assessment of risk unless they ‘conform to’ international standards.”145 Article 5.2 then describes factors to be taken into account in risk assessments, which include:

141 Zarrilli (2005, p. 45)142 Phillips (2003, p. 5)143 Zarrilli (2005) offers a detailed account of the various regimes impacting trade of GMOs.144 Zarrilli (2005, p. 46)145 Howse & Meltzer (2002, p. 485)

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“…available scientific evidence; relevant processes and production methods; relevant inspection, sampling and testing methods; prevalence of specific diseases or pests; existence of pest- or disease-free areas; relevant ecological and environmental conditions; and quarantine or other treatment”.146

It is noteworthy that the SPS Agreement’s objective is to facilitate, not hinder trade - all measures taken under the SPS Agreement must take into account the objective of ‘minimizing negative trade effects.’147

The SPS Agreement allows for temporary precautionary measures, a key word here is ‘temporary’. The degree to which the precautionary principle can be applied within the SPS has been the focus of disputes between the EU and the United States on the issue of hormones in meat products. In a case that did not directly consider the aforementioned Article 5.7, the Appellate Body ruled that the precautionary principle cannot overrule Articles 5.1 and 5.2 of the SPS, because:

“…the risk evaluated in a risk assessment must…be an ascertainable risk; theoretical uncertainty is not the kind of risk which, under Article 5.1, is to be assessed.”148

This approach was upheld in another case involving Japan and the United States. In this case, it was ruled that Article 5.7 did not apply because Article 5.7 refers to cases where scientific evidence is insufficient, not to scientific uncertainty. Based on these rulings, one analyst has suggested that the implication is that:

“…the present inconclusiveness of scientific evidence related to the actual or potential impact of GMOs on human and animal health and on the environment cannot be regarded as a reason for taking precautionary measures under Article 5.7 of the SPS Agreement”.149

Crucially, this differs from the Cartagena Protocol, in which Article 10.6 allows for parties to invoke the precautionary principle in situations of both scientific uncertainty as well as insufficient information.150

4.1.2 WTO – Technical Barriers to Trade (TBT)

As previously introduced in Report 2, this agreement “tries to ensure that regulations, standards, testing and certification procedures do not create unnecessary obstacles.”151 It permits governments to introduce TBT regulations to, amongst other things, protect human health or safety, animal or plant life or health, or the environment. It encourages the use of international standards and discourages any methods that would give domestic products an unfair competitive advantage. The approach for ensuring this hinges on the WTO interpretation of like products:

“Measures should not discriminate between imported products and ‘like’ products of domestic origin. If GMOs and GM products are considered ‘like’ products in relation to conventional products, then there are no grounds for applying any special treatment to them, including mandatory labelling schemes.”152

146 http://www.wto.org/english/docs_e/legal_e/15sps_01_e.htm147 http://www.wto.org/english/docs_e/legal_e/15sps_01_e.htm148 Zarrilli (2005, p. 32)149 Zarrilli (2005, p. 33)150 Zarrilli (2005)151 http://www.wto.org/english/thewto_e/whatis_e/tif_e/agrm4_e.htm152 Zarrilli (2005, p. 33)

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4.1.3 GATT 1994 and the product/process distinction

It appears to be the 1994 GATT, through Article III which discusses the non-discrimination between domestic and imported goods. Debate under this clause has tended to attempt to determine what exactly constitutes ‘like’ products and the debate has focused on whether the analysis should take account solely of the product or also of the process. This remains an open question.153

Article XX of GATT 1994 is equally important for GMOs, since it legally gives countries support to invoke measures:

“b) necessary to protect human, animal or plant life or health;…

g) relating to the conservation of exhaustible natural resources if such measures are made effective in conjunction with restrictions on domestic production or consumption”154

A prominent case involving shrimp suggests that jurisprudence has “evolved to interpret Article XX as covering measures that distinguish products on the basis of the production processes”.155 Whether this will remain the case for GMOs remains unclear. As bioethicist Peter Singer (2002) has noted, “Whenever a dispute has required a choice between free trade and support for a non-discriminatory national policy intended to protect the environment, the WTO’s verdict before November 2001 was that the policy is an illegal barrier to trade.”156

4.1.4 Cartagena Biosafety Protocol and WTO – potential areas of dispute

i. Cartagena Protocol - background

In a general sense, it has been observed that there are two principle differences between the approach of the Cartagena Protocol and the WTO. One is that the former supports a process-based regulatory approach and the latter a product-based approach in which GM products are considered to be ‘like’ products. The second is that where the WTO has non-discrimination as its underlying regulatory principle, the Cartagena Protocol has advance informed agreement:

“…while the WTO aims at removing governments from the act of deciding market access, the Cartagena Protocol elevates the role of government, making the transboundary movement of living modified organisms a government-to-government activity”.157

The Cartagena Protocol has the primary task of preventing the risks of biotechnology to biodiversity, also taking into account human health. It enables a precautionary approach and mandates a Biosafety Clearing-House to facilitate information exchange on living modified organisms.158 The Protocol defines LMO as “any living organism that possesses a novel combination of genetic material obtained through the use of modern biotechnology.”159 It divides LMOs into three categories, those for voluntary release into the environment (e.g. GM fish), LMOs destined for contained use, and LMOs intended for direct use as food or feed or processing. The Protocol does not apply to pharmaceuticals.

153 Zarrilli (2005)154 GATT 1994 Article XX as cited in Singer (2002, p. 66) and Zarrilli (2005, p. 34)155 Zarrilli (2005)156 Singer (2002, p. 68)157 Isaac (2003, p. 120)158 www.biodiv.org/biosafety/background2.aspx (Site visited June 28, 2005)159 http://www.biodiv.org/biosafety/background2.aspx# (Site visited June 28, 2005)

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http://www.biodiv.org/biosafety/background2.aspx#

http://www.biodiv.org/biosafety/background2.aspx

As of 9 September, 2005, 125 countries had ratified the protocol. This excludes some major proponents of biotechnology, including the United States.

ii. Potential conflicts between the Cartagena Biosafety Protocol (CBP) and WTO law

Although not merely focused on GM animals, an analysis of discrepancies between the Cartagena Biosafety Protocol (CBP) and the intents and purposes of the CBP and WTO may conflict, depending on how these agreements are interpreted. For example, the preamble of the CBP:

“…insists that the WTO and CBP should be mutually supportive while denying that the protocol affects rights and obligations under any other international agreement (and thus the WTO)…”160

However, there are no provisions to clarify how conflicts between WTO and CBP (or CBD Convention) law, leaving this open to interpretation from varying parties:

“There are, on the one hand, those, mainly in civil society, who emphasize the crucial importance of the independent application, uninhibited by WTO rules, of the protocol and its precautionary approach. There are, on the other hand, advocates of producer interests, mainly in countries with predominant agricultural export interests, including the United States, who insist on the unrestricted application of WTO rules on market access.”161

Since both approaches grant preference to one of the two systems, it has been noted that there needs to be an operational connection between the two systems. “This is a major challenge, primarily for trade law and policy”,162 despite some suggestions that the CBP’s more elaborate risk assessment and management provisions might be applied convergently with WTO Agreements.

In particular, there appear to be numerous ways in which Cartagena Biosafety Protocol may overlap with the SPS Agreement, examples include:

a) the precautionary principle and the scope for legitimate government action short of conclusive scientific evidence;

b) risk assessment and risk management;

c) the socio-economic factors that may be taken into account in the decision-making process; and

d) documentation obligations163

a) The WTO, in its Hormones case, did not comment on whether the precautionary principle is a general principle of international law.164 Thus whether or not (and to what extent) WTO law accounts for the precautionary principle is difficult to determine. However, under GATT XX(g) and following the ShrimpTurtle case, some have argued “it is possible to accept the precautionary principle enshrined in Article 11(8) of the [Cartagena] protocol.”165 This would seem consistent with other analyses which have concluded:

160 Cottier (2002, p. 469)161 Cottier (2002, p. 469)162 Cottier (2002)163 Zarrilli (2005, p. 27)164 Howse & Meltzer (2002)165 Cottier (2002, p. 474)

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“In practice…most regulations relating to genetically modified organisms (GMOs) will not effectively be challenged under Article III of GATT, nor do they need to be justified under Article XX.”166

This led these analysts to focus on the SPS agreement. The Cartagena Protocol differs from SPS as it permits countries to ban products because of lack of scientific certainty, and further, these countries would not be obliged to seek the information necessary to reach scientific certainty. This differs from the SPS, which allows countries temporary bans but requires them to seek additional information and review the SPS measure within a reasonable time frame.167 Thus there is the potential for dispute concerning the use of precaution in decision making:

“The inclusion of the precautionary approach in the Cartagena Protocol raises fundamental questions about its compatibility with the WTO’s requirement that any risk assessment must be science-based…The Cartagena Protocol’s use of the precautionary approach differs from that of the SPS Agreement in that there is no limitation on the duration of its use and no explicit requirement to review the scientific basis for the decision.”168

b) Article 15 of the CBP requires that scientifically sound risk assessments are the basis for deciding upon imports of LMOs. The SPS also deals with risk assessment – to human, animal or plant life or health – but stresses through Article 5.4 that appropriate levels of sanitary and phytosanitary protection should take into account the objective of minimizing negative trade effects. The Cartagena Protocol makes no reference to minimizing negative trade effects.169

c) It has been observed that the Cartagena Protocol could allow trade-restrictive measures to be justified if LMOs might “lead to a loss of cultural traditions, knowledge and practices, particularly among indigenous and local communities.”170

This contrasts with the SPS Agreement, where, despite that its risk assessment procedures leave some scope for socio-economic considerations (Article 26), it has been noted that Article 5.5 imposes ‘discipline’ on this decision. Other interpretations, however, maintain that Article 26 could also allow for trade-restrictive measures, since “what constitutes a socio-economic factor is open to considerable interpretation.”171 As a result:

“Article 26, without carefully considered limits, could become a tool for trade protectionism…given the open nature of Article 5(2) of the SPS Agreement, there appears to remain scope to rely on Article 26 in order to ban imports while remaining consistent with the SPS Agreement.”172

Nonetheless, in an early (non LMO-related) dispute, a GATT panel set a precedent in rejecting socio-economic arguments used to restrict trade.173

166 Howse & Meltzer (2002, p. 484)167 Zarrilli (2005)168 Brack et al. (2003, p. 7)169 Zarrilli (2005)170 Zarrilli (2005, p. 29)171 Howse & Meltzer (2002, p. 491)172 Howse & Meltzer (2002, p. 491)173 Zarrilli (2005, p. 29). The argument was focused on how cheap imports would undermine the traditional livelihoods of a minority population.

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d) A trade dispute resulting from risk management could be related to the Cartagena Protocol’s identification requirements for LMO trade, which require that products that may contain LMO’s be identified. It has been pointed out that if GATT 1994 deems a GM product to be ‘like’ a non-GM product then, depending on the Protocol’s identification scheme (as of 9 September, 2005, it has yet to be negotiated), the mandatory identification requirements “may be classified as a technical barrier under the TBT Agreement or as a health and safety-related measure under the SPS Agreement.”174 For example, if GMOs and GM products were to be considered ‘like’ products, “then there are no grounds for applying any special treatment to them, including mandatory documentation and identification schemes.”175

A final area not specifically of overlap but potentially leading to tension is that not all WTO members are parties to the Cartagena Protocol (and potentially vice-versa):

“WTO members that are not parties to the Protocol, such as the United States, may wish to ensure that only WTO rules apply to their trade in genetically modified organisms, and may at a future point challenge biosafety rules and measures. The US challenge against the European Union’s GM regulations, although not directly aimed at the Cartagena Protocol, is indicative of the potential for future conflicts once parties have started taking decisions required or authorized by the Protocol.”176

How disputes might be resolved between parties and non-parties of the Cartagena Protocol is another potentially contentious issue, on which “no substantive progress”177 has been made. There thus remains the possibility that the compatibility of the Cartagena Protocol and WTO law might be challenged:

“This is because the economic interests involved in international trade in GMOs are huge; public opinion is still very much divided on whether agro-biotechnology is a risk or an opportunity; the United States...on one hand has actively participated in the negotiations on the Protocol but, on the other hand, is not a party to it and is very unlikely to join it..., and the Protocol is already being interpreted in divergent ways.”178

iii. Potential conflicts between TBT Agreement and Cartagena Protocol

It has been noted that the TBT requirement that trade restricting measures are not “more trade-restrictive than necessary” could lead to trade disputes involving LMOs, given the polarised views that exist on the risks of LMOs. However, Zarrilli (2005) has noted that the only issue is whether a trade restriction is necessary to protect biodiversity, and given this, “a country could implement strict technical regulations regarding GMOs, even though the regulations might have a considerable trade-restrictive impact, on condition that they were not more trade-restrictive than necessary.”179 This perspective has also been maintained by Howse & Meltzer:

“Interpreting the TBT Agreement in light of the protocol, a panel might well find that in this respect the protocol is a kind of lex specialis, of course only among parties to both the protocol and the TBT Agreement. Accordingly, LMO-related measures that are necessary to prevent adverse effects and that have been based upon a risk assessment that

174 Brack et al. (2005, p. 7)175 Zarrilli (2005, p. 30)176 Brack et al. (2005, p. 7)177 Zarrilli (2005, p. 39)178 Zarrilli (2005, p. 39-40)179 Zarrilli (2005, p. 42)

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meets the criteria in the protocol should be presumed not to have prepared, adopted or applied with a view to or with the effect of creating unnecessary obstacles to trade.”180

As discussed earlier, another potential dispute lies in how products are determined to be ‘like’ conventional counterparts:

“If the claimant contends that a technical regulation is incompatible with Article 2.1 of the TBT because it subjects imported genetically modified products to less favourable treatment than conventional products of national or foreign origin, the Panel, in order to determine incompatibility with Article 2.1 of the TBT, would have to establish, inter alia, that the genetically modified and conventional products involved are ‘like products.’”181

It should be noted that this issue has been brought to the WTO TBT Committee but remains an open subject.

iv. International standards

The harmonization of regulatory standards is often an objective in trading societies. The SPS Agreement encourages harmonization of standards, as does the TBT Agreement, by requirements to base regulations on international standards. Of potential dispute is whether the Cartagena Biosafety Protocol may be viewed of as an international standard. For example, in the SPS Agreement, standards of other organizations are only recognized for ‘matters not covered’ by the Codex Alimentarius.182 This might mean that only issues outside of food safety would refer to the Cartagena Protocol. Whether or not disputes arise over this issue remains to be seen.

v. Resolving disputes between the Cartagena Biosafety Protocol (CBP) and WTO law

Lex specialis and lex posterior are two common means of resolving disputes involving two legal treaties. One could side with the CBP because it is more specific (lex specialis) or with SPS because it was established earlier (lex posterior). However, any dispute settled in WTO dispute settlement procedures would be addressed from the point of view of WTO law.183

vi. The role of precedence in trade disputes

As most international law is based on precedence, it is noteworthy to point out that trade disputes on GM animals can in many cases be expected to follow examples set in the debates over GM crops. Thus disputes, particularly between the US and EU, should be followed closely. Zarrilli (2005) notes that a WTO panel is expected to produce a report sometime in 2005 that should comment on whether the EC has not consistently fulfilled its obligations under the SPS and TBT Agreements as well as GATT 1994. Brack et al. (2003) comment that concerning GM crops, “…it does seem that the weight of arguments, and the precedents set by previous disputes under the SPS Agreement, appear to favour the EU.”184 Either way, they note, the WTO decision will have significant implications for international trade of GMOs.

