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 D40239 Duesseldorf, Germany
1
Innogen (ESRC Centre for Social and Economic Research on Innovation in Genomics),
University of Edinburgh, High School Yards, Edinburgh, Scotland
AHRC Centre for Studies in Intellectual Property and Technology Law, University of
Edinburgh, Old College, Edinburgh, Scotland
2
3
Genesis Faraday Partnership, Roslin BioCentre, Roslin, Midlothian, Scotland
4
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
9.2.3 Technical aspects ................................................................................... 84
9.2.4 Drivers .................................................................................................... 84
9.2.5 Regulation .............................................................................................. 84
9.2.6 Special Issues ........................................................................................ 84
9.2.7 Public attitudes ....................................................................................... 85
9.2.8 EU Competitiveness ............................................................................... 85
9.2.9 Alternative approaches ........................................................................... 85
9.3 GM animals for food ...................................................................................... 87
9.3.1 Aim ......................................................................................................... 87
9.3.2 Markets................................................................................................... 87
9.3.3 Technical aspects ................................................................................... 87
9.3.4 Drivers .................................................................................................... 87
9.3.5 Regulation .............................................................................................. 87
9.3.6 Special issues......................................................................................... 88
9.3.7 Public attitudes ....................................................................................... 88
9.3.8 EU Competitiveness ............................................................................... 88
9.3.9 Alternative approaches ........................................................................... 88
9.4 GM Pets ........................................................................................................ 90
9.4.1 Aim ......................................................................................................... 90
9.4.2 Markets................................................................................................... 90
9.4.3 Technical aspects ................................................................................... 90
9.4.4 Drivers .................................................................................................... 90
9.4.5 Regulation .............................................................................................. 90
9.4.6 Special issues......................................................................................... 90
9.4.7 Public attitudes ....................................................................................... 90
9.4.8 EU Competitiveness ............................................................................... 90
9.4.9 Alternative approaches ........................................................................... 90
9.5 Xenotransplantation....................................................................................... 92
9.5.1 Aim ......................................................................................................... 92
9.5.2 Markets................................................................................................... 92
9.5.3 Technical aspects ................................................................................... 92
9.5.4 Drivers .................................................................................................... 92
9.5.5 Regulation .............................................................................................. 92
9.5.6 Special issues......................................................................................... 92
9.5.7 Public attitudes ....................................................................................... 92
9.5.8 EU Competitiveness ............................................................................... 92
9.5.9 Alternative approaches ........................................................................... 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 Summary
There 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 foodproducing 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 premarket assessment of products, with the onus on the producers to demonstrate
1
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.
2
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.
3
SECTION 1 INTRODUCTION
1.1 Introduction
The 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.
4
A one-day ‘hearing’ was held at Innogen on Sept. 5th to bring a number of different
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.
5
SECTION 2 OVERVIEW OF THE LEGAL FRAMEWORK
2.1 Overview of the legal frameworks
There 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 legislation
In 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-bystep 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
6
favourable, proposes a draft Decision to the Regulatory Committee composed of
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.
7
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.
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
5
http://www.emea.eu.int/htms/aboutus/emeaoverview.htm site visited September 2005
6
http://www.coe.int/T/E/Social_Cohesion/Health/Recommendations/Rec(1997)15.asp
8
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
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.
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_cooperation/Bioethics/Activities/Xenotransplantation/INF_2003_12e%20xeno%20ER.pdf
9
http://www.bundesaerztekammer.de/30/Richtlinien/Empfidx/Xenotrans1.html
9
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.
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 5th 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
10
Subcomisión de Xenotrasplante de la Comisión Permanente de Trasplantes del Consejo
Interterritorial del Sistema Nacional de Salud
11
UK XIRA, 5th Annual Report
(http://www.advisorybodies.doh.gov.uk/ukxira/fifthannualreport04.pdf)
10
2.3 The regulation of GM animals worldwide
It 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
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
Law
Animals
FDA
FFDCA
Animals producing toxic substances
EPA
TSCA
USDA – FSIS
MIA; PPIA; EPIA
GMO Derived Products
Meat, poultry, eggs
12
Miller& Matheson, 1996