180 Howse & Meltzer (2002, p. 493)181 Zarrilli (2005, p. 42-43)182 Howse & Meltzer (2002, p. 495)183 Cottier (2002)184 Brack et al. (2003, p. 10)

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4.2 Additional potential trade issues4.2.1 Implications of international agreements for Developing Countries

It is often noted that developing countries are at a disadvantage in the global trade of GMOs – and thus GM animals, food and products derived from GM animals and also cloned animals. This is partially because of the great expenses required to establish adequate regulatory systems or patenting systems. Partially for these reasons, some have pointed out that benefits of advances in livestock biotechnology have not easily reached, or been applicable to, the developing world.185

The lack of funds to develop appropriate infrastructures, and general lack of internal biotechnology innovation and general lack of financial resources helps explain one common trend in the negotiation of trade agreements – producers of GMOs/LMOs argue for strict science-based risk assessment principles while developing countries have argued for consideration of socio-economic concerns, risks to agriculture and risks to conservation and sustainable use of biological diversity.186 Such tensions explain clauses like Article 26 of the Cartagena Protocol, which while although it calls for consideration of socio-economic concerns, has been argued as being “very weak owing to pressure by industrialized countries to protect their structural advantages in trade and development.”187

Whether or not developing countries continue to believe that trade and other multi-lateral agreements protect the interests of industrialized countries might have a profound impact on the extent to which developing countries adopt and employ livestock biotechnologies. This in turn could lead to trade disputes.

4.2.2 Unanticipated and illegal trade

It has been observed that several aspects of transgenic animal trade have not adequately been anticipated by regulatory systems. Trade in germplasm, semen, embryos, as well as the constructs, stem cells and vectors used to create transgenic animals may all be expected to be traded internationally.188Trade regimes have not yet considered these in enough detail. In 2001 it was observed that of several international regulations, only Australia’s animal health regulations even referred to the possibility of trade in transgenic animals.189 Similarly, the AEBC (2002) noted that UK regulations on the import of semen, ova and embryos are designed to implement EU animal health requirements but do not specifically address GM or cloned reproductive material. Without sufficient oversight of these types of products, it is difficult to see how their trade could occur safely and efficiently without eventually leading to disputes.

Another problematic issue concerns illegal trade such as the smuggling of GM animals or derived products. Also, without labelling and notice, it would be nearly impossible for examiners to detect import products or animals as GM or cloned. Perhaps the best that can be hoped for with regards to illegal trade is that international systems adequately anticipate the various means through which GM animals and their derived products cross borders:

“No international system…will be able to guard completely against the adventitious or deliberate spreading of some GM animals, particularly fish or insects…This has occurred many times throughout history with

185 e.g. Madan (2005)186 Secretariat for the Convention on Biological Diversity (2003)187 Egziabher (2002)188 AEBC (2002), Howard et al. (2001)189 Howard et al. (2001)

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conventional foreign species which have been introduced into a different eco-system”.190

4.3 LabellingAn important issue in debates over GM crops concerned their labelling and traceability. Much of this discussion was focused on the consumer’s right to choose. As with GM crops, there is likely to be consumer demand for non-GM meat or animal products, which necessitates product segmentation through comprehensive labelling and traceability systems.191

Such systems would begin with means to identify transgenic animals. It would also be necessary to be able to distinguish between transgenic animals approved for human consumption and those that are not, such as, for example, transgenic animal bioreactors.192

Such systems could burden trade between large agricultural exporters (e.g. Canada, United States) and agricultural importers (e.g. Japan). Japan, for example, imports almost all of its food, and the United States is the largest source of these food imports. With GM plants, Japan has requested non-GM food and, following the EU, required the labelling of products containing GMOs.193

Thus as labelling of transgenic animals emerges as a serious issue, the pathway ahead “could be contentious”194. The remainder of this section will focus on the different labelling provisions in various regulatory regimes.

4.3.1 The Codex Alimentarius

As described in Report 2, the Codex Alimentarius is designed to protect the health of consumers and to ensure fair trade practices in the food trade, and to promote coordination of all food standards work undertaken by international governmental and non-governmental organizations. The Codex Alimentarius Commission (CAC), an intergovernmental body, was created in 1963 by FAO and WHO to develop food standards, guidelines and related texts such as codes of practice under the Joint FAO/WHO Food Standards Programme. As the international agency dealing with health, the WHO bears the main responsibility for the health and safety aspects of Codex standards, guidelines and recommendations so that they appropriately protect the health of consumers.

Ever since the Codex Committee on Food Labelling (CCFL) started discussing the implications of biotechnology for food labelling in the early 1990s the topic has been on the agenda of each CCFL Session. A Working Group was established which produced Draft Guidelines for the Labelling of Foods Obtained through Certain Techniques of Genetic Modification/Genetic Engineering. During the 9-13 May meeting of the Codex Committee on Food Labelling (CCFL) in Kota Kinabalu, Malaysia, no consensus was achieved with regard to labelling biotech foods that differed from their conventional counterparts. Several countries objected to the guidelines as they currently stand, which allow for labelling of biotech foods that are (1) substantially different in terms of composition, nutritional value, or allergenic content, (2) composed of or containing GMOs, or (3) produced from but no longer containing GMOs. Their suggestion is to limit the Guidelines’ coverage to the first category of GM foods. The Chair of the session attempted to reach a compromise

190 AEBC (2002, p. 40)191 AEBC (2002)192 Howard et al. (2001), Pew Initiative (2001)193 Inaba & Macer (2003)194 Howard et al. (2001, p. E7)

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between the two positions by suggesting a split between mandatory and optional labelling provisions. Thus, ‘Mandatory’ labels would apply to substantially different GM foods, while ‘Optional’ labelling would apply to GM foods that are different because they have been produced through genetic modification. The CCFL guideline, if adopted, will ensure that any nation requiring labelling of genetically modified food cannot be challenged at the World Trade Organization (WTO).195

Once a Codex standard has been adopted, member countries are encouraged to incorporate it into any relevant domestic legislation. However, under the SPS Agreement, member countries retain the right to unilaterally impose more stringent food safety measures they deem necessary to ensure consumer protection. The only condition is that these standards are scientifically justifiable and consistent with SPS rules.

4.3.2 The WTO

As stated previously, the three possible regulations of the labelling of food derived from biotechnology are GATT, the SPS Agreement and the TBT Agreement. This covers the labelling of any type of food, whether cloned or genetically modified. Such labels will always need to be measured against the GATT and the two agreements to determine whether any labelling measure violates international trade law.

4.3.3 Labelling in individual jurisdictions

Most countries have either mandatory or voluntary labelling schemes for food containing or consisting of GMOs in place.

i. Europe

In 1997 the EU first introduced mandatory labelling to indicate the presence of GMOs as such or in a product. With the coming into force of Directive 2001/18/EC on 17 October 2002, Member States had to take all necessary measures to ensure labelling of products consisting of or containing GMOs at all stages of the placing on the market.

For pre-packaged products consisting of or containing GMOs, Regulation (EC) No 1830/2003 requires a label stating that “This product contains genetically modified organisms”. For non-pre-packaged products offered to final consumers, these words must appear on, or in connection with, the display of the product. Such food products delivered to the final consumer or to mass caterers must be labelled in accordance with Regulation (EC) No 1829/2003, regardless of whether or not the final product contains DNA or protein resulting from genetic modification. The labelling obligation also applies to highly refined products, such as oil obtained from genetically modified maize.

In January 2000, the Commission adopted Regulation (EC) 50/2000 ensuring that also additives and flavourings have to be labelled if either the DNA or a protein of GMO origin is present in the final product.

ii. USA

The Food and Drug Administration (FDA) regulates the labelling of food products, including foods that are produced using genetic modification. In 1992, the FDA published a policy providing guidance to industry on scientific and regulatory issues related to bioengineered foods. In this guidance, special labelling requirements for bioengineered foods were not established. Only if a food, including a bioengineered food, is significantly different from its conventional counterpart, this information is required in the labelling of the product.

195 http://www.fao.org/es/ESN/food/risk_biotech_label_en.stm

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iii. Canada

Health Canada and the Canadian Food Inspection Agency are jointly responsible for federal food labelling policies in Canada under the Food and Drugs Act. Since 1993, there have been three major consultations on the labelling of novel foods derived from genetic engineering. Based on these consultations, a set of guidelines were developed. Accordingly, mandatory labelling is required if there is a health or safety concern, in must be ensured that the labelling is understandable, truthful and not misleading, voluntary positive labelling must be permitted on the condition that the claim is not misleading or deceptive and the claim itself is factual and voluntary negative labelling must be permitted on the condition that the claim is not misleading or deceptive and the claim itself is factual. 196 These principles are consistent with the policy for all foods under the Food and Drugs Act.

To facilitate the use of voluntary labelling, the Canadian government supported the development of a national standard for the voluntary labelling of foods derived from biotechnology. This process was sponsored by the Canadian Council of Grocery Distributors, under the guidance of the Canadian General Standards Board.197

iv. Australia and New Zealand

On 28 July 2000 Health Ministers of the Australian States and Territories, the Australian Commonwealth and New Zealand agreed to new labelling requirements for genetically modified food under Standard 1.5.2 of the Australia New Zealand Food Standards Code. The Ministerial Council formally approved the revised standard on 24 November 2000, which came into effect on 7 December 2001. The standard requires that all foods produced using gene technology must be assessed and approved before sale and use; and that all genetically modified food and ingredients, as defined in the standard, must be labelled if they contain novel DNA and/or novel protein in the final food, or have altered characteristics. This exempts food with ingredients made from animals raised on GM feed, including milk, meat, eggs and honey. It also exempts food with highly-refined GM ingredients, such as cooking oil, sugar and starches. Most processed food falls into this category.

v. China

Since June 2001, China has required that all GM products imported into China for the purposes of research, production or processing have safety certificates from the agricultural ministry to ensure safety for human consumption, animals and environment. Furthermore, all listed transgenic biological products must be labelled. However, this legislation only applies to five categories of plant GMOs, namely soybean, corn seeds, rapeseeds, cotton seeds and tomato seeds.

vi. Japan

In Japan, the jurisdiction for food labelling is shared between two laws and two ministries: The Food Sanitation Law administered by the Ministry of Health, Labour and Welfare for public health, and the Law concerning Standardization and Proper Quality Labelling of Agricultural and Forestry Products administered by the Ministry of Agriculture, Forestry, and Fisheries to enable consumers to make informed choices. While the Japanese government rejected the labelling of GM food in 1997, this position underwent a drastic change due to the pressure by the consumer’s movement. In August 2000, the Ministry of Agriculture, Forestry and Fisheries decided to introduce mandatory labelling when genetically modified material is present in the top three raw ingredients and amounts to 5% or more of the total weight of the product. Exceptions from the labelling requirements are feedstuffs,

196 http://www.inspection.gc.ca/english/sci/biotech/labeti/response.shtml197 http://www.inspection.gc.ca/english/sci/biotech/labeti/vole.shtml

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alcoholic beverages and processed foods such as soya sauce, corn flakes and vegetable oils.

vii. South Korea

Mandatory labelling of GM food became effective in July 2001. Accordingly, labelling for GMOs or product containing GM ingredients is mandatory if the GM ingredient amounts to at least 3%.

viii. Japan, Thailand and Taiwan

These countries have adopted labelling schemes similar to the Australian model. However, the schemes are more limited in scope and do not apply to all foodstuffs, applying a GMO threshold of 5%.

4.4 TraceabilityTo be traceable something must a have a tag or mark. This mark must be unique or at least highly restricted in occurrence. For a GM animal or product the only mark would be the transgene DNA or potentially some unique aspect of the transgene encoded product. All other cellular components will be common to all animals of that species, or at the very least be common to large numbers within a given species.

We have considered four ‘types’ of GM event:

i. transgene is distinct from host animal genes

ii. transgene is from host animal species

iii. GM event involves single base changes

iv. host gene deletion.

i. Transgene is distinct from host animal species

If the transgene is known then a relatively easy, quick and cheap PCR assay could be established. Tracing, however, would not be possible with current technology if the sequence of the transgene was not known. We anticipate that DNA sequencing technology will advance and within a 10-20 year timescale whole genome sequencing will be possible at a relatively low cost. If this was to happen then even an animal for which the transgene was unknown could be identified. It may also be possible to use antibody based tracing assays that detect the presence of the novel transgene encoded protein.

ii. Transgene is from host animal species

Two GM events are considered under this aspect; addition of more copies of a host gene and replacement of a host gene. Tracing of the former would again be possible with standard molecular biology assays as long as the transgene identity was known. Tracing of the latter would be very difficult if not impossible due to the identical sequence nature of this GM event, unless a selection marker or some other sequence tag had been incorporated into the transgene. In this case, as long as the sequence tag was known a PCR assay could be established. If no sequence tag was present then even genome sequencing (when it becomes easily affordable) would not allow tracing.

iii. GM event involves a single-base change

Given that this type of event occurs in nature there will be no method that will allow tracing. Even an audit trail will be limited by the ability of such mutations to occur naturally in a given population.