www.aphis.usda.gov/vs/ceah/cei/EmergingMarketConditions_files/animal_pharming.htm
13
Howard et al. 2001, E2
11
Genetically Modified Products
Agency
Law
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
(CVB)
–
APHIS 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:
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
14
Vanderbergh et al. 2002, 161
15
Vanderbergh et al. 2002, 161
16
Pew Initiative (2003)
12
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
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
17
Pew Initiative (2003)
18
Cited in Lewis (2001)
19
Pew Initiative (2003, p. 53)
13
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
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 riskbased 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
20
http://www.inspection.gc.ca/english/sci/biotech/gen/anibioe.shtml
21
http://www.inspection.gc.ca/english/anima/vetbio/abu/abumainprine.shtml
22
http://www.hc-sc.gc.ca/hpfb-dgpsa/bgtd-dpbtg/aboutus_e.html
23
Health Canada, Biologics and Genetic Therapy Directorate, Factsheet Xenotransplantation,
1 March 2001
14
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
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
15
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
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,
24
http://www.moh.govt.nz/moh.nsf/aa6c02e6249e7359cc256e7f0005521d/ff5646c096e846e7cc
256a880003bdb4?OpenDocument
25
Ministry for the Environment (2004)
26
Ministry for the Environment (2004, p. 16)
16
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
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 3rd annual report: ‘…the likelihood
27
Yamanouchi, K., (2005)
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, Korea
28
17
of whole organ xenotransplantation…being available within a clinically worthwhile
timeframe may be starting to recede.’30
2.4 International regulation
2.4.1 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
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 Foods
Nutraceuticals 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.
30
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/>
32
Turner (2002, p. 51)
18
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
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
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)
36
Miller & Matheson (1996)
37
American Diabetic Association (2004)
19
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 animals
Intellectual 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
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.
(http://www.webdietitians.org/Public/GovernmentAffairs/92_adap1099.cfm, visited August 10,
2005)
20
The Budapest Treaty on the International Recognition of the Deposit of Microorganisms 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;
(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.
21
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 EUwide 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
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.
38
De Simone, F. and Serratosa, J., 2005
22
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
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
23
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
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
39
2002 SCC 76. File No.:28155
Canadian Biotechnology Advisory Committee, “Advisory Memorandum: higher life forms
and the Patent Act”, February 24, 2003
40
41
2004 SCC 34
24
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).
“IPR protection of biological innovations”, Trade Related Aspects of Intellectual Property
Rights, Staff Research Paper, Productivity Commission
42
“IPR protection of biological innovations”, Trade Related Aspects of Intellectual Property
Rights, Staff Research Paper, Productivity Commission
43
25
SECTION 3 RISKS AND RISK ASSESSMENT
3.1 Risks from GM animals
A 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
26
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.
27
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 assessment
It 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
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.htm
46
http://europa.eu.int/comm/food/food/biotechnology/authorisation/decision_comm_en.htm
47
http://europa.eu.int/comm/food/food/biotechnology/authorisation/decision_comm_en.htm
28
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
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
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.htm
49
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.html
52
Appendix II, Directive 2001/18/EC
53
http://www.efsa.eu.int/science/gmo/catindex_en.html,
http://www.efsa.eu.int/science/ahaw/catindex_en.html
29
‘transgenic animal’, ‘genetically modified animal’ did not yield any relevant
documents or notes.54
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 drugproducing 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
54
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;
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.html
55
Stix (2005)
56
http://www.transgenics.com/pressreleases/pr091605.html
57
http://pewagbiotech.org/buzz/display.php3?StoryID=82
58
http://www.fda.gov/cvm/transgen.htm (site visited 6 September 2005)
30
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
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
59
http://www.fda.gov/cvm/FOI/UIUCLetter.htm
60
Miller & Matheson (1996)
61
Miller & Matheson (1996)
62
FDA (2003)
31
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
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)
63
Pew Initiative (2001)
64
http://www.cfsan.fda.gov/~lrd/biotechm.html#pres
65
Vanderbergh et al. (2002)
66
http://www.neavs.org/programs/papers/birdsreasearch_7_conclusion_kdavis.htm
67
Pew Initiative (2001, p.22)
32
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.
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 caseby-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
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.htm
33
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
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
73
CFR is the Code of Federal Regulations
74
http://www.aphis.usda.gov/vs/ceah/cei/EmergingMarketConditions_files/animal_pharming.htm
(site visited 21 June 2005).
75
Howard et al.(2001, p.E2)
76
http://www.aphis.usda.gov/vs/ceah/cei/EmergingMarketConditions_files/animal_pharming.htm
77
http://www.fda.gov/cvm/transgen.htm
34
pre-market approval from CVM, for those fish that have an added genebased 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
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
xenotransplantation
and
regulation
of
transgenic
a) USA – FDA regulation of xenotransplants
78
http://www.fda.gov/cvm/transgen.htm (site visited 6 September 2005)
79
Pew Initiative (2003, p.48)
80
Pew Initiative (2003, p. 59)
35
animals
used
in
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
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.,
proteins/hormones at receptors); and