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iv. Gene deletion

Tracing would be possible with standard molecular biology assays as long as the GM event was known. If it is unknown then only access to genome sequencing will allow tracing.

In summary only some GM events allow for easy tracing. Some evens are untraceable even if the precise genetic change is known. Knowledge of the identity and nature of the GM event will, in most cases, allow for easy, quick and cheap assays to be established which will enable robust tracing. A major advance in the ability to trace a GM animal would be the development of cheap genome sequencing technology (predicted in 10-20 years). Tracing of products made up of mixture of GM and non-GM or of processed GM products will be very difficult due to the dilution effect caused by the mixing.

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SECTION 5 ANIMAL WELFARE5.1 Welfare of GM animals5.1.1 Introduction

We have restricted our analysis to physiological aspects of animal welfare and are not addressing wider aspects of well-being.

To evaluate welfare of a GM animal two aspects of the GM event need to be considered. First is the nature of the transgene and second what secondary changes in gene activity are induced as a consequence of transgene activity.

a) Transgene activity

What is encoded by this DNA sequence and what activity is conferred by the transgene product? In addition where and when is the transgene active with respect to development of the animal and the various body systems in an animal. There is already a reasonable level of control of transgene activity conferred by current transgene designs, and it is anticipated that within a 5-10 year period significant improvements will be achieved.

b) Secondary changes in gene activity

Regardless what activity is conferred by the transgene product it is expected that a number, in some cases a large number of host gene activities will be altered. Advances in ‘omics technologies, e.g. proteomics, will allow these changes to be identified, tracked and analysed.

The first GM non-murine animal was reported in 1995. Since then many GM animals have been generated however the total number is insignificant compared to the total number of animals breed using natural reproduction regimes. Given these two considerations, very few studies directly evaluating welfare have been performed to date. Most studies have focussed on animals generated for xenotransplantation.

Each GM event is likely to be associated with potentially different welfare issues. As such, a case-by-case evaluation will be required. Predictions can be established prior to a study but for many aspects only retrospective monitoring will enable a full evaluation to be achieved. In this report we aim to illustrate the types of concerns which may arise rather than provide a comprehensive list.

We have also excluded discussion of issues surrounding the use of animals during the generation phase, i.e. issues associated with egg manipulation and transgene delivery (the technical aspects of this is discussed in Report 1). Indeed, it is this aspect that has attracted most effort and debate up till now. A generally accepted ‘success’ rate is around 1-2% normal animals produced (Clark and Whitelaw, 2003). As more animals are generated and bred it will be welfare issues associated with GM animal populations that will be of major concern in the future.

5.1.2 Physiological issues

Most if not all GM events will alter the physiology of the animal. Most of these changes will be very minor and not carry any welfare risk. For example, animals producing a human pharmaceutical protein in the milk will have altered milk composition. The expectation is that this would not have an affect in other aspects of the animal and this is been born out through a number of studies. However, in some cases, where the pharmaceutical protein was present in an active form, e.g. erythropoietin, in those animals were some ‘leakage’ of protein in the circulating blood system was evident the animals displayed systemic physiological effects.

It is anticipated that for most applications that aim to alter physiology, minor changes will be generated. It is expected that major changes would be severely detrimental to

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the animal. More extreme examples would include GM events that are designed to dramatically alter physiology of the animal. This is most likely to occur in a scientific context rather than a commercial context.

5.1.3 Health issues

Animals may be generated that are predisposed to certain diseases, or as discussed above, with altered physiology. Both applications may carry attendant health risks. Management of these conditions will be similar to that of non-GM animals with comparable health problems.

5.1.4 Behavioural issues

Predicting changes to physiology will be relatively easy from knowledge of gene activity, however, given our current understanding of the genetics of behaviour in animals it will be harder to predict behavioural changes. Initial ‘bench marking’ of comparable non-GM populations will be required.

What are acceptable behavioural traits to society have to be debated. It will be relatively easy to say what gross changes in behaviour are not acceptable. However, it may be harder to achieve a consensus in a debate on subtle behavioural changes.

5.1.5 Conclusions on comparison of GM and non-GM animals

Welfare issues will need to be assessed for most GM animals on a case-by-case basis. This will require both a predictive assessment and continued monitoring. In some cases the GM event will be designed to alter phenotype in such a way that it will cause welfare issues. It is anticipated that for most cases welfare concerns will be minor and manageable. Test populations will allow welfare issues to be identified and addressed.

5.2 Regulation on animal welfareThis was covered under Report 2 (section 5.2) as the legislation relating to animal welfare relates both to cloned and GM animals. In summary, most jurisdictions have focussed legislation with regard to welfare of animals used for scientific purposes rather than agricultural purposes. Legislation on farm animal welfare exists in the EU (Directive 98/58/EC) but it is not clear how this would be interpreted with reference to GM animals, for example what would be identified as poor welfare (e.g. would information be required on more than one generation of GM animals, what kind of information would be required etc.).

Concerns have been expressed (e.g. by the UK Farm Animal Welfare Council, 2004) that the GM regulation that exists also does not require an assessment of the welfare of GM animals before any importation (perhaps not surprisingly since this is not an issue with GM plants).

A report from the UK Agriculture and Environment Biotechnology Commission (AEBC, 2002) expressed concern that there is a regulatory gap with respect to GM animals where the modification made can be considered intrinsically objectionable but does not give rise to clear animal welfare, animal or human health, or environmental concerns, such as animals with radically altered patterns of behaviour. The AEBC also recommended post-commercialisation monitoring of GM (and cloned) farm animals to look for unexpected welfare or health problems.

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SECTION 6 PUBLIC ATTITUDES6.1 IntroductionThe remit for this report was specifically not to focus on ethical aspects and public attitudes as these are being covered by the Specific Support Action ‘Farm animal cloning and the public’. Therefore, only a very cursory consideration of these aspects is included in this report. Given the likely importance of these factors to the development of GM animal technology, it was not possible to ignore public attitudes altogether.

Public attitudes have been assessed by opinion poll surveys and focus groups. Opinion poll data measure attitude to specific questions at a specific point in time, in a specific context and may not explain why respondents hold the attitudes that they do. This can make them difficult to interpret. Focus groups access smaller numbers of individuals but achieve more in-depth understanding of the motivations for specific attitudes. On the other hand, focus group results are relevant only to the small number of individuals who take part and cannot be generalised to the population level in the same way as a randomly sampled opinion poll. It should also be noted that asking the public to talk about current uses may be of limited use for evaluating GM animal technology as a whole, as future uses may be very different from those currently envisaged. Furthermore, conceptions of the future and future uses of animals may be relatively unformed and may well develop over time.

We have found survey data available for the EU (notably through Eurobarometer) and USA (Pew initiative). Information over a number of years is also available for Japan. We found more sporadic information available for other countries. Most surveys have been carried out in the wider context of biotechnology (or even science). We have been able to locate a small amount of focus group data for UK, USA and Japan.

6.2 Attitudes to GM animals6.2.1 Europe

Gaskell (Gaskell et al., 1999) in a review of European and US attitudes during the period 1996-1997 found that from a list of potential applications, xenotransplantation received the least support (GM medicines and genetic testing received the most support, GM crops intermediate support). Despite the often-made assumption that the US is generally positive to GM applications, it was notable that in this survey the average US respondent was opposed to xenotransplantation. In a more recent Eurobarometer survey (Gaskell et al., 2003) responses from 1996 were compared to responses in 2002. Support for xenotransplantation during this period increased from 56% to 73%, whilst opposition fell from 45% to 27%. The authors do not attempt to explain the causes of this rather large change. Questions were also asked about GM food, but it is likely that respondents would understand this to mean GM food derived from plants rather than animals.

A recent Eurobarometer survey of attitudes of consumers to farm animal welfare (Eurobarometer, 2005a) found that a majority of EU citizens (55%) thought that animal welfare did not receive enough importance in agricultural policy, although it should be borne in mind that nearly one in five (19 %) respondents thought no legislation on animal welfare on farms exists in the EU.

Another recent Eurobarometer survey on values and science (Eurobarometer, 2005b) found that for 53% of EU citizens, decisions about science and technology should be based primarily on the risks and benefits involved. For one in three, moral and ethical issues should be prioritised in such decision-making. This highlights the importance that moral values have in the mind of the European publics.

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Ouedraogo (2004) studied public perceptions of reproductive biotechnologies in France and UK during the period 2000-2003 using focus groups. He found that the majority of respondents did not accept or understand why they should have to pay more for animal products produced to higher standards. This is an interesting contrast to the Fair Trade movement that has persuaded some consumers to pay more for products in order to benefit developing countries.

One major concern in the groups appeared to be that priority is given to economic competitiveness at the expense of sustainable development, for example, one respondent expressed this as follows (p186):

“The stakes these issues cover are far from being purely scientific. The actual problem is socio economic and it deals with the increasing influence of industrial firms in the society. Genetics represents today and especially will represent in the near future a huge economic potential that European do not want to leave in American hands”

In the UK a series of focus groups were carried out as part of a report for the Agricultural and Environmental Biotechnology Commission on GM animals (Mcnaghten, 2004). These focus groups consisted exclusively of people with experience of animals in different contexts plus two ‘control’ focus groups without this experience. Mcnaghten concluded that:

“people tended to accept (or at least to tolerate) the suffering of the animals concerned when there existed a genuine and authentic need, typically expressed in the need to cure life-threatening diseases. Such a need had to be justified in human rather than commercial criteria and was only seen as justified when alternatives were not available” (p540)

6.2.2 USA

In the USA, a series of public polls have been published by the Pew Initiative on Food and Biotechnology. In the 2003 survey (Pew, 2003) respondents were substantially less comfortable with modifications of animals than plants with 58% opposed to research on GM animals. Within GM animals, acceptance was highest for producing bullet-proof vests from goats milk (58% thought this was a good reason for GM) with declining acceptance respectively for xenotransplantation (57%), leaner beef (51%) and cheaper fish (45%). Nearly every purpose that involved plants was considered a better reason to pursue genetic modification than those which involved animals e.g. 81% said that producing more affordable pharmaceuticals was a good reason for modifying plants but just 49% said it was a good reason to genetically modify animals.

A similar survey in 2004 (Pew, 2004) found that a large majority of US consumers support the labelling of GM food (92%). The survey also confirmed the findings in 2003 that respondents were generally opposed to GM animals – 57% said they opposed this type of research (46% strongly). Focus group data suggested that much of the opposition was based moral, ethical and religious beliefs. Analysis by religious affiliation indicated that the values underlying the opposition to GM animals appeared across the religious-secular divide.

6.2.3 Japan

A series of surveys has been conducted in Japan over a period of time (Inaba and Macer, 2003). A survey on attitudes to biotechnology in 2001 found strong support for animal rights that people should not violate (75%). A majority was satisfied that current regulation will protect people from any risks linked to GM food (65%) but only 19% would not object if they found food they were consuming in a restaurant contained GM ingredients. With respect to using GM pigs as heart donors, the

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proportion of respondents who found this morally unacceptable fell from 39% in 1997 to 24% in 2000. As with other surveys, application of genetic modification to plants was more acceptable than to animals. In a survey in 2000, use of genetic modification to produce healthier meat was approved of by 53% of respondents, cows to produce more milk by 39% of respondents, as compared to 66% approval rating for tomatoes with better taste and 54% for disease resistant crops (note that the question asked for approval conditional on no direct risk to humans and only very remote risks to the environment). We should perhaps note that consideration of xenotransplantation in Japan is in a particular context since organs from human cadavers and organs from brain dead patients have not been widely used in Japan due to cultural resistance (Inaba and Macer, 2003).

6.2.4 Developing countries

We were only able to locate cursory opinion poll data from developing countries (e.g. Curtis et al. 2004). This report refers to a Chinese study, where only 9% of the survey respondents had a somewhat negative or negative opinion concerning the use of biotechnology in foods. In a study in Colombia quoted in the same report, almost 75% of respondents agreed that there may be some risk associated with GM foods, but almost as many respondents were willing to try GM foods anyway. Curtis and colleagues suggest that the more positive perception towards GM foods is due to more urgent needs in terms of food and nutrients. They also suggest that the perceived level of risk may be smaller. However, detailed information on these surveys was not available and it is not clear whether respondents would be purely thinking of GM crops rather than GM animals. We may conclude that there is an absence of evidence in this area.

6.3 Ethical discussions around GM animalsEthical aspects of genetic modification of animals have been extensively discussed.

An example of an influential document in the UK was the Report of the Committee to Consider the Ethical Implications of Emerging Technologies in the Breeding of Farm Animals (‘the Banner Committee Report’, Banner,1995). This set out a framework for ethical evaluation that has subsequently been used by other bodies. The framework consists of a 3-step approach:

Harms of a certain degree and kind ought under no circumstances to be inflicted upon an animal.

Any harm to an animal, even if not absolutely impermissible, nonetheless requires justification and must be outweighed by the good which is realistically sought in so treating it.

Any harm which is justified by the second principle ought, however, to be minimised as far as is reasonably possible.

From a literature survey from a range of bodies, the main arguments made against genetically modified animals can be summarised as:

The animal suffering involved

The technique is very ‘hit and miss’

Slippery-slope to humans

Commodifying animals

GM represents an insult to the ‘intrinsic value’ or ‘telos’ of animals

The existence of patents encourages a wrong approach to animals

This is being done for the wrong motive (profit rather than real social need)

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It is being done in secret (in commercial companies)

There are often better alternative methods of achieving the same aim.

GM has been subject to excessive hype by its advocates and has yet to demonstrate any successes

GM demonstrates the wrong way of doing agriculture by increasing intensification

GM animals may disadvantage small farmers

GM is of no benefit to developing countries.

It is notable that that ‘risk’ from GM animals is not currently part of the wider discussion. However, regulatory efforts tend to focus on risk and to some extent animal welfare as issues which can be legislated. Ethical issues tend to be very contentious, reflect considerable disagreement among publics and therefore, in most cases, pose difficulties for policy makers and regulators, for example under 5.2 we noted the concern expressed by some that there is no regulation relating to use of genetic modification that may be considered objectionable because of its impact on the ‘integrity’ of an animal, if there is no impact on welfare.

6.4 Dilemma of human – animal relationshipsOne of the issues this report was tasked with was to arrive at a socio-economic cost-benefit evaluation for uses of GM animals. One of the difficulties of arriving at such calculations is that we do not have an agreed evaluation of the ‘worth’ of a non-human animal as compared to human. These human-animal distinctions are disappearing in the minds of at least some people, for example as expressed by the UK Farm Animal Welfare Council (1998),p 4.

“It is not clear that a radical distinction between human and non-human is now defensible, either biologically or ethically, nor that any such disjunction is sufficient to warrant the treatment of other living creatures merely as means. We owe respect to other animals, and especially to those which we choose to domesticate.”

The UK’s Nuffield Council on Bioethics (2005) recently identified three different views of the human-animal relationships (p 24):

There is something special about humans that is present in all humans but not in non-human animals

There is a hierarchy of moral importance with humans at the apex and invertebrates near the bottom

There is no categorical distinction between human and non-human animals.

Views on the appropriateness or otherwise of genetically modifying animals are likely to be strongly influenced by differences in views about the moral distinctiveness of humans from non-human animals.

The advocacy group ‘Genewatch’ further suggests that processes such as genetic modification may themselves affect how we view human-animal relationships.

“It is important that society as a whole is engaged in the debate about what is acceptable and desirable before the technology progresses to a point where transgenic animals become a normal part of production process and the relationship between humans and animals is changed irrevocably” (Rutovitz & Mayer, 2002, p8)

Finally, we may note the conclusions from Macnaghten from his focus groups (referred to earlier under 6.1.1) the ambivalence felt by people in the context of developing a culture of care for animals but at the same time eating them.

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“Many people saw themselves as being ‘in denial’, choosing to eat meat yet at the same time distancing themselves from actively confronting the realities of modern farming; colluding with abattoirs, supermarkets, advertisers and food producers in dislocating meat from its corporeal production” (Mcnaghten 2004, p539)

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SECTION 7 POLICY CONTEXTIt is beyond the remit of this report to consider the full-range of policy contexts within which genetically modified animals exist and only a brief summary of some issues is provided here.

7.1 Ethical PolicySome attempts have been made within the European policy making context to address issues around the ethical acceptability of GM animals, notably through the Group of Advisers on the Ethical Implications of Biotechnology to the European Commission.198 The Group considered genetic modification would add to rather than replace existing techniques and saw its utility in making models of human disease, providing an alternative source of tissues and organs for xenotransplantation and to obtain improved desired features of farm animals. The Group offered the opinion that “genetic modification may contribute to human wellbeing and welfare, but is acceptable only when the aims are ethically justified and when it is carried out under ethical conditions.”

They encouraged licensing bodies to consider, at least:

The objectives – transparency and ethical acceptability

The risks – to human health and the environment

Animal health, welfare and care

The proportionality of means and ends

The quality of GM procedures and

The possibility of alternatives

7.2 EC Biotechnology StrategyThe European Commission set out its strategy for Life Sciences and Biotechnology in 2002 (Commission of the European Communities, 2002) which states that (p5):

“The Commission proposes a strategy to respond with responsible, science-based, and people-centred policies on an ethical basis. This strategy aims to allow Europe to benefit from the positive potential of life sciences and biotechnology…, to ensure proper governance…, and to meet Europe’s global responsibilities…This is a proposal for an integrated strategy – its different elements are interdependent and mutually reinforcing.”

Relevant actions from this strategy include:

Engaging in a structured dialogue at various levels to develop an understanding and information exchange on life sciences and biotechnology (Action 13)

Identifying areas where it is possible to establish consensus on ethical guidelines/standards or best practice (suggested areas include xenotransplantation) (Action 16)

Redefining national research towards an appropriate mix of traditional techniques and new technologies in agriculture, based on priorities developed with local farmers (Action 25)

Supporting the conservation and sustainable use of genetic resources in developing countries and the equitable sharing of benefits arising from their use (Action 26).

198 Opinion of the group of advisers on the ethical implications of biotechnology to the European Commission. Ethical aspects of genetic modification of animals, 21 May1996

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7.3 Industry context: pharmaceutical and agriculturalAs well as the agricultural context, the pharmaceutical industry context is also important when considering the potential application of GM animals. There is insufficient space in this report to provide a fully comprehensive account of a complex industry sector, but a few key elements are noted below.

Tait and Mittra (2004) note that traditional pharmaceutical companies are facing increasing competition from emerging Asian-based multinationals, with strategies based on starting from a base in commodity drugs. Perhaps most relevantly to consideration of products from GM animals, the pharmaceutical industry has limited production capacity for biological products and there is potential for the emergence of ‘biogenerics’ markets.

The general agricultural context was described in Report 2, section 7.3. We may however, note in addition the very different way in which GM animals are presented in different countries for example comparing web site statements from New Zealand and the UK. For example the New Zealand Ministry of Research, Science and Technology highlights New Zealand’s research strengths as including large animal-based biotechnologies and refers to

“the team at Ruakura is regarded as a world leader in cattle cloning”

“New Zealand has developed a capability in transgenesis in cattle/sheep to express high-value proteins in milk for biopharmaceutical purposes. This expertise is coupled with New Zealand’s high animal health status …and provides an advantage over other countries”199

This is in contrast to much more cautious statements made by the UK Department for Environment, Food and Rural Affairs which on its web site states for example:

“The government has an open mind about GM animals. Its first priority is to protect human health and the environment. The Government is pro-science and pro-consumer choice. However, government also realises that there are issues surrounding GM animals that are different to those surrounding GM plants and micro-organisms.”

And

“The Government is aware that it is difficult to envisage any circumstances in which the release of a GM fish would be permitted. There are no GM fish held in aquatic pens in this country and no approval has yet been sought or granted for commercial production of GM fish.”200

Nevertheless we should perhaps be cautious about putting too much weight on individual statements made by specific ministries.

There may also be other important cultural factors to take into account that are specific to individual countries, for example the presence of Maori culture in New Zealand with different approached to the natural world. Individual countries also face different production conditions for example Japan is very different from the USA. Inaba and Macer (2003) report that Japan imports almost all of its food and note that the average family spends more of their income on food in Japan than in other OECD countries. The farms are generally small in size and government taxation policy favours the maintenance of small farms, therefore they argue that any financial

199 http://www.morst.govt.nz/?CHANNEL=Large+animal&PAGE=Large+animal (Site visited 29th June 2005)200 http://www.defra.gov.uk/environment/gm/background/animals.htm - Site accessed 13/9/05

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http://www.defra.gov.uk/environment/gm/background/animals.htm

http://www.morst.govt.nz/?CHANNEL=Large+animal&PAGE=Large+animal

benefit from GM technologies to Japanese farmers may be insignificant. Japanese traditional culture also stresses ‘seasonality’ (e.g. cherry season) and the presence of something transient. Thus, for some people, products that are available throughout the year may be less valuable. Despite this, Inaba and Macer note that the majority of Japanese view themselves as consumers in a global market.

Another of the factors that should be taken into account is the structure of the supply chain of breeding stock to farmers and the role of commercial companies in this. The industry structure is very different in the supply of animal breeding stock compared to seeds. Whereas the crop breeding industry is now dominated by multinational seed companies (often part of pesticide-producing companies), the livestock breeding industry has much more variety. Poultry breeding is dominated by commercial companies (e.g. 3 companies provide 80-95% of Europe’s egg producing market and 75% of the world market, 4 companies produce 35-60% of the world markets in poultry meat)201 However, despite their influence, these companies are still relatively small. In pigs, 50% of European pig breeding organisations are privately owned companies and 50% co-operatives but no single pig breeding company has more than 25% of the European market. With respect to cattle there are more farmer’s co-operatives active in Europe and less commercial companies. Genetic improvement of fish stock started late but has grown rapidly. There are for example, five main companies involved in salmon breeding.

7.4 Developing countries’ contextGM crops were advocated partly on the basis of their contribution to alleviating world hunger. This claim was treated with scepticism by many groups. To what extent are the same arguments being made for GM animals? And what might their contribution be to developing countries?

We have found little evidence of genetic modification of animals being justified on the basis that it is an essential technology for feeding the world, with the exception of GM fish.

A paper produced for the International Food Policy Research Institute (Delgado et al.1999) looking at livestock production in developing countries to 2020 notes that livestock are extremely important to the livelihoods of rural poor in developing countries. The poor earn a higher share of their income from livestock than do the wealthy, in part because they tend to own less land and therefore require the higher returns from the land available from animals rather than crops. However, the report cautions that the current rapid trend to intensification may be a threat to the poorest farmers because this will make them uncompetitive compared to large farmers. Large producers are likely to find it easier than small producers for example to vertically integrate with processors.

The paper notes that the context for livestock agriculture worldwide includes:

Rapid increase in consumption of livestock products

Major increase in the share of livestock production and consumption in developing countries. Developing country share of worldwide meat and milk consumption is expected to rise from 31 and 25 % respectively in the early 1980s to 60 and 52 % respectively in 2020 (p60).

Change of livestock production from a multipurpose activity to food production in a global market

Emergence of rapid technological change in livestock production and processing

201 http://www.eadgene.info/animalbreeding.html - site accessed 18/10/05

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We might conclude from this that GM animals, if adopted for agriculture in developing countries, have the potential to disadvantage the poorest farmers. Madan (2005) broadly echoes the above conclusion and stresses that resource poor farmers do not feel that applying new technologies is worth the effort, cost and risk involved. Madan notes that little research is conducted for the benefit of developing countries, probably because there are unlikely to be returns on investment for commercial companies. Furthermore, developing countries find it difficult to develop their own biotechnological resources because the facilities and infrastructure are lacking and international agencies spend only a small percentage of their funds on animal biotechnology.

The advent of GM plants raised concerns about the need to recognise and reward indigenous knowledge about valuable plant properties and to protect developing countries from having their genetic resources unfairly exploited. Similar concerns have been expressed with regard to GM animals.

“On one hand, the role of traditional livestock keepers in breed conservation and development must be rewarded, while on the other hand they must be protected from bio-piracy and other interventions which undermine their control over their animal genetic resources.” (Koehler-Rollefson, 2002 p39)

We might conclude that some of the same concerns may exist for GM animals as for GM plants regarding their likely impact on developing countries. However, production of GM animals does not appear to be driven by the need to ‘feed the world’.

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SECTION 8 META-ANALYSIS OF GOVERNMENTAL TECHNOLOGY FORESIGHTS AND ASSESSMENTS8.1 IntroductionThe enormous increase of animal biotechnology research (animal cloning and genetic modification) and its products presents many challenges and opportunities for government regulators and the public in all nations. Animal biotechnology is often controversially discussed even within one country. The complexities multiply when trying to understand the governance of animal biotechnology in several nations. Given the important public policy implications of animal biotechnology and its regulation, it is essential to understand how different counties are assessing, validating and judging this technology in order to make the subsequent regulation most efficient and safe.

8.2 Aim and objectiveThe metaanalysis of (inter)national technology assessments gives an overview of the existing animal biotechnology assessments from government advisory bodies in the international arena. For this purpose 7 International TA Institutes202, 10 International

202 STOA – Scientific and Technological Options Assessment: is the Technology Assessment Unit at the European Parliament of the EU(Luxembourg/Brussels).

IPTS – Institute for Prospective Technological Studies in Sevilla, Spain. A Joint Research Centre of the European Commission.

DESIA – Decision Support and Integrated Assessment Sector: a research group within the Institute for Systems Informatics and Safety (ISIS). The latter is one of the European Commission's Institutes, located at the Joint Research Centre, Ispra, Italy

DHCTA – Division for Health Care Technology Assessment of the International Federation for Medical and Biological Engineering (IFMBE), is an international organisation covering around 35 countries.

UNU/INTECH – United Nations University / Institute of New Technologies

Institute for New Technologies – of the United Nations University: policy research on the economic and social impact of new technologies in the developing world

Technopolis – an international research and consulting organisation focusing on science, technology and innovation policy

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TA Federations/Associations203 and more than 80 national TA units204 have been examined and analysed on their work performed referring to animal biotechnology.

The Foresight metaanalysis explores the results from existing foresight initiatives and foresight meta-analyses in order to quantify and qualify the future potential of animal biotechnology as national S&T priorities and to gain a better understanding of the expectable evolution during the next two decades.

8.3 Findings: (inter)national technology assessmentsOur metaanalysis of statements, views and recommendations from (inter) national Scientific and Technological Options Assessment Institutes205 and government advisory bodies found, that animal biotechnology issues were either not addressed or received little attention from these national TA institutions (particularly after the year 2000, when the uproar around Dolly decreased) and that in most of the assessments, cloned animals and transgenic animals are (for various reasons) treated as being the same.206

Instead, technology assessments on animal biotechnology seem to be spread among various institutes and organisations with little or no coordination, even within one 203 NTA – Netzwerk TA: homepage of the German speaking TA community network (founded in 2004): offers a discussion list, an events calender and other TA related information, such as calls, job offers etc.

ESTO – European Science and Technology Observatory, a network under the auspices of IPTS

EPTA – European Parliamentary TA – the European umbrella organization of parliamentary TA institutions

ETAN – European Technology Assessment Network on the CORDIS server of the EU

STRATA – Strategic analysis of specific science & technology policy issues: sponsored by the European Commission, this is somehow the successor of the ETAN network

EASST – The European Association for the Study of Science and Technology

SSSS (4S) – Society for Social Studies of Science: An International Interdisciplinary Association for the Study of Science and Technology

IATAFI – The International Association for TA and Forecasting Institutions has been established under the auspices of the United Nations, with its secretariat at STATOIL in Bergen, Norway. The goal of the IATAFI is to advance international co-operation among technology assessment (TA) and forecasting institutions (TF) for the purpose of supporting sound decision-making regarding sustainable development in response to global change. The Website is now joined with Agenda21.