device biocompatibility”.84
cross-species
activity
of
secreted
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
81
http://www.fda.gov/cber/xap/xap.htm
82
http://www.fda.gov/cber/xap/comp.htm
83
FDA (2003)
84
FDA (2003)
85
FDA (2003)
36
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
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)
86
FDA (2005), published in March, 2005.
87
Ministry for the Environment (2004, p. 7)
88
Ministry for the Environment (2004, p. 13)
89
http://www.foodstandards.gov.au/_srcfiles/Standard_1_5_2_GM_v70.doc
90
FSANZ (2004)
37

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
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
91
FSANZ (2004)
92
http://www.ermanz.govt.nz/resources/publications/pdfs/ER-QG-18-3.pdf
93
The
following
link
describes
the
rapid
assessment
http://www.ermanz.govt.nz/resources/publications/policy/no/lrgmo.html
38
rules.

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
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
94
ERMA (2003)
95
ERMA (1999)
96
ERMA (2003)
97
http://www.ermanz.govt.nz/news-events/archives/media-releases/2002/mr-20021001.asp
98
http://www.ermanz.govt.nz/news-events/archives/media-releases/2002/mr-20021001.asp
39
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
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.
99
http://www.ermanz.govt.nz/news-events/archives/media-releases/2000/mr-20001031.asp
100
http://www.ermanz.govt.nz/news-events/archives/media-releases/2000/mr-20001031.asp
101
http://www.ermanz.govt.nz/news-events/focus/gm-salmon.asp#media
102
http://www.ermanz.govt.nz/news-events/focus/gm-salmon.asp#taste
40
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
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, microorganisms and small laboratory animals but do not contemplate GM fish or
103
http://www.moh.govt.nz/moh.nsf/aa6c02e6249e7359cc256e7f0005521d/ff5646c096e846e7cc
256a880003bdb4?OpenDocument
104
http://www.moh.govt.nz/moh.nsf/aa6c02e6249e7359cc256e7f0005521d/ff5646c096e846e7cc
256a880003bdb4?OpenDocument
105
http://www.moh.govt.nz/moh.nsf/aa6c02e6249e7359cc256e7f0005521d/ff5646c096e846e7cc
256a880003bdb4?OpenDocument
106
http://www.mhlw.go.jp/english/topics/food/3-3.html
107
http://www.mhlw.go.jp/english/topics/food/3-3.html
108
http://www.mhlw.go.jp/english/topics/qa/dna/index.html
41
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
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:
109
http://www.s.affrc.go.jp/docs/sentan/eguide/eguide.htm
110
http://www.s.affrc.go.jp/docs/sentan/eguide/eguide.htm
42
“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

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
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)
114
Codex Alimentarius (2003)
43
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
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
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)
119
FAO/WHO (2003, p. 11)
44

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 postmarket 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

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
120
FAO/WHO (2003, p.16)
45
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 animalderived 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
Notes
Phenotypic 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
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
121
WHO (2005, p. 19)
122
http://www.biodiv.org/biosafety/issues/risk.aspx# (Site visited July 28, 2005)
46
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
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
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
127
http://www.oie.int/eng/Edito/en_edito_feb05.htm
128
http://www.ictsd.org/biores/05-06-10/story3.htm (Site visited August 5, 2005)
47
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
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
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)
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.)
48
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

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.
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 biotechnologyderived 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)
138
WHO (2005, p. 31)
139
WHO (2005, p. 31)
49