INAHTA – International Network of Agencies for Health Technology Assessment

ita – Projektträger Innovations- und Technikanalyse (ita) des deutschen Bildungs- und Forschungsministeriums , VDI-ZTC

TA network Baden-Württemberg – (for TA links follow WWW-Links button) 204 Austria (23), Belgium (4), Canada (1), Czech Republic (1), Denmark (3), Finland (3), France (3), Germany (11), Greece (2), Hungary (2), India (1), Israel (1), Italy (2), Japan (5), Netherlands (5), Norway (2), Portugal (1), Spain (1), Sweden (3), Switzerland (19), U.K. (5), USA (8)205 http://www.oeaw.ac.at/ita/www.htm for an inventory of Technology Assessment Institutes. This interactive link collection provided by the Institute of Technology Assessment (ITA), Vienna, and maintained with the help of the international TA community.206 Transgenic animals or plants are produced by adding or removing genes, or by altering the expression of their existing genes. Cloned animals are produced using bioengineering techniques but are intended to be biological copies of existing animals.

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http://www.oeaw.ac.at/ita/www.htm

country; and a clarification of the relationship between these national Agencies and Committees seems to be compelling.

Among these assessments a few pointed at the potential uses and benefits of animal cloning and genetic modification:

in the field of medicine and medical research, to improve genetic and physiological knowledge, to make models for human diseases, to produce at lower cost proteins like milk proteins to be used for therapeutic aims, to provide source of organs or tissues for xenotransplantation;

in agriculture and agronomical research, to improve the selection of animals or to reproduce animals having specific qualities (longevity, resistance,...) either innate, or acquired by transgenesis.

From the point of view of animal breeding, the technology could be useful, in particular if it increases the medical and agricultural benefits expected from transgenesis (genetic modification of animals). By using genetic modification and selection in cultured cell lines, rather than in adult animals, it could become possible to remove genes, such as those provoking allergic reactions, as well as adding genes, for the benefit of human health.207

Only a few assessments spotlighted future needs for close collaboration and synergy among all involved in animal biotechnology and its regulation; and emphasized the importance of gaining credibility through open communication with the general public, in which animal tracking will play an important role.208

Some other technology assessment institutes considered the animals’ welfare and the risks to the environment if genetically modified animals are released; and stated that there may be hazards to human health if using the techniques leads to the development and spreading to humans of new disease carrying viruses. 209

Many assessments conclude that the use of biotechnological techniques on animals should not be allowed without further justification and ethical consideration and that any use of biotechnology on animals including cloning and genetic modification must be evaluated based on a principle of proportionality. Most assessments stressed that considerations on integrity should be included in the ethical evaluation but notes at the same time that the concept of integrity causes controversy and cultural conflict.

A few assessments also addressed potential benefits of cloned and/or GM animals, which might be realized in the near-to-medium term, such as improved animal production and product quality and novel animal products. Other applications that might be realized over the longer term include use of GM animals as bioindicators, for biological control, and for xenotransplantation. It was unanimously agreed that effort should be invested in making GM animals safer from the outset, e.g. by wise selection of breeding goals, improved techniques such as design of vectors, and

207 These opinions are displayed, for instance, by the European Parliament 1997, the Group of advisers to the EC on the ethical implications of biotechnology 1997, the European Commission 2002, the European Forum of Farm Animal Breeders 2005, the European Animal Disease Genomics Network of Excellence for Animal Health and Food Safety 2005.208 for instance the Food Standards Australia New Zealand 2003, the Australian Academy of Science 1999, the Canadian Food Inspection Agency 2004, the Danish Centre for Bioethics and Risk Assessment (CeBRA) 2005, and many others.209 For instance, the Danish Institute for Studies in Research and Research Policy, 2002, the Sustainable European Farm Animal Breeding and Reproduction 2004, the Irish Agriculture and Environment Biotechnology Commission 2002, the Director of the Food Policy Institute of the Consumer Federation of America 2003, and the US International Center for Technology Assessment 2005.

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avoidance of unnecessary DNA sequences such as marker genes that raise safety concerns.

8.4 Findings: (inter)national technology foresightIn the light of the strategic function “technology foresight”210 has gained in the European Commission, the statements and visions on animal biotechnology displayed in international foresight exercises and foresight meta-analyses 211 were explored, in order to quantify and qualify the future potential of animal biotechnology in the European Union and to gain a better understanding of the expectable evolution during the next two decades.212

Even though biotechnology is an issue in many foresight exercises assuming the role of "underpinning", “converging” or key technologies, the statements on transgenic animals in prospective initiatives are very limited and rather ad hoc, possibly because these are documented more explicitly elsewhere, e.g. in national regulation initiatives and ethics debates. Genetically engineered and cloned animals are very often mentioned in foresight studies as one of many issues of biotechnology development, rather than representing a visionary field in itself. However, optimism about the relevance and the transformative potential of reproductive biotechnology was often portrayed.

Concrete statements were made on artificially produced genetically identical organisms through cloning, which will likely be significant for engineered crops, livestock, and research animals.

210 Foresight is understood in the European Commission as a tool for policy design and policy shaping with the major strategic function of priority setting in European Union policy making.

The foresight unit in the European Commission (www.cordis.lu/rtd2002/foresight/home.html ) has recently established a European platform for cooperation in foresight. www.efmn.net.211 Besides foresight exercises conducted by governments (EU Members, EU Candidate Countries and Non-Members), industrial foresight activities and other foresight-like activities (such as visions, and scenarios) from academia and other public bodies and international organisations have been explored.

Metaanalyses such as:

- Reiß T.; Cuhls, K.; Hafner, S.; Zimmer, R. (2004), Metaanalyse aktueller Zukunftsstudien zu international beobachtbaren Trends und Themen im Bereich Gesundheit, Bericht an die Helmholtz-Gemeinschaft Deutscher Forschungszentren, Karlsruhe.

- Seiler, P., Holtmannspötter, D., Albertshauser, U. (2004), Internationale Technologieprognosen im Vergleich, Übersichtsstudie (Band 52), Hrsg.: VDI Technologiezentrum GmbH.

- Braun, A. (2004): Roadmap für die e-Health-Entwicklungen der Zukunft, The IPTS Report - Issue 81 - February 2004, http://www.jrc.es/home/report/english/articles/vol81/EDI1E816.htm

- Braun, A. et al (2003).: Healthcare Technologies Roadmapping,: http://esto.jrc.es/docs/HealthcareTechnologiesRoadmapping.pdf.

212 In a three steps approach, the future potential of animal biotechnology was examined and exploited:

(1) The statements and visions on genetically engineered and cloned animals in International Foresights and Forecasts have been selected,

(2) they have been summarised and clustered into table A in order to portray how animal biotechnology acquires its identity and legitimisation in foresight exercises

(3) and they have been converted into “roadmaps” on potential foreseeable implications even though they do not attempt to predict or forecast exact events and timetables, since the dates in some studies are relatively approximate.

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http://esto.jrc.es/docs/HealthcareTechnologiesRoadmapping.pdf

http://www.jrc.es/home/report/english/articles/vol81/EDI1E816.htm

http://www.efmn.net/

Major technology advances are predicted for the next 5-10 years for humanized animals for organ transplants in the industrial technology foresight studies from Canada, Ireland, and Uruguay (2000) and in the Hungarian Delphi exercise (1999); in the area of cell therapy, biopharming, xenotransplantation by the New Zealand Future Watch, study (2004), for animal reproduction / cloning to protect endangered species by the South African Department of Trade (2004) and for the use of knock-out organisms and for engineered livestock and research animals in the US RAND Technology Foresight (2001).

By far the most detailed and distinct statements on animal biotechnology were found in the foresight exercises from New Zealand (2004), South Africa (2004) and in the US RAND Study (2001).

The New Zealand study investigates how farm animals could contribute in the future to human health (biopharming, new classes of antibiotic, xenotransplantation) and for animal health applications (diagnostics and therapeutics, companion animals. aquaculture). The study predicts a major research thrust in the reduction of developmental problems that occur in some cloned animals, thought to happen because they develop from adult body cells rather than embryonic cells. This in turn will increase the cloning success rate, which will improve economic viability and animal welfare. The study is predicting that between 2007 and 2014 animal cell therapies (such as brain and pancreatic islet cells), and external therapies like the liver cell treatment, could establish themselves clinically – due to the lessened risk of immune rejection.

The South African study forecasts the development of animal cloning and gene knockouts, and estimates the potential for animal biotechnology to enhance human medical applications (xenotransplantation, "pharm" animals), to enhance animal products, environmental and conservation efforts, and endangered species conservation. The study suggests, for instance, animal cloning to become a tool for zoo researchers for helping them to save endangered species. The study suggests that biotechnology can make dramatic improvements to animal products that humans consume and use. Improved animal health conditions from vaccines, medicines and diagnostic tests result in safer foods for consumers. However, biotechnology has made great strides in enhancing animal products at a cellular level through transgenic and cloning technology. Biotechnology techniques for working with endangered species have not just been limited to cloning. Some researchers are using genetic samples to study the distribution of species and track the interrelations between different groups of animals. These studies may help to prevent excessive interbreeding among small groups of animals.

The US-RAND study suggests that the use of knock-out organisms will not only make the effects of certain (distant) genetic sequences possible but also lead to an analysis of the interdependency of certain genetic functions or components with the whole organism.

8.5 OutlookThere are a number of organisations in each country which are involved in the identification of emerging technologies and the analysis of their risk / benefit and their commercial potential. The approaches pursued by these organisations range from the scanning of scientific publications to comprehensive technology assessments. This is reflected in the different types of organisation tasked with technology assessment and/or foresight, which include public-sector research institutes, statutory bodies, NGOs and industry.

For Europe it seems as if the current national efforts need to be better coordinated in order to provide the required comprehensive technology assessment information

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background needed for regulation. While several federal agencies, bodies, advisors contribute independently to animal biotechnology assessment, it does not appear to be a priority for governments.

The current policy commitment is insufficient and there is a role for stronger coordination activities across countries. This process could be initiated by the EU in order to develop a coordinated European approach on animal biotechnology assessment.

It is recommended to use the existing animal biotechnology assessments to develop shared (European) goals and strategies, that help defining a common (European) regulation process.

Among short-term actions, the networking of technology assessment and foresight institutes seems to be an important choice as an instrument for the creation of a common European science and technology reference system.

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SECTION 9 CASE STUDIESFive case studies are presented to illustrate the range of potential uses of GM animals. Each Case Study is followed by a roadmap.

Our approach to mapping is supported by a software programme, Decision Explorer213, which has been used to develop the examples given here. The roadmaps are based on the following conventions:

Roadmaps consist of ‘nodes’ or ‘concepts’, joined by ‘links’. Concepts are colour-coded so a range of different attributes and processes can be distinguished on a single roadmap.

Concepts are expressed as short statements, each covering a single idea or notion, for example the causes driving the introduction of cloned animals

Links Concepts are linked by arrows indicating a causal link i.e. A ‘may lead to’ B. Links act in the direction of the arrow and are positive except where a negative sign is attached to the causal link, in which case the link is negative.

Different colours are used for different types of concept:

Pink – indicates the central concept

Yellow – indicates regulatory issues

Blue- indicates commercial issues

Green – indicates public acceptability issues

Purple – indicates technical issues

Bright green – indicates an environmental issue

These maps are a way of summarising the information given in the case studies and demonstrating clearly the linkages between various aspects of the different applications of GM that will enable comparison between GM and cloned animals (as presented in Report 2).

9.1 GM animals as bioreactors9.1.1 Aim

The aim is to produce the desired pharmaceutical (or nutraceutical) in animal products. Applications have been in a wide range of species e.g. cattle, sheep, pigs, goats, chickens and fish. A wide range of production systems have been reported e.g. in milk, in saliva, in muscle, blood/serum and egg white (birds), although milk is the most commonly used. There has been considerable commercial interest in this area. Over the years a large number of different therapeutic proteins have been produced but as yet, none are on the market.

9.1.2 Markets

Single biggest applications of GM to animals attempted so far. Between 5-10 products are thought to be progressing through clinical trials. Two products may be on the market in the EU in the next year. Approximately 15 companies world-wide are working in this area – notably in N.America, S.America and Asia. Four European companies are working in the area (2 in France, 1 each in the Netherlands and UK). The sector is dominated by SME’s with cloning and/or GM experience and their collaborators within larger pharmaceutical or in one case a brewing company.

Financial viability in this sector appears to be a problem, possibly linked to the long time frame for getting products to market (in large part due to regulatory

213 Banxia Software. Decision Explorer, www.banxia.com

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requirements). The earliest products to market in this sector are likely to be those that already have an established market. In the longer-term (10+ years), human mono- and polyclonal antibodies may become available from GM animals (probably GM and cloned animals).

9.1.3 Technical aspects

GM in chickens has proved to be difficult due to the biology of chickens. Long gestation time is an issue in cattle. The limited number of antibodies that can be produced is also a factor. Techniques depend increasingly on the use of cloning and GM together, with associated issues around the efficiency of these procedures.

9.1.4 Drivers

The high value of the pharmaceutical market allied with the practical aspects of producing pharmaceuticals, as opposed to food, from GM animals, namely the smaller number of animals required. Also, the high production costs and relatively low yields of biopharmaceuticals from cell-based systems, make biopharming attractive, at least in theory.

9.1.5 Regulation

In the EU, the Medicines and Healthcare Products Regulatory Agency has oversight of pharmaceuticals produced in GM animals.

Biopharming may be affected by regulation on GM or cloning in other aspects (such as welfare, ethics and environment) e.g. the company Pharming reputedly moved its GM and cloning work to USA and Belgium from the Netherlands, following an effective ban on cloning animals in the Netherlands214.

Regulatory precedent may be important. The first drug coming to market is expected to be a major landmark.

9.1.6 Special issues

Carcases from GM animals for pharmaceutical production are unlikely to be approved for human consumption and are therefore likely to be disposed of by incineration rather than through slaughterhouses. However, reliable identification systems for GM animals may be difficult to apply if these animals become widely used. Production is of necessity in species used also for food production so this is not a possible means of segregation (unlike plants).

9.1.7 Public attitudes

Generally attitudes to GM animals are more negative than for the same application in GM plants, hence production of pharmaceuticals in plants is more positively viewed than production in animals. Production of pharmaceuticals in GM animals may be more acceptable than some other applications of genetic modification, but we have not been able to identify extensive and detailed data on acceptability of different products e.g. milk vs. eggs or pharmaceuticals to treat different diseases.

9.1.8 EU Competitiveness

The EU appears to be internationally competitive in this area in terms of technical capacity and current activities. This may be because of the strong veterinary and embryology science base in the EU (the latter built up during second half of last century).

9.1.9 Alternative approaches

Harnessing the metabolic capacity of animals to produce proteins has advantages over other methods currently available:214 Enserink, M. (1998)

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Animal cell line fermenters have limited capacity.

Bacterial fermenters produce proteins which are slightly different than those produced in animals

Plant cell bioreactors may produce proteins which are slightly different than those produced in animals but have advantages in that they do not carry pathogens that may be harmful for human health and do not contain any similar proteins reducing difficulties in purification.

Fungal systems may also produce proteins that are slightly different than those produced in animals

Baculovirus systems have yet to be scaled-up to industrial levels.

GM plants, these may produce proteins that are slightly different than those produced in animals, but may have advantages in terms of disease risk and purification. Containment of GM plants may be an issue in order to avoid ‘contamination’ of the food chain.

Some people question whether different techniques for developing complex drugs may become more effective in the longer-term future e.g. human cell culture replacing the use of whole animals.

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Figure 1 Roadmap demonstrating the drivers for GM animals as bioreactors

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Production ofpharmed products in

EU

Small number of GManimals required

Development ofcompeting

technologies

Pressure frompatient groups

Negative publicattitudes

Ethical concerns

Welfare concerns

Positive publicattitudes

Pharmaceuticals areavailable in the EUfrom GM animals

Production ofpharmed products

outside the EU

High value ofpharmaceuticals

Approval from FDA orother relevantregulatory body

Approval from EMEA

Research ondeveloping pharming

Development ofpotentially usefulapplications for

pharming

Setting up ofspin-out companiesto develop pharming

products

Work with existingcompanies to producecommercial products

Availabilitly offunding

Poor efficiency ofGM/cloningtechniques

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-

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9.2 Faster growth rate from GM animals9.2.1 Aim

Initial experiments with GM animals involved attempts to modify growth by modifying the growth hormone gene in some way. These have largely been abandoned due to welfare and other problems, except in fish.

9.2.2 Markets

Faster-growing GM salmon have been developed in North America and are awaiting regulatory approval for sale to fish farming markets in N. America, Asia and S. America. At least eight species of fish have been genetically modified for growth enhancement. To our knowledge, none have been approved for commercial production.


Salmon naturally only express growth hormone in particular seasons. In one example, salmon have been genetically modified to express this hormone all year round and hence grow faster. Other methods have also been used.

Escape of GM fish into the environment and their subsequent impact if this happens is one of the key areas of concern with this application. Fish can be sterilized but currently 100% reliable fish sterilization methods do not exist, so production currently may have to be in land-based tanks.

9.2.4 Drivers

FAO predicts global aquaculture will more than double over the coming decade215. It is argued that faster-growing GM fish would provide cheaper and more environmentally-friendly source of omega-3 rich fish.

Others argue that GM fish are unlikely to alleviate pressure on wild stocks. The culture of carnivorous fish such as salmon and trout mean that wild stocks of fish are depleted to feed these fish. The concentration of fish means there are issues around outputs from aquaculture and their impacts on the environment (local eutrophication, build-up in sediments of feed-borne antibiotics).216.

9.2.5 Regulation

Genetically modified fish, unlike terrestrial GM animals, have real questions around the environmental consequences of accidental (or deliberate) release to the environment, in particular the consequences of interbreeding between wild fish and escaped transgenics.

US regulation has been critiqued in that FDA is not seen as the appropriate body to regulate environmental impact.

It has been suggested that regulators may in future demand that all fish farming (including conventional fish) move to contained ponds. This might make GM fish production more attractive217.

9.2.6 Special Issues

None identified

215 Reichhardt, 2000216 Ramseyer, 2002217 Reichhardt, 2000

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Very little data is available. Pew opinion poll data suggested cheaper fish was the least attractive of the different applications presented to the respondents. It is reported that two companies (Otter Ferry Salmon in Scotland and New Zealand King Salmon Company) abandoned their GM salmon research after unfavourable publicity218.


The EU does not appear to have companies involved in this area. However, fish farming is important in the EU and should use of faster growing GM fish become prevalent throughout the world, this may affect EU competitiveness.


In most species, traditional approaches are effective at slowly increasing growth rates over subsequent generations and continues to be so. GM however, potentially offers dramatic changes in growth rate to be acquired on one generation

218 Reichhardt, 2000

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Figure 2 Roadmap demonstrating drivers for products from faster growing GM fish becoming available in the EU

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Products from fastergrowing GM fish

available in the EU

GM fish producedsomewhere in the

world

Unauthorised GM f ishproducts enter foodchain accidentally

or deliberately

Technology exists toproduce faster

growing GM f ish

GM fish approved toenter the food chainsomewhere in the

world

GM fish 'escape'into the wild

GM fish interbreedwith wild f ish

Development ofreliable

sterilizationmethods

Commercial advantage(reduced production

cost) of fastergrowing f ish

Enterprises are setup to produce

faster-growing GMfish

Fish producedexclusively in

land-based tanks

Increasingworld-wide demand

for f ish

Wild f ish stocks arereduced

Increasingdevelopment of f ish

farming

Wild f ishpopulations are

damaged

Growing humanpopulationworld-wide

Increasing focus onhealth-promoting

foods

Increased f ishconsumption due tohealth benefits of

omega-3 fatty acids



Involvement ofcommercial companies

Benefit perceived tobe primarily

economic

GM fish productsappear in world

markets

GM fish meet EUlabelling

requirements

GM fish meet EUtraceabilityrequirementsGM fish meet EU GM

food safetyassessments

GM fish productsavailable on EU

markets

Companies apply toplace GM f ishproducts on EU

markets

--

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9.3 GM animals for food9.3.1 Aim

Examples of agricultural applications that are being developed include:

Reducing the environmental impact of pigs by decreasing phosphorus excretion

Changing the nutritional composition of meat and milk

Improved disease resistance. Two main approached are being considered at the experimental level

Knock-down of the PrP gene – associated with susceptibility to diseases such as BSE. Being applied to ruminants. Often the motivation for this research has been to improve the safety of products from bioreactors.

Using RNAi and gene knockdown against viral diseases (see Report 1 for details)

Altering disease resistance, whilst currently theoretical, has the potential to profoundly affect the production systems and markets in specific areas e.g. increasing resistance to African Swine Fever in pigs could have a dramatic impact in Africa.

9.3.2 Markets

The current expectation is that GM animals will not appear on the market in the near future but that longer term (10+ years) some applications may become competitive.


As with all GM applications, there are technical challenges around the production of GM animals, particularly ensuring site-specific integration of inserted genes, with control of the number of copies of the gene inserted and in particular with respect to GM animals for food, the need to use markers. Where GM is used in conjunction with cloning, there are technical challenges around GM donor cells senescing before SCNT can be carried out.

Large improvements in efficiency of producing GM animals have recently been achieved in research labs using lentiviruses and further improvement may occur (see Report 1 for details).

One of the most prominent technical barriers to the use of GM livestock in food production is that of integrating genetically modified animals into the production systems.

9.3.4 Drivers

Technological possibilities, which at the same time may meet human needs are perhaps the main drivers.

Opposition to GM animals is on argued on the basis of ethics and animal welfare.

9.3.5 Regulation

EU regulation is in place, but largely influenced by the development of GM crops. This requires a case-by-case assessment of the risks to human health and the environment of any GM animal before release into the environment. Traceability requirements are also in place for GM animals and mean that anyone placing a product on the market in the EU has to be able identify the supplier of the GM product and the companies to which the product has been supplied.

Regulation in the USA will depend on the application of the animal. Many GM animals will be treated as “new animal drugs” and as such, they will require pre-market review (unlike GM crops).

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Many countries have labelling schemes for food containing or consisting of Genetically Modified Organisms e.g. EU, Japan, South Korea, Thailand, Taiwan, Australia and New Zealand, although the exact labelling requirements vary. Voluntary labelling is in place in Canada.

Trade issues around GM organisms have not yet all been resolved.


No data available.


Surveys generally suggest that consumers are more comfortable with genetic modification of plants and are substantially less comfortable with modification of animals. Within GM animals different applications have different approval ratings, but data is not available in detail on all possible proposed applications.

Some data suggest that much of the opposition is for moral, ethical and religious reasons rather than because of safety concerns.


No data available


Alternative approaches will depend on the specific application being considered.

For example, phosphorus excretion could be addressed by:

Addition of the enzyme phytase to pig feed – the enzyme may be produced from GM micro-organisms

Genetic modification of pig feed to reduce phytate content

Improved waste management systems (e.g. recycle phosphorus excreted as detergent feedstock)

Reduce phosphorus pollution at the ‘system’ level by developing farming systems that match nutrient outputs from livestock to nutrient requirements by crops.

Changing the nutritional composition of animal products may be achieved in some cases by selection on naturally occurring variation or changing feed composition.

Disease resistance may be addressed by use of prophylaxis, vaccination, selection on naturally occurring variation to increase resistance to disease. Good biosecurity may also be important in reducing disease incidence.

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Figure 3 Roadmap demonstrating the drivers for GM animal food products in the EU

Food from GM animalsavailable in the EU


Negative connotationwith intensive

agriculture

Negativeconnotations with GM

crops

Negativeconnotations of

commercial companyinvolvement

Cocnerns about pooranimal welfare

Concerns aboutappropriate

treatment of animals

GM animal productsmeet EU traceability

requirements

GM animal productsmeet EU labelling

requirements

GM animal productssatisfy EU food

safety requirements

GM animals satisfyGM deliberate

release regulations

Farmers keep GManimals on EU farms

Products from GM areproduced

Application is madeto delibrately

release GM animals

Commercially viableapplication of GM toanimals is produced

Companies adopt GManimals and make

breeding stockavailable for EU

farmers

EU animal welfarelegislation finds GManimal acceptable

Companies outsidethe EU adopt GManimals and makethem available to

farmers

Farmers outside theEU keep GM animals

Products from GManimals are

available on worldmarkets

GM animals satisfylocal regulations

Application is madeto import animal

product to EU

GM animal productsare accidently or

deliberatlyintroduced into thefood chain without

satisfyingregulations -

90

9.4 GM Pets9.4.1 Aim

Fluorescent-coloured transgenic fish are already on sale as pets in the USA. Zebra fish are usually black and silver in colour. Through genetic manipulation varieties that radiate green or red fluorescent colour have been produced and have been sold.

It has also been suggested that GM cats which lack the properties to produce an allergic reaction in humans, could also be developed.

9.4.2 Markets

Originally produced in Singapore as a method of detecting environmental pollutants, these fish have found a market as pets in USA (and possibly also Taiwan).


There are no special technical aspects.

9.4.4 Drivers

The development of coloured fish appears to have been serendipitous.

9.4.5 Regulation

In the USA, these fish are completely unregulated. Both the FDA and EPA decided the fish fell outside their regulatory remit as it is neither a food nor a threat to the US environment. The state of California has however banned the sale of these fish.


No special issues have been identified.


No data available.


No data available


None obvious

91

Figure 4 Roadmap demonstrating the drivers encouraging availability of pet GM fish in the EU

GM pet fishavailable in the EU

GM pet fish meet EUdeliberate release

regulations

Permission fordeliberate release

is sought

Import licenses toEU countries are

sought

Pet GM fish becomeavailable oninternational

markets

Companies are set upoutside EU countriesto produce GM pet

fish

Licenses becomeavailable to other

commercial companies

Companies are set upin the EU to produce

GM pet fish

New methods ofproducing GM fish

are developed

Scientificdevelopments allow

creation offluorescent GM fish

Wild populations aredamaged

Pet GM fish 'escape'into the wild in

conditions wherethey can establish

or cross-breed withwild populations

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9.5 Xenotransplantation9.5.1 Aim

Work is ongoing world-wide with most of the research being undertaken in cloned and GM pigs.

9.5.2 Markets

Xenotransplants are currently at the experimental stage. Generally, organ transplants from GM pigs are expected to be at least 10 years away.


Xenotransplantation presents huge technical challenges, not least because multiple transgenes are needed if this application is to be realistic. Transgenesis is required to overcome multiple immune mechanisms. Furthermore GM may be needed to overcome risks to human health from endogenous pig retroviruses (PERVs).

9.5.4 Drivers

Driver is the shortage of transplant organs resulting in long waiting lists for replacement organs and potentially death of some patients while on the waiting list. This shortage is itself the consequence of successes in other areas of human endeavour e.g. reduction in the number of fatalities in traffic accidents and reduction in deaths from brain haemorrhage.

Opponents focus on ethical issues, animal welfare and the question of whether organs function as expected in the recipient due to physiological differences between species.

9.5.5 Regulation

Regulation has been focussed on the risks to humans from PERVs, although small studies indicate that it is not the problem that it was first thought to be. Animal welfare issues have also been addressed by regulators. The EU does not have a uniform regulatory system across the member states.


No special issues have been identified


Public attitudes in opinion polls have been quite negative but have also become more positive over time.


No data available


Alternative approaches include reducing the need for organ transplants, increasing the supply of organs e.g. by presuming consent to organ donation unless a person has ‘opted out’ and alternative technologies to replace xenotransplants e.g. the potential use of stem cell therapies.