Asia-Pacific Economic Cooperation has held ‘High Level Policy Dialogues’ on
numerous topics related to agricultural biotechnology, including the
‘harmonization of regulatory frameworks.’140
140
http://www.apec.org/apec/apec_groups/other_apec_groups/agricultural_biotechnology.html
50
SECTION 4 INTERNATIONAL TRADE AND LABELLING ISSUES
4.1 International regulation of trade in GM animals and related products
With 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)
51
“…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
146
http://www.wto.org/english/docs_e/legal_e/15sps_01_e.htm
147
http://www.wto.org/english/docs_e/legal_e/15sps_01_e.htm
148
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.htm
52
grounds for applying any special treatment to them, including mandatory
labelling schemes.”152
4.1.3 GATT 1994 and the product/process distinction
It appears to be the 1994 GATT, through Article III which discusses the nondiscrimination 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
152
Zarrilli (2005, p. 33)
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)
53
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.
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 decisionmaking 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
159
http://www.biodiv.org/biosafety/background2.aspx# (Site visited June 28, 2005)
160
Cottier (2002, p. 469)
161
Cottier (2002, p. 469)
162
Cottier (2002)
163
Zarrilli (2005, p. 27)
164
Howse & Meltzer (2002)
54
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:
“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
165
Cottier (2002, p. 474)
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)
55
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
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
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.
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)
56
regarding GMOs, even though the regulations might have a considerable traderestrictive 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
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
179
Zarrilli (2005, p. 42)
180
Howse & Meltzer (2002, p. 493)
181
Zarrilli (2005, p. 42-43)
182
Howse & Meltzer (2002, p. 495)
183
Cottier (2002)
57
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.
4.2 Additional potential trade issues
4.2.1 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 multilateral 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
184
Brack et al. (2003, p. 10)
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)
58
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
conventional foreign species which have been introduced into a different
eco-system”.190
4.3 Labelling
An 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.
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)
59
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
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
195
http://www.fao.org/es/ESN/food/risk_biotech_label_en.stm
60
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.
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
196
http://www.inspection.gc.ca/english/sci/biotech/labeti/response.shtml
197
http://www.inspection.gc.ca/english/sci/biotech/labeti/vole.shtml
61
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,
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 Traceability
To 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.
62
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.
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.
63
SECTION 5 ANIMAL WELFARE
5.1 Welfare of GM animals
5.1.1 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
64
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 welfare
This 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.
65
SECTION 6 PUBLIC ATTITUDES
6.1 Introduction
The 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 animals
6.2.1 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.
66
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
67
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 animals
Ethical 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
68

This is being done for the wrong motive (profit rather than real social need)

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 relationships
One of the issues this report was tasked with was to arrive at a socio-economic costbenefit 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 nonhuman 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)
69
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.
“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)
70
SECTION 7 POLICY CONTEXT
It 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 Policy
Some 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 Strategy
The 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)
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
71

Supporting the conservation and sustainable use of genetic resources in
developing countries and the equitable sharing of benefits arising from their use
(Action 26).
7.3 Industry context: pharmaceutical and agricultural
As 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 animalbased 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 proscience 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
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
72
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
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 cooperatives 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’ context
GM 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
201
http://www.eadgene.info/animalbreeding.html - site accessed 18/10/05
73
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
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’.
74
SECTION
8
META-ANALYSIS
OF
FORESIGHTS AND ASSESSMENTS
GOVERNMENTAL
TECHNOLOGY
8.1 Introduction
The 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 objective
The 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
TA Federations/Associations203 and more than 80 national TA units204 have been
examined and analysed on their work performed referring to animal biotechnology.
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
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
75
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 assessments
Our 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
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
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.
76
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
avoidance of unnecessary DNA sequences such as marker genes that raise safety
concerns.
8.4 Findings: (inter)national technology foresight
In 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
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.
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.
209
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
77
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.
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 knockout 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
(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.
78
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 Outlook
There 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
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.
79
SECTION 9 CASE STUDIES
Five 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 colourcoded 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 bioreactors
9.1.1 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.
213 Banxia Software. Decision Explorer, www.banxia.com
80
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
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).
214
Enserink, M. (1998)
81
9.1.9 Alternative approaches
Harnessing the metabolic capacity of animals to produce proteins has advantages
over other methods currently available:

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.
82
Figure 1 Roadmap demonstrating the drivers for GM animals as bioreactors
Pharmaceuticals are
available in the EU
from GM animals
Production of
pharmed products
outside the EU
Availabilitly of
funding
Poor efficiency of
GM/cloning
techniques
Ethical concerns
-
Welfare concerns
High value of
pharmaceuticals
Research on
developing pharming
Negative public
attitudes
Setting up of
spin-out companies
to develop pharming
products
Positive public
attitudes
Development of
potentially useful
applications for
pharming
Work w ith existing
companies to produce
commercial products
Pressure from
patient groups
-
Production of
pharmed products in
EU
Approval from FDA or
other relevant
regulatory body
-
Approval from EMEA
83
Small number of GM
animals required
Development of
competing
technologies
9.2 Faster growth rate from GM animals
9.2.1 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.
9.2.3 Technical aspects
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, 2000
216
Ramseyer, 2002
217
Reichhardt, 2000
84
9.2.7 Public attitudes
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.
9.2.8 EU Competitiveness
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.
9.2.9 Alternative approaches
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
85
Figure 2 Roadmap demonstrating drivers for products from faster growing GM fish becoming available in the EU
Wild f ish
populations are
damaged
Fish produced
exclusively in
land-based tanks
Technology exists to
produce faster
growing GM f ish
-
GM fish interbreed
with wild f ish
-
Development of
reliable
sterilization
methods
-
Unauthorised GM f ish
products enter f ood
chain accidentally
or deliberately
GM fish 'escape'
into the wild
Enterprises are set
up to produce
f aster-growing GM
f ish
GM fish approved to
enter the f ood chain
somewhere in the
world
GM fish meet EU GM
f ood saf ety
assessments
GM fish meet EU
labelling
requirements
GM fish products
appear in world
markets
Increasing
world-wide demand
f or f ish
Increasing f ocus on
health-promoting
f oods
Involvement of
commercial companies
GM fish products
available on EU
markets
Wild f ish stocks are
reduced
Growing human
population
world-wide
Benef it perceived to
be primarily
economic
Negative public
attitudes
Positive public
attitudes
GM fish produced
somewhere in the
world
Increasing
development of f ish
f arming
Commercial advantage
(reduced production
cost) of faster
growing f ish
Products f rom f aster
growing GM f ish
available in the EU
Companies apply to
place GM f ish
products on EU
markets
Increased f ish
consumption due to
health benef its of
omega-3 f atty acids
86
GM fish meet EU
traceability
requirements
9.3 GM animals for food
9.3.1 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.
9.3.3 Technical aspects
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 premarket review (unlike GM crops).
87
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.
9.3.6 Special issues
No data available.
9.3.7 Public attitudes
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.
9.3.8 EU Competitiveness
No data available
9.3.9 Alternative approaches
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.
88
Figure 3 Roadmap demonstrating the drivers for GM animal food products in the EU
Food from GM animals
available in the EU
GM animal products
are accidently or
deliberatly
introduced into the
food chain without
satisfying
regulations
-
Negative connotation
with intensive
agriculture
Negative public
attitudes
GM animal products
meet EU traceability
requirements
GM animal products
meet EU labelling
requirements
GM animal products
satisfy EU food
safety requirements
Products from GM
animals are
available on world
markets
Cocnerns about poor
animal welfare
Negative
connotations with GM
crops
Negative
connotations of
commercial company
involvement
Concerns about
appropriate
treatment of animals
Application is made
to import animal
product to EU
Products from GM are
produced
EU animal welfare
legislation finds GM
animal acceptable
Farmers keep GM
animals on EU farms
Farmers outside the
EU keep GM animals
GM animals satisfy
local regulations
GM animals satisfy
GM deliberate
release regulations
Companies outside
the EU adopt GM
animals and make
them available to
farmers
Commercially viable
application of GM to
animals is produced
89
Application is made
to delibrately
release GM animals
Companies adopt GM
animals and make
breeding stock
available for EU
farmers
9.4 GM Pets
9.4.1 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).
9.4.3 Technical aspects
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.
9.4.6 Special issues
No special issues have been identified.
9.4.7 Public attitudes
No data available.
9.4.8 EU Competitiveness
No data available
9.4.9 Alternative approaches
None obvious
90
Figure 4 Roadmap demonstrating the drivers encouraging availability of pet GM fish in
the EU
GM pet fish
available in the EU
New methods of
producing GM fish
are developed
Companies are set up
in the EU to produce
GM pet fish
Licenses become
available to other
commercial companies
Scientific
developments allow
creation of
fluorescent GM fish
Wild populations are
damaged
Companies are set up
outside EU countries
to produce GM pet
fish
Pet GM fish 'escape'
into the wild in
conditions where
they can establish
or cross-breed with
wild populations
GM pet fish meet EU
deliberate release
regulations
Permission for
deliberate release
is sought
Import licenses to
EU countries are
sought
Pet GM fish become
available on
international
markets
91
9.5 Xenotransplantation
9.5.1 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.
9.5.3 Technical aspects
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.
9.5.6 Special issues
No special issues have been identified
9.5.7 Public attitudes
Public attitudes in opinion polls have been quite negative but have also become more
positive over time.
9.5.8 EU Competitiveness
No data available
9.5.9 Alternative approaches
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.
92
Figure 5 Roadmap demonstrating the drivers to the availability of xenotransplants in
the EU
Xenotransplants
available in the EU
Positive public
attitudes
-
Negative public
attitudes
Regulatory approval
is gained from human
health aspects
Regualtory approval
is gained from
animal welfare
aspects
Submision is made
for regulatory
approval in the
relevant member
state
Scientists in EU
develop
xenotransplants to
the point where they
are viable
Techniques are made
availble in the EU
-
Scientists outside
the EU devlelop
xentoransplants to
the point where they
are viable
Less funding for
Xenotransplant
research
Alternative
therapies are
developed
Supply of donor
organs increases
dramatically
93
SECTION 10 REFLECTIONS
Genetically 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 fullydeveloped 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
94
(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
95
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.
96
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100
SECTION 12 APPENDICES
Appendix 1 - Acronyms
ACGM: Advisory Committee
Genetic Modification (UK)
on
FUFOSE
Functional
Sciences in Europe
Food
AEBC: Agriculture and Environment
Biotechnology Commission (UK)
GATT: General Agreement on Tariffs
and Trade
APEC:
Asia-Pacific
Cooperation
GM: Genetically modified
Economic
GMO: Genetically modified organism
APHIS: Animal and Plant Health
Inspection Service (USDA, USA)
ART:
Assisted
Reproductive
Technologies
GVHD: Graft versus host disease
HSE: Health & Safety Executive (UK)
CBER: Center for Biologics Evaluation
and Research (FDA, USA)
HSNO Act: Hazardous Substances
and New Organisms Act 1996 (New
Zealand)
CBP: Cartagena Biosafety Protocol
LMO: Living Modified Organism
CFIA: Canadian
Agency
LOS: Large Offspring Syndrome
Food
Inspection
MAFF:
Ministry
for
Agriculture,
Forestry and Fisheries (Japan)
CFSAN: Centre for Food Safety and
Applied Nutrition (FDA, USA)
CVB: Centre for Veterinary Biologics
MHLW: Ministry of Health, Labour and
Welfare (Japan)
CVM: Centre for Veterinary Medicine
(FDA, USA)
NAS: National Academy of Sciences
(USA)
EFSA:
European
Authority
Safety
OECD: Organization for Economic Cooperation and Development
Medicines
OIE: World Organization for Animal
Health
Food
EMEA:
European
Evaluation Agency
SCNT: Somatic Cell Nuclear Transfer
ERMA:
Environmental
Risk
Management Authority (New Zealand)
SPS: Sanitary and
Measures (WTO)
EUFIC: European Food Information
Council
FAO:
Food
Organization
and
TBT: Technical Barriers to Trade
(WTO)
Agriculture
TEP:
TransAtlantic
Partnership
FDA: Food and Drug Administration
(USA)
WHO: World Health Organization
FSANZ: Food Standards Australia
New Zealand
&
Economic
USDA: United States Department of
Agriculture
FFDCA: Federal Food, Drugs and
Cosmetics Act (USA)
FSIS: Food Safety
Service (USDA, USA)
Phytosanitary
WTO: World Trade Organization
XIRA: Xenotransplantation
Regulatory Authority (UK)
Inspection
101
Interim
Appendix 2 - Selected Web sites
www.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
102
Appendix 3 - ANNEX II of EU Directive 2001/18/EC: Environmental Risk
Assessment
Principles 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 nonmodified organism from which it is derived and its use under corresponding
situations;
103

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);
104

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.
105
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
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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.
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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 nonmodified 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
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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.
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