93

Figure 5 Roadmap demonstrating the drivers to the availability of xenotransplants in the EU

Xenotransplantsavailable in the EU

Scientists in EUdevelop

xenotransplants tothe point where they

are viable

Scientists outsidethe EU devlelop

xentoransplants tothe point where they

are viable

Techniques are madeavailble in the EU

Submision is madefor regulatory

approval in therelevant member

state

Regulatory approvalis gained from human

health aspectsRegualtory approval

is gained fromanimal welfare

aspects



Supply of donororgans increases

dramatically

Less funding forXenotransplant

research

Alternativetherapies are

developed

-

--

94

SECTION 10 REFLECTIONSGenetically modified animals were first created at the research level in 1985 and arguably, relatively little progress has taken place since then (with the exception of mice). In Report 1, we noted that there appears little prospect of GM animals designed for the food chain appearing in commercial use within the next 10 years. Given the commercialisation of GM crops it is perhaps surprising that so little development appears to have taken place in animals. There may be a number of reasons for this:

Only a limited number of single genes that could be usefully introduced have been identified

The biology of animals is different, so that a lot of effort and time would be required to replace existing livestock with GM varieties, unlike plants where this change can be undertaken within one season simply by planting a different variety.

GM animals have been difficult to produce and techniques have been inefficient. The use of somatic cell nuclear transfer (cloning), in conjunction with genetically modified cell lines has opened up more possibilities, but the techniques are still relatively inefficient and expensive. Furthermore, a satisfactory gene targeting system to allow controlled genetic changes to be made has yet to be fully-developed for farm livestock. The development of lentivirus based systems to produce GM animals with vastly greater efficiency may increase the feasibility of producing GM animals, but it is unlikely that a virus-based system would be used in the food chain.

The IP situation with animals may also have a bearing. Unlike crop plants, there is no breeder’s rights system to protect new varieties (breeds). Patenting is therefore the only way of protecting intellectual property in terms of livestock breeding. Given the controversial nature and uncertainty over the applicability of patents to animals, this may also act as a disincentive.

Finally, the negative public reaction to GM crops is likely to be one of the major reasons for not developing GM animals for food.

Regulation is well developed for GM crops, although there are still areas of dispute, particularly with regard to international trade. These regulations will apply to GM animals, but they may not always be entirely appropriate for them.

In contrast to GM animals for food production, there has been development in the area of using GM animals to produce pharmaceuticals (‘pharming’). However, the timescale from research idea to product on the market is very long, and to date there are no products from pharming on the market, although two products appear to be in late clinical trials. It seems that regulatory issues are the major reason for this long delay, and the consequent difficulty of maintaining investor confidence and financing to the point at which products are available on the market.

With xenotransplantation, the initial enthusiasm seems to have been moderated by technical difficulties in overcoming several rejection mechanisms and recognition of the potential risks from zoonoses. However there is ongoing work in this area, particularly in Asia and USA, but also in Europe. It is suggested that xenotransplantation products will not be available for at least another 10 years. Several jurisdictions have considered the regulatory aspects of xenotransplantation, including both the animal welfare and human safety aspects. It appears that some initiatives have also begun to establish consistency in Europe-wide regulation.

The application of GM to the pet fish sector appears to have been serendipitous. Whilst there has been discussion of the possibility of using GM for ‘artistic’ purposes

95

(e.g. the possible use of the gene for Green Fluorescent Protein to produce novel colouring in rabbits), the production of GM fluorescent fish appears not to have been planned in advance. The US regulatory system considers these fish not to require regulation.

Overall, there appears to be a big range of potential applications of GM animals, but it is noteworthy that small numbers of companies and individual scientists are involved in any single application.

With regard to regulation, the issues are a little different with animals as compared to crops, for example environmental risk is not perceived to be a major concern with food-producing animals, with the exception of fish. Risk issues are therefore more concentrated on risks to human health. On the other hand, animal welfare issues are important with respect to GM animals.

As with GM crops, GM animals are subject to international regulation on the transboundary movement of Living Modified Organisms under the auspices of the Cartagena Protocol. There would appear to be scope for disputes with respect to international trade resulting from different interpretations of the various international agreements, such as those relating to WTO. Furthermore international regulation relating to animal welfare or ethics have not been developed and this may lead to further concerns about import of animals or animal products which may be deemed to have unacceptable welfare or to be an unacceptable modification, in some jurisdictions.

For the EU the question of segregation may become an issue if GM animals become part of the food chain in other jurisdictions. Although international regulations increasingly require labelling of GM products, these regulations may be difficult to enforce. Introduced genes may be identifiable if the introduced gene is known, however GM animals with an introduced gene from same species would be difficult or impossible to trace. This could potentially be overcome if DNA fingerprints were required to be stored from GM animals. This would allow checks to be carried out for ‘known’ GM animals but not for others. This information would also be lost at the level of processed products. Traceability systems in commodity markets are difficult to enforce and easily open to fraud. All these issues already exist for GM crops.

The question of EU competitiveness with respect to the potential use of GM animals in food production raises the question of what is the role of livestock production in Europe and where will Europe’s food be produced in the future? As noted in Report 2, most nations are struggling to balance the needs of international markets which bring pressures to reduce costs, and the needs of local markets where quality and other factors come into play. If it is cheaper to keep animals overseas, then the expectation is likely to be that mass production of animals will increasing be done outside Europe.

The expected growth in demand for animal products, particularly in developing countries should also be noted. If this growth is primarily driven with a view to access to exports, then technological developments may well be constrained by regulatory requirements of the importing countries. The situation may be different if the driver is domestic consumption. In either case, increasing livestock production is likely to have side-effect in terms of pressure on land use and the environmental impact of livestock production. Regulation in these areas may influence the way in which future livestock production develops. These issues are common to all technological developments and are not unique to GM animals.

One of the most contentious issues with regard to use of GM animals is the surrounding welfare and ethical issues. Relatively little information appears to be available on attitudes to particular applications for specific purposes, rather than GM

96

animals in general. Ethical reflection has taken place, particularly with respect to xenotransplants. No information is available on whether animals that are both GM and cloned would be viewed differently from GM animals, although intuitively it seems unlikely that cloned and GM animals would be more publicly acceptable than GM animals.

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Cottier T. (2002) ‘Implications for trade law and policy towards convergence and integration’, In: Bail C., Falkner R. & Marquard H. (eds.) The Cartagena Protocol on Biosafety: Reconciling Trade in Biotechnology with Environment & Development? (London: The Royal Institute of International Affairs).

Curtis, K.R., McCluskey, J.J. and Wahl, T.I. (2004) ‘Consumer acceptance of genetically modified food products in the developing world.’ AgBioForum, 7(1&2), 70-75 available at http://www.agbioforum.org

Delgado, C., Rosegrant, M., Steinfeld, H., Ehui, S. and Courbois, C. (1999) Livestock to 2020. The Next Food Revolution. Food, Agriculture and the Environment Discussion Paper 28, International Food Policy Research Institute, Food and Agriculture Organization of the United Nations and International Livestock Research Institute, May 1999

De Simone, F. and Serratosa, J., “Biotechnology, animal health and animal welfare within the framework of European Union legislation” (2005)) Rev. sci. tech. Off. Int. Epiz. 24 (1)

Egziabher T.B.G. (2002) ‘Balancing Biosafety, Trade and Economic Development Interests in the Implementation of the Cartagena Protocol: A Developing Country Perspective’ In: Secretariat of the Convention on Biological Diversity (2002) Cartagena protocol on Biosafety: From Negotiation to Implementation (Montreal: Secretariat of the Convention on Biological Diversity).

Enserink, M. (1998) ‘Dutch pull the plug on cow cloning’, Science 279 (5356), 1444

ERMA (1999) Identifying Risks for applications under the Hazardous New Organisms Act 1999. Available from: www.ermanz.govt.nz.

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ERMA (2003) Genetic Modification: An Overview, ERMA New Zealand Information Sheet No. 2 (November). Available from:

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Farm Animal Welfare Council (2004) FAWC Report on the welfare implications of animal breeding and breeding technologies in commercial agriculture, FAWC, London, June

FAO/WHO (2003) FAO/WHO Expert Consultation on the Safety Assessment of Foods Derived From Genetically Modified Animals, Including Fish (Rome: FAO) (Available from: http://www.fao.org/documents/show_cdr.asp?url_file=/DOCREP/006/Y5316E/y5316e01.htm)

FDA (1995) Points to Consider in the Manufacture and Testing of Therapeutic Products for Human Use Derived from Transgenic Animals. Available from: http://www.fda.gov/cber/gdlns/ptc_tga.txt.

FDA (2003) Guidance for Industry: Source Animal, Product, Preclinical, and Clinical Issues Concerning the Use of Xenotransplantation Products in Humans (Available from: http://www.fda.gov/cber/gdlns/clinxeno.htm#v).

FDA (2005) Precautionary Measures to Reduce the Possible Risk of Transmission of Zoonosis by Blood and Blood Products from Xenotransplantation Product Recipients and Their Contacts: Draft Guidance (Available from: www.fda.gov/cber/gdlns/zooxeno.pdf)

FSANZ (2004) Guidelines for the Safety Assessment of Genetically Modified Foods (Available from: http://www.foodstandards.gov.au/_srcfiles/ACF6A4.doc).

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Gaskell, G., Bauer, M.W, Durant, J. and Allum, NC (1999) ‘Worlds Apart? The Reception of Genetically Modified Foods in Europe and the U.S.’ Science, 285, 16th July, 384-387

Gaskell, G., Allum,N. and Stares, S. (2003) Europeans and Biotechnology in 2002. Eurobarometer 58.0, 2nd edition, March 21st 2003. Available at http://europa.eu.int/comm/public_opinion/archives/eb_special_en.htm

Howse R. & Meltzer J. (2002) ‘The significance of the protocol for WTO dispute settlement’, In: Bail C., Falkner R. & Marquard H. (eds.) The Cartagena Protocol on Biosafety: Reconciling Trade in Biotechnology with Environment & Development? (London: The Royal Institute of International Affairs).

Inaba M. & Macer D. (2003) ‘Attitudes to biotechnology in Japan in 2003’, Eubios Journal of Asian and International Bioethics, Vol. 13: 78-90.

Issac G.E. (2003) ‘The WTO and the Cartagena Protocol: International Policy Coordination or Conflict?’ Current Agriculture, Food & Resource Issues, No. 4, pp. 116-123 (Available from: www.cafri.org).

Koehler-Rollefson, I. (2002) ‘Why we need “Livestock Keepers’ Rights” to save livestock genetic diversity ‘in Livestock Diversity: Keepers’ Rights, Shared

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http://www.cafri.org/

http://europa.eu.int/comm/public_opinion/archives/eb_special_en.htm

http://www.foodstandards.gov.au/_srcfiles/ACF6A4.doc

http://www.fda.gov/cber/gdlns/clinxeno.htm#v

http://www.fao.org/documents/show_cdr.asp?url_file=/DOCREP/006/Y5316E/y5316e01.htm

http://www.fao.org/documents/show_cdr.asp?url_file=/DOCREP/006/Y5316E/y5316e01.htm

http://www.ermanz.govt.nz/resources/alphabetical.asp

Benefits and Pro-Poor Policies, Documentation of a Workshop with NGOs, Herders, Scientists and FAO, NGO/CSO Forum for Food Sovereignty, Rome, 13 June

Lewis C. (2001) A New Kind of Fish Story: The Coming of Biotech Animals, FDA Consumer, January-February. (Available from:

http://www.cfsan.fda.gov/~dms/fdbiofsh.html)

Macnaghten, P. (2004) Animals in their nature: a case study on public attitudes to animals, genetic modification and ‘nature’. Sociology 38(3) 533-551

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Miller W.A. & Matheson J.C. (1996) ‘Food Safety Evaluation of Transgenic Animals’, FDA Veterinarian Newsletter, Vol. 11(2). Available from: http://www.fda.gov/cvm/4404.htm#RTFToC19

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http://pewagbiotech.org/research/2003update/4.php

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http://appli1.oecd.org/olis/2005doc.nsf/43bb6130e5e86e5fc12569fa005d004c/c3f7f7bdd1480b40c1256fb00050c343/$FILE/JT00179087.DOC

http://appli1.oecd.org/olis/2005doc.nsf/43bb6130e5e86e5fc12569fa005d004c/c3f7f7bdd1480b40c1256fb00050c343/$FILE/JT00179087.DOC

http://www.nuffieldbioethics.org/go/print/ourwork/animalresearch/publication_178.html

http://www.nuffieldbioethics.org/go/print/ourwork/animalresearch/publication_178.html

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Yamanouchi, K., “Regulatory considerations in the development and application of biotechnology in Japan”, (2005) Rev Sci Tech Off Int Epiz 24 (1) 109-115

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SECTION 12 APPENDICESAppendix 1 - AcronymsACGM: Advisory Committee on Genetic Modification (UK)

AEBC: Agriculture and Environment Biotechnology Commission (UK)

APEC: Asia-Pacific Economic Cooperation

APHIS: Animal and Plant Health Inspection Service (USDA, USA)ART: Assisted Reproductive Technologies

CBER: Center for Biologics Evaluation and Research (FDA, USA)

CBP: Cartagena Biosafety Protocol

CFIA: Canadian Food Inspection Agency

CFSAN: Centre for Food Safety and Applied Nutrition (FDA, USA)

CVB: Centre for Veterinary Biologics

CVM: Centre for Veterinary Medicine (FDA, USA)

EFSA: European Food Safety Authority

EMEA: European Medicines Evaluation Agency

ERMA: Environmental Risk Management Authority (New Zealand)

EUFIC: European Food Information Council

FAO: Food and Agriculture Organization

FDA: Food and Drug Administration (USA)

FFDCA: Federal Food, Drugs and Cosmetics Act (USA)

FSANZ: Food Standards Australia New Zealand

FSIS: Food Safety & Inspection Service (USDA, USA)

FUFOSE Functional Food Sciences in Europe

GATT: General Agreement on Tariffs and Trade

GM: Genetically modified

GMO: Genetically modified organism

GVHD: Graft versus host disease

HSE: Health & Safety Executive (UK)

HSNO Act: Hazardous Substances and New Organisms Act 1996 (New Zealand)

LMO: Living Modified Organism

LOS: Large Offspring Syndrome

MAFF: Ministry for Agriculture, Forestry and Fisheries (Japan)

MHLW: Ministry of Health, Labour and Welfare (Japan)

NAS: National Academy of Sciences (USA)

OECD: Organization for Economic Co-operation and Development

OIE: World Organization for Animal Health

SCNT: Somatic Cell Nuclear Transfer

SPS: Sanitary and Phytosanitary Measures (WTO)

TBT: Technical Barriers to Trade (WTO)

TEP: TransAtlantic Economic Partnership

USDA: United States Department of Agriculture

WHO: World Health Organization

WTO: World Trade Organization

XIRA: Xenotransplantation Interim Regulatory Authority (UK)

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Appendix 2 - Selected Web siteswww.aebc.gov.uk

www.aphis.usda.gov/brs/index.html

www.bio.org

www.biodiv.org/biosafety

www.coe.int

www.efsa.eu.int

www.emea.eu.int

www.ermanz.govt.nz

www.europa.eu.int

www.fao.org

www.fda.gov

www.foodstandards.gov.au/

www.fsis.usda.gov/.

www.gm.govt.nz

www.foodstandards.gov.au/

www.mhlw.go.jp

www.oecd.org

www.oie.int

http://pewagbiotech.org/

www.who.int

http://pewagbiotech.org/

http://www.oecd.org/

http://www.gm.govt.nz/

http://www.fsis.usda.gov/

http://www.fda.gov/

http://www.ermanz.govt.nz/

http://www.efsa.eu.int/

http://www.coe.int/

http://www.bio.org/

Appendix 3 - ANNEX II of EU Directive 2001/18/EC: Environmental Risk AssessmentPrinciples For The Environmental Risk Assessment

This Annex describes in general terms the objective to be achieved, the elements to be considered and the general principles and methodology to be followed to perform the environmental risk assessment (e.r.a.) referred to in Articles 4 and 13. It will be supplemented by guidance notes to be developed in accordance with the procedure laid down in Article 30(2). These guidance notes shall be completed by 17 October 2002.

With a view to contributing to a common understanding of the terms "direct, indirect, immediate and delayed" when implementing this Annex, without prejudice to further guidance in this respect and in particular as regards the extent to which indirect effects can and should be taken into account, these terms are described as follows:

"direct effects" refers to primary effects on human health or the environment which are a result of the GMO itself and which do not occur through a causal chain of events;

"indirect effects" refers to effects on human health or the environment occurring through a causal chain of events, through mechanisms such as interactions with other organisms, transfer of genetic material, or changes in use or management.

Observations of indirect effects are likely to be delayed;

"immediate effects" refers to effects on human health or the environment which are observed during the period of the release of the GMO. Immediate effects may be direct or indirect;

"delayed effects" refers to effects on human health or the environment which may not be observed during the period of the release of the GMO, but become apparent as a direct or indirect effect either at a later stage or after termination of the release.

A general principle for environmental risk assessment is also that an analysis of the "cumulative long-term effects" relevant to the release and the placing on the market is to be carried out. "Cumulative long-term effects" refers to the accumulated effects of consents on human health and the environment, including inter alia flora and fauna, soil fertility, soil degradation of organic material, the feed/ food chain, biological diversity, animal health and resistance problems in relation to antibiotics.

A. Objective

The objective of an e.r.a. is, on a case by case basis, to identify and evaluate potential adverse effects of the GMO, either direct and indirect, immediate or delayed, on human health and the environment which the deliberate release or the placing on the market of GMOs may have. The e.r.a. should be conducted with a view to identifying if there is a need for risk management and if so, the most appropriate methods to be used.

B. General Principles

In accordance with the precautionary principle, the following general principles should be followed when performing the e.r.a.:

identified characteristics of the GMO and its use which have the potential to cause adverse effects should be compared to those presented by the non-modified organism from which it is derived and its use under corresponding situations;

the e.r.a. should be carried out in a scientifically sound and transparent manner based on available scientific and technical data;

the e.r.a. should be carried out on a case by case basis, meaning that the required information may vary depending on the type of the GMOs concerned, their intended use and the potential receiving environment, taking into account, i.e., GMOs already in the environment;

if new information on the GMO and its effects on human health or the environment becomes available, the e.r.a. may need to be readdressed in order to:

determine whether the risk has changed;

determine whether there is a need for amending the risk management accordingly.

C. Methodology

C.1. Characteristics of GMOs and releases

Depending on the case the e.r.a. has to take into account the relevant technical and scientific details regarding characteristics of:

the recipient or parental organism(s);

the genetic modification(s), be it inclusion or deletion of genetic material, and relevant information on the vector and the donor;

the GMO;

the intended release or use including its scale;

the potential receiving environment; and

the interaction between these.

Information from releases of similar organisms and organisms with similar traits and their interaction with similar environments can assist the e.r.a.

C.2. Steps in the e.r.a.

In drawing conclusions for the e.r.a. referred to in Articles 4, 6, 7 and 13 the following points should be addressed:

Identification of characteristics which may cause adverse effects:

Any characteristics of the GMOs linked to the genetic modification that may result in adverse effects on human health or the environment shall be identified. A comparison of the characteristics of the GMO(s) with those of the non-modified organism under corresponding conditions of the release or use, will assist in identifying the particular potential adverse effects arising from the genetic modification. It is important not to discount any potential adverse effect on the basis that it is unlikely to occur.

Potential adverse effects of GMOs will vary from case to case, and may include:

disease to humans including allergenic or toxic effects (see for example items II.A.11. and II.C.2(i) in Annex III A, and B 7 in Annex III B);

disease to animals and plants including toxic, and where appropriate, allergenic effects (see for example items II.A.11. and II.C.2(i) in Annex III A, and B 7 and D 8 in Annex III B);

effects on the dynamics of populations of species in the receiving environment and the genetic diversity of each of these populations (see for example items IV B 8, 9 and 12 in Annex III A);

altered susceptibility to pathogens facilitating the dissemination of infectious diseases and/or creating new reservoirs or vectors;

compromising prophylactic or therapeutic medical, veterinary, or plant protection treatments, for example by transfer of genes conferring resistance to antibiotics used in human or veterinary medicine (see for example items II.A.11(e) and II.C.2(i)(iv) in Annex III A);

effects on biogeochemistry( biogeochemical cycles), particularly carbon and nitrogen recycling through changes in soil decomposition of organic material (see for example items II.A.11(f) and IV.B.15 in Annex III A, and D 11 in Annex III B).

Adverse effects may occur directly or indirectly through mechanisms which may include:

the spread of the GMO(s) in the environment,

the transfer of the inserted genetic material to other organisms, or the same organism whether genetically modified or not,

phenotypic and genetic instability,

interactions with other organisms,

changes in management, including, where applicable, in agricultural practices.

2. Evaluation of the potential consequences of each adverse effect, if it occurs

The magnitude of the consequences of each potential adverse effect should be evaluated.

This evaluation should assume that such an adverse effect will occur. The magnitude of the consequences is likely to be influenced by the environment into which the GMO(s) is (are) intended to be released and the manner of the release.

3. Evaluation of the likelihood of the occurrence of each identified potential adverse effect

A major factor in evaluating the likelihood or probability of adverse effects occurring is the characteristics of the environment into which the GMO(s) is intended to be released, and the manner of the release.

4. Estimation of the risk posed by each identified characteristic of the GMO(s)

An estimation of the risk to human health or the environment posed by each identified characteristic of the GMO which has the potential to cause adverse effects should be made as far as possible, given the state of the art, by combining the likelihood of the adverse effect occurring and the magnitude of the consequences, if it occurs.

5. Application of management strategies for risks from the deliberate release or marketing of GMO(s)

The risk assessment may identify risks that require management and how best to manage them, and a risk management strategy should be defined.

6. Determination of the overall risk of the GMO(s)

An evaluation of the overall risk of the GMO(s) should be made taking into account any risk management strategies which are proposed.

D. Conclusions on the potential environmental impact from the release or the placing on the market of GMOs

On the basis of an e.r.a. carried out in accordance with the principles and methodology outlined in sections B and C, information on the points listed in sections D1 or D2 should be included, as appropriate, in notifications with a view to assisting in drawing conclusions on the potential environmental impact from the release or the placing on the market of GMOs:

D.1. In the case of GMOs other than higher plants

1. Likelihood of the GMO to become persistent and invasive in natural habitats under the conditions of the proposed release(s).

2. Any selective advantage or disadvantage conferred to the GMO and the likelihood of this becoming realised under the conditions of the proposed release(s).

3. Potential for gene transfer to other species under conditions of the proposed release of the GMO and any selective advantage or disadvantage conferred to those species.

4. Potential immediate and/or delayed environmental impact of the direct and indirect interactions between the GMO and target organisms (if applicable).

5. Potential immediate and/or delayed environmental impact of the direct and indirect interactions between the GMO with non-target organisms, including impact on population levels of competitors, prey, hosts, symbionts, predators, parasites and pathogens.

6. Possible immediate and/or delayed effects on human health resulting from potential direct and indirect interactions of the GMO and persons working with, coming into contact with or in the vicinity of the GMO release(s).

7. Possible immediate and/or delayed effects on animal health and consequences for the feed/food chain resulting from consumption of the GMO and any product derived from it, if it is intended to be used as animal feed.

8. Possible immediate and/or delayed effects on biogeochemical processes resulting from potential direct and indirect interactions of the GMO and target and non-target organisms in the vicinity of the GMO release(s).

9. Possible immediate and/or delayed, direct and indirect environmental impacts of the specific techniques used for the management of the GMO where these are different from those used for non-GMOs.

D.2. In the case of genetically modified higher plants (GMHP)

1. Likelihood of the GMHP becoming more persistent than the recipient or parental plants in agricultural habitats or more invasive in natural habitats.

2. Any selective advantage or disadvantage conferred to the GMHP.

3. Potential for gene transfer to the same or other sexually compatible plant species under conditions of planting the GMHP and any selective advantage or disadvantage conferred to those plant species.

4. Potential immediate and/or delayed environmental impact resulting from direct and indirect interactions between the GMHP and target organisms, such as predators, parasitoids, and pathogens (if applicable).

5. Possible immediate and/or delayed environmental impact resulting from direct and indirect interactions of the GMHP with non-target organisms, (also taking into account organisms which interact with target organisms), including impact on

population levels of competitors, herbivores, symbionts (where applicable), parasites and pathogens.

6. Possible immediate and/or delayed effects on human health resulting from potential direct and indirect interactions of the GMHP and persons working with, coming into contact with or in the vicinity of the GMHP release(s).

7. Possible immediate and/or delayed effects on animal health and consequences for the feed/food chain resulting from consumption of the GMO and any products derived from it, if it is intended to be used as animal feed.

8. Possible immediate and/or delayed effects on biogeochemical processes resulting from potential direct and indirect interactions of the GMO and target and non-target organisms in the vicinity of the GMO release(s).

9. Possible immediate and/or delayed, direct and indirect environmental impacts of the specific cultivation, management and harvesting techniques used for the GMHP where these are different from those used for non-GMHPs.

Appendix 4 - Annex III of the Cartagena Biosafety Protocol: Risk Assessment (Available from: http://www.biodiv.org/biosafety/articles.asp?lg=0&a=bsp-43).Objective

1. The objective of risk assessment, under this Protocol, is to identify and evaluate the potential adverse effects of living modified organisms on the conservation and sustainable use of biological diversity in the likely potential receiving environment, taking also into account risks to human health.

Use of risk assessment

2. Risk assessment is, inter alia, used by competent authorities to make informed decisions regarding living modified organisms.

General principles

3. Risk assessment should be carried out in a scientifically sound and transparent manner, and can take into account expert advice of, and guidelines developed by, relevant international organizations.

4. Lack of scientific knowledge or scientific consensus should not necessarily be interpreted as indicating a particular level of risk, an absence of risk, or an acceptable risk.

5. Risks associated with living modified organisms or products thereof, namely, processed materials that are of living modified organism origin, containing detectable novel combinations of replicable genetic material obtained through the use of modern biotechnology, should be considered in the context of the risks posed by the non-modified recipients or parental organisms in the likely potential receiving environment.

6. Risk assessment should be carried out on a case-by-case basis. The required information may vary in nature and level of detail from case to case, depending on the living modified organism concerned, its intended use and the likely potential receiving environment.

Methodology

7. The process of risk assessment may on the one hand give rise to a need for further information about specific subjects, which may be identified and requested during the assessment process, while on the other hand information on other subjects may not be relevant in some instances.

8. To fulfil its objective, risk assessment entails, as appropriate, the following steps:

a) An identification of any novel genotypic and phenotypic characteristics associated with the living modified organism that may have adverse effects on biological diversity in the likely potential receiving environment, taking also into account risks to human health;

b) An evaluation of the likelihood of these adverse effects being realized, taking into account the level and kind of exposure of the likely potential receiving environment to the living modified organism;

c) An evaluation of the consequences should these adverse effects be realized;

d) An estimation of the overall risk posed by the living modified organism based on the evaluation of the likelihood and consequences of the identified adverse effects being realized;

e) A recommendation as to whether or not the risks are acceptable or manageable, including, where necessary, identification of strategies to manage these risks; and

f) Where there is uncertainty regarding the level of risk, it may be addressed by requesting further information on the specific issues of concern or by implementing appropriate risk management strategies and/or monitoring the living modified organism in the receiving environment.

Points to consider

9. Depending on the case, risk assessment takes into account the relevant technical and scientific details regarding the characteristics of the following subjects:

a) Recipient organism or parental organisms. The biological characteristics of the recipient organism or parental organisms, including information on taxonomic status, common name, origin, centres of origin and centres of genetic diversity, if known, and a description of the habitat where the organisms may persist or proliferate;

b) Donor organism or organisms. Taxonomic status and common name, source, and the relevant biological characteristics of the donor organisms;

c) Vector. Characteristics of the vector, including its identity, if any, and its source or origin, and its host range;

d) Insert or inserts and/or characteristics of modification. Genetic characteristics of the inserted nucleic acid and the function it specifies, and/or characteristics of the modification introduced;

e) Living modified organism. Identity of the living modified organism, and the differences between the biological characteristics of the living modified organism and those of the recipient organism or parental organisms;

f) Detection and identification of the living modified organism. Suggested detection and identification methods and their specificity, sensitivity and reliability;

g) Information relating to the intended use. Information relating to the intended use of the living modified organism, including new or changed use compared to the recipient organism or parental organisms; and

h) Receiving environment. Information on the location, geographical, climatic and ecological characteristics, including relevant information on biological diversity and centres of origin of the likely potential receiving environment